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in the past three decades non - gaussian time series have attracted a lot of interest , see e.g. cox ( 1981 ) , kaufmann ( 1987 ) , kitagawa ( 1987 ) , shephard and pitt ( 1997 ) , and durbin and koopman ( 2000 ) , among others . in the context of regression modelling , generalized linear models ( mccullagh and nelder , 1989 ; dobson , 2002 ) offer a solid theoretical basis for statistical analysis of independent non - normal data . a general framework for dealing with time series data is the dynamic generalized linear model ( dglm ) , which considers generalized linear modelling with time - varying parameters and hence it is capable to model time series data for a wide range of response distributions . dglms have been widely adopted for non - normal time series data , see e.g. west _ et al . _ ( 1985 ) , gamerman and west ( 1987 ) , fahrmeir ( 1987 ) , frhwirth - schnatter , s. ( 1994 ) , lindsey and lambert ( 1995 ) , chiogna and gaetan ( 2002 ) , hemming and shaw ( 2002 ) , godolphin and triantafyllopoulos ( 2006 ) , and gamerman ( 1991 , 1998 ) . dynamic generalized linear models are reported in detail in the monographs of west and harrison ( 1997 , chapter 14 ) , fahrmeir and tutz ( 2001 , chapter 8) , and kedem and fokianos ( 2002 , chapter 6 ) . in this paper we propose a unified treatment of dglms that includes approximate bayesian inference and multi - step forecasting . in this to end we adopt the estimation approach of west _ et al . _ ( 1985 ) , but we extend it as far as model diagnostics and forecasting are concerned . in particular , we discuss likelihood - based model assessment as well as bayesian model monitoring . in the literature , discussion on the dglms is usually restricted to the binomial and the poisson models , see e.g. fahrmeir and tutz ( 2001 , chapter 8) . even for these response distributions , discussion is limited on estimation , while forecasting and in particular multi - step forecasting does not appear to have received much attention . we provide detailed examples of many distributions , including binomial , poisson , negative binomial , geometric , normal , log - normal , gamma , exponential , weibull , pareto , two special cases of the beta , and inverse gaussian . we give numerical illustrations for all distributions , except for the normal ( for which one can find numerous illustrations in the time series literature ) using real and simulated data . the paper is organized as follows . in section [ dglm ] we discuss bayesian inference of dglms . section [ examples ] commences by considering several examples , where the response time series follows a particular distribution . section [ discussion ] gives concluding comments . the appendix includes some proofs of arguments in section [ examples ] . suppose that the time series @xmath0 is generated from a probability distribution , which is a member of the exponential family of distributions , that is @xmath1 where @xmath2 , known as the natural parameter , is the parameter of interest and other parameters that can be linked to @xmath3 , @xmath4 , @xmath5 and @xmath6 are usually referred to as nuisance parameters or hyperparameters . the functions @xmath4 , @xmath5 and @xmath6 are assumed known , @xmath7 , @xmath8 is twice differentiable and according to dobson ( 2002 , 3.3 ) @xmath9 the function @xmath10 is usually a simple function in @xmath11 and in many cases it is the identity function ; an exception of this is the binomial distribution . if @xmath12 , distribution ( [ exp ] ) is said to be in the _ canonical _ or _ standard _ form . dobson ( 2002 , 3.3 ) gives expressions of the score statistics and the information matrix , although the consideration of these may not be necessary for bayesian inference . the idea of generalized linear modelling is to use a non - linear function @xmath13 , which maps @xmath14 to the linear predictor @xmath15 ; this function is known as link function . if @xmath16 , this is referred to as _ canonical link _ , but other links may be more useful in applications ( see e.g. the inverse gaussian example in section [ continuous ] ) . in glm theory , @xmath15 is modelled as a linear model , but in dglm theory , the linear predictor is replaced by a state space model , i.e. @xmath17 where @xmath18 is a @xmath19 design vector , @xmath20 is a @xmath21 evolution matrix , @xmath22 is a @xmath19 random vector and @xmath23 is an innovation vector , with zero mean and some known covariance matrix @xmath24 . it is assumed that @xmath23 is uncorrelated of @xmath25 ( for @xmath26 ) and @xmath23 is uncorrelated of @xmath27 , for all @xmath28 . it is obvious that if one sets @xmath29 ( the @xmath21 identity matrix ) and @xmath30 ( i.e. its covariance matrix is the zero matrix ) , then the above model is reduced to a usual glm . for the examples of section [ examples ] we consider simple state space models , which assume that @xmath31 , @xmath32 , @xmath33 are time - invariant . however , in the next sections , we present bayesian inference and forecasting for time - varying @xmath18 , @xmath20 , @xmath24 in order to cover the general situation . suppose that we have data @xmath34 and we form the information set @xmath35 , for @xmath36 . at time @xmath37 we assume that the posterior mean vector and covariance matrix of @xmath38 are @xmath39 and @xmath40 , respectively , and we write @xmath41 . then from @xmath42 , it follows that @xmath43 , where @xmath44 and @xmath45 . the next step is to form the prior mean and variance of @xmath15 and @xmath22 , that is @xmath46 \right|y^{t-1 } \sim \left(\left [ \begin{array}{c } f_t \\ \end{array}\right ] , \left [ \begin{array}{cc } q_t & f_t'r_t \\ r_tf_t & r_t \end{array } \right ] \right),\ ] ] where @xmath47 and @xmath48 . the quantities @xmath49 and @xmath50 are the forecast mean and variance of @xmath15 . in order to proceed with bayesian inference , we assume the conjugate prior of @xmath2 , so that @xmath51 for some known @xmath52 and @xmath53 . these parameters can be found from @xmath54 and @xmath55 , @xmath56 , which are known from ( [ prior : p2 ] ) . the normalizing constant @xmath57 can be found by @xmath58 where the integral is lebesque integral , so that it includes summation / integration of discrete / continuous variables . we note that in most of the cases , the above distribution will be recognizable ( e.g. gamma , beta , normal ) and so there is no need of evaluating the above integral . one example that this is not the case is the inverse gaussian distribution ( see section [ continuous ] ) . then observing @xmath11 , the posterior distribution of @xmath2 is @xmath59 in many situations we are interested in parameters that are given as functions of @xmath2 . in such cases we derive the prior / posterior distributions of @xmath2 as above and then we apply a transformation to obtain the prior / posterior distribution of the parameter in interest . the examples of section [ examples ] are illuminative . finally , the posterior mean vector and covariance matrix of @xmath22 are approximately given by @xmath60 with @xmath61 where @xmath62 and @xmath63 can be found from @xmath54 and the posterior ( [ post : g1 ] ) . the priors ( [ prior : p2 ] ) , ( [ prior : g1 ] ) and the posteriors ( [ post : g1 ] ) , ( [ post : th1 ] ) provide an algorithm for estimation , for any @xmath36 . for a proof of the above algorithm the reader is referred to west _ et al . _ ( 1985 ) . an alternative approach for the specification of @xmath52 and @xmath53 is to make use of _ power discounting _ and this is briefly discussed next . the idea of power discounting stem in the work of smith ( 1979 ) ; power discounting is a method of obtaining the prior distribution at time @xmath64 , from the posterior distribution at time @xmath28 . here we consider a minor extension of the method by replacing @xmath64 by @xmath65 , for some positive integer @xmath66 . then , according to the principle of power discounting , the prior distribution at time @xmath65 is proportional to @xmath67 , where @xmath68 is a discount factor . thus we write @xmath69 this ensures that the prior distribution of @xmath70 is flatter than the posterior distribution of @xmath2 . the above procedure assumes that @xmath71 and @xmath72 , which implicitly assumes a random walk type evolution of the posterior / prior updating , in the sense that bayes decisions in the interval @xmath73 remain constant , while the respective expected loss ( under step loss functions ) increase ( smith , 1979 ) . suppose that the time series @xmath0 is generated by density ( [ exp ] ) and let @xmath74 be the information set up to time @xmath28 . then the @xmath66-step forecast distribution of @xmath75 is @xmath76 where @xmath77 and @xmath78 are evaluated from @xmath79 and @xmath80 , the mean and variance of @xmath81 , and the distribution of @xmath82 , which takes a similar form as the distribution of @xmath83 . model assessment can be done via the likelihood function , residual analysis , and bayesian model comparison , e.g. based on bayes factors . the likelihood function of @xmath84 , based on information @xmath85 is @xmath86 where the first probability in the product is the distribution ( [ exp ] ) and the second indicates the evolution of @xmath2 , given @xmath87 . then the log - likelihood function is @xmath88 the likelihood function can be used as a means of model comparison ( for example looking at two model specifications , which differ in some quantitative parts , we choose the model that has larger likelihood ) . for model assessment the likelihood function can be used in order to choose some hyperparameters ( discount factors , or nuisance parameters ) so that the likelihood function is maximized in terms of these hyperparameters . the evaluation of ( [ logl ] ) requires the distribution @xmath89 . this depends on the state space model for @xmath15 used . in the examples of section [ examples ] we look at these probabilities , based mainly on gaussian random walk evolutions for @xmath15 , but also we consider a linear trend model for @xmath15 . note that the consideration of @xmath23 following a gaussian distribution does not imply that @xmath90 follows a gaussian distribution too , since the distribution of @xmath27 may not be gaussian . for the sequential calculation of the bayes factors ( which for gaussian responses are discussed in salvador and gargallo , 2005 ) , a typical setting suggests the formation of two models @xmath91 and @xmath92 , which differ in some quantitative aspects , e.g. some hyperparameters . then , the cumulative bayes factor of @xmath91 against @xmath92 is defined by @xmath93 where @xmath94 , for all @xmath28 , and @xmath95 denotes the joint distribution of @xmath96 , given @xmath97 , for some integer @xmath98 and @xmath99 . then preference of model 1 would imply larger forecast distribution of this model ( or @xmath100 ) ; likewise preference of model 2 would imply @xmath101 ; @xmath102 implies that the two models are probabilistically equivalent in the sense they provide the same forecast distributions . the binomial distribution ( johnson _ et al . _ , 2005 ) is perhaps the most popular discrete distribution . it is typically generated as the sum of independent success / failure bernoulli trials and in the context of generalized linear modelling is associated with logistic regression ( dobson , 2002 ) . consider a discrete - valued time series @xmath0 , which , for a given probability @xmath103 , follows the binomial distribution @xmath104 where @xmath105 denotes the binomial coefficient . it is easy to verify that the above distribution is of the form ( [ exp ] ) with @xmath106 , @xmath107 , @xmath108 , @xmath109 , and @xmath110 . the logarithmic , known also as logit , link @xmath111 maps @xmath103 to the linear predictor @xmath15 , which with the setting @xmath112 and @xmath113 , generates the dynamic evolution of the model . the prior of @xmath114 , follows by the prior of @xmath83 and the transformation @xmath115 as beta distribution @xmath116 , with density @xmath117 where @xmath118 denotes the gamma function and @xmath119 . then , observing @xmath11 , the posterior of @xmath120 is @xmath121 . in the appendix it is shown that , with @xmath49 and @xmath50 the prior mean and variance of @xmath15 , an approximation of @xmath52 and @xmath53 is given by @xmath122 in order to proceed with the posterior moments of @xmath90 as in ( [ post : th1 ] ) , we can see that @xmath123 where @xmath124 denotes the digamma function ( see the poisson example and the appendix ) . in the appendix approximations of @xmath124 and of its first derivative ( also known as trigamma function ) are given . these definitions as well as the parameters of the beta prior are slightly different from the ones obtained by west and harrison ( 1997 ) , as these authors use a different parameterization , which does not appear to be consistent with the prior / posterior updating . given information @xmath74 , the @xmath66-step forecast distribution is obtained by first noting that @xmath125 where @xmath77 and @xmath78 are given by @xmath52 and @xmath53 , if @xmath49 and @xmath50 are replaced by @xmath126 and @xmath127 , which are calculated routinely by the kalman filter ( see section [ dglm ] ) . then the @xmath66-step forecast distribution is given by @xmath128 we can use conditional expectations in order to calculate the forecast mean and variance , i.e. @xmath129 and @xmath130 for the specification of @xmath52 and @xmath53 , we can alternatively use power discounting ( see section [ dglm ] ) . this yields @xmath131 where @xmath68 is a discount factor and @xmath132 are initially given . for the evolution of @xmath15 via @xmath22 , the obvious setting is the random walk , which sets @xmath133 . from the logit link we have @xmath134 and so the evolution of @xmath22 yields @xmath135 which gives the evolution of @xmath103 , given @xmath136 , as a function of the gaussian shock @xmath23 . then the distribution of @xmath137 is @xmath138 and so from ( [ logl ] ) the log - likelihood function is @xmath139 the bayes factors are easily computed from ( [ bf1 ] ) and the forecast distribution @xmath140 . if we use a linear trend evolution on @xmath22 , we can specify @xmath141\left[\begin{array}{c } \theta_{1 t } \\ \theta_{2t}\end{array}\right ] \quad \textrm{and } \quad \left[\begin{array}{c } \theta_{1 t } \\ \theta_{2t}\end{array}\right ] = \left[\begin{array}{cc } 1 & 1 \\ 0 & 1 \end{array}\right ] \left[\begin{array}{c } \theta_{1,t-1 } \\ \theta_{2,t-1}\end{array}\right ] + \left[\begin{array}{c } \omega_{1 t } \\ \omega_{2t}\end{array}\right].\ ] ] here @xmath142'$ ] is a 2-dimensional random vector and @xmath143'$ ] follows a bivariate normal distribution with zero mean vector and some known covariance matrix . then , conditional on @xmath136 , from the logit link function we can recover the relationship of @xmath103 as @xmath144 to illustrate the binomial model , we consider the data of godolphin and triantafyllopoulos ( 2006 ) , consisting of quarterly binomial data over a period of 11 years . in each quarter @xmath145 bernoulli trials are performed and @xmath11 , the number of successes , is recorded . the data , which are plotted in figure [ fig1 ] , show a clear seasonality and therefore , modelling this data with glms is inappropriate . the data exhibit a trend / periodic pattern , which can be modelled with a dglm , by setting @xmath112 and @xmath113 , where the design vector @xmath146 has dimension @xmath147 and the @xmath148 evolution matrix @xmath149 comprises a linear trend component and a seasonal component . one way to do this is by applying the trend / full harmonic state space model @xmath150 \quad \textrm{and } \quad g=\left [ \begin{array}{ccccc } 1 & 1 & 0 & 0 & 0 \\ 0 & 1 & 0 & 0 & 0 \\ 0 & 0 & \cos ( \pi/2 ) & \sin ( \pi/2 ) & 0 \\ 0 & 0 & -\sin ( \pi/2 ) & \cos ( \pi/2 ) & 0 \\ 0 & 0 & 0 & 0 & -1 \end{array}\right],\ ] ] where @xmath149 is a block diagonal matrix , comprising the linear trend component and the seasonal component , for the latter of which , with a cycle of @xmath151 , we have @xmath152 harmonics and the frequencies are @xmath153 for harmonic 1 and @xmath154 for harmonic 2 ( the nyquist frequency ) . similar models , with gaussian responses , are described in west and harrison ( 1997 ) , and harvey ( 2004 ) . the covariance matrix @xmath155 of @xmath23 is set as the block diagonal matrix @xmath156 , where @xmath157 corresponds to the linear trend component , @xmath158 corresponds to the seasonal component and it is chosen so that the trend has more variability than the seasonal component ( west and harrison , 1997 ) . the priors @xmath159 and @xmath160 are set as @xmath161'$ ] and @xmath162 , suggesting a weakly informative prior specification . figure [ fig1 ] plots the one - step forecast mean of @xmath0 against @xmath0 . we see that the forecasts fit the data very closely proposing a good model fit . in the context of generalized linear models , the poisson distribution ( johnson _ et al . _ , 2005 ) is associated with modelling count data ( dobson , 2002 ) . in a time series setting count data are developed as in jung _ ( 2006 ) . suppose that @xmath0 is a count time series , so that , for a positive real - valued @xmath163 , @xmath164 follows the poisson distribution , with density @xmath165 where @xmath166 denotes the factorial of @xmath11 . we can easily verify that this density is of the form ( [ exp ] ) , with @xmath12 , @xmath167 , @xmath168 , @xmath169 , and @xmath170 . we can see that @xmath171 and @xmath172 . from the prior of @xmath83 and the transformation @xmath168 , we obtain the prior of @xmath173 as a gamma distribution , i.e. @xmath174 , with density @xmath175 for @xmath176 . then it follows that the posterior of @xmath177 is the gamma @xmath178 . for the definition of @xmath52 and @xmath53 we use the logarithmic link @xmath179 or @xmath180 . based on an evaluation of the mean and variance of @xmath181 and a numerical approximation of the digamma function ( see appendix ) , we can see @xmath182 where @xmath49 and @xmath50 are the mean and variance of @xmath15 . for the computation of @xmath183 and @xmath184 , the posterior mean and variance of @xmath2 , first define the digamma function @xmath124 as @xmath185 , where @xmath118 denotes the gamma function and of course @xmath186 . then we have @xmath187 which can be computed by the recursions @xmath188 and @xmath189 . using the approximations @xmath190 and @xmath191 , we can write @xmath192 with @xmath52 , @xmath53 , @xmath183 and @xmath184 we can compute the first two moments of @xmath90 as in ( [ post : th1 ] ) . for a detailed discussion on digamma functions the reader is referred to abramowitz and stegun ( 1964 , 6.3 ) . defining @xmath77 and @xmath78 according to @xmath79 and @xmath80 and equation ( [ eq : poisson : rt ] ) , the @xmath66-step forecast distribution of @xmath193 is given by @xmath194 which is a negative binomial distribution . the forecast mean and variance can be calculated by using conditional expectations , i.e. @xmath195 and @xmath196 the power discounting yields @xmath197 considering the random walk evolution for @xmath22 so that @xmath133 , where @xmath198 , for some variance @xmath155 , we can see that @xmath199 since @xmath200 . then from the normal distribution of @xmath23 , the distribution of @xmath201 is @xmath202 which is a log - normal distribution ( see section [ continuous ] ) . tnen from ( [ logl ] ) the log - likelihood function is @xmath203 bayes factors can be calculated using ( [ bf1 ] ) and the negative binomial one - step ahead forecast probability functions @xmath204 . in order to illustrate the poisson model we consider us annual immigration data , in the period of 1820 to 1960 . the data , which are described in kendall and ord ( 1990 , page 13 ) , are shown in figure [ fig2 ] . the nature of the data fits to the assumption of a poisson distribution , but it can be argued that , after applying a suitable transformation , some gaussian time series model can be appropriate . the data are non - stationary and a visual inspection shows that they exhibit a local level behaviour . one simple model to consider is the random walk evolution of @xmath205 as described above . we use power discounting with @xmath206 , which is a low discount factor capable to capture the peak values of the data . figure [ fig2 ] shows the one - step forecast mean against the actual data and as we see the forecasts capture well the immigration data . the negative binomial distribution ( johnson _ et al . _ , 2005 ) arises in many practical situations and it can be generated via independent bernoulli trails or via the poisson / gamma mixture . in time series analysis , an application of negative binomial responses is given in houseman _ we note that the negative binomial distribution includes the geometric as a special case ( see below ) . suppose that the time series @xmath0 is generated from the negative binomial distribution , with probability function @xmath207 where @xmath103 is the probability of success and @xmath208 is the number of successes . this distribution belongs to the exponential family ( [ exp ] ) , with @xmath12 , @xmath167 , @xmath209 , @xmath210 , and @xmath211 . then it follows that @xmath212 and @xmath213 . we note that by setting @xmath214 and @xmath215 , the time series @xmath216 follows a geometric distribution and thus all what follows applies readily to the geometric distribution too . by using the prior of @xmath83 and the transformation @xmath209 , the prior of @xmath114 is the beta distribution @xmath217 and the posterior of @xmath120 is the beta @xmath218 . using the logit link , as in the binomial example , the definitions of @xmath52 and @xmath53 are @xmath219 and the posterior moments @xmath183 and @xmath184 are @xmath220 which can be approximated by @xmath221 and @xmath222 thus we can compute the moments of @xmath90 as in ( [ post : th1 ] ) and so we obtain an approximation of the quantities @xmath77 and @xmath78 , as functions of @xmath79 and @xmath80 . the @xmath66-step forecast distribution is given by @xmath223 the forecast mean and variance of @xmath75 are given by @xmath224 and @xmath225 the power discounting yields @xmath226 where as usual @xmath68 is a discount factor . considering the random walk evolution for @xmath133 , the link @xmath227 , yields the evolution for @xmath103 @xmath228 given that @xmath229 , for a known variance @xmath155 , the distribution of @xmath137 is @xmath230 and so from ( [ logl ] ) the log - likelihood function is @xmath231 bayes factors can be computed using ( [ bf1 ] ) and the predictive distribution @xmath204 . to illustrate the above model we have simulated 100 observations from the above model ; we simulate one draw from @xmath232 so that @xmath233 , we simulate 100 innovations @xmath234 from a @xmath235 , then using ( [ nb : pi ] ) we generate @xmath236 and finally , for each time @xmath28 , we simulate one draw from a negative binomial with parameters @xmath237 and @xmath103 . figure [ fig2a ] shows the simulated data ( solid line ) together with the one - step ahead forecast means @xmath238 . for the fit , we pretend we did not have knowledge of the simulation process and so we have specified @xmath239'$ ] , @xmath240 ( the @xmath241 identity matrix ) , @xmath242'$ ] , and @xmath243 , the last indicating a weakly informative prior specification ( i.e. @xmath244 ) . we observe that the forecasts follow the data closely indicating a good fit . we have found that as it is well known for gaussian time series , these prior settings are insensitive to forecasts , since prior information is deflated with time . normal or gaussian time series are discussed extensively in the literature , see e.g. west and harrison ( 1997 ) for a bayesian treatment of gaussian state - space models . here we discuss gaussian responses in the dglm setting , for completeness purposes , but also because the normal distribution has many similarities with the log - normal distribution that follows . suppose that @xmath0 is a time series generated from a normal distribution , i.e. @xmath245 , with density @xmath246 where @xmath247 is the level of @xmath11 . the variance @xmath248 of the process can be time - varying , but for simplicity here , we assume it time - invariant . here , this variance is assumed known , while @xmath247 is assumed unknown . if @xmath248 is unknown , bayesian inference is possible by assuming that @xmath249 follows a gamma distribution and this model leads to a conjugate analysis ( resulting to a posterior gamma distribution for @xmath249 and to a student @xmath28 distribution for the forecast distribution of @xmath75 ) . this model is examined in detail in west and harrison ( 1997 , chapter 4 ) . returning to the above normal density , we can easily see that @xmath250 is of the form of ( [ exp ] ) , with @xmath12 , @xmath251 , @xmath252 , @xmath253 and @xmath254 . the prior for @xmath255 is the normal distribution @xmath256 and the posterior of @xmath257 is the normal distribution @xmath258 the link function is the identity link , i.e. @xmath259 and so we have @xmath260 , which implies @xmath261 and @xmath262 . by replacing these quantities in the above prior and posterior densities , we can verify the kalman filter recursions . it turns out that the @xmath66-step forecast distribution is also a normal distribution , i.e. @xmath263 the power discounting yields @xmath264 adopting the random walk evolution for @xmath265 , from the identity link @xmath266 , we have that @xmath267 , where @xmath229 . from ( [ logl ] ) the log - likelihood function is @xmath268 bayes factors can be easily computed from the forecast density @xmath204 and the bayes factor formula ( [ bf1 ] ) . the log - normal distribution has many applications , e.g. in statistics ( johnson _ et al . _ , 1994 ) , in economics ( aitchison and brown , 1957 ) , and in life sciences ( limpert _ et al . _ , 2001 ) . suppose that the time series @xmath0 is generated from a log - normal distribution , with density @xmath269 where @xmath270 . we will write @xmath271 . this distribution is of the form of ( [ exp ] ) , with @xmath272 , @xmath251 , @xmath273 , @xmath253 and @xmath274 . from the normal part we can see @xmath275 and from the log - normal part we can see @xmath276 from the latter of which the logarithmic link can be suggested , i.e. @xmath277 . from the normal distribution of @xmath278 , it follows that the prior distribution of @xmath173 is @xmath279 and the posterior distribution of @xmath280 is @xmath281 where @xmath52 and @xmath53 are calculated as in the normal case , i.e. @xmath261 and @xmath262 . with the definitions of @xmath77 and @xmath78 , we have that the @xmath66-step forecast distribution of @xmath75 is @xmath282 the forecast mean of @xmath75 is @xmath283 where @xmath79 and @xmath80 are the respective mean and variance of @xmath284 , given information @xmath74 . considering power discounting , the updating of @xmath52 and @xmath53 is @xmath285 adopting the random walk evolution for @xmath133 , the distribution of @xmath201 is normal , i.e. @xmath286 , where @xmath155 is the variance of @xmath23 . from ( [ logl ] ) the log - likelihood function is obtained as @xmath287 bayes factors can be calculated from ( [ bf1 ] ) and the log - normal predictive density @xmath204 . as an example , consider the comparison of two models @xmath91 and @xmath92 , which differ in the variances @xmath288 and @xmath289 , respectively . then , by denoting @xmath290 , @xmath291 , @xmath292 and @xmath293 , the values of @xmath52 , @xmath53 , for @xmath294 @xmath295 , we can express the logarithm of the bayes factor @xmath296 as @xmath297 by comparing @xmath298 to 0 , we can conclude preference of @xmath91 or @xmath92 , i.e. if @xmath299 we favour @xmath91 , if @xmath300 we favour @xmath91 , while if @xmath301 the two models are equivalent , in the sense that they both produce the same one - step forecast distributions . .mean square error ( mse ) and log - likelihood function @xmath302 for several values of the discount factor @xmath68 for the log - normal data . [ cols="^,^,^,^,^,^,^,^,^,^ " , ] the inverse gaussian or wald ( chhikara and folks , 1989 ; johnson _ et al . _ , 1994 ) is a skewed distribution that can describe phenomena in economics and in many other sciences . this distribution is known as the first passage time distribution of brownian motion with positive drift . recently , huberman _ ( 1998 ) used an inverse gaussian distribution to model internet flow and internet traffic . suppose that the time series @xmath0 is generated from an inverse gaussian distribution , that is for given @xmath247 and @xmath177 , the density function of @xmath11 is @xmath303 this is a unimodal distribution , which converges to the normal distribution , as @xmath304 . to the following we will assume that @xmath177 is a known parameter and interest will be placed on @xmath247 ; hence we write @xmath305 . we can see that the above distribution is of the form of ( [ exp ] ) , with @xmath12 , @xmath306 , @xmath307 , @xmath308 , @xmath309 and @xmath310 . then we can verify that @xmath311 and @xmath312 the canonical link maps @xmath247 to @xmath2 , or @xmath313 , but this is not convenient , since @xmath314 and hence we need to find an appropriate definition of @xmath146 and @xmath149 in the state space representation of @xmath54 in order to guarantee @xmath315 . the logarithmic link , @xmath316 , seems to work better , since it maps @xmath247 to the real line and so @xmath317 is defined easily . the prior distribution of @xmath247 can be defined via the prior distribution of @xmath2 and the transformation @xmath308 . in the appendix it is shown that @xmath318 in the appendix it is shown that @xmath319 the posterior distribution of @xmath247 is obtained from the posterior distribution of @xmath2 as @xmath320 where in the appendix it is shown that @xmath321 the approximation of @xmath52 and @xmath53 is difficult , since the moment generating function of @xmath322 ( which is needed in order to compute @xmath52 and @xmath53 ) is not available in close form . thus power discounting should be applied . from the posterior of @xmath323 , given by ( [ post : g1 ] ) , we have @xmath324 and so from the prior of @xmath325 ( equation ( [ prior : g1 ] ) ) and the power discounting law we obtain @xmath326 with @xmath71 and @xmath72 , the @xmath66-step forecast distribution of @xmath193 is @xmath327 where the normalizing constant @xmath328 is @xmath329 the @xmath66-step forecast mean can be deduced by ( [ ig : prior : m ] ) as @xmath330 of course the above power discounting specifies @xmath52 and @xmath53 , for a random walk type evolution for the prior ( [ eq : igaussian:2 ] ) . following this , we can specify @xmath331 , with @xmath229 , and so @xmath332 which leads to the density @xmath333 therefore , using ( [ logl ] ) , the log - likelihood function is @xmath334 bayes factors can be easily computed from @xmath204 and the bayes factor formula ( [ bf1 ] ) . to illustrate the inverse gaussian distribution we consider data consisting of 30 daily observations of toluene exposure concentrations ( tec ) for a single worker doing stain removing . the data can be found in takagi _ ( 1997 ) who propose a simple model fit using maximum likelihood estimation for the inverse gaussian distribution . however , it may be argued that these data are autocorrelated and so an appropriate time series should be fitted . figure [ fig : ig1 ] shows one - step forecasts means against the tec data . the forecast means are computed using the above dglm model for the inverse gaussian response , using @xmath335 . the results show that a low value of the discount factor @xmath206 and a low value of @xmath336 yield the best forecasts . the posterior mean @xmath337 is plotted in figure [ fig : ig2 ] , from which we can clearly see that there is a time - varying feature of the parameters of the inverse gaussian distribution . this is failed to be recognized in takagi _ these authors propose estimates for the mean and the scale of the inverse gaussian distribution as 16.7 and 6.4 , which are both larger than the mean of the posterior means @xmath338 and @xmath336 . we note that from figure [ fig : ig1 ] as @xmath339 increases , the forecast performance deteriorates so that a value of @xmath339 near 6.4 would yield poor forecast accuracy . the model we propose here exploits the dynamic behaviour of @xmath247 and it is an appropriate model for forecasting . in this paper we discuss approximate bayesian inference of dynamic generalized linear models ( dglms ) , following west _ et al . _ ( 1985 ) and co - authors . such an approach allows the derivation of the multi - step forecast distribution , which is a useful consideration for carrying out error analysis based on residuals , on the likelihood function , or on bayes factors . we explore all the above issues by examining in detail several examples of distributions including binomial , poisson , negative binomial , geometric , normal , log - normal , gamma , exponential , weibull , pareto , two special cases of the beta , and inverse gaussian . we believe that dglms offer a unique statistical framework for dealing with a range of statistical problems , including business and finance , medicine , biology and genetics , and behavioural sciences . in most of these areas , researchers are not well aware of the advantages that bayesian inference for dglms can offer . in this context we believe that the present paper offers a clear description of the methods with detailed examples of many useful response distributions . first we calculate the mean and variance of the log - gamma and the log - beta distributions . let @xmath340 follow the gamma distribution with parameters @xmath341 and @xmath342 , with density function @xmath343 where @xmath118 denotes the gamma function and @xmath344 . the density function of @xmath345 is @xmath346 the moment generating function of @xmath347 is @xmath348 and the cumulant generating function is @xmath349 . then we have @xmath350 where @xmath124 is the digamma function , which is defined by @xmath185 and the derivative @xmath124 is known as the trigamma function ( abramowitz and stegun , 1964 ) . for the log - beta distribution , let @xmath340 follow the beta distribution , with density function @xmath351 where @xmath344 and @xmath352 . the density function of @xmath353 is @xmath354 with moment generating function @xmath355 for @xmath356 . the cumulant generating function is @xmath357 and so @xmath358 thus , for the calculation of @xmath52 and @xmath53 in equation ( [ eq : binom : rt ] ) , from the prior @xmath116 , we have @xmath364 and @xmath365 we obtain ( [ eq : binom : rt ] ) by solving ( [ rt : solv1 ] ) and ( [ st : solv1 ] ) for @xmath52 and @xmath53 . the calculation of @xmath52 and @xmath53 of ( [ eq : poisson : rt ] ) follows a similar pattern . to this end , we note the gamma prior @xmath366 and with the logarithmic link we have @xmath367 and @xmath368 equation ( [ eq : poisson : rt ] ) is obtained by the solution of ( [ rt : solv2 ] ) and ( [ st : solv2 ] ) for @xmath52 and @xmath53 . since @xmath49 and @xmath50 are only guides of the mean and variance of the prior of @xmath15 , the above approximations of @xmath360 and @xmath362 can be used even when @xmath359 is small . the posterior quantities @xmath62 and @xmath369 are calculated in a similar way , but here we use the full approximations @xmath370 and @xmath191 , the details of which can be found in abramowitz and stegun ( 1964 ) . the prior distribution of @xmath2 is @xmath371 this is not a known distribution and so we need to use integration in order to find the constant @xmath372 . since @xmath373 , we need to evaluate @xmath374 by applying the substitution @xmath375 we have @xmath376 now @xmath377 can be written as @xmath378 integral @xmath379 can be evaluated via the gaussian integral , i.e. @xmath380 for @xmath381 we use the substitution @xmath382 and so we get @xmath383 thus , combining @xmath377 , @xmath379 and @xmath381 , we obtain @xmath384 the required prior distribution of @xmath247 is immediately obtained by density ( [ app1 ] ) , if we apply the transformation @xmath308 and we use @xmath372 as above . proceeding with the proof of ( [ ig : prior : m ] ) we have @xmath385 where @xmath386 . to evaluate integral @xmath387 we note that @xmath388 and by applying the substitution @xmath389 and using the gaussian integral , we have @xmath390 the required mean ( [ ig : prior : m ] ) is obtained as @xmath391 . durbin , j. and koopman , s.j . ( 2000 ) time series analysis of non - gaussian observations based on state space models from both classical and bayesian perspectives ( with discussion ) . _ journal of the royal statistical society series b _ , * 62 * , 3 - 56 . ferreira , m.a.r . and gamerman , d. ( 2000 ) dynamic generalized linear models . in generalized linear models : a bayesian perspective _ , d.k . dey , s.k . ghosh and b.k . mallick ( eds . ) . marcel dekker , new york . houseman , e.a . , coull , b.a . and shine , j.p . ( 2006 ) a nonstationary negative binomial time series with time - dependent covariates : enterococcus counts in boston harbor . _ journal of the american statistical association _ , * 101 * , 1365 - 1376 .

the purpose of this paper is to provide a discussion , with illustrating examples , on bayesian forecasting for dynamic generalized linear models ( dglms ) . adopting approximate bayesian analysis , based on conjugate forms and on bayes linear estimation , we describe the theoretical framework and then we provide detailed examples of response distributions , including binomial , poisson , negative binomial , geometric , normal , log - normal , gamma , exponential , weibull , pareto , beta , and inverse gaussian . we give numerical illustrations for all distributions ( except for the normal ) . putting together all the above distributions , we give a unified bayesian approach to non - gaussian time series analysis , with applications from finance and medicine to biology and the behavioural sciences . throughout the models we discuss bayesian forecasting and , for each model , we derive the multi - step forecast mean . finally , we describe model assessment using the likelihood function , and bayesian model monitoring . _ some key words : _ bayesian forecasting , non - gaussian time series , dynamic generalized linear model , state space , kalman filter .

Atlanta (CNN) Six-year-old Nhaijah Russell swallowed three or four squirts of seemingly innocuous liquid hand sanitizer at school. It tasted good, she said, like strawberry. It also contained enough alcohol to make her dangerously drunk. She arrived at the emergency room slurring her words and unable to walk. Since 2010, poison control center hotlines across the United States have seen a nearly 400% increase in calls related to children younger than 12 ingesting hand sanitizer, according to new analysis by the Georgia Poison Center Hydrocarbons, such as lighter fluids, can get into a child's lungs when ingested. They can cause coughing, choking, fever, pneumonia and death, according to the National Capitol Poison Center. Hydrocarbons – Hydrocarbons, such as lighter fluids, can get into a child's lungs when ingested. They can cause coughing, choking, fever, pneumonia and death, according to the National Capitol Poison Center. Cigarettes aren't the only smoking-related product that needs to be kept out of reach of kids. Liquid nicotine used to refill e-cigarettes can make a child sick if it is ingested or spilled on skin, according to the Georgia Poison Center. Liquid nicotine – Cigarettes aren't the only smoking-related product that needs to be kept out of reach of kids. Liquid nicotine used to refill e-cigarettes can make a child sick if it is ingested or spilled on skin, according to the Georgia Poison Center. Insecticides and weedkillers contain chemicals that are dangerous if ingested. Glyphosate, a chemical in weedkillers, can cause vomiting, breathing difficulties and even death. Bug- and weedkillers – Insecticides and weedkillers contain chemicals that are dangerous if ingested. Glyphosate, a chemical in weedkillers, can cause vomiting, breathing difficulties and even death. Some vitamins, such as adult iron supplements, look like candy to children. The amount of iron in an adult tablet can be a toxic dose to a small child, according to the National Capital Poison Center. Vitamins and supplements – Some vitamins, such as adult iron supplements, look like candy to children. The amount of iron in an adult tablet can be a toxic dose to a small child, according to the National Capital Poison Center. Painkillers such as acetaminophen account for 10% of poison exposures in children younger than 6 and 7% of poison exposures in children ages 6 to 12 years, according to the American Association of Poison Control Centers. Painkillers – Painkillers such as acetaminophen account for 10% of poison exposures in children younger than 6 and 7% of poison exposures in children ages 6 to 12 years, according to the American Association of Poison Control Centers. Household cleaning products are the second-leading cause of poison exposures in children younger than 6, according to the American Association of Poison Control Centers. Household cleaners – Household cleaning products are the second-leading cause of poison exposures in children younger than 6, according to the American Association of Poison Control Centers. Cosmetics and personal care products are the leading cause of poison exposures in children younger than 6, according to the American Association of Poison Control Centers. Personal care products – Cosmetics and personal care products are the leading cause of poison exposures in children younger than 6, according to the American Association of Poison Control Centers. Since 2010, poison control center hotlines across the United States have seen a nearly 400% increase in calls related to children younger than 12 ingesting hand sanitizer , according to an analysis by the Georgia Poison Center. Biting into laundry detergent packets can cause serious injury or even death, according to the National Capital Poison Center. Calls to poison control centers about detergent packets increased 17% from 2013 through 2014, according to an analysis of national data . A study published in 2017 showed an increase in the number of young children with eye injuries linked to the packets. Researchers for a study published in the Annals of Emergency Medicine in 2016 looked at 294 cases of peroxide ingestion over a 10-year period. They found that a large number of cases where patients swallowed high-concentration peroxide resulted in critical illness, some with continued disability or death. "Kids are getting into these products more frequently, and unfortunately, there's a percentage of them going to the emergency room," said Dr. Gaylord Lopez, the center's director. The amount of alcohol in hand sanitizer ranges from 45% to 95%. Ingesting even small amounts -- as little as two or three squirts in some cases -- can cause alcohol poisoning. By comparison, wine and beer contain about 12% and 5% alcohol, Lopez said. Nhaijah's blood-alcohol level was .179, twice what's considered legally drunk in an adult, according to Dr. Chris Ritchey, who treated her in the emergency room at Gwinnett Medical Center near Atlanta. Doctors had to watch Nhaijah overnight at a nearby children's hospital for signs of brain trauma, since the alcohol had caused her to fall and hit her head, he said. "That was very scary," Nhaijah's mother, Ortoria Scott, said. "It could have been very lethal for my child." JUST WATCHED Teens drinking hand sanitizer Replay More Videos ... MUST WATCH Teens drinking hand sanitizer 02:01 Alcohol poisoning can cause confusion, vomiting and drowsiness. In severe cases, a child can stop breathing. Lopez said 3,266 hand sanitizer cases related to young children were reported to poison control centers in 2010. In 2014, the number increased to 16,117 cases. Last week, Lopez sent a letter to Georgia's school systems warning about children drinking hand sanitizer. He explained that some children do it intentionally in order to get drunk, while others do it on a dare from friends. Still others, he said, drink sanitizer because it looks tasty. "A kid is not thinking this is bad for them," Lopez said. "A lot of the more attractive (hand sanitizers) are the ones that are scented. There are strawberry, grape, orange-flavored hand sanitizers that are very appealing to kids." Lopez recommends parents and teachers store hand sanitizer out of reach of children and monitor its use. He said nonalcohol based products or sanitizing wipes can also be used. ||||| Hand sanitizer the new fad for minors looking to get drunk Poison control centers reveal an increase in hand sanitizer related calls, some which land kids in the hospital Parents are warned right away that chemicals need to be locked up and kept away from children. Poison control centers around the country respond to calls daily about mishaps involving minors swallowing chemicals, some ending more tragically than others. However lately call centers are plagued with an even bigger problem, as the new fad among kids searching for a buzz is to ingest hand sanitizer. “Kids are getting into these products more frequently, and unfortunately, there’s a percentage of them going to the emergency room,” said Dr. Gaylord Lopez. Lopez is the director of the Georgia Poison Center, and has witnessed the increase in calls firsthand. According to The Standard Daily, poison control centers have had a 400% increase since 2010 in calls regarding young ones who had swallowed hand sanitizer. Many of them were ingesting it willingly to get drunk, as hand sanitizer consists of 45-95% alcohol, whereas wine contains 12% and beer only 5%. On the other hand, younger children often ingest the cleaning fluid because it smells good. This was the case for 6-year-old Nhaijah Russell, who swallowed four squirts of the substance because it tasted like strawberries. Experts point out that only 2-3 squirts can lead to alcohol poisoning. Nhaijah, who had a blood alcohol content (BAC) of .179, twice the level in a legally drunk adult, was rushed to the emergency room. “That was very scary,” said Orotia Scott, Nhaijah’s mother. Luckily, Nhaijah recovered, but the scare it gave her mother ushered her to issue out a warning to other parents. “It could have been very lethal for my child.” Lopez suggested that schools switch to non-alcohol based sanitizer or wipes be used for the time being, and that classrooms who don’t switch should monitor their supply and put it in a high place where children cannot reach it. “A kid is not thinking this is bad for them,” Lopez said. “A lot of the more attractive [hand sanitizers] are the ones that are scented. There are strawberry, grape, orange-flavored hand sanitizers that are very appealing to kids.”

– Think you're good at locking up common household poisons from young kids? You may be forgetting one that looks surprisingly appealing to a small child: hand sanitizer. The number of cases of kids younger than 12 reported to poison control centers for ingesting hand sanitizer, which now comes in "fun" scents such as grape and strawberry, nearly quadrupled across the US in just a few years, according to an analysis by the Georgia Poison Center, jumping from 3,266 cases in 2010 to 16,117 in 2014, reports CNN. While beer and wine tend to contain about 5% and 12% alcohol, respectively, hand sanitizer can range from 45% to 95%, a concentration so high that just a few squirts can actually cause alcohol poisoning. "A kid is not thinking this is bad for them," the poison center's director tells CNN. "There are strawberry-, grape-, orange-flavored hand sanitizers that are very appealing to kids." When Nhaijah Russell, who's 6, recently swallowed three or four squirts of strawberry-flavored hand sanitizer at her school, she began to slur her words, and by the time she reached the emergency room she could hardly walk. Nhaijah's blood-alcohol level was .179, twice the legal limit for an adult. "That was very scary," her mother said. "It could have been very lethal for my child." Some kids reportedly ingest hand sanitizer on purpose, to get drunk or as a dare, and NewsQuench adds that schools that don't switch to non-alcohol-based sanitizers should at least store them out of reach. (Some people have to "quit" hand sanitizer.)

BEIRUT/AMMAN Mystery surrounded the whereabouts of Syrian President Bashar al-Assad on Thursday, a day after a bomber killed and wounded his security chiefs and rebels closed in on the centre of Damascus, vowing to "liberate" the capital. The Syrian leader made no public appearance and no statement on Wednesday after a bomber killed his powerful brother-in-law, his defense minister and a top general. By the early hours of Thursday morning, residents had reported no let-up in the heaviest fighting to hit the capital in a 16-month revolt against Assad's rule. Fighting on Wednesday had come to within sight of the presidential palace, near the security headquarters where the bomber struck a crisis meeting of defense and security chiefs. Assad's brother-in-law Assef Shawkat, who served as a top commander and one of the pillars of the Assad clan's rule, was killed in the blast along with Defense Minister Daoud Rajha. Another senior general also was killed and the heads of intelligence and the Interior Ministry were wounded, deeply damaging the security apparatus of the Assad family, which has ruled the country with an iron fist for four decades. Intense clashes were reported late on Wednesday in the capital's central districts of Mezze and Kafar Souseh, while a police station in the Hajar al-Aswad district was in flames. The army was shelling its own capital from the surrounding mountains as night fell. Government troops, having vowed retaliation on Wednesday for the assassination, fired machineguns into the city from helicopters. A security source said the bomber who struck inside the security headquarters was a bodyguard entrusted with protecting the closest members of Assad's circle. State television said it was a suicide bomber. Anti-Assad groups claimed responsibility. Washington, which fears a spillover into neighboring states, said the situation seemed to be spinning out of control. Russian Foreign Minister Sergei Lavrov said "the decisive fight" was under way in Damascus. The U.N. Security Council put off a scheduled vote on a Syria resolution on Wednesday and U.S. President Barack Obama phoned Russia's Vladimir Putin, Assad's main world power protector, to try to persuade Moscow to drop support for him. CORE OF CRISIS UNIT KILLED The generals killed and wounded in Wednesday's bombing form the core of Assad's crisis unit to crush the revolt, which grew out of protests inspired by Arab Spring uprisings that unseated leaders in Tunisia, Egypt and Libya. The armed forces chief of staff, Fahad Jassim al-Freij, quickly took over as defense minister on Wednesday to avoid giving any impression of official paralysis. "This cowardly terrorist act will not deter our men in the armed forces from continuing their sacred mission of pursuing the remnants of these armed terrorist criminal gangs," Freij said on state television. "They will cut off every hand that tries to hurt the security of the nation or its citizens." The explosion appeared to be part of a coordinated assault on the capital that has escalated since the start of the week. Rebel fighters call it the "liberation of Damascus" after months of clashes which activists say have killed 17,000 people. "This is the final phase. They will fall very soon," Abdelbasset Seida, a leader of the opposition Syrian National Council, told Reuters in Qatar. "Today is a turning point in Syria's history. It will put more pressure on the regime and bring an end very soon, within weeks or months." U.S. Defense Secretary Leon Panetta said: "This is a situation that is rapidly spinning out of control." He called for maximum global pressure on Assad to step down. FEAR OF DESTABILISATION Western leaders fear the conflict, which has been joined by al Qaeda-style jihadists, could destabilize Syria's neighbors: Israel, Lebanon, Turkey, Iraq and Jordan. Syrian forces hit rebel positions across the capital after the attack on the security meeting, with activists saying government troops and pro-government militia were flooding in. State television broadcast footage it said was filmed on Wednesday showing men in blue army fatigues ducking for cover and firing - the first time official media has shown clashes in the heart of the capital. Government troops used heavy machineguns and anti-aircraft guns against rebels in residential neighborhoods, armed mostly with small arms and rocket-propelled grenades. Rebels were jubilant at their success in penetrating into the capital and at the deaths of the security chiefs. Abdullah al-Shami, a rebel commander based in Turkey, said: "I expect a speedy collapse of the regime ... and it means we will not be in need of outside intervention, with the regime beginning to crumble much faster than we envisaged." Yet some opposition figures said victory would still not be easy. "It is going to be difficult to sustain supply lines and the rebels may have to make a tactical withdrawal at one point, like they did in other cities," veteran opposition activist Fawaz Tello said from Istanbul. "But what is clear is that Damascus has joined the revolt." (Additional reporting by Dominic Evans and Erika Solomon in Beirut, Khaled Yacoub Oweis in Amman, Suleiman Al-Khalidi in Antakya, Turkey and Regan Doherty in Doha; Writing by Peter Graff; Editing by Louise Ireland) ||||| Photo Advertisement Continue reading the main story BEIRUT, Lebanon — The killing on Wednesday of President Bashar al-Assad’s key security aides in a brazen bombing attack, close to Mr. Assad’s own residence, called into question the ability of a government that depends on an insular group of loyalists to function effectively as it battles a strengthening opposition. The strike dealt a potent blow to the government, as much for where it took place as for the individuals who were targeted: the very cabinet ministers and intelligence chiefs who have coordinated the government’s iron-fisted approach to the uprising. The defense minister and the president’s brother-in-law were both killed, and others were seriously wounded. The attack on the leadership’s inner sanctum as fighting raged in sections of the city for the fourth day suggested that the uprising had reached a decisive moment in the overall struggle for Syria. The battle for the capital, the center of Assad family power, appears to have begun. Though there was no indication he was wounded, Mr. Assad stayed out of public view — unusual but not unprecedented in a secretive country where the government has long tried to present an image of quiet control. Photo In Washington, Defense Secretary Leon E. Panetta said that Syria “is rapidly spinning out of control,” and warned Mr. Assad’s government to safeguard its large stockpile of chemical weapons. “It’s obvious what is happening in Syria is a real escalation,” he said at a joint news conference with the British defense minister, Philip Hammond. The impact of the day’s events reverberated on multiple levels, piercing the psychological advantage that Mr. Assad’s superior military strength has provided in preserving the loyalty of his forces and frightening much of the public into staying home. With the opposition energized and the government demoralized, analysts wondered if other military units and trusted lieutenants would be more inclined to switch sides — and if the government would retaliate with an escalation of violence. Advertisement Continue reading the main story The idea that a poorly organized, lightly armed opposition force could somehow get so close to the seat of power raised questions about the viability of a once unassailable police state. The Assad family has for decades relied on overlapping security forces and secret police to preserve its lock on power. At best, for Mr. Assad, the system failed. At worst, for Mr. Assad, defectors or turncoats helped carry out an inside operation. The government said that the attack was the work of a suicide bomber, while an officer with the Free Syrian Army said it was a remotely detonated explosive. Photo The most significant victim was Asef Shawkat — the husband of the president’s older sister, Bushra — who was the deputy chief of staff of the military after years as a top intelligence official. The others killed were Gen. Dawoud A. Rajha, the defense minister and the most prominent Christian in the government; and Maj. Gen. Hassan Turkmani, a previous defense minister serving as the top military aide to Vice President Farouk al-Sharaa. Advertisement Continue reading the main story “Who will replace these people?” asked Elias Hanna, a retired Lebanese military officer and a military analyst knowledgeable about Syria. “They are irreplaceable at this stage; it’s hard to find loyal people now that doubt is sown everywhere. Whoever can get to Asef Shawkat can get to Assad.” “Everyone, even those close to the inner circle, will now be under suspicion,” he said. State television also said the minister of the interior, Lt. Gen. Mohamed al-Sha’ar, had been gravely wounded but was in stable condition. Hisham Ikhtiar, the head of general security, was reported by some activist organizations among those in critical condition, along with some junior officers, but the official news media did not confirm that. Photo The bombing took place in a small, nondescript building in a neighborhood that is home to the country’s elite. The building housed a research center run by the national security agency, one of many overlapping intelligence agencies. “It was at the heart of the government’s nexus of control,” said an analyst with long experience in Damascus, speaking anonymously because he still travels there often. “If the regime had a center, that was it.” But the government mounted a show of normality. It quickly appointed a new defense minister, Gen. Fahd Jassem al-Freij, the military chief of staff who had previously been responsible for trying to squash the uprising in northern Idlib Province. He appeared briefly on television, vowing that the military would not be deterred by the attack from “cutting off every hand that harms the security of the homeland and citizens.” The military also issued a statement saying in part, “This terrorist act will only increase our insistence to purge this country from the criminal terrorist thugs and to protect the dignity of Syria and its sovereignty.” Photo Activists reported an even harsher crackdown, with government soldiers firing indiscriminately in several embattled neighborhoods or from helicopters, especially on the southern part of Damascus where fighting first erupted Sunday. Dozens of people were killed, and defections soared, activists said. “The regime reacted hysterically to the attack,” said Rami al-Sayyed, an activist in Damascus. “The security forces and thugs infiltrated various neighborhoods, committing all kinds of crimes. Today we cut the head of the snake, but we still have the tail.” Like any event in Damascus, details surrounding the attack were murky. There were competing accounts of how the attack occurred and competing claims of responsibility. The Free Syrian Army based in Turkey said it had helped carry out the attack. Also, a brigade from a group with a seemingly religious bent called the Islamic Battalions said it was responsible. Lt. Malik al-Kurdi, the second in command of the Free Syrian Army troops in Turkey, said it was not a suicide bombing but “bombs planted around the national security building” that were set off by remote control. Photo Since the uprising began in March 2011, claiming an estimated 17,000 victims, Syria has been run by an ever tighter circle of army and security officials close to the president. General Rajha was one of the prominent minority figures used by the Assad government to put a face of pluralism on the military and security services dominated by the president’s Alawite sect. Advertisement Continue reading the main story Advertisement Continue reading the main story “The Syrian regime has started to collapse,” said the activist who leads the Syrian Observatory, who goes by the pseudonym Rami Abdul-Rahman for reasons of personal safety. The attack heightened the perception globally that after months of clashes, Syria was embroiled in a civil war. On the other end of the scale, Hassan Nasrallah, the leader of Hezbollah, delivered an emotional speech live on television, saying that the Syria of Mr. Assad and Mr. Shawkat was the backbone of the Arab confrontation with Israel. The attack came as diplomatic maneuvers to seek a cease-fire remained deadlocked by differences between Syria’s international adversaries and sponsors, principally Russia. The United Nations Security Council is scheduled to vote on a Western-sponsored resolution that would threaten Mr. Assad’s government with economic sanctions if it does not implement a peace plan negotiated by the special envoy Kofi Annan more than three months ago. Photo The resolution, which Russia has threatened to veto, would extend the mission of 300 unarmed United Nations monitors, whose work has been suspended because of the violence. Security Council members agreed to delay the vote, originally scheduled for Wednesday, until Thursday at Mr. Annan’s request, to allow more time for diplomats to resolve their differences over the resolution’s wording. But in Moscow, Deputy Foreign Minister Gennady Gatilov, offering Russia’s first official commentary on the Damascus bombing, said via his Twitter account that the attack had put consensus between members of the Security Council even further out of reach. “A dangerous logic: While discussions on settling the Syrian crisis are being held in the U.N. Security Council, militants intensify terrorist attacks, frustrating all attempts,” he wrote. In Syria, the information minister, Omran al-Zoubi, appeared on a talk show to reject claims by those calling it the beginning of the end. “The morale of our people is very high and our armed forces are at their highest level,” he said. But residents of Damascus had been shaken as never before. Residents reached by telephone said that after the news broke around noon, people rushed out to buy food and then rushed back home again. City streets appeared deserted, with not even taxis circulating after dark. “All the stores and shops are closed,” said an activist in Damascus reached via Skype. “Some people are scared and some are happy; you can hear people firing off gunshots in many places.” A video from Hama showed opposition members distributing candy to celebrate Mr. Shawkat’s death.

– A regime-shaking suicide attack on the National Security building has killed Bashar al-Assad's defense minister and brother-in-law, according to the country's state-run TV. The New York Times calls the death of defense minister Daoud Rajha the "first assassination of a prominent official" in the entirety of the uprising. As for Assef Shawkat, who was married to Assad's older sister, the AP calls him "among the most feared figures in Assad's inner circle." Unconfirmed reports say the suicide bomber worked as a bodyguard for that inner circle. The location of the attack is significant in more ways than one, notes BBC correspondent Mike Wooldridge: "Not only does the target add an entirely new dimension to the conflict, it is also close to the presidential residence. Most of the previous fighting has been on the southern side of the center of the capital." In another blow to the regime, Reuters reports that high-level defectors continue to pour across the border. Another 600 Syrians reportedly made their way to Turkey last night, and two Syrian brigadier-generals were said to be among the group. If true, that brings the tally of Syrian generals now in Turkey to 20.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Belarus Democracy Reauthorization Act of 2006''. SEC. 2. FINDINGS. Section 2 of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) is amended to read as follows: ``SEC. 2. FINDINGS. ``Congress makes the following findings: ``(1) The Government of the Republic of Belarus has engaged in a pattern of clear and uncorrected violations of human rights and fundamental freedoms. ``(2) The Government of Belarus has engaged in a pattern of clear and uncorrected violations of basic principles of democratic governance, including through a series of fundamentally flawed presidential and parliamentary elections undermining the legitimacy of executive and legislative authority in that country. ``(3) The most recent presidential elections in Belarus held on March 19, 2006, failed to meet the commitments of the Organization for Security and Cooperation in Europe (OSCE) for democratic elections and the arbitrary use of state power and widespread detentions show a disregard for the basic rights of freedom of assembly, association, and expression, and raise doubts regarding the willingness of authorities in Belarus to tolerate political competition. ``(4) The regime of Aleksandr Lukashenka has maintained power in Belarus by orchestrating an illegal and unconstitutional referendum that enabled him to impose a new constitution, abolish the duly-elected parliament, the 13th Supreme Soviet, install a largely powerless National Assembly, extend his term of office, and remove applicable term limits. ``(5) The Government of Belarus has failed to make a credible effort to solve the cases of disappeared opposition figures Yuri Zakharenka, Viktor Gonchar, and Anatoly Krasovsky in 1999 and journalist Dmitry Zavadsky in 2000, even though credible allegations and evidence exist linking top officials of the Lukashenka regime with these disappearances. ``(6) Political opposition figures Aleksandr Kozulin, Tsimafei Dranchuk, Mikalay Astreyka, Artur Finkevich, Mikalay Razumau, Katsyaryna Sadouskaya, Zmitser Dashkevich, Mikhail Marynich, Mikalay Statkevych, Pavel Sevyarinets, Andrei Klimau, Valery Levaneusky, and Siarhei Skrebets have been imprisoned or served `corrective labor' sentences because of their political activity. ``(7) Hundreds of pro-democratic political activists have been subjected to frequent harassment and jailings, especially during, and in the aftermath of the fatally flawed March 19, 2006, presidential elections in Belarus. ``(8) The Government of Belarus has attempted to maintain a monopoly over the country's information space, targeting independent media for systematic reprisals and elimination, while suppressing the right to freedom of speech and expression of those dissenting from the regime. ``(9) The Belarusian authorities have perpetuated a climate of fear in Belarus by mounting a systematic crackdown on civil society through the harassment, repression, and closure of nongovernmental organizations and independent trade unions. ``(10) The Lukashenka regime has increasingly subjected leaders and members of minority and unregistered religious communities to harassment, including the imposition of heavy fines, denying permission to meet for religious services, prosecutions, and jail terms for activities in the practice of their faith. ``(11) The Belarusian authorities have further attempted to silence dissent through retribution against human rights and pro- democracy activists through threats, firings, expulsions, beatings and other forms of intimidation.''. SEC. 3. STATEMENT OF POLICY. The Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) is amended-- (1) by striking section 8; (2) by redesignating sections 3 through 7 as sections 4 through 8, respectively; and (3) by inserting after section 2 the following new section: ``SEC. 3. STATEMENT OF POLICY. ``It is the policy of the United States-- ``(1) to call upon the immediate release without preconditions of all political prisoners in Belarus; ``(2) to support the aspirations of the people of the Republic of Belarus for democracy, human rights, and the rule of law; ``(3) to support the aspirations of the people of the Republic of Belarus to preserve the independence and sovereignty of their country; ``(4) to seek and support the growth of democratic movements and institutions in Belarus, with the ultimate goal of ending tyranny in that country; ``(5) to refuse to accept the results of the fatally flawed March 19, 2006, presidential elections held in Belarus and support the call for new presidential elections; ``(6) to refuse to recognize any possible referendum, or the results of any referendum, that would affect the sovereignty of Belarus; and ``(7) to work closely with other countries and international organizations, including the European Union, to promote the conditions necessary for the integration of Belarus into the European community of democracies.''. SEC. 4. ASSISTANCE TO PROMOTE DEMOCRACY AND CIVIL SOCIETY IN BELARUS. (a) Purposes of Assistance.--Section 4(a) of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended-- (1) in paragraph (1), by striking ``regaining their freedom and to enable them'' and inserting ``their pursuit of freedom, democracy, and human rights and in their aspiration''; (2) in paragraph (2)-- (A) by striking ``free and fair'' and inserting ``free, fair, and transparent''; and (B) by adding at the end before the period the following: ``and independent domestic observers''; and (3) in paragraph (3), by striking ``restoring and strengthening institutions of democratic governance'' and inserting ``the development of a democratic political culture and civil society''. (b) Activities Supported.--Section 4(c) of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended-- (1) by redesignating paragraphs (6) and (7) as paragraphs (7) and (8), respectively; (2) by striking paragraphs (1) through (5) and inserting the following new paragraphs: ``(1) expanding independent radio and television broadcasting to and within Belarus; ``(2) facilitating the development of independent broadcast, print, and Internet media working within Belarus and from locations outside the country and supported by nonstate-controlled printing facilities; ``(3) aiding the development of civil society through assistance to nongovernmental organizations promoting democracy and supporting human rights, including youth groups, entrepreneurs, and independent trade unions; ``(4) supporting the work of human rights defenders; ``(5) enhancing the development of democratic political parties; ``(6) assisting the promotion of free, fair, and transparent electoral processes;''; and (3) in paragraph (7) (as redesignated), by inserting ``enhancing'' before ``international exchanges''. (c) Authorization of Appropriations.-- (1) Amendment.--Section 4(d)(1) of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended by striking ``2005 and 2006'' and inserting ``2007 and 2008''. (2) Rule of construction.--The amendment made by paragraph (1) shall not be construed to affect the availability of funds appropriated pursuant to the authorization of appropriations under section 4(d) of the Belarus Democracy Act of 2004 (as redesignated) before the date of the enactment of this Act. SEC. 5. RADIO AND TELEVISION BROADCASTING TO BELARUS. (a) Purpose.--Section 5(a) of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended by striking ``radio broadcasting'' and inserting ``radio and television broadcasting''. (b) Authorization of Appropriations.--Section 5(b) of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended by striking ``radio broadcasting'' and inserting ``radio and television broadcasting''. (c) Conforming Amendment.--Section 5 of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended in the heading by striking ``radio broadcasting'' and inserting ``radio and television broadcasting''. SEC. 6. SANCTIONS AGAINST THE GOVERNMENT OF BELARUS. Section 6 of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended to read as follows: ``SEC. 6. SANCTIONS AGAINST THE GOVERNMENT OF BELARUS. ``(a) Application of Sanctions.--The sanctions described in subsections (c) through (f) should apply with respect to the Republic of Belarus until the President determines and certifies to the appropriate congressional committees that the Government of Belarus has made significant progress in meeting the conditions described in subsection (b). ``(b) Conditions.--The conditions referred to in subsection (a) are the following: ``(1) The release of individuals in Belarus who have been jailed based on political or religious beliefs. ``(2) The withdrawal of politically motivated legal charges against all opposition activists and independent journalists in Belarus. ``(3) A full accounting of the disappearances of opposition leaders and journalists in Belarus, including Victor Gonchar, Anatoly Krasovsky, Yuri Zakharenka, and Dmitry Zavadsky, and the prosecution of those individuals who are in any way responsible for their disappearances. ``(4) The cessation of all forms of harassment and repression against the independent media, independent trade unions, nongovernmental organizations, youth groups, religious organizations (including their leadership and members), and the political opposition in Belarus. ``(5) The prosecution of senior leadership of the Government of Belarus responsible for the administration of fraudulent elections. ``(6) A full accounting of the embezzlement of state assets by senior leadership of the Government of Belarus, their family members, and other associates. ``(7) The holding of free, fair and transparent presidential and parliamentary elections in Belarus consistent with OSCE standards and under the supervision of internationally recognized observers and independent domestic observers. ``(c) Denial of Entry Into the United States of Senior Leadership of the Government of Belarus.--Notwithstanding any other provision of law, the President may exercise the authority under section 212(f) of the Immigration and Nationality Act (8 U.S.C. 1182(f)) to deny the entry into the United States of any alien who-- ``(1) holds a position in the senior leadership of the Government of Belarus; ``(2) is an immediate family member of a person inadmissible under subparagraph (A); or ``(3) through his or her business dealings with senior leadership of the Government of Belarus derives significant financial benefit from policies or actions, including electoral fraud, human rights abuses, or corruption, that undermine or injure democratic institutions or impede the transition to democracy in Belarus. ``(d) Prohibition on Loans and Investment.-- ``(1) United states government financing.--It is the sense of Congress that no loan, credit guarantee, insurance, financing, or other similar financial assistance should be extended by any agency of the Government of the United States (including the Export-Import Bank of the United States and the Overseas Private Investment Corporation) to the Government of Belarus, except with respect to the provision of humanitarian goods and agricultural or medical products. ``(2) Trade and development agency.--It is the sense of Congress that no funds available to the Trade and Development Agency should be available for activities of the Agency in or for Belarus. ``(e) Multilateral Financial Assistance.--The Secretary of the Treasury should instruct the United States Executive Director of each international financial institution to which the United States is a member to use the voice and vote of the United States to oppose any extension by those institutions of any financial assistance (including any technical assistance or grant) of any kind to the Government of Belarus, except for loans and assistance that serve humanitarian needs. ``(f) Blocking of Assets and Other Prohibited Activities.-- ``(1) Blocking of assets.--It is the sense of Congress that the President should block all property and interests in property, including all commercial, industrial, or public utility undertakings or entities, that, on or after the date of the enactment of the Belarus Democracy Reauthorization Act of 2006-- ``(A) are owned, in whole or in part, by the Government of Belarus, or by any member or family member closely linked to any member of the senior leadership of the Government of Belarus, or any person who through his or her business dealings with senior leadership of the Government of Belarus derives significant financial benefit from policies or actions, including electoral fraud, human rights abuses, or corruption, that undermine or injure democratic institutions or impede the transition to democracy in Belarus; and ``(B) are in the United States, or in the possession or control of the Government of the United States or of any United States financial institution, including any branch or office of such financial institution that is located outside the United States. ``(2) Prohibited activities.--Activities prohibited by reason of the blocking of property and interests in property under paragraph (1) should include-- ``(A) payments or transfers of any property, or any transactions involving the transfer of anything of economic value by any United States person, to the Government of Belarus, to any person or entity acting for or on behalf of, or owned or controlled, directly or indirectly, by that government, or to any member of the senior leadership of the Government of Belarus; ``(B) the export or reexport to any entity owned, controlled, or operated by the Government of Belarus, directly or indirectly, of any goods, technology, or services, either-- ``(i) by a United States person; or ``(ii) involving the use of any air carrier (as defined in section 40102 of title 49, United States Code) or a vessel documented under the laws of the United States; and ``(C) the performance by any United States person of any contract, including a contract providing a loan or other financing, in support of an industrial, commercial, or public utility operated, controlled, or owned by the Government of Belarus. ``(3) Payment of expenses.--All expenses incident to the blocking and maintenance of property blocked under paragraph (1) should be charged to the owners or operators of such property. Such expenses may not be paid from blocked funds. ``(4) Rule of construction.--Nothing in this subsection shall be construed to prohibit any contract or other financial transaction with any private or nongovernmental organization or business in Belarus. ``(5) Exceptions.--Paragraphs (1) and (2) do not apply to-- ``(A) assistance authorized under section 4 or 5 of this Act; or ``(B) medicine, medical equipment or supplies, food, as well as any other form of humanitarian assistance provided to Belarus as relief in response to a humanitarian crisis. ``(6) Penalties.--Any person who violates any prohibition or restriction imposed under this subsection should be subject to the penalties under section 6 of the International Emergency Economic Powers Act (50 U.S.C. 1705) to the same extent as for a violation under that Act. ``(7) Definitions.--In this subsection: ``(A) Air carrier.--The term `air carrier' has the meaning given that term in section 40102 of title 49, United States Code. ``(B) United states person.--The term `United States person' means-- ``(i) any United States citizen or alien admitted for permanent residence to the United States; ``(ii) any entity organized under the laws of the United States; and ``(iii) any person in the United States.''. SEC. 7. MULTILATERAL COOPERATION. Section 7 of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) (as redesignated) is amended-- (1) by striking ``to coordinate with'' and inserting ``the support of''; and (2) by striking ``a comprehensive'' and inserting ``for a comprehensive''. SEC. 8. DEFINITIONS. Section 9(3) of the Belarus Democracy Act of 2004 (22 U.S.C. 5811 note) is amended-- (1) in subparagraph (A), by inserting ``governors, heads of state enterprises,'' after ``Chairmen of State Committees,''; and (2) in subparagraph (B)-- (A) by striking ``who is'' and inserting the following: ``who-- ``(i) is''; (B) by striking ``and'' at the end and inserting ``or''; and (C) by adding at the end the following new clause: ``(ii) is otherwise engaged in public corruption in Belarus; and''. Speaker of the House of Representatives. Vice President of the United States and President of the Senate.

Belarus Democracy Reauthorization Act of 2006 - (Sec. 3) Amends the Belarus Democracy Act of 2004 to state that it is U.S. policy to: (1) call for the immediate release of all political prisoners in Belarus; (2) support the aspirations of the people of the Republic of Belarus for democracy, human rights, the rule of law, and to preserve their country's independence; (3) support the growth of democratic movements and institutions in Belarus; (4) refuse to accept the results of the March 2006 presidential elections in Belarus and support new presidential elections; (5) refuse to recognize any referendum that would affect Belarus' sovereignty; and (6) work with other countries and international organizations to promote Belarus' integration into the European community of democracies. (Sec. 4) Revises the activities which may be supported by assistance under this Act, including support for youth groups, independent trade unions and entrepreneurs, human rights defenders, independent media, democratic political parties, and international exchanges. Extends authorization of appropriations through FY2008 for such purposes. (Sec. 5) Includes television broadcasting within the scope of increased support and funding for U.S. government and surrogate broadcasting to Belarus. (Currently, such support is limited to radio broadcasting.) (Sec. 6) Establishes specified economic and U.S. entry sanctions against Belarus until the President certifies to the appropriate congressional committees that the government of Belarus has made progress in meeting specified conditions respecting: (1) release of political and religious prisoners and accounting for the disappearances of opposition leaders and journalists; (2) cessation of political harassment; (3) prosecution of senior government leaders for embezzlement of state assets and administration of fraudulent elections; and (4) holding free presidential and parliamentary elections under independent supervision. Authorizes the President to deny U.S. entry to any alien who: (1) is in the senior leadership of the government of Belarus; (2) is an immediate family member of such person; or (3) through business dealings with senior government leadership derives significant financial benefit from policies or actions that undermine democratic institutions or impede Belarus' transition to democracy. Expresses the sense of Congress that: (1) no loan, credit guarantee, insurance, financing, or other similar financial assistance should be extended by any U.S. agency (including the Export-Import Bank and the Overseas Private Investment Corporation) to the government of Belarus, except for humanitarian goods and agricultural or medical products; and (2) no funds available to the Trade and Development Agency should be available for Agency activities in or for Belarus. Expresses the sense of Congress that the President should block all property and property interests that on or after the date of the enactment of this Act: (1) are owned in whole or in part by the government of Belarus, or by any member or family member closely linked to senior government leadership, or any person who through business dealings with senior government leadership derives significant financial benefit from policies or actions that undermine or injure democratic institutions or impede Belarus' transition to democracy; and (2) are in the United States, or in the possession or control of the U.S. government or of any U.S. financial institution, including any branch or office located outside the United States. States that activities prohibited by the blocking of such property interests should include: (1) payments or transfers of property or anything of economic value by any U.S. person to the government of Belarus or to any entity or person acting on its behalf, or to any member of its senior leadership; (2) the export or reexport to any entity owned, controlled, or operated by the government of Belarus of any goods, technology, or services, either by a U.S. person or involving the use of any air carrier or a vessel documented under U.S. law; and (3) the performance by any U.S. person of any contract, including a contract providing a loan or other financing, in support of an industrial, commercial, or public utility operated, controlled, or owned by the government of Belarus. Exempts from such prohibitions: (1) assistance under sections 4 or 5 of this Act; or (2) medicine, medical equipment, food, or other humanitarian assistance provided to Belarus in response to a humanitarian crisis. States that such prohibitions shall be not construed to prohibit financial transactions with any private or nongovernmental organization or business in Belarus. Subjects violators of such asset and property prohibitions to specified penalties under the International Emergency Economic Powers Act. (Sec. 8) Amends the definition of "senior leadership of the government of Belarus."

the implementation of a universal two - qubit gate involving an entanglement operation on two quantum bits represents a necessary step toward the construction of a scalable quantum computer @xcite . intense research on solid state nano - devices during the last decade has established the possibility to combine quantum coherent behavior with the existing integrated - circuit fabrication technology . in particular , based on superconducting technologies , a variety of high - fidelity single qubit gates are nowadays available @xcite , two - qubit logic gates @xcite and violations of bell s inequalities @xcite have been demonstrated , high - fidelity bell states generated @xcite . the recent demonstrations of simple quantum algorithms @xcite and three - qubit entanglement @xcite are further important steps toward a practical quantum computation with superconducting circuits . the requirements for building an elementary quantum processor are however quite demanding on the efficiency of the protocols . this includes both a severe constraint on readout and a sufficient isolation from fluctuations to reduce decoherence effects . solid - state noise sources are often characterized by broad - band and non - monotonic power spectrum . similar noise characteristics have been reported in implementations based on cooper - pair - boxes ( cpb ) @xcite , in persistent current @xcite and phase qubits @xcite . usually , the spectrum of at least one of the noise sources is @xmath0 at low - frequencies @xcite . at the system s eigen - frequencies instead ( @xmath4 ghz ) indirect measurements indicate white or ohmic spectrum @xcite . sometimes spurious resonances of various physical origin have been observed @xcite . at the single - qubit level , the effects of the environmental degrees of freedom responsible for the various parts of the spectrum have been clearly identified leading to a convenient classification in terms of _ quantum noise _ and _ adiabatic noise _ effects @xcite . understanding how these mechanisms affect an entanglement - generating two - qubit gate is a relevant issue not yet investigated and it is the subject of the present article . the picture for a single qubit can be summarised as follows . noise at frequencies of the order of the system s splittings may induce incoherent energy exchanges between qubit and environment ( _ quantum noise _ ) . relaxation processes occur only if the qubit - environment interaction induces spin flips in the qubit eigenbasis , i.e. for transverse noise . weakly - coupled markovian noise can be treated by a born - markov master equation @xcite . it leads to relaxation and decoherence times denoted respectively @xmath1 and @xmath2 in nuclear magnetic resonance ( nmr ) @xcite . for transverse noise they are related by @xmath5 . longitudinal noise does not induce spin flips , but it is responsible for pure dephasing with a decay - time denoted @xmath6 @xcite . in general , both relaxation and pure dephasing processes occur and the resulting decoherence time is @xmath7^{-1}$ ] . since quantum measurements require averages of measurements runs , the main effect of fluctuations with @xmath0 spectrum is defocusing , similarly to inhomogeneous broadening in nmr @xcite . fluctuations with large spectral components at low frequencies can be treated as stochastic processes in the adiabatic approximation ( _ adiabatic noise _ ) . the short - times decay of qubit coherences depends on the symmetry of the qubit - environment coupling hamiltonian . for transverse noise , the time dependence is algebraic @xmath8^{-1/4}$ ] , for longitudinal noise it is exponential quadratic @xmath9 ( `` static - path '' @xcite or `` static - noise '' @xcite approximation ) . the simultaneous presence of adiabatic and quantum noise can be treated in a multi - stage approach @xcite . in simplest cases , the effects of the two noise components add up independently in the coherences time - dependence . defocusing is minimized when noise is transverse with respect to the qubit hamiltonian @xcite . the qubit is said to operate at an `` optimal point '' characterised by algebraic short - times behavior followed by exponential decay on a scale @xmath10 . in the present article we perform a systematic analysis of the effects and interplay of adiabatic and quantum noise on a universal two - qubit gate , extending the multi - stage elimination approach introduced in ref . @xcite . understanding these effects is crucial in the perspective of implementing solid - state complex architectures . our system consists of two coupled qubits each affected by transverse and longitudinal noise with broad - band and non - monotonic spectrum . such a general situation has not being studied in the literature . previous studies concentrated on harmonic baths with monotonic spectrum relying on master equation and/or perturbative redfield approach @xcite , or on numerical methods @xcite , or on formal solutions for selected system observables @xcite . we quantify entanglement via the concurrence @xcite . to compare with bit - wise measurements , single qubit switching probabilities are also evaluated . our analysis is based on approximate analytic results and exact numerical simulations . our main results are : ( i ) the identification of characteristic time scales of entanglement decay due to adiabatic noise , quantum noise and their interplay ; ( ii ) the characterization of relaxation and dephasing for an entanglement operation via the time scales @xmath11 , @xmath12 , @xmath13 and @xmath14 . we point out the dependence of these scales on the symmetry of the hamiltonian describing the interaction between each qubit and the various noise sources ; ( iii ) the demonstration that a universal two - qubit gate can be protected against noise by operating at an `` optimal coupling '' , extending the concept of single - qubit `` optimal point '' . the article is organized as follows . in section 2 we introduce the hamiltonian model for two - qubit entanglement generation in the presence of independent noise sources affecting each unit . in section 3 the general features of the power spectra of these fluctuations , as observed in single qubit experiments , are summarized . the relevant dynamical quantities are introduced and the multi - stage approach to eliminate noise variables and obtain a reduced description of the two - qubit system is illustrated . in sections 4 and 5 we derive separately the effect of quantum noise within a master equation approach and the leading order effect ( quasi - static approximation ) of adiabatic noise . finally , in section 6 we discuss their interplay and introduce the relevant time scales characterizing loss of coherence and entanglement of a universal two - qubit gate in a solid - state environment . results are summarized in and in . in [ appendix - cpb ] the entanglement generating model is derived for capacitive coupled cooper pair boxes ( cpbs ) including fluctuations of all control parameters . in [ appendix : sc ] the effect of selected impurities strongly coupled to the device is pointed out and we speculate on the possibility to extend the `` optimal coupling '' scheme under these conditions . entanglement - generating two qubit gates have been implemented based on different coupling strategies . in the standard idea of gate - based quantum computation , the coupling between the qubits is switched on for a quantum gate operation and switched off after it . the easiest way to realize this scheme is to tune the qubits in resonance with each other for efficient coupling and move them out of resonance for decoupling . employing a fixed coupling scheme two - qubit logic gates have been implemented @xcite and high - fidelity bell states have been generated in capacitive coupled phase qubits @xcite . a different idea is to introduce an extra element between the qubits : an adjustable coupler , which can turn the coupling on and off @xcite . alternatively , two - qubit gates are generated by applying microwave signals of appropriate frequency , amplitude and phase @xcite . the core of the entangling operation of most of the above coupling schemes consists of two resonant qubits with a coupling term transverse with respect to the qubits quantization axis , as modeled by @xmath15 here @xmath16 are pauli matrices and @xmath17 is the identity , in qubit-@xmath18 hilbert space ( @xmath19 ) . in our notation , @xmath16 is the qubit-@xmath18 quantization axis and we put @xmath20 . this model applies in particular to the fixed , capacitive or inductive , coupling of superconducting qubits @xcite , where individual - qubit control allows an effective switch on / off of the interaction . eigenvalues and eigenvectors of eq . are reported in . in order to maintain the single qubit identities , the coupling strength , @xmath21 , must be one - to - two orders of magnitudes smaller than the single qubit level spacing , @xmath22 . thus eigenvalues form a doublets structure , as schematically illustrated in . the hilbert space factorizes in two subspaces spanned by @xmath23 and @xmath24 . ccc @xmath25 & @xmath26 & @xmath27 + 0 & @xmath28 & @xmath29 + 1 & @xmath30 & @xmath31 + 2 & @xmath32 & @xmath33 + 3 & @xmath34 & @xmath35 + a couple of qubits described by ( [ h0 ] ) is suitable to demonstrate entanglement generation . the system prepared in the factorized state @xmath36 freely evolves to the entangled state @xmath37/\sqrt 2 $ ] in a time @xmath38 , realizing a @xmath3 operation . the dynamics takes place inside the @xmath23 subspace , which we name `` swap - subspace '' . the orthogonal subspace will be instead named `` z - subspace '' . and @xmath39 mix and an energy splitting @xmath40 develops between the eigenstates @xmath41 , spanning the swap subspace . product states @xmath42 and @xmath43 weakly mix and split , with @xmath44 . the eigenstates @xmath45 span the z subspace . longitudinal noise in the computational basis is responsible for inter - doublet relaxation processes ( effective transverse inter - doublet ) indicated by red wavy lines ( eq . ) . transverse noise in the computational basis originates incoherent energy exchanges inside each subspace ( effective transverse intra - doublet ) indicated by blue wavy lines ( eqs . , ) . , scaledwidth=80.0% ] fluctuations of the control parameters used for the manipulation of individual qubits couple the circuit to environmental degrees of freedom . we consider the general situation where each qubit is affected both by longitudinal noise ( coupled to @xmath16 ) and by transverse noise ( coupled to @xmath46 ) , as described by the interaction hamiltonian @xmath47 \otimes \mathbb{i}_{2 } - \frac{1}{2 } \mathbb{i}_{1 } \otimes \left [ \hat{x}_{2 } \ , \sigma_{2x}+ \hat{z}_{2 } \ , \sigma_{2z } \right ] \,.\ ] ] here @xmath48 and @xmath49 are collective environmental quantum variables coupled to different qubits degrees of freedom . for instance , in the case of two cpb - based qubits at the charge optimal point @xcite , the charge operator is @xmath46 , and the josephson operator is @xmath16 . fluctuations of the gate charge are described by a transverse coupling term , @xmath50 , and noise in the superconducting phase by the longitudinal term , @xmath51 @xcite ( see [ appendix - cpb ] for the derivation ) , irrespective of the working point . thus , @xmath48 and @xmath49 describe physically different processes only at selected operating points . usually , this is the case at the single qubit s optimal points , see [ appendix - cpb ] . ] . the complete device hamiltonian reads @xmath52 , where @xmath53 denotes the free hamiltonian of all environmental variables . in order to identify relaxation and pure dephasing processes for the coupled qubit setup we project @xmath54 in the 4-dim hilbert space generated by the eigenstates of @xmath55 , @xmath56 , @xmath57 , where we may rewrite @xmath58 \ , + \ , \sqrt{\omega^2 + ( \omega_c/2)^2 } \ , \big [ |3\rangle \langle 3| - | 0\rangle \langle 0| \big ] \\ \!\!\!\!\!\!\!\!\!\!\!\!\!\!\ ! \mathcal{h}_\mathrm{i } & = & \frac{1}{2 } ( \hat{x}_{1 } + \hat{x}_{2 } ) \ , \big [ a_- |2\rangle \langle 0| + a_+ |2\rangle \langle 3| + { \rm h.c . } \big ] \ , + \nonumber \\ & + & \frac{1}{2 } ( \hat{x}_{1 } - \hat{x}_{2 } ) \ , \big [ - a_+ |1\rangle \langle 0| + a_- | 1\rangle \langle 3| + { \rm h.c . } \big ] \nonumber\\ & - & \frac{1}{2 } ( \hat{z}_{1 } - \hat{z}_{2 } ) \ , \big [ |1\rangle \langle 2| + |2\rangle \langle 1|\big ] \label{hi - proj}\\ & - & \frac{1}{2 } ( \hat{z}_{1 } + \hat{z}_{2 } ) \ , \big [ \ , \cos \varphi \ , ( |0\rangle \langle 0| - | 3\rangle \langle 3| ) + \sin \varphi \ , ( |0\rangle \langle 3| + | 3\rangle \langle 0|)\ , \big ] \nonumber\end{aligned}\ ] ] where @xmath59/\sqrt 2 $ ] , with @xmath60 . in ( [ hi - proj ] ) we distinguish `` effective longitudinal '' and `` effective transverse '' terms . the first ones are diagonal in the eigenbasis @xmath56 and are responsible for pure dephasing processes . `` effective transverse '' terms instead are off - diagonal and originate both intra- and inter - doublet relaxation processes . specifically we have : + * swap subspace @xmath61 * : longitudinal noise in the computational basis @xmath62 , originates `` effective transverse '' noise in the swap - subspace , i.e. the restriction of @xmath54 to @xmath61 reads @xmath63 - \frac{1}{2}(\hat{z}_{1 } - \hat{z}_{2 } ) \ , \big [ |1\rangle \langle 2| + |2\rangle \langle 1|\big ] \label{h - trunc - swap}\ ] ] note that if both qubits were affected by the same longitudinal noise no effective transverse noise in this subspace would be present . this situation may occur in the presence of totally correlated noise affecting both qubits @xcite . + * z subspace @xmath64 * : longitudinal noise in the computational basis originates both `` effective transverse '' and `` effective longitudinal '' noise in the z - subspace , i.e. the projection of @xmath54 on @xmath65 reads @xmath66 \nonumber \\ & + & ( \hat{z}_{1 } + \hat{z}_{2 } ) \ , \big [ \ , \cos \varphi \ , ( |0\rangle \langle 0| - | 3\rangle \langle 3| ) + \sin \varphi \ , ( |0\rangle \langle 3| + | 3\rangle \langle 0|)\ , \big ] \ , . \label{h - trunc - z } \end{aligned}\ ] ] effective longitudinal and transverse components are modulated via the mixing angle , @xmath67 , similarly to a single qubit with operating point @xmath67 . + * inter - doublet processes * : the only effect of transverse noise in the computational basis is to mix the two subspaces via `` effective transverse '' inter - doublet terms ( fig.[splittings ] ( c ) ) @xmath68 \nonumber \\ \ , & + & \ , \frac{1}{2}(\hat{x}_{1 } - \hat{x}_{2 } ) \ , \big [ - a_+ |1\rangle \langle 0| + a_- | 1\rangle \langle 3| + { \rm h.c . } \big ] \label{h - inter}\end{aligned}\ ] ] these inter - doublet terms are responsible , in particular , for relaxation processes from the swap - subspace to the ground state . we will demonstrate that the resulting `` global '' relaxation time sets the upper limit to all other gate operation times , including other decoherence time scales . the considered entanglement generating operation takes place in the presence of broad - band and non - monotonic noise . in this section we review the multi - stage elimination approach to deal with this problem . the method has been introduced for a single qubit in ref . @xcite where the various approximations have been checked by comparing with the exact numerical solution of the system evolution . this approach allowed to accurately explain the observed dynamics in different experiments @xcite , confirming its appropriateness to deal with the more complex system studied in the present article . the method has been extended to a multi - qubit gate in ref . @xcite , here we summarize the main steps . the multi - stage elimination approach is based on a classification of the noise sources according to their effects and circumvents the problem of a microscopic description of noise sources , which are often non gaussian and non markovian @xcite . in this perspective , the required statistical information on the environment depends on the specific quantum operation performed and on the measurement protocol . even if the statistical characterization of the environment requires going beyond the second order cumulant , often knowledge of the power spectrum of the bath variables , here @xmath69 and @xmath70 denoted generically as @xmath71 , @xmath72 \ , , \label{sealpha}\ ] ] is sufficient . where @xmath73 denotes the equilibrium average with respect to @xmath53 and we assumed stationary processes with @xmath74 . the typical power spectrum reported in various single qubit experiments is sketched in . to make explicit reference to some practical situations , in we summarize the characteristics of transverse and longitudinal noise spectra at low- and high - frequencies reported in a cpb - based circuit @xcite and in the recent experiment on a flux qubit @xcite . the low - frequency part of the spectra of each variable is @xmath0 , @xmath75 . the amplitude @xmath76 can be estimated from spectral measurements . if @xmath77 and @xmath78 denote respectively the low- and high - frequency cut - offs of the @xmath0 region , then @xmath79^{-1}$ ] , where @xmath80 is the variance , @xmath81 . it can be approximated as @xmath82 where @xmath83 is the overall acquisition time for a single data point which results from averaging over several measurement trials . spectrum depends on the specific microscopic source and it is usually not detectable in experiments . in the present article we discuss measurements protocols where the details of the behavior of the power spectrum below @xmath77 and around @xmath78 are not relevant and results depend logarithmically on the ratio @xmath84 . ] the high - frequency power spectrum is usually inferred indirectly from measurements of the qubit relaxation times under various protocols @xcite . from the resulting figures the expected spectra for the corresponding quantum variables @xmath85 at the relevant frequencies , @xmath86 and @xmath87 are derived . experiments tuning the single qubit level spacing @xmath22 reveal either ohmic @xcite or white @xcite power spectrum in the ghz range . evidence of spurious resonances in the spectrum have often been reported , they show up as beatings in time resolved measurements @xcite . ( logarithmic scale ) . measurements of @xmath0 noise usually extend between @xmath88 hz and @xmath89 mhz , whereas the ohmic or white spectrum region typically ranges around @xmath90 ghz @xcite . the region classified as adiabatic noise and quantum noise are indicated . , scaledwidth=50.0% ] ccc & charge - phase qubit & flux qubit + @xmath91 & @xmath92 & @xmath93 + @xmath94 & @xmath95 & @xmath96 + @xmath97 & @xmath98s@xmath99 & @xmath100s@xmath99 + @xmath101 & @xmath102 s@xmath99 & - + in our analysis noise sources belong to three classes . low frequency noise with @xmath0 spectrum is adiabatic since it does not induce transitions , but mainly defocuses the signal , we classify it as _ adiabatic noise_. noise at frequencies of the order of the qubits splittings is responsible for dissipation and ultimately for spontaneous decay , thus it is classified as _ quantum noise_. possible resonances in the spectrum pertain to the class named _ strongly coupled noise_. noise sources belonging to different classes act on different frequency scales and are treated via specific approximation schemes . the distiction can be illustrated as follows . we are interested to a reduced description of the @xmath103-qubit system , expressed by the reduced density matrix ( rdm ) , @xmath104 obtained by tracing out environmental degrees of freedom from the total density matrix @xmath105 , which depends on quantum ( q ) , adiabatic ( a ) and strongly coupled ( sc ) bath variables . since bath s degrees of freedom belonging to different classes of noise act of different time scales we separate in each part of the interaction hamiltonian , @xmath106 ( @xmath107 ) , the contribution from various noise classes as follows @xmath108 adiabatic noise , @xmath109 , is typically correlated on a time scale much longer than the inverse of the qubit s frequencies , @xmath110 , then in the spirit of the born - oppenheimer approximation it can be seen as a classical stochastic field @xmath111 . this approach is valid when the contribution of adiabatic noise to spontaneous decay is negligible , a necessary condition being @xmath112 . this condition is usually satisfied at short enough times , since @xmath113 is substantially different from zero only at frequencies @xmath114 . this fact suggests how to trace - out different noise classes in the appropriate order . the total density matrix parametrically depends on the specific realization of the slow random drives @xmath115 and may be written as @xmath116 . the first step is to trace out quantum noise . in the simplest cases this requires solving a master equation . in a second stage , the average over all the realizations of the stochastic processes , @xmath115 , is performed . this leads to a reduced density matrix for the @xmath103-qubit system plus the strongly coupled degrees of freedom . these latter have to be traced out in a final stage by solving the heisenberg equations of motion , or by approaches suitable to the specific microscopic hamiltonian or interaction . for instance , the dynamics may be solved exactly for some special quantum impurity models at pure dephasing , when impurities are longitudinally coupled to each qubit @xcite . the multi - stage elimination can be formally written as @xmath117 \ , p[\vec e(t ) ] \ ; tr_{\rm q } \big [ \ , \rho^{\rm q , sc}\big(t | \vec e(t)\big ) \ , \big]\right\ } \ , , \ ] ] where @xmath118 and @xmath119 indicate respectively the trace over the q and sc degrees of freedom . in the following sections we apply the multi - stage approach to the two - qubit gate by tracing out first quantum noise and secondly the adiabatic noise . in [ appendix : sc ] the effect of a sc impurity will be analyzed . we focus on the @xmath3 operation @xmath120/\sqrt{2}$ ] which generates by free evolution an entangled state at @xmath121 . as a unambiguous test of entanglement generation and its degradation due to noise , we calculate the evolution of concurrence during the gate operation . introduced in ref . @xcite , the concurrence quantifies the entanglement of a pair of qubits , being @xmath122 for separable states and @xmath123 for maximally entangled states . for the situations discussed in the present article and specified in the following sections , the two - qubits rdm takes the `` x - form '' , i.e. the rdm expressed in the eigenstates basis is non - vanishing only along the diagonal and anti - diagonal at any time . under these conditions , the concurrence can be evaluated in analytic form @xcite . in general , it depends both on diagonal and off - diagonal elements of the rdm . in order to directly compare with experiments where bit - wise readout is performed , we also evaluate the qubit 1 switching probability @xmath124 , i.e. the probability that it will pass to the state @xmath125 starting from the state @xmath126 ; and the probability @xmath127 of finding the qubit 2 in the initial state @xmath128 . in terms of the two qubit rdm in the eigenstate basis they read ( @xmath129 denotes partial trace over qubit @xmath25 of the two - qubit density matrix ) @xmath130 + \rho_{00}(t ) \nonumber \\ & + & \left [ \ , \rho_{33}(t ) - \rho_{00}(t ) \right ] \sin^2 \frac{\varphi}{2 } + { \rm re}[\rho_{12}(t ) ] + { \rm re } [ \rho_{03}(t ) ] \sin \varphi \label{eq : psw1 } \\ p_2(t ) & = & _ 2 \ ! \langle - | { \rm tr}_1 \rho(t ) | - \rangle_2 = \frac{1}{2 } \left [ \ , \rho_{11}(t ) + \rho_{22}(t ) \right ] + \rho_{00}(t ) \nonumber \\ & + & \left [ \ , \rho_{33}(t ) - \rho_{00}(t ) \right ] \sin^2 \frac{\varphi}{2 } - { \rm re}[\rho_{12}(t ) ] + { \rm re}[\rho_{03}(t ) ] \sin \varphi . \label{eq : psw2}\end{aligned}\ ] ] for preparation in the state @xmath131 , in the absence of external fluctuations the above probabilities read @xmath132 the cyclic anti - correlation of the probabilities signals the formation of the entangled state , as reported in various recent experiments @xcite . both the concurrence and the switching probabilities depend on combinations of populations and coherences in the eigenbasis . therefore the relevant time scale to quantify the `` quality factor '' or the efficiency of the universal two - qubit gate is not simply related to a specific rdm element , as a difference with a single qubit gate , where the decay time of the qubit coherence quantifies the quality factor of the operation ( with @xmath2 due partly to relaxation processes ( @xmath133 ) , partly to markovian pure dephasing processes @xmath6 or originated from inhomogeneous broadening ) . in the following we will study the time dependence of coherences and populations , and identify the environmental processes ( transverse , longitudinal , low frequency , high frequency , etc . ) which originate various decay times . based on this analysis we will discuss the resulting effect on the decay of the switching probabilities and of the concurrence . to begin with , we consider the effect of quantum noise replacing in @xmath134 . the system dynamics is obtained by solving the born - markov master equation for the rdm . in the system eigenstate basis and performing the secular approximation ( to be self - consistently checked ) it takes the standard form @xcite : @xmath135 the rates @xmath136 , @xmath137 and the frequency shifts @xmath138 , where @xmath139 , depend respectively on the real and imaginary parts of the lesser and greater green s functions which describe emission ( absorption ) rates to ( from ) the reservoirs @xmath140 in terms of the corresponding power spectra they read @xmath141 where @xmath142 denotes the principal value of the integral . due to the symmetry of @xmath143 , eqs . - , the only independent emission rates , @xmath144 , are @xmath145 , @xmath146 , @xmath147 , @xmath148 , see . symmetric relations hold between the corresponding absorption rates @xmath149 . these processes originate from `` effective transverse '' noise , in particular transverse fluctuations ( @xmath150 ) enter the rates connecting the swap and the z subspaces , whereas longitudinal fluctuations ( @xmath151 ) enter the intra - subspace rates , @xmath147 , @xmath148 , cfr eqs . - . they read @xmath152 \qquad \ , { \rm inter - subspace } \\ \label{gamma20 } \gamma_{20 } = \frac{1}{8 } \ , ( 1-\sin \varphi ) \ , [ c_{x_1}(\omega_{20 } ) + c_{x_2}(\omega_{20 } ) ] \qquad \ , { \rm inter - subspace } \\ \label{gamma30 } \gamma_{30 } = \frac{1}{4 } \ , \sin^2 \varphi \ , [ c_{z_1}(\omega_{30 } ) + c_{z_2}(\omega_{30 } ) ] \qquad \qquad \ , { \rm intra - subspace } \\ \label{gamma21 } \gamma_{21 } = \frac{1}{4 } \ , [ c_{z_1}(\omega_{21 } ) + c_{z_2}(\omega_{21 } ) ] \qquad \qquad \qquad \ ; \ ; \;{\rm intra - subspace } \end{array } \label{eq : ratesgeneral}\end{aligned}\ ] ] absorption rates have the same form with @xmath153 replaced by @xmath154 . the imaginary parts of the corresponding terms take similar forms . they enter the frequency shifts as reported in [ appendix : shifts ] . in the secular approximation , the swap and z coherences decay exponentially with rates @xmath155 \label{gamma12tilde}\\ \widetilde \gamma_{30 } & = & \frac{1}{2 } \ , [ \gamma_{10 } + \gamma_{01 } + \gamma_{20 } + \gamma_{02 } + \gamma_{30 } + \gamma_{03 } ] + \gamma^*_z\ , , \end{aligned}\ ] ] both inter - subspace and intra - subspace rates enter the decay of the swap and z coherences . note that the decay rate of the coherence @xmath156 is only originated from dissipative processes ( intra- or inter- effective transverse ) since no pure dephasing processes ( effective longitudinal noise ) inside the swap subspace exist , cfr eq . . on the contrary , the coherences in the z subspace also decay because of the effective longitudinal terms @xmath157 , which originate @xmath158 $ ] . this pure dephasing factor adds up to a decoherence rate due to intra - subspace effective transverse noise having the characteristic form @xmath159^{-1 } = ( \gamma_{30}+ \gamma_{03})/2 $ ] , as implied by , and to inter - doublet relaxation rates . equations for the populations do not decouple even in the secular limit . general solutions are quite cumbersome , so here we report expressions in the small temperature limit with respect to the uncoupled qubits splittings , @xmath160 . in this regime , if the system is initially prepared in the state @xmath161 , level @xmath162 is not populated , @xmath163 , and the z - coherences vanish , @xmath164 . the remaining populations are conveniently expressed in terms of the escape rates from levels @xmath88 and @xmath103 @xmath165 which enter the evolution of the populations in the following combinations @xmath166 for the chosen initial conditions the populations read @xmath167 \ , e^{-\gamma_k t } \label{population1 } \\ \rho_{22}(t ) & = & \frac{1}{2(\gamma_- - \gamma_+ ) } \sum_{k=\pm } k \left [ \gamma_{12 } - \gamma_k + \gamma_1^{\rm e } \right ] \ , e^{-\gamma_k t } \label{population2 } \\ \label{population0 } \rho_{00}(t ) & = & 1 -(\rho_{11}(t ) + \rho_{22}(t ) ) \ , .\end{aligned}\ ] ] note that , since @xmath168 , thermal excitation processes internal to the swap subspace , expressed via the absorption rate @xmath169 , can not be neglected and @xmath170 . on the contrary , inter - doublet thermal excitation processes are exponentially suppressed with respect to the corresponding decay rates , @xmath171 , with @xmath172 . thus the swap coherences decay rate is approximately half the sum of the escape rates ( [ eq : escape ] ) @xmath173 in order to observe generation of entanglement inside the swap subspace it is necessary that relaxation processes to the ground state take place on a sufficiently long time scale . this is guaranteed when inter- and intra - subspace rates satisfy the condition @xmath174 , which requires that the spectra of the originally transverse and longitudinal fluctuations are @xmath175 ( from ) . in this regime , the swap decoherence rate is due to effective transverse processes internal to the subspace @xmath176 \ , , \ ] ] and the scales entering the populations take the approximate forms @xmath177 \qquad \qquad { \rm relaxation \ , to \ , the \ , ground \,state } \\ \label{gammaminus } \gamma_- & \approx & \gamma_{12 } + \gamma_{21 } \qquad \qquad \quad \ , { \rm relaxation \ , inside \ , the \ , swap \ , subspace}\end{aligned}\ ] ] with @xmath178 . therefore , the time scales resulting from quantum noise , considering that @xmath168 , when @xmath175 , are * `` global '' relaxation time to the ground state , analogous to the single qubit @xmath1 : its order of magnitude is the spectrum of _ transverse fluctuations _ in the computational basis at frequency @xmath22 @xmath179 where the approximate form comes from eq . ( [ eq : ratesgeneral ] ) , where @xmath180 . * relaxation / decoherence times inside the swap subspace : they are due to `` effective transverse '' fluctuations inside this subspace , physically originated from _ longitudinal noise _ on each qubit at frequency @xmath21 . since there is no effective longitudinal noise in the swap subspace , relaxation and dephasing times are related by the typical relation @xmath181 where @xmath182 we now briefly comment on the validity of the secular approximation . it consists in separating the evolutions of elements @xmath183 and @xmath184 provided that @xmath185 , where @xmath186 denotes the typical evolution time scale of the system @xcite . in the present case this condition is fulfilled if @xmath187 . this constraint , on the other side , _ needs _ to be satisfied in order to observe generation of entanglement in the presence of quantum noise , as expressed for instance from anti - correlation of the probabilities ( [ eq : psw1 ] ) and ( [ eq : psw2 ] ) . thus it can be regarded as a _ necessary condition _ , whose validity has to be checked case by case and requires ( from ) @xmath188 in conclusion , entanglement generation in the presence of transverse and longitudinal quantum noise is guaranteed when @xmath189 under these conditions , the `` global '' relaxation time and the swap relaxation and decoherence times are given respectively by eqs . and , . we note that , as a limiting case , the @xmath3 operation can be realized also releasing the condition @xmath178 , provided both rates are much smaller than the coupling strength @xmath21 , and @xmath190 . for instance , when @xmath191 in eq . @xmath192 and the rates @xmath193 are still given by eqs . , leading to @xmath194 and @xmath195 . the swap dephasing time in this case also depends on trasverse fluctuations , @xmath196 $ ] . in the secular approximation , for preparation at @xmath197 in @xmath198 and for @xmath160 , the probabilities and take the simpler form @xmath199 + { \rm re}[\rho_{12}(t ) ] + \cos^2\left ( \frac{\varphi}{2}\right ) \\ \label{switch2 } p_2(t ) = & - & \frac{1}{2 } \ , \cos \varphi \ , \left [ \rho_{11}(t ) + \rho_{22}(t ) \right ] - { \rm re}[\rho_{12}(t ) ] + \cos^2\left ( \frac{\varphi}{2}\right ) \ , .\end{aligned}\ ] ] where @xmath200 and @xmath201 are given by eqs . , and @xmath202 anti - correlation of the above probabilities directly follows from the coherence @xmath156 entering with different signs in @xmath124 and in @xmath127 . in order to check the efficiency of the gate we will therefore consider only the qubit 1 switching probability . neglecting the frequency shift of @xmath203 ( see [ appendix : shifts ] ) , @xmath124 can be approximated as @xmath204 \ , + \ , \cos^2\left ( \frac{\varphi}{2}\right ) \ , .\ ] ] here we explicitly see that , in order to perform the @xmath3 operation , it is necessary that @xmath205 . efficient entanglement generation is guaranteed when @xmath206 , i.e. when transverse and longitudinal quantum noise are such that @xmath175 . under this condition , the efficiency of the gate is limited by @xmath13 , i. e. by longitudinal noise in the computational basis , @xmath207 , which is responsible for the short - times behavior . decay towards the equilibrium value @xmath208 occurs in a time of the order of @xmath11 , due to transverse noise in the computational basis . ccc & qubit 1 & qubit 2 + @xmath91 & @xmath209 & @xmath210 + @xmath94 & @xmath211 & @xmath212 + @xmath213 & @xmath214s@xmath99 & @xmath214s@xmath99 + @xmath215 & @xmath216 s@xmath99 & @xmath217s@xmath99 + : the relevant rates can be estimated in this specific case and are reported in [ appendix - cpb ] . for the charge - phase two - ports architecture , control is via the gate voltage , @xmath218 and magnetic flux dependent phase , @xmath219 , entering the josepshon energy . the single qubit optimal point is at @xmath220 , @xmath221 . the resonant condition between the two qubits with a capacitive coupling is achieved by displacing one of the two qubits from the `` double '' optimal point . in order to limit the sensitivity to charge noise , resonance is achieved tuning @xmath222 . the noise characteristics are reported in , where we note that @xmath175 . because of the operating conditions , absorption ( and emission ) rates due to phase noise on qubit 2 dominate over rates due both to charge noise and to phase noise on qubit 1 . relaxation of the populations takes place on a scale @xmath223 due to transverse ( charge ) noise on both qubits , whereas the swap coherence decay rate is dominated by longitudinal ( phase ) noise on qubit 2 , @xmath224 . the efficiency of the @xmath3 gate is mainly limited by phase noise on qubit 2 , which gives @xmath225 ns . we note that , under these conditions , @xmath13 is comparable with the decoherence time of qubit 2 , @xmath226 \approx 2/s_{z2}(0 ) \approx 2/s_{z2}(\omega_c)$ ] . the phase - dominated behavior is followed by a slower charge - dominated decay towards the equilibrium value @xmath227 . these features are illustrated in ( left ) where for comparison the real part of the swap coherence is shown in the inset . we note that the contribution of high - frequency charge noise to the efficiency of the @xmath3 gate is relatively small . indeed if only polarization fluctuations were present , we could approximate @xmath228 \ , e^{- t / t_2^{swap}}\ , + \ , \cos^2\left ( \frac{\varphi}{2}\right ) \ ] ] and @xmath229 @xmath230s . this situation is illustrated in ( right ) . note that for the estimated noise figures , the condition for the secular approximation , @xmath231 , is satisfied . and @xmath215 reported in . the long - time decay is due to charge noise entering the populations of levels @xmath88 and @xmath103 . inset : the real part of the swap coherence which is responsible for the short - time behavior of the switching probability due to phase noise on qubit @xmath103 . right panel : switching probability of qubit 1 in the presence of charge noise with white spectrum , @xmath232s@xmath99 . , title="fig:",scaledwidth=40.0% ] and @xmath215 reported in . the long - time decay is due to charge noise entering the populations of levels @xmath88 and @xmath103 . inset : the real part of the swap coherence which is responsible for the short - time behavior of the switching probability due to phase noise on qubit @xmath103 . right panel : switching probability of qubit 1 in the presence of charge noise with white spectrum , @xmath232s@xmath99 . , title="fig:",scaledwidth=40.0% ] for the considered initial condition , the rdm takes the `` x - form '' @xcite and the concurrence is given by @xmath233)^2 } -|\sin \varphi| \rho_{00}(t ) , \nonumber \\ & & |\sin \varphi| \rho_{00}(t ) - \sqrt { ( \rho_{11}(t ) + \rho_{22}(t ) ) ^2 - ( 2{\rm re } [ \rho_{12}(t)])^2 } \big ] \ , . \label{concurrence - general}\end{aligned}\ ] ] at times shorter than the global relaxation time , @xmath11 , the ground state is almost unpopulated , @xmath234 , and @xmath235 is given by the second term in @xmath236^{1/2 } - |\sin \varphi | \ , ( 1- e^{-t / t_r } ) \ , , \ ] ] for @xmath237 , the concurrence is approximately given by the swap coherence @xmath238 . like the switching probabilities , the concurrence evolves with the swap coherence decay time , @xmath13 , due to originally longitudinal noise . : the concurrence for the charge - phase 2-qubit gate is illustrated in . we note that the long - time behavior is instead due to populations relaxation to the ground state and @xmath235 is given by the third term in @xmath239^{1/2 } \nonumber \\ & \approx & - |\sin \varphi| \rho_{00}(t ) \to |\sin \varphi |\end{aligned}\ ] ] the finite asymptotic value @xmath240 , reflects the entangled thermalized state . because of the interaction between the two qubits the phenomenon of entanglement sudden death does not take place @xcite . and for quantum noise values @xmath213 and @xmath215 reported in . inset : at short times @xmath241 ( diamonds ) . , scaledwidth=50.0% ] let s consider now the effect of low frequency fluctuations , replacing in @xmath242 . in the adiabatic and longitudinal approximation @xcite populations do not evolve and the system dynamics is related to instantaneous eigenvalues , @xmath243 , which depend on the noise realization , @xmath115 . they enter the coherences in the eigenbasis of @xmath244 in the form @xmath245 \ , p[\vec e(s ) ] \ , e^{-i \int_0^t ds \ , \omega_{ij}(\vec e(s ) ) } \ , \label{path - int}\ ] ] where the probability of the realization @xmath246 , @xmath247 $ ] , also depends on the measurement protocol . a standard approximation of the path - integral consists in replacing @xmath248 with statistically distributed values @xmath249 at each repetition of the measurement protocol . the `` static - path approximation '' ( spa ) @xcite or `` static - noise '' approximation @xcite gives the leading order effect of low - frequency fluctuations in repeated measurements . in the spa , the level splittings @xmath250 are random variables , with standard deviation @xmath251 , where @xmath252 . the coherences reduce to ordinary integrals @xmath253 where the probability density , in relevant cases , can be taken of gaussian form , @xmath254 with @xmath255/\sqrt{2 \pi } \sigma_{e_\alpha}$ ] @xcite . the splittings @xmath250 come both from `` effective longitudinal '' and from `` effective transverse '' terms in ( [ hi - proj ] ) . this is analogous to a single qubit , where longitudinal noise gives the leading order linear terms and transverse noise is responsible for second order terms which dominate at the optimal point , where the first order longitudinal contributions vanish @xcite . here , the z - splitting @xmath256 has a linear contribution due to the effective longitudinal noise @xmath257 in . the swap splitting @xmath258 instead , in the absence of leading - order effective - longitudinal intra - doublet terms in , comes from higher order contributions due to `` effective transverse '' noise . evaluating them requires considering the complete hilbert space of the coupled qubit system ( inter - doublet processes included ) . the systematic approach to obtain these contributions consists in treating in perturbation theory effective transverse terms in @xmath259 , where , in the adiabatic approximation , @xmath260 and @xmath261 are replaced by classical stochastic fields @xmath262 and @xmath263 . we obtain @xmath264 where @xmath60 . the swap - splitting has been evaluated up to @xmath265 order @xcite , whereas the z splitting expansion is considered up to second order since the fourth - order terms are much smaller , scaling with @xmath266 . the z - splitting consists of a linear term due to the effective longitudinal noise , which dominates with respect to the quadratic term due to effective transverse intra - subspace noise ( scaling with @xmath267 ) . transverse inter - doublet noise gives an additional second order contribution . performing the average ( including in the @xmath268 and @xmath265 order terms in only the contributions @xmath269 ) we obtain the swap coherence in the spa @xmath270 \label{eq : spa - swap}\ ] ] where @xmath271 and @xmath272 $ ] is the k - bessel function of order zero @xcite . in the absence of mixed terms in the expansion , different contributions to the z - coherence factorize and lead to @xmath273 here we assumed the same variance for the transverse noise components , @xmath274 . instead we maintained @xmath275 and @xmath276 distinct , considering that the two qubits may operate at different working points ( [ appendix - cpb ] ) . in the exponential factor comes from linear terms in due to effective longitudinal noise in the z - subspace . the algebraic decay instead comes from quadratic terms in the expansion of @xmath277 , due to effective transverse inter - doublet processes . + we remark that the applicability of the gaussian approximation to the fields @xmath278 depends on the relation between each @xmath278 and the fluctuations of the system s physical parameters . for instance , for a charge - phase @xmath3 gate the resonant condition occurs for @xmath279 , @xmath280 ( [ appendix - cpb ] ) . thus it is @xmath281 , where @xmath282 ( not @xmath283 ) is reasonably assumed gaussian distributed . this would result in a modification of the terms @xmath284 in eqs . and . for instance , the integral over @xmath283 in @xmath285 would reduce to @xmath286 , instead of @xmath287 . the quantitative effect in @xmath288 ( and similarly in @xmath289 ) is however negligible , because of the smallness of longitudinal noise at the optimal point , @xmath290 ( see ) . validity regime of the spa : the adiabatic approximation is tenable for times shorter than the relaxation times , for this problem this condition requires that @xmath291 . the static approximation is exact for times smaller that @xmath292 ( in case of a sharp high frequency cut - off ) . we verified that it is a good approximation also for times @xmath293 if @xmath294 and the @xmath0 spectrum is originated from an ensemble of bistable fluctuators with switching rates @xmath295 $ ] , leading to a @xmath296 decay above @xmath78 ( numerical simulations and analytic first correction to the spa @xcite ) . exploiting the band structure of coupled nano - devices it is possible to reduce the influence of @xmath0 fluctuations @xcite . the basic idea of `` optimal tuning '' is to fix control parameters to values which minimize the variance of the splittings @xmath250 , @xmath297 . this naturally results in a enhancement of the decay time of the corresponding coherence due to inhomogeneous broadening , i. e. of @xmath298 . this is simply understood considering the short times expansion of @xmath299 @xmath300 the short - times decay of the coherence in the spa is therefore given by @xmath301 resulting in reduced defocusing for minimal variance @xmath302 . for a single - qubit gate , the `` optimal tuning '' idea immediately leads to the well - known `` magic point '' . in fact , if @xmath303 is monotonic in a region @xmath304 , we can approximate @xmath305 ^ 2 \sigma_{e_\alpha}^2 $ ] , thus the variance attains a minimum for vanishing differential dispersion . for the charge - phase two - port architecture , control is via gate voltage , @xmath306 , and magnetic - flux dependent phase @xmath219 , thus @xmath278 corresponds to the fluctuations @xmath307 and the optimal point , @xmath308 , is at the a saddle point of the energy bands @xcite . when bands are non - monotonic in the control parameters , minimization of defocusing necessarily requires their tuning to values depending on the noise variances . for a multi - qubit gate , the optimal choice has to be done considering the most relevant coherence for the considered operation . here we show how this program applies to the coherence in the swap subspace and partly to @xmath288 . . panels ( a ) and ( b ) : @xmath309 from numerical diagonalization of @xmath143 . in panel ( b ) a zoom around the origin highlights the interplay of @xmath310 and @xmath265 order terms of the expansion , the barrier height is @xmath311 . panel ( c ) : swap exact splitting ( blue ) , expansion ( [ eq : splittingswap ] ) for @xmath312 , @xmath313 ( dashed ) , @xmath310 order expansion ( dash - dotted green ) , @xmath314 splitting ( red ) from and single qubit dispersion ( diamonds ) . panel ( d ) : longitudinal dispersions in the swap ( blue ) and z ( red ) subspaces . , title="fig:",width=264 ] . panels ( a ) and ( b ) : @xmath309 from numerical diagonalization of @xmath143 . in panel ( b ) a zoom around the origin highlights the interplay of @xmath310 and @xmath265 order terms of the expansion , the barrier height is @xmath311 . panel ( c ) : swap exact splitting ( blue ) , expansion ( [ eq : splittingswap ] ) for @xmath312 , @xmath313 ( dashed ) , @xmath310 order expansion ( dash - dotted green ) , @xmath314 splitting ( red ) from and single qubit dispersion ( diamonds ) . panel ( d ) : longitudinal dispersions in the swap ( blue ) and z ( red ) subspaces . , title="fig:",width=283 ] . panels ( a ) and ( b ) : @xmath309 from numerical diagonalization of @xmath143 . in panel ( b ) a zoom around the origin highlights the interplay of @xmath310 and @xmath265 order terms of the expansion , the barrier height is @xmath311 . panel ( c ) : swap exact splitting ( blue ) , expansion ( [ eq : splittingswap ] ) for @xmath312 , @xmath313 ( dashed ) , @xmath310 order expansion ( dash - dotted green ) , @xmath314 splitting ( red ) from and single qubit dispersion ( diamonds ) . panel ( d ) : longitudinal dispersions in the swap ( blue ) and z ( red ) subspaces . , title="fig:",width=264 ] . panels ( a ) and ( b ) : @xmath309 from numerical diagonalization of @xmath143 . in panel ( b ) a zoom around the origin highlights the interplay of @xmath310 and @xmath265 order terms of the expansion , the barrier height is @xmath311 . panel ( c ) : swap exact splitting ( blue ) , expansion ( [ eq : splittingswap ] ) for @xmath312 , @xmath313 ( dashed ) , @xmath310 order expansion ( dash - dotted green ) , @xmath314 splitting ( red ) from and single qubit dispersion ( diamonds ) . panel ( d ) : longitudinal dispersions in the swap ( blue ) and z ( red ) subspaces . , title="fig:",width=264 ] a key feature is that the swap splitting , @xmath203 in eq . is non - monotonic in the small coupling @xmath40 . this is due to the fact that effective transverse fluctuations originate both from longitudinal and transverse noise , and give rise respectively to intra - swap and inter - doublet transitions , see , . for instance , second order corrections to @xmath315 from effective transverse intra - doublet processes are @xmath316 , from effective transverse inter - doublet transitions are @xmath317 . non - monotonicity in @xmath21 results in a competition between @xmath310 and @xmath265 order @xmath262-terms in and in non - monotonic band structure , ( panels ( a ) and ( b ) ) . because of this subtle feature , identification of the best operating condition necessarily requires consideration of the noise characteristics . indeed the _ optimal coupling _ which minimizes the swap variance @xmath318 + \frac{\sigma_{z_2}^4}{2 } \right \ } \label{eq : variance}\ ] ] is given by @xmath319 where we assumed @xmath290 . the effectiveness of the optimal coupling choice has been discussed in details in ref . the advantage of operating at optimal coupling with respect to a generic @xmath21 can be parametrized by the error of the gate at time @xmath320 when system should be in the entangled state @xmath321/\sqrt 2 $ ] , @xmath322 . as shown in for two cpb - qubits , in the presence of moderate amplitude transverse ( charge ) noise , at the optimal coupling the error can be reduced even one order of magnitude with respect to a generic coupling . ccc @xmath323 & @xmath324 & @xmath325 + @xmath326 & @xmath327 & @xmath328 + @xmath329 & @xmath330 & @xmath331 + @xmath332 & @xmath333 & @xmath334 + @xmath335 & @xmath336 & @xmath337 + @xmath338 & @xmath339 & @xmath340 + @xmath341 & @xmath342 & @xmath343 + the splitting in the z - subspace , on the contrary , is monotonic both in @xmath262 and in @xmath263 , similarly to a single qubit operating at @xmath344 and at the two different @xmath345 , , panels ( c ) and ( d ) . the most relevant contribution to z - variance is given by the effective longitudinal noise @xmath346 which can be reduced only by increasing the qubit s coupling strength @xmath21 , which is however limited by single qubit splittings @xmath22 . therefore , no special optimal point exists if the two - qubit operation involves the dynamics inside the z - subspace . a comparison of the evolution of the coherences in the two subspaces and of the single qubit - coherence is shown in for two cpb - based qubits . in order to keep the advantage of optimal tuning in the swap - subspace , the two - qubit operation should not involve the z - subspace . . the dashed red line is the coherence in the swap - subspace for optimal coupling , @xmath347 . the z coherence does not appreciably change by changing @xmath21 and decays similarly to a single qubit at the double optimal point . noise characteristics are reported in . , scaledwidth=50.0% ] finally , we remark that the above results only follow considering the 4-level spectrum of the coupled devices . in fact , because of mixing between subspaces , limiting the analysis to noise projections inside the subspaces would miss a relevant part of the defocusing processes coming from originally transverse fluctuations @xmath348 , see eqs . , . this is clear if we consider the evolution of the swap coherences truncating the system hilbert space to the swap subspace . since the reduced hamiltonian is , effective transverse intra - doublet noise would lead to quadratic corrections to the swap - splitting . in fact , treating in perturbation theory @xmath263 up to second order , we would get @xmath349 and the swap coherence would decay algebraically , as it is typically originated from `` effective transverse '' low frequency noise @xmath350 under this approximation , reduction of defocusing could only be achieved by increasing the coupling strength . similarly , reducing the analysis to the z - subspace , cfr eq . , would miss the quadratic dependence of the z - splitting due to transverse noise . in the multi - stage elimination approach , where quantum noise is traced out first and adiabatic noise is retained as a classical stochastic drive , we have to replace in eqs . - and in @xmath351 , @xmath352 with @xmath353 and perform the path - integral over the realizations of @xmath115 . note that the dependence on adiabatic noise enters also the rates , which should be averaged . if the dependence of the power spectra on the splittings is sufficiently smooth , it can be neglected and the effect of low frequency noise reduces to averaging phase factors in the coherences and @xmath263 enter parametrically also in the frequency shifts resulting from the solution of the master equation . here we neglect this dependence , see [ appendix : shifts ] . ] . thus , provided that the dependence on @xmath354 of @xmath355 and @xmath356 can be neglected , the effects of quantum and adiabatic noise can be treated independently and lead to @xmath357 this result is confirmed by numerical solution of the stochastic schrdinger equation for classical fluctuations leading to dynamical @xmath0 noise ( @xmath358 hz and @xmath359 hz ) . the evolution of populations is only due to quantum noise ( in the adiabatic approximation they do not evolve ) , thus they are given by eqs . - and the switching probabilities are given by eqs . , ( [ switch2 ] ) where @xmath183 are replaced by and . these matrix elements enter also the concurrence which reads , for times @xmath237 , @xmath360)^2 } - |\sin \varphi| \rho_{00}(t)$ ] . the relevant time scales characterizing the efficiency of the @xmath3 operation depend both on the swap coherence and on the populations of the first three levels . due to the interplay of adiabatic and quantum noise , the time dependence is not a superposition of exponentials . we can distinguish two time regions : a asymptotic long - time regime and a intermediate - to - short time regime . cc time scale & physical origin + relaxation to the ground state & transverse noise + @xmath361 & at frequency @xmath22 + swap relaxation time & longitudinal noise + @xmath362 & at frequency @xmath203 + swap decoherence time & longitudinal noise + @xmath363 & at frequency @xmath203 + swap dephasing time @xmath14 & low frequency noise + @xmath364 & ( longitudinal and transverse ) + swap total decoherence time & if @xmath365 i. e. + @xmath366^{-1}$ ] & @xmath367 + the asymptotic behavior is entirely due to populations relaxation to the ground state , it is exponential and takes place with the `` global '' relaxation time @xmath368 , resulting from `` effective transverse '' inter - doublet processes , whose order of magnitude is the spectrum of transverse fluctuations at frequencies of order @xmath22 . in order to avoid leakage from the swap - subspace , any two - qubit operation has to take place on a time much shorter than @xmath11 . this constraint also applies to the swap decoherence times . + the intermediate - to - short time behavior , @xmath237 , gives more relevant information on the gate performance . in this time regime , relevant quantities are populations and coherences in the swap subspace . we distinguish a intermediate time regime , characterized by @xmath369 and @xmath370 due to _ effective transverse _ quantum noise inside this subspace , physically originated from longitudinal noise on each qubit . adiabatic noise leads to additional decay of the swap coherence , @xmath371 . the resulting defocusing is analogous to a `` pure dephasing '' process , we may name the typical time scale @xmath372 , defined as the time at which @xmath373 . the time @xmath372 is found by numerical inversion of . the _ intermediate - time _ behavior of the two - qubit gate is characterized by @xmath374 and @xmath375 , analogously to a two - state system . these time scales and the responsible processes are summarized in . switching probability @xmath124 ( red ) and probability @xmath127 ( blue ) to find qubit @xmath103 in the initial state @xmath376 in the presence of @xmath0 and white noise for @xmath377 and for optimal coupling @xmath378 ( gray ) . to emphasize the robustness of the optimal coupling choice here we consider @xmath0 charge noise of large amplitude , @xmath379 . the remaining noise figures are those reported in . left panel : plot of @xmath124 showing the exponential short - time behavior at @xmath380 and the algebraic decay for generic coupling . right panel : @xmath124 and @xmath381 anti - phase oscillations for @xmath380 ( main ) , @xmath382 ( inset ) . , title="fig:",scaledwidth=45.0% ] switching probability @xmath124 ( red ) and probability @xmath127 ( blue ) to find qubit @xmath103 in the initial state @xmath376 in the presence of @xmath0 and white noise for @xmath377 and for optimal coupling @xmath378 ( gray ) . to emphasize the robustness of the optimal coupling choice here we consider @xmath0 charge noise of large amplitude , @xmath379 . the remaining noise figures are those reported in . left panel : plot of @xmath124 showing the exponential short - time behavior at @xmath380 and the algebraic decay for generic coupling . right panel : @xmath124 and @xmath381 anti - phase oscillations for @xmath380 ( main ) , @xmath382 ( inset ) . , title="fig:",scaledwidth=41.0% ] on the other side , in a quantum information perspective , it is important to estimate the time behavior ( of concurrence or of switching probabilities ) at times of the order of @xmath121 , the first moment in which the entangled state is reached by free evolution . in order to generate entanglement within the swap subspace it is necessary that @xmath383 . it is therefore relevant to estimate the system behavior at short - times @xmath384 . both for the concurrence and the switching probability , the swap - coherence rules the short - time limit which is approximately latexmath:[\[\label{short - limit } the leading contribution , linear or quadratic , does not only depend on the noise amplitude but also on the operating point . in fact @xmath21 enters the swap - splitting variance @xmath386 and , in principle , also the swap decoherence time due to quantum noise @xmath387 . this is expected to be a smooth dependence . for the present considerations we assume a white spectrum in the relevant frequency range . for optimal coupling the short - time behavior is linear ( since the effect of low frequency noise is considerably reduced ) whereas for a different coupling strength the behavior is typically algebraic ( see ) . the short - time expansion is valid at @xmath388 if @xmath383 . in we consider two illustrative cases . for the expected noise characteristics as reported in , for couplings @xmath389 we have @xmath390 . thus the short - time expansion is valid up to @xmath388 . note that for the optimal coupling @xmath391 is about one order of magnitude larger than @xmath386 ( left panel ) , thus @xmath392 . for a larger amplitude of @xmath0 transverse noise , @xmath393 , we have @xmath394 ( right panel ) . also in this case the short - time expansion holds up to @xmath388 . in this case however even for optimal coupling the linear and quadratic terms are comparable . the various possible short - times behaviors and validity regimes are summarized in . ( red ) and of @xmath395 ( blue ) as a function of @xmath323 ( logarithmic scale ) for @xmath396 ( left panel ) and @xmath397 ( right panel ) . the dashed line marks the optimal coupling eq . . , title="fig:",scaledwidth=45.0% ] ( red ) and of @xmath395 ( blue ) as a function of @xmath323 ( logarithmic scale ) for @xmath396 ( left panel ) and @xmath397 ( right panel ) . the dashed line marks the optimal coupling eq . . , title="fig:",scaledwidth=45.0% ] ccc short times & validity & expansion + expansion & conditions & up to @xmath388 if + @xmath398 & optimal coupling and @xmath399 & @xmath400 + @xmath401 & generic coupling or @xmath402 & @xmath403 + in the present article we have identified the relevant decoherence times of an entangling operation due to the different decoherence channels originated from broad - band and non - monotonic noise affecting independently two qubits . results depend on the interplay of noise at low and at high frequencies ( with respect to both the single qubit splittings , @xmath22 , and the qubits coupling strength , @xmath21 ) and on the symmetries of the qubit - environment coupling hamiltonian . in addition , `` optimal '' operating conditions for the universal two - qubit gate have been identified . even if the relevant dynamics is within the swap subspace , the important time scales ( both due to quantum and to adiabatic noise ) can only be predicted considering the whole multilevel nature of the coupled systems . in particular , relaxation processes from the swap subspace to the ground state only depend on _ transverse _ noise at frequency @xmath22 . decoherence processes internal to the swap subspace are instead originated from _ longitudinal _ noise at frequency @xmath21 . this apparently counter - intuitive result simply follows from the symmetries of the hamiltonian expressed in the eigenbasis of coupled qubits , cfr eqs . - . as a consequence , the conditions to generate entangled states within the swap - subspace involve the spectra of transverse and longitudinal fluctuations at two different frequencies . an efficient @xmath3 operation can be realized when @xmath404 . the long - to - intermediate time behavior and the relevant decoherence times are summarized in . defocusing processes instead originate both from transverse and longitudinal adiabatic noise . remarkably , consideration of the coupled systems band structure allows identification of operating conditions of reduced sensitivity to low frequency fluctuations . an `` optimal coupling '' can be identified where defocusing is minimized . the error at the first @xmath3 operation at optimal coupling can be reduced of a factor of @xmath405-to-@xmath406 with respect to operating at generic coupling strength . the possibility of optimal tuning is ultimately due to the absence of effective longitudinal noise in the swap - subspace and to the interplay of effective transverse intra- and inter - doublet fluctuations . the orthogonal z - subspace instead , because of the presence of effective longitudinal noise , turns out to be much more sensitive to low - frequency noise which can not be limited by properly choosing system parameters . therefore , populating this subspace may severely limit the gate efficiency . the short - times behavior of the relevant dynamical quantities crucially depends on adiabatic noise and its interplay with quantum noise . the dependence turns from quadratic to linear depending on the largest component , parametrized by the swap - splitting variance resulting from adiabatic noise , @xmath386 , and the swap - decoherence rate due to quantum noise @xmath407^{-1}$ ] , as summarized in . the considerable protection from 1/f noise achievable in the swap - subspace for optimal coupling may suggest to use this subspace to encode a single quantum bit , similarly to a decoherence - free - subspace @xcite . such an encoding would be convenient if the swap decoherence time was about two orders of magnitude larger than the qubit decoherence time @xmath2 . in fact , because of the smaller swap oscillation frequency , @xmath408 , the quality factor of a single qubit rotation within this subspace would be @xmath409 , therefore @xmath410 if @xmath411 . realizing this condition requires improving the relaxation times with respect to present day experiments . a more realistic possibility is instead to employ the swap subspace as a single qubit quantum memory . the requirement in this case would be satisfying the weaker condition , @xmath412 . finally , we would like to comment on the effects of selected impurities strongly coupled to the two - qubit gate . the detrimental effect of charged bistable fluctuators on single qubit charge or charge - phase gates has been observed in experiments @xcite and explained in theory @xcite . effects on a two - qubit gate may even be worse , as reported in the recent experiment on two coupled quantronium @xcite . explanation of the rich physics which comes out when selected impurities couple to the nano - device is beyond the scope of the present article . in the following [ appendix : sc ] , we illustrate the possible scenario when an impurity considerably changes the 4-level spectrum of the coupled qubits and we speculate on the possibility to limit its effects by proper tuning the system parameters , somehow extending the optimal tuning recipe . the usefulness of such a choice however critically depends on the interplay with quantum noise at intermediate frequencies , an information unavailable in present day experiments . the analysis in [ appendix : sc ] is the first step towards the identification of parameter regimes where a multilevel nano - device may be protected also from strongly coupled degrees of freedom of a structured bath . stimulating discussions with g. schn and u. weiss are gratefully acknowledged . the hamiltonian @xmath413 in eq . is the central model of any non trivial two - qubit gate based on a fixed coupling scheme . in particular , it describes coupled superconducting qubits in the various implementations @xcite . with @xmath414 , given in , it includes independent fluctuations responsible for incoherent processes of different physical origin . in this section we derive @xmath415 for capacitive coupled cooper - pair - box - based ( cpb ) nano - devices . the cpb is the main building block of many superconducting qubits @xcite . here we consider two charge - phase qubits ( quantronia ) @xcite electrostatically coupled via a fixed capacitor , as schematically illustrated in . each qubit is operated via two control parameters , the gate voltage @xmath416 and the magnetic flux across the junction loop , @xmath417 . they enter the cpb hamiltonian via the dimensionless parameters @xmath418 and @xmath419 : @xmath420 here @xmath421 and @xmath422 is the josephson energy , modulated by the phase @xmath219 around the zero phase value @xmath423 . charge @xmath424 and phase @xmath425 are conjugate operators , @xmath426=\rmi$ ] . the loop capacitance @xmath427 is the sum of the gate @xmath428 and the junctions @xmath429 capacitances . the two cpbs are coupled by inserting a fixed capacitance @xmath430 between the two islands . the presence of the coupling capacitance leads to a renormalization of the cpb charging energies @xmath431 , being @xmath432 the cpb charging energy of the uncoupled qubit @xmath18 , @xmath433 the total inverse capacitance of the device . the coupling energy is @xmath434 , and the full device hamiltonian reads @xmath435 ^ 2 - e_{\alpha,\mathrm{j}}(\delta_\alpha ) \cos \hat{\varphi}_\alpha , \nonumber \\ \mathcal{h}_\mathrm{c } = e_{\mathrm{cc } } [ \hat{q}_1 - q_{1,\mathrm{x } } \mathbb{i}_{1 } ] \otimes [ \hat{q}_2 - q_{2,\mathrm{x } } \mathbb{i}_{2 } ] , \label{eq:2qbham - coupl}\end{aligned}\ ] ] where the control parameters @xmath436 and @xmath345 , and the charge @xmath437 and phase operators @xmath438 play the same role as in the single qubit case . . each qubit has the characteristic two - port design , with control parameters the gate voltage @xmath439 and the magnetic flux @xmath440 threading the superconducting loop @xcite.,scaledwidth=60.0% ] at sufficiently low temperatures , the evolution of each cpb approximately takes place within the bi - dimensional subspace spanned by the lowest energy eigenstates of @xmath441 , @xmath442 with a splitting depending on the control parameters @xcite , @xmath443 , where the projection operator reads @xmath444 and @xmath445 . the restricted dynamics of the coupled cpbs can be described in a pseudo - spin formalism by projection in the eigenstates basis @xmath446 . in this subspace the charge and josephson operators are expressed in terms both of @xmath447 and of the transverse component @xmath448 as follows @xmath449 where @xmath450 the restriction of the device hamiltonian to @xmath451 is to indicate @xmath452 , @xmath453 . ] @xmath454 ( q_{\beta,++ } + q_{\beta,--}- 2 q_{\beta , x } ) \nonumber \\ \!\!\!\!\ ! \!\!\!\!\ ! + e_{\mathrm{cc } } \prod_\alpha \left [ - \frac{1}{2 } ( q_{\alpha,++ } - q_{\alpha,-- } ) \sigma_{\alpha z } + q_{\alpha,+- } \sigma_{\alpha x } \right ] \label{eq : htrunc}\end{aligned}\ ] ] note that because of the coupling , in addition to interaction terms between the two qubits , each qubit is effectively displaced from its own operating point ( second term in ) . because of fluctuations of control parameters the device couples to the external environment . the form of interaction terms can be easily deduced considering classical fluctuations of @xmath436 and @xmath345 , i.e. by replacing in and , @xmath455 and @xmath456 . we therefore obtain @xmath457 , where @xmath458 fluctuations of each cpb hamiltonian and of the coupling term read @xmath459 where @xmath460 is related to gate charge fluctuations , @xmath461 and @xmath462 to fluctuations of the phase or equivalently of the josephson energy , @xmath463 , where @xmath464 , and we put @xmath465 . in the computational subspace the additional terms reduce to @xmath466 and @xmath467 \otimes \mathbb{i}_{2 } \nonumber \\ \!\!\!\!\!+ g_1 x_1 \mathbb{i}_{1 } \otimes \left [ - \frac{1}{2 } ( q_{2,++ } - q_{2,-- } ) \sigma_{2 z } + q_{2,+- } \sigma_{2 x}+ \frac{1}{2 } ( q_{2,++ } + q_{2,-- } ) \mathbb{i}_{2 } \right ] .\end{aligned}\ ] ] in conclusion , the coupled cpbs hamiltonian at a general working point , in the four dimensional subspace @xmath451 , including fluctuations of the control parameters and neglecting constant terms , takes the form @xmath468 with @xmath469 given in eq . and @xmath470 \nonumber \\ \!\!\!\!\ ! \!\!\!\!\ ! \!\!\!\!\ ! \!\!\!\!\ ! \!\!\!\!\ ! \!\!\!\!\ ! \!\!\!\!\ ! + g_2 x_2 \left [ \frac{1}{2 } ( q_{1,-- } - q_{1,++ } ) \sigma_{1 z } + q_{1,+- } \sigma_{1 x } \right ] + g_1 x_1 \left [ \frac{1}{2 } ( q_{2,-- } - q_{2,++ } ) \sigma_{2 z } + q_{2,+- } \sigma_{2 x } \right ] \end{aligned}\ ] ] note that due to the capacitive coupling a cross - talk effect takes place , gate charge fluctuations of qubit @xmath18 being responsible for fluctuations of the polarization of qubit @xmath471 . effects are scaled with the coupling energy @xmath472 , thus they are expected to be less relevant compared to fluctuations acting directly on each qubit . a detailed analysis of cross - talk and correlations between gate charge fluctuations has been reported in @xcite . in our analysis we disregarded cross - talk and correlations between noise sources acting on each qubit . lll parameter & qubit 1 & qubit 2 + @xmath473 ( ghz ) & 9.997 & 10.41 + @xmath423 ( ghz ) & 14.16 & 15.62 + @xmath427 ( ff ) & 7.73 & 7.42 + @xmath474 ( ghz ) & 12.666 & 13.81 + @xmath475 ( ghz ) & 9.92 & 10.33 + @xmath22 ( ghz ) & 12.645 & 13.79 + the implementation of a two qubit gate in a fixed coupling scheme requires the qubits to be at resonance during gate operation . because of experimental tolerances on bare parameters ( about @xmath406% ) , the resonant condition can only be achieved by a proper choice of the single - qubit working points via tuning @xmath476 and @xmath345 . this is a critical choice since at least one qubit has to be moved away from the working point of minimal sensitivity to parameters variations , the `` optimal point '' , @xmath477 , @xmath478 @xcite . since cpb - based devices are severely affected by low - frequency charge noise it is desirable to maintain the charge optimal point , @xmath479 and modulate resonance / detuning by tuning the phases @xmath345 . the most reasonable choice consists in maintaining one qubit at its own phase optimal point , @xmath279 and tune the phase of the other qubit , @xmath480 . for set of parameters close to those planned in experiments @xcite ( see ) resonance occurs for @xmath481 . since at @xmath479 it results @xmath482 and @xmath483 , the projected charge is transverse and the josephson operator is longitudinal with respect to each hamiltonian @xmath484 . therefore , the truncated hamiltonian is of the form @xmath485 given by eqs . and respectively @xmath486 \otimes \mathbb{i}_{\beta } \label{eq : hreson - noise } \end{aligned}\ ] ] where @xmath487 , @xmath488 etc . denote the specific values taken by these matrix elements at the resonance point obtained for a specific choice of @xmath480 . values of the charge and phase matrix elements at this working point are reported in table [ tab : meanvalues ] and lead to @xmath489 ghz . the interaction hamiltonian @xmath490 results from @xmath491 considering the quantized version of the classical fluctuations @xmath492 and @xmath493 . where , since @xmath279 we have @xmath494 whereas for @xmath280 it results @xmath495 . ccc & qubit 1 & qubit 2 + @xmath496 & 0 & 0 + @xmath497 & -0.5962161 & -0.5891346 + @xmath498 & 0.7049074 & 0.7396952 + @xmath499 & 0 & 0 + the accuracy of the truncation of the multistate device hamiltonian to the lowest four eigenstates has been checked numerically by exact diagonalization of using the numerical values of the physical parameters reported in and considering 14 charge states for each qubit , see . fluctuations of the control parameters @xmath500 , @xmath345 have different physical origin . they partly stem from microscopic noise sources , partly from the circuitry itself . the resulting stochastic processes are sometimes non - gaussian , therefore complete characterization of the processes requires in principle higher - order cumulants . such a complete description is often unavailable in experiments , whereas it is usually possible to provide a characterization of the power spectrum of the various stochastic processes . noise characteristics for the two quantronia are summarized in table [ tab : noise ] ( ) . experiments on various josephson implementations have revealed the presence of spurious resonances in the spectrum which manifest themselves as beatings in time resolved measurements @xcite . in charge and charge - phase qubits they are due to strongly coupled ( sc ) background charges and may severely limit the reliability of these devices @xcite . in the following [ appendix : sc ] we will discuss the detrimental effect of a single strongly - coupled impurity on the visibility of a @xmath3 operation . finally , we mention that in the present analysis we have not explicitly considered fluctuations of the josephson energy due to critical current fluctuations . the effect of @xmath423 noise may be straightforwardly included in our analysis within the multistage approach . experiments on various josephson implementations have revealed the presence of spurious resonances in the spectrum which manifest themselves as beatings in time resolved measurements @xcite . in charge and charge - phase qubits they are due to strongly coupled ( sc ) background charges and may severely limit the reliability of these devices @xcite . several experiments have shown that these impurities can be modeled as bistable fluctuators ( bf ) , switching between states @xmath501 and @xmath88 with a rate @xmath502 . often the qubit - bf coupling is transverse , i.e. of the form @xmath503 with @xmath504 @xcite . each bistable state corresponds to a different qubit splitting , @xmath22 for @xmath505 and @xmath506 $ ] for @xmath507 ( @xmath508 ) . the parameter quantifying the strength of the qubit - bf coupling is @xmath509 @xcite . when @xmath510 the impurity is strongly coupled and it is visible both in spectroscopy and in the time - resolved dynamics . similarly , a single bf acting on one of the two qubits forming a universal gate induces a bi - stability in the swap - splitting : @xmath511 for @xmath505 and @xmath512 $ ] for @xmath507 ( in this case the stronger condition on the qubit - bf coupling has been assumed @xmath513 ) . the strong coupling condition for the @xmath3 gate is therefore @xmath514 . considering the above expansions and the constraint @xmath515 the two ratios satisfy the condition @xmath516 . therefore the visibility of a specific bf is expected to be reduced in a two - qubit operation with respect to a single qubit gate . the effect of a single bf fluctuator depends on the way experimental data are collected . for spectroscopic measurements the single - shot time is about @xmath517 ns and the acquisition time of a single point in the spectrum requires about @xmath518 repetitions , resulting in a recording time for a single data point of about @xmath328 s @xcite . therefore a single bf will be visible in spectroscopy if its switching time is @xmath519 . for instance a bf switching at @xmath520 khz can be averaged during the spectroscopic measurements and it is visible if it is sufficiently strongly coupled to one qubit , for instance this is the case for @xmath521 . the expected effect of this impurity in spectroscopy is shown in where it results in the simultaneous presence of two avoided crossings depending on the impurity state . the occurrence of a similar bf represents a major problem for charge and charge - phase implementations @xcite . effects are also visible in time resolved measurements . if the considered bf is one out of the several ones responsible for @xmath0 noise , the global effect of the structured bath is a considerable reduction of the oscillation amplitude , as shown in . under these conditions , in principle , an `` optimal coupling '' can still be identified . since the main problem is the beating pattern , optimal tuning is defined by the condition that the average @xmath522 vanishes , rather than minimizing the swap - splitting variance . in the presence of only charge noise , this condition leads to a modified `` optimal coupling '' , @xmath523 , at which effectively the swap visibility is improved ( ) . the efficiency of such a choice however critically depends on the details ( presently not available ) of transverse noise at frequencies in the khz - mhz range . relaxation processes due to quantum noise at these frequencies may in fact represent an additional liming factor for the gate fidelity . for qubit - qubit coupling @xmath524 ( blue ) and for uncoupled qubits ( black ) . in the presence of a bf coupled to one qubit with strength @xmath525 the coupled qubits ( @xmath524 ) eigenenergies are shifted ( red ) . right : numerical simulations of the switching probabilities in the presence of the above bf ( orange / cyan ) , and of the bf plus @xmath0 noise with @xmath526 ( blue and red ) . for optimal coupling , @xmath523 , a considerable recover of the signal can be obtained ( gray ) . , title="fig:",scaledwidth=47.0% ] for qubit - qubit coupling @xmath524 ( blue ) and for uncoupled qubits ( black ) . in the presence of a bf coupled to one qubit with strength @xmath525 the coupled qubits ( @xmath524 ) eigenenergies are shifted ( red ) . right : numerical simulations of the switching probabilities in the presence of the above bf ( orange / cyan ) , and of the bf plus @xmath0 noise with @xmath526 ( blue and red ) . for optimal coupling , @xmath523 , a considerable recover of the signal can be obtained ( gray ) . , title="fig:",scaledwidth=45.0% ] in this appendix we report the frequency shifts entering the off - diagonal elements of the rdm as resulting from the solution of the master equation in the secular approximation reported in . the frequency shifts take the simple form @xmath527 \\ \tilde \omega_{03 } - \omega_{03 } \,= \,\frac{1}{2 } \ , \left [ \sum_{k \neq 0 } { \mathcal e}_{0k } - \sum_{k \neq 3 } { \mathcal e}_{3k } \right ] \ , . \end{array } \label{shifts}\end{aligned}\ ] ] for the swap coherence the different contributions read @xmath528 \nonumber \\ { \mathcal e}_{13 } & = & \frac{1}{8 } \ , ( 1-\sin \varphi ) \,[{\mathcal e}_{x_1}(\omega_{13 } ) + { \mathcal e}_{x_2}(\omega_{13 } ) ] \nonumber \\ { \mathcal e}_{20 } & = & \frac{1}{8 } \ , ( 1-\sin \varphi ) \,[{\mathcal e}_{x_1}(\omega_{20 } ) + { \mathcal e}_{x_2}(\omega_{20 } ) ] \nonumber \\ { \mathcal e}_{23 } & = & \frac{1}{8 } \ , ( 1+\sin \varphi ) \,[{\mathcal e}_{x_1}(\omega_{23 } ) + { \mathcal e}_{x_2}(\omega_{23 } ) ] \nonumber \\ { \mathcal e}_{21 } & = & \frac{1}{8 } \ { [ \mathcal{e}_{z_1 } ( \omega_{21 } ) + \mathcal{e}_{z_2 } ( \omega_{21 } ) ] \nonumber \\ { \mathcal e}_{12 } & = & \frac{1}{8 } \ { [ \mathcal{e}_{z_1 } ( \omega_{12 } ) + \mathcal{e}_{z_2 } ( \omega_{12 } ) ] \nonumber \end{aligned}\ ] ] from single qubit measurements , as reported in , charge noise at frequencies of order of @xmath22 is white . assuming that also the phase variables @xmath529 have white spectrum at frequencies of order @xmath21 , results in @xmath530s@xmath99 . the spectrum of @xmath531 takes instead the ohmic form @xmath532 , where @xmath533s@xmath99 . under these conditions , phase shifts due to polarization noise and phase fluctuations on qubit 2 identically vanish ( from ) . a frequency shift contribution results from ohmic phase noise on qubit 1 , similarly to a qubit affected by transverse noise @xcite , as it can be argued from @xmath534 = { \mathcal p } \int_{-\infty}^{\infty } \frac{d \omega}{4\pi } \ , \frac{s_{z_1}(\omega)}{1+e^{-\omega / k_b t } } \ , \frac{\omega_{21}}{\omega^2 -\omega_{21}^2 } \ , . \label{shift - 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controlled generation of entangled states of two quantum bits is a fundamental step toward the implementation of a quantum information processor . in nano - devices this operation is counteracted by the solid - state environment , characterized by broadband and non - monotonic power spectrum often @xmath0 at low frequencies . for single qubit gates , incoherent processes due to fluctuations acting on different time scales result in peculiar short- and long - time behaviors . markovian noise originates exponential decay with relaxation and decoherence times , @xmath1 and @xmath2 , simply related to the symmetry of the qubit - environment coupling hamiltonian . noise with @xmath0 power spectrum at low frequencies is instead responsible for defocusing processes and algebraic short - times behavior . in this article we identify the relevant decoherence times of an entangling operation due to the different decoherence channels originated from solid state noise . entanglement is quantified by the concurrence , which we evaluate in analytic form employing a multi - stage approach . `` optimal '' operating conditions of reduced sensitivity to noise sources are identified . we apply this analysis to a superconducting @xmath3 gate for experimental noise spectra .

weakly sequentially complete banach spaces were introduced in @xcite . since then , properties of weakly sequentially complete spaces were investigated in a number of papers , see e.g. @xcite and @xcite and the references therein . important result on weakly sequentially complete banach spaces is given by rosenthal in @xcite . if @xmath0 is weakly sequentially complete , then @xmath0 is either reflexive or contains a subspace isomorphic to @xmath1 in the present paper we prove sufficient conditions for a banach space @xmath0 to be weakly sequentially complete . these sufficient conditions are expressed in terms of existence of directional derivatives for cone convex mappings . cone convex mappings appear in variational analysis in topological vector spaces and in construction of efficient iterative schemes for solving vector optimization problems . newton method for solving smooth unconstrained vector optimization problems under partial order induced by general closed convex pointed cone can be found in @xcite . the organization of the paper is as follows . in section 2 we discuss basic facts concerning weakly sequentially complete banach spaces . in section 3 we prove some properties of cone convex mappings . section 4 is devoted to the constructions of convex functions that take values in given points . section 5 contains the main result namely the proof of the fact that the existence of directional derivatives at any point and any direction for any cone convex mapping implies that the banach space @xmath0 is weakly sequentially complete . in section 6 we discuss properties of the mapping @xmath2 constructed in theorem [ main ] . let us present some known facts about weakly sequentially complete banach spaces . a sequence @xmath3 in a banach space @xmath0 is weak cauchy if @xmath4 exists for every @xmath5 we say that a banach space @xmath0 is weakly sequentially complete if every weak cauchy sequence weakly converges in @xmath0 . a weak cauchy sequence @xmath3 is called nontrivial if it does not weakly converge . nontrivial weak cauchy sequences were investigated by @xcite . any weak cauchy sequence @xmath3 in a banach space @xmath0 is norm - bounded by the uniform boundedenss principle ( @xcite , p. 38 ) . in @xcite we can find a well know fact about reflexive space ( @xcite corollary 4.4 ) . if @xmath6 is reflexive , then @xmath0 is weakly sequentially complete . however , in some nonreflexive spaces , sequences can be found which are weak cauchy but not weakly convergent . let us present some examples , c.f . @xcite . * let @xmath7 and let us consider @xmath8 , where @xmath9 is basic vector in @xmath10 we have @xmath11 and @xmath3 is weak cauchy sequence . since @xmath3 converges @xmath12 to the element @xmath13 it is not weakly convergent . * if we take @xmath14 which is a compact hausdorff space , then @xmath15 is weakly sequentially complete if and only if @xmath14 is finite . * space @xmath16 $ ] of all continuous functions on @xmath17 $ ] is not weakly sequentially complete . * for every measure @xmath18 , the space @xmath19 is weakly sequentially complete . any closed subspace @xmath20 of a weakly sequentially complete banach space @xmath0 is weakly sequentially complete banach space . consider a weak cauchy sequence @xmath3 in @xmath21 . then it is weak cauchy in @xmath0 . since @xmath0 is weakly sequentially complete , @xmath3 weakly converges to some @xmath22 thus , @xmath23 lies in the weak closure of @xmath21 . since @xmath21 is closed and convex , by mazur s theorem , weak closure of @xmath21 coincides with @xmath24 hence @xmath25 [ podciag ] let @xmath26 be a nontrivial weak cauchy sequence . then each subsequence of @xmath3 is also nontrivial weak cauchy . by contradiction , assume that there exists a subsequence @xmath27 weakly converging to @xmath28 let @xmath29 . there exists @xmath30 such that for all @xmath31 @xmath32 since @xmath3 is weak cauchy , there exists @xmath33 such that @xmath34 for all @xmath35 since @xmath36 we have @xmath37 in the present paper we consider cone ordering relations in @xmath0 generated by convex closed cones . if we assume that @xmath0 is a banach lattice , then we get the following characterization ( @xcite ) . if @xmath0 is a banach lattice , then @xmath0 is weakly sequentially complete if and only if it does not contain any subspace isomorphic to @xmath38 . let us underline that if we consider the concept of weak completeness in terms of nets ( see @xcite for the definition ) , then we can not expect weak completeness in the infinite dimensional case . a net @xmath39 in a topological vector space @xmath0 is cauchy if for every neighbourhood @xmath40 of zero there exists @xmath41 such that @xmath42 for every @xmath43 topological vector space @xmath0 is complete if each cauchy net converges ( see @xcite p.356 ) . first countable spaces , including metric spaces , have topologies that are determined by their convergent sequences . in an arbitrary first countable space , a point @xmath44 is in the closure of a subset @xmath45 if and only if there is a sequence in @xmath45 converging to @xmath46 if @xmath0 is an infinite dimensional banach space , regardless of whether or not it is separable in the norm topology , then the weak topology on @xmath0 is not first countable , and is not characterized by its convergent sequences alone . for the weak topology in an infinite - dimensional space , there exist weak cauchy nets which are not weakly convergent . this result can be found in @xcite and is deeply tied with axiom of choice and helly s theorem . the weak topology on infinite - dimensional normed space is never complete . let @xmath47 , @xmath0 be real linear vector spaces and let @xmath48 be a convex cone inducing the standard ordering relation @xmath49 analogously , we write @xmath50 if and only if @xmath51 we use the notation @xmath52 if @xmath14 is clear from the context . let @xmath53 . we say that the mapping @xmath2 is @xmath14-convex on a convex set @xmath54 if @xmath55.\ ] ] as in the scalar case @xcite we have the following characterization of cone convexity of @xmath2 in terms of the epigraph of @xmath2 , @xmath56 , defined as @xmath57 . let @xmath48 be a closed convex cone . a mapping @xmath53 is @xmath14-convex on @xmath58 if and only if @xmath56 is a convex set in @xmath59 . let us assume that @xmath2 is @xmath14-convex on @xmath45 . let @xmath60 and @xmath61.$ ] from the definition of @xmath56 we have @xmath62 and @xmath63 for some @xmath64 since @xmath14 is convex , @xmath65 from @xmath14-convexity of @xmath2 on @xmath45 we get @xmath66 the converse implication follows directly from the definition of @xmath67 let @xmath0 be a banach space with the dual space @xmath68 let @xmath14 be a closed convex cone in @xmath69 dual cone @xmath70 of @xmath14 is defined as @xmath71 . let @xmath48 be a closed convex cone in @xmath69 the cone @xmath14 can be represented as @xmath72 the following lemma provides another characterization of @xmath14-convex mappings . the finite - dimensional case of this lemma has been used in @xcite . [ lemma - convex ] let @xmath58 be a convex subset of @xmath47 . let @xmath48 be a closed convex cone and let @xmath73 be a mapping . the following conditions are equivalent . 1 . @xmath74 2 . @xmath75 . the implication @xmath76 follows directly from the definition of @xmath77 we prove the converse implication by contradiction . suppose that for some @xmath61,$ ] @xmath78 we have @xmath79 by ( [ biduall ] ) , there exists @xmath80 such that @xmath81 which , by proposition [ biduall ] , contradicts the convexity of @xmath82 on @xmath45 . in this section we construct convex function which take given values at a countable number of points . some constructions of convex functions are present in the literature . for example , in @xcite we can find the proof that a continuous convex function @xmath83 defined on @xmath84 , @xmath85 , @xmath86 is everywhere compactly differentiable but not frchet differentiable at zero . in @xcite we can find an extension of a function @xmath87 to some convex function @xmath88 , @xmath89 , @xmath90 is a convex set , such that @xmath91 for all @xmath92 let us start with the following proposition . [ konstrukcja1 ] for every nonnegative decreasing and convergent sequence @xmath93 there exists a subsequence @xmath94 @xmath95 , and a convex nonincreasing function @xmath96 such that @xmath97 let @xmath98 , @xmath99 let @xmath100 be defined as @xmath101 let @xmath102 be such that @xmath103 we have @xmath104 by taking @xmath105 + 1 $ ] where @xmath106 $ ] is the largest integer not greater than @xmath46 we define @xmath107 as @xmath108 suppose that we have already defined @xmath109 , @xmath110 we define @xmath111 in the following way . let @xmath112 be such that @xmath113 we have @xmath114 by taking @xmath115 + 1 $ ] we define @xmath116 as @xmath117 we define @xmath118 by formula @xmath119 clearly function @xmath120 is convex on @xmath121 let us show that @xmath122 by construction of @xmath123 we have @xmath124 and @xmath125 next from monotonicity of @xmath126 we get @xmath127 and @xmath128 to get ( [ nierownosci - konstrukcja1 ] ) we multiply above inequality by @xmath129 let us assume that @xmath130 then from ( [ rano ] ) @xmath131 we get @xmath132 analogous we can prove first inequality in ( [ nierownosci - konstrukcja1 ] ) for @xmath133 by ( [ nierownosci - konstrukcja1 ] ) , function @xmath120 is decreasing and @xmath97 in proposition [ konstrukcja1 ] we constructed function @xmath120 when @xmath134 is nonnegative , decreasing and @xmath135 , @xmath136 , @xmath137 is a subsequence of integers . now we consider the case when @xmath126 is arbitrary and @xmath135 is a decreasing sequence of reals . [ lemat1 ] let @xmath138 be sequences with @xmath139 decreasing . if @xmath140 there exists a convex function @xmath96 such that @xmath141 for each @xmath142 , let @xmath143 be defined as @xmath144 we show that for @xmath142 we have @xmath145 if @xmath146 then multiplying both sides of by @xmath147 we get @xmath148 which is equivalent to @xmath149 analogously if @xmath150 we get @xmath151 we show that the function @xmath118 defined as @xmath152satisfies the requirements of the lemma [ lemat1 ] on @xmath121 indeed , @xmath120 is convex as supremum of convex functions . by the first inequality of ( [ nierownoscc ] ) and the monotonicity of @xmath139 we get @xmath153 by the second inequality of ( [ nierownoscc ] ) we get @xmath154 this gives that @xmath155 observe that , we have the following property : @xmath156 indeed , by the first inequality of ( [ nierownoscc ] ) and the monotonicity of @xmath139 we get @xmath157 by the second inequality of ( [ nierownoscc ] ) and from the fact that @xmath158 we get @xmath159 we apply the above lemma to construct a convex function @xmath120 starting with any nonnegative converging sequence @xmath160 with positive limit . [ propozycja22a ] let @xmath161 be a converging sequence of nonnegative reals with limit @xmath162 there exist a subsequence @xmath163 , a sequence @xmath164 , @xmath165 and a convex function @xmath166 such that @xmath167 where @xmath168 if @xmath169 is nonincreasing and @xmath170 , @xmath171 , @xmath172 , if @xmath169 is nonincreasing and @xmath173 , @xmath174 , if @xmath169 is increasing and @xmath173 , @xmath175 , @xmath176 , if @xmath169 is increasing and @xmath170 . we can assume that @xmath177 for @xmath142 . two cases should be considered : 1 . @xmath178 contains an infinite subsequence @xmath179 , @xmath180 2 . @xmath178 contains an infinite subsequence @xmath179 , @xmath181 to prove the assertion we show that in both cases condition of lemma [ lemat1 ] is satisfied . case 1 . without loss of generality we can assume that @xmath182 . moreover , we can assume that @xmath178 is decreasing ( in case when @xmath178 is constant the existence of the function @xmath120 satisfying the requirements of the proposition follows trivially from lemma [ lemat1 ] ) . consider first the case when @xmath170 . by eliminating eventually a finite number of @xmath183 we can assume that @xmath184 for @xmath142 . let @xmath185 and @xmath186 for @xmath142 . both sequences are decreasing . let @xmath187 , @xmath188 . since @xmath178 and @xmath189 are decreasing , the number @xmath90 defined below is positive , i.e. @xmath190 since @xmath191 , there exists @xmath192 such that @xmath193 put @xmath194 . we have @xmath195{l } < \frac{t_{1}t_{2}}{a_{2}-a_{1}}(z_{2}-z_{1 } ) = \frac{t_{1}a_{2}-t_{2}a_{1}+t_{2}a_{2}-t_{2}a_{2}}{a_{2}-a_{1 } } = \frac{t_{2}(a_{2}-a_{1})-a_{2}(t_{2}-t_{1 } ) } { a_{2}-a_{1}}\\ = t_{2}-\frac{a_{2}(t_{2}-t_{1})}{a_{2}-a_{1 } } < t_{2}-\frac{a_{2}(t_{2}-t_{1})}{a_{2}-a_{1}}+ \frac{a_{m_{3}}(t_{2}-t_{1})}{a_{2}-a_{1}}. \end{array}\ ] ] the last inequality follows from the fact that @xmath196 . thus , @xmath197 which proves that @xmath198 assume that we have already defined @xmath199 , @xmath200 . by induction with respect to @xmath201 , starting from @xmath202 and @xmath203 we choose @xmath123 be repeating the reasoning above with @xmath202 and @xmath203 instead @xmath204 and @xmath205 , respectively , and with @xmath206 . in this way we choose @xmath123 and we prove condition of lemma [ lemat1 ] . when @xmath173 it is enough to take @xmath207 and @xmath208 for arbitrary @xmath172 for @xmath142 . again both sequences are decreasing . hence , we can repeat the above reasoning with these sequences and get the existence of the function @xmath120 satisfying the requirements . as previously , without loss of generality , we can assume that @xmath182 . consider the case @xmath173 . by eliminating eventually a finite number of @xmath183 we can assume that @xmath209 for @xmath142 . let @xmath210 and @xmath211 . let @xmath187 , @xmath188 . since @xmath212 is decreasing and @xmath178 is increasing , the number @xmath90 defined below is negative , i.e. @xmath213 since @xmath214 there exists @xmath192 such that @xmath215 put @xmath194 . we have @xmath216{l } \ge\frac{t_{1}t_{2}}{t_{2}-t_{1}}(z_{2}-z_{1 } ) = \frac{t_{2}a_{1}-t_{1}a_{2}+t_{2}a_{2}-t_{2}a_{2}}{t_{2}-t_{1 } } = \frac{a_{2}(t_{2}-t_{1})-t_{2}(a_{2}-a_{1 } ) } { t_{2}-t_{1}}\\ = a_{2}-\frac{t_{2}(a_{2}-a_{1})}{t_{2}-t_{1 } } > a_{2}-\frac{t_{2}(a_{2}-a_{1})}{t_{2}-t_{1}}+ \frac{t_{m_{3}}(a_{2}-a_{1})}{t_{2}-t_{1}}. \end{array}\ ] ] the last inequality follows from the fact that @xmath217 . thus , @xmath218 as previously , this proves that @xmath198 assume that we have already defined @xmath199 , @xmath200 . by induction with respect to @xmath201 , starting from @xmath202 and @xmath203 we choose @xmath123 be repeating the reasoning above with @xmath202 and @xmath203 instead @xmath204 and @xmath205 , respectively , and with @xmath206 . in this way we choose @xmath123 and we prove condition of lemma [ lemat1 ] . when @xmath170 it is enough to take @xmath219 for some @xmath176 and @xmath220 we can repeat the above reasoning with these sequences and get the existence of the function @xmath120 satisfying the requirements . in consequence , in all cases , by lemma [ lemat1 ] , we get the function @xmath118 defined by formula @xmath221 such that @xmath222 where @xmath223 , @xmath224 , are as in the proof of lemma [ lemat1 ] . proposition [ propozycja22a ] allows us to formulate the following corollary used in the proof of the main result ( theorem [ main ] ) . [ propozycja22 ] let @xmath0 be a normed space and let @xmath225 be such that the sequence @xmath226 converges to @xmath227 for a certain @xmath228 . there exist a subsequence @xmath229 , a functional @xmath230 and a convex function @xmath166 such that @xmath167 where 1 . @xmath231 , @xmath232 if @xmath233 is nonicreasing and @xmath170 , 2 . @xmath234 , @xmath235 , for some @xmath172 , if @xmath233 is nonicreasing and @xmath173 , 3 . @xmath236 , @xmath237 , if @xmath233 is increasing and @xmath173 , 4 . @xmath238 , @xmath239 for some @xmath176 , if @xmath233 is increasing and @xmath240 the proof follows directly from proposition [ propozycja22a ] . indeed , let us observe that we can always find some @xmath241 , @xmath242 for a certain @xmath243 such that @xmath244 is a converging sequence of nonnegative reals with the limit point @xmath245 . let @xmath47 be a vector space and @xmath0 be a real banach space . let @xmath246 be a mapping defined on a subset @xmath45 of @xmath47 . [ pochodna ] we say that the mapping @xmath246 is directionally differentiable at @xmath247 in the direction @xmath248 such that @xmath249 for all @xmath250 sufficiently small if the limit @xmath251 exists . the element @xmath252 is called the directional derivative of @xmath2 at @xmath253 in the direction @xmath254 let @xmath58 be a convex subset of @xmath255 let @xmath246 be a @xmath14-convex mapping on @xmath45 , where @xmath48 is a closed convex cone in @xmath0 . by elementary calculations @xcite one can prove that for any @xmath14-convex mappings @xmath2 on @xmath45 , for all @xmath256 , @xmath257 , @xmath258 for all @xmath250 sufficiently small , the difference quotient @xmath259 is nondecreasing as a function of @xmath250 . our aim is to prove the following theorem . [ main ] let @xmath47 be a real linear vector space and let @xmath0 be a banach space . if for every closed convex cone @xmath260 and every @xmath14-convex mapping @xmath246 , @xmath58 is a convex subset of @xmath47 , @xmath261 the directional derivative @xmath262 exists for any @xmath263 @xmath248 such that @xmath264 for all @xmath250 sufficiently small , then @xmath0 is weakly sequentially complete . by contradiction , assume that @xmath0 is not weakly sequentially complete . this means that there exists a nontrivial weak cauchy sequence @xmath265 in @xmath0 , i.e. @xmath266 and @xmath265 is not weakly convergent in @xmath0 . basing ourselves of the existence of the above sequence we construct a closed convex cone @xmath48 and a @xmath14-convex mapping @xmath246 such that for a given direction @xmath267 @xmath268 let us observe first that we can always find a functional @xmath269 such that @xmath270 since otherwise @xmath271 would weakly converge to zero . let us note that without losing generality we can assume that @xmath245 . consequently , by neglecting eventually a finite number of elements we can also assume that @xmath272 , @xmath142 . let @xmath273 be defined as @xmath274 the cone @xmath275 is a half - line emanating from @xmath276 in the direction of @xmath277 . this is a closed pointed convex cone in @xmath278 let @xmath279 by ( [ zbiega ] ) , @xmath280 . the cone @xmath14 is closed and convex . by proposition [ propozycja22 ] , there exist a sequence @xmath281 , a subsequence @xmath282 and a convex function @xmath283 such that @xmath284 , where 1 . @xmath231 , @xmath232 if @xmath233 is nonicreasing and @xmath170 , 2 . @xmath234 , @xmath235 , where @xmath172 , if @xmath233 is nonicreasing and @xmath173 , 3 . @xmath236 , @xmath237 , if @xmath233 is increasing and @xmath173 , 4 . @xmath238 , @xmath239 for some @xmath176 , if @xmath233 is increasing and @xmath240 now we construct @xmath14-convex mappings @xmath285 satisfying the requirements of the theorem , where @xmath286 for some @xmath257 , @xmath287 . we limit our attention to the case 1 . and the case 3 .. the case 2 . and the case 4 . require only minor changes . we construct a @xmath14-convex mapping @xmath288 such that @xmath289 where @xmath135 and @xmath290 are such that @xmath291 and @xmath233 are as in the case 1 . let @xmath292 @xmath293 be defined as follows . let @xmath294 be defined as @xmath295 for any @xmath95 , @xmath296 and any @xmath297 , @xmath298 we define @xmath299 as follows@xmath300.\end{cases}\ ] ] we start by showing that the mapping @xmath246 defined as @xmath301 is well defined . to this aim it is enough to observe that for any @xmath302 with @xmath297 , where @xmath303 , for any @xmath33 we have @xmath304 consequently , for @xmath303 , we have @xmath305 it is easy to see that for @xmath306 we have @xmath307 moreover , @xmath308 we show that the mapping @xmath2 is @xmath14-convex on @xmath45 with respect to cone @xmath14 defined by ( [ eq - cone ] ) . to this aim we use lemma [ lemma - convex ] , precisely , we start by showing that for @xmath302 , @xmath297 , @xmath298 we have @xmath309 where function @xmath120 is as in proposition [ propozycja22 ] . indeed , if @xmath310 $ ] for some @xmath311 , then by ( [ 55 ] ) and ( [ funkcja ] ) , @xmath312 if @xmath306 , then @xmath313 now , take any @xmath314 by the definition of @xmath70 , @xmath315 for some @xmath316 and by convexity of @xmath120 we get @xmath317 by lemma [ lemma - convex ] , this proves that @xmath2 is @xmath14-convex on @xmath45 . we take @xmath234 and @xmath318 where @xmath319 with this choice @xmath135 , @xmath320 , @xmath321 by repeating the reasoning from case 1 . we get the required mapping @xmath322 case 3 . we construct a @xmath14-convex mapping @xmath285 such that @xmath323 where @xmath135 and @xmath324 are such that @xmath135 and @xmath325 are as in the case 3 . let @xmath299 , @xmath293 be defined as follows . let @xmath326 be defined as @xmath327 for any @xmath95 , @xmath296 and any @xmath302 , @xmath297 , @xmath298 we define @xmath299 as follows@xmath328.\end{cases}\ ] ] now the mapping @xmath285 is defined as in case 1 . by formula ( [ funkcja ] ) . as previously , for @xmath306 we have @xmath329 and @xmath308 for any @xmath330 the convexity of function @xmath331 is proved by the same arguments as in case 1 . in the proof of ( [ 02 - 10 ] ) . we have @xmath238 and @xmath239 for some @xmath332 with this choice @xmath135 , @xmath320 , @xmath321 by repeating the reasoning from case 3 . we get the required mapping @xmath322 in all the cases , the directional derivative of @xmath2 at zero in the direction @xmath257 equals @xmath333 summing up the considerations above we get the following formulas : @xmath334 for the respective sequences @xmath335 and @xmath336 on the other hand , by proposition [ podciag ] , the subsequences @xmath324 appearing in the above formulas are not weakly convergent . hence , we constructed a cone @xmath14 and a @xmath14-convex mapping @xmath2 on @xmath45 which is not directionally differentiable at @xmath276 in the direction @xmath337 which completes the proof . when @xmath47 is a hilbert space we can extend the mapping @xmath2 from theorem [ main ] to the half - space @xmath338 where @xmath339 is as in theorem [ main ] . [ kolacja ] let @xmath47 be a hilbert space and @xmath340 let set @xmath341 mapping @xmath342 and cone @xmath14 be defined as in the proof of theorem [ main ] . then there exists a convex extension @xmath343 of @xmath2 to the half - space @xmath344 let @xmath345 set @xmath45 , cone @xmath346 and mapping @xmath2 be defined as in the proof of theorem [ main ] . let @xmath343 be defined as follows @xmath347 let @xmath348 and @xmath61.$ ] @xmath14-convexity of mapping @xmath349 on @xmath350 follows from @xmath14-convexity of mapping @xmath2 on @xmath341 @xmath351 in view of the above proposition we can formulate the following theorem . let @xmath47 be a hilbert space and let @xmath0 be a banach space . if for every closed convex cone @xmath352 and every @xmath14-convex mapping @xmath353 on @xmath354 for all @xmath257 , @xmath355 the directional derivative @xmath262 exists , then @xmath0 is weakly sequentially complete . without loss of generality , in theorem [ main ] , we can define @xmath14-convex mapping @xmath2 on @xmath356 where direction @xmath257 is such that @xmath357 from proposition [ kolacja ] we can extend the @xmath14-convex mapping @xmath2 on @xmath45 to the @xmath14-convex mapping @xmath349 on @xmath358 since , @xmath359 the directional derivative of @xmath349 at @xmath276 in the direction @xmath339 is equal to @xmath360 the directional derivative of @xmath2 at zero in the direction @xmath257 does not exist which completes the proof . in @xcite directional derivatives of cone convex mappings are defined via the concept of infimum of the set @xmath361 . let @xmath14 be a pointed cone . an element @xmath362 is the infimum of @xmath45 if @xmath362 is a lower bound , i.e. @xmath363 and , for any lower bound @xmath364 of @xmath45 , we have @xmath365 ( c.f . @xcite ch.7 , par.1 , nr 8 , @xcite ch.2 , p.18 ) . without additional assumptions about cone @xmath14 one can not expect the equality @xmath366 let @xmath367 be a hausdorff topological vector space ordered by the closed convex pointed cone @xmath14 . if the net @xmath368 is nonincreasing and convergent to @xmath369 then @xmath370 is bounded below and @xmath371 on the other hand , in @xcite we can find the following example . let @xmath373 and let us consider partial order generated by the cone @xmath374 , @xmath375 is a pointed closed convex cone . the sequence @xmath376 defined ( for @xmath377 fixed ) @xmath378 is nonincreasing , and @xmath379 but @xmath380 does not converge to its infimum . we prove the cone convexity of the mapping @xmath2 constructed in the proof of theorem [ main ] ( and in the proof of theorem 6.2 ) for the cone @xmath14 @xmath381 this cone is not pointed , so the concept of the infimum of the set is not defined . let us note that the concept of directional derivative introduced in definition [ pochodna ] is well defined independently on whether cone @xmath14 is pointed or not . 1 f. albiac , n. j. kalton , topics in banach spaces , springer - verlag , 2000 s. banach , thorie des oprations linaires , warsaw , monografie matematyczne , vol . i , ( 1932 ) c. bilek , c. jermann , a. neumaier , global optimization and constraint satisfaction , springer , 2003 n. bourbaki , algebra ii , chapters 4 - 7 , springer - verlat berlin heidelberg tokyo , 1980 e. casini , e. miglierina , cones with bounded and unbounded bases and reflexivity , nonlinear analysis , 72 ( 2010 ) , pp . 2356 - 2366 j. b. conway , a course in functional analysis - 2nd ed . , springer - verlag , new york berlin heidelberg , 1990 c. costara , d. popa , exercises in functional analysis , springer science+business media b.v . , 2003 l. m. graa drummond , f. m.p . raupp , b.f . svaiter , a quadratically convergent newton method for vector optimization , optimization , 63 no 5 , ( 2014 ) , pp . 661 - 677 j. diestel , sequences and series in banach spaces , springer - verlag , new york heidelberg berlin , 1984 r. engelking , general topology , heldermann verlag berlin , 1989 w. a. eberlein , weak compactness in banach spaces , proc . 33 ( 1947 ) , pp . 317 - 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we provide sufficient conditions for a banach space @xmath0 to be weakly sequentially complete . these conditions are expressed in terms of the existence of directional derivatives for cone convex mappings with values in @xmath0 . weakly sequentially complete banach spaces , directional derivatives of cone convex mappings , cone convex mappings , directional derivatives 26a51 , 06a06 , 46b45 , 46b40

mixtures of colloidal particles and non - adsorbing polymers dispersed in a solvent provide experimentalists and theoreticians with a very flexible model system to explore the statics and dynamics of phase transitions , including fluid fluid demixing , crystalization , gelation or glass transitions@xcite , as well as the interfacial properties associated with phase coexistence . the flexibility of this model system stems from the fact that its properties can be easily tuned by varying , among others , the size ratio of the two components ( e.g. by controlling the degree of polymerization ) , their concentrations , or the quality of the solvent which determines whether the polymer coils behave essentially like interacting self avoiding walks ( saw ) , or more like ideal non interacting polymers ( under @xmath0solvent conditions ) . more specifically if , as will be done in this paper , one adopts an effective one component representation ( by tracing out the polymer degrees of freedom ) the resulting effective interactions between the colloidal particles , obtained from the well known depletion mechanism@xcite , are easily tuned by varying the above physical parameters : the depth of the effective attraction between colloids is essentially controlled by the polymer concentration , while the range depends on the polymer size ( radius of gyration ) . the resulting phase diagrams are very sensitive to changes in the depletion induced pair potential between colloids@xcite . recent experimental@xcite and theoretical@xcite efforts have focused on interfacial and wetting properties of colloid - polymer mixtures , either near solid substrates ( hard walls ) or at fluid fluid phase coexistence . the density profiles near a glass wall and the surface tension at fluid fluid phase coexistence were measured@xcite and very recently the first direct observation of capillary fluctuations at the fluid fluid interface was reported@xcite . various versions of density functional theory ( dft ) of inhomogeneous fluids have been used to determine the density profiles , adsorption and surface tension of colloid polymer mixtures near a hard wall , either in the one component@xcite or two component@xcite representations , or at the phase separated fluid fluid interface@xcite . most of the theoretical work so far focused on mixtures of hard sphere colloids and ideal ( non interacting ) polymers within the classic model of asakura and oosawa@xcite and of vrij@xcite ( the ao model ) , although some attempts have been made to extend the dft calculations to the case of non ideal ( interacting ) polymer coils@xcite , pointing to very significant differences between the two situations . this paper presents a unified dft description of wall fluid and fluid fluid interfaces within an effective one component representation . the dft theory is a perturbative one with respect to the polymer induced depletion attraction between hard sphere colloids , and applies to mixtures of colloids and non interacting , as well as interacting polymer coils . apart from a systematic comparison of the density profiles and surface tensions obtained for these two cases , the present theory also leads to the first estimate of the depletion potential between two walls induced by colloid - polymer mixtures . the paper is organized as follows . section [ eff ] briefly summarizes the effective one and two component representations of colloid - polymer mixtures . the dft formulation used in this paper is presented in section [ dff ] . results for colloid density profiles near a hard wall in the presence of ideal or interacting polymers are presented in section [ dphw ] , while the resulting wall surface tension of the mixtures is calculated in section [ wst ] . the depletion potential between hard walls , induced by colloid polymer mixtures is described in section [ dihw ] . the fluid fluid interfacial properties calculated within the same dft approximation are presented in section [ ff ] , while conclusions are drawn in section [ conc ] . consider a binary mixture of @xmath1 colloidal particles and @xmath2 polymer coils in an external field ( e.g. the confining field of a hard wall ) . the total hamiltonian of the system may be written as @xmath3 where the colloid colloid , polymer polymer and colloid polymer terms @xmath4 , @xmath5 and @xmath6 will be assumed to be sums of pair interactions between the centres of mass ( cm ) @xmath7 ( @xmath8 ) and @xmath9 ( @xmath10 ) of the colloids and polymers , respectively . within this assumption , the individual monomer degrees of freedom of the polymer coils have been traced out , and the resulting effective pair potential between polymer cm s is a state dependent free energy@xcite ; similarly the colloid polymer pair potential is a state dependent free energy resulting from a statistical average over monomer degrees of freedom for a fixed distance between the cm s of the two particles@xcite . hence , @xmath11 while @xmath12 where @xmath13 and @xmath14 are direct external interactions acting on colloidal particles and polymers , respectively . note that @xmath15 is once more an effective potential acting on the polymer cm . the colloid colloid pair potential will henceforth always be considered to be of the hard sphere form . the ao model for non interacting polymers further assumes that @xmath16 with @xmath17 ( @xmath18 being the colloidal radius ) , @xmath19 and @xmath20 , where @xmath21 is the radius of gyration of the polymer coils . a generalization of rosenfeld s fundamental measure theory ( fmt ) free energy functional for additive hard spheres@xcite has been worked out for the non additive hard sphere mixture given by eq [ nonad ] @xcite , and applied to colloid polymer interfacial properties@xcite . an alternative approach is to trace out the polymer degrees of freedom to derive an effective hamiltonian involving only the colloid degrees of freedom@xcite . within the semi grand canonical ensemble , with fixed @xmath1 and fixed chemical potential @xmath22 of the polymers ( or equivalently , fixed number density @xmath23 of the polymers in a reservoir ) , the effective hamiltonian is : @xmath24 where @xmath25 is the grand potential of the inhomogeneous fluid of polymers , which depends parametrically on the positions @xmath26 of the colloidal particles . @xmath25 can be systematically be expanded in terms corresponding to the number of colloids@xcite : @xmath27 @xmath28 is the free energy of the pure polymer solution at chemical potential @xmath22 , in the volume @xmath29 of interest , @xmath30 is the free energy cost of inserting independent single colloids , @xmath31 takes pairwise colloid - colloid interactions into account , and so forth for higher order terms . such an expansion can also be carried out near a single wall of area @xmath32 , where the first few terms are : @xmath33 where @xmath34 is the effective wall colloid depletion potential induced by the presence of polymers , @xmath35 is the osmotic pressure of the bulk polymer solution , and @xmath36 is the surface tension induced by the flat wall . surface tensions are defined throughout relative to the position of the hard wall , at @xmath37 . inserting a single colloid into a bulk polymer solution costs a free energy @xmath38 , and @xmath34 describes the correction to that insertion free energy when the colloid is at a distance @xmath39 from the wall . @xmath40 is the effective interaction between two colloids , induced by the polymer solution . the next higher order contributions to @xmath25 include a a three body colloid term , a three body colloid - colloid - wall term , etc ... these will be ignored in the present work . brader et al . systematically worked out this expansion for an ao mixture near a flat wall , finding @xcite : @xmath41 ( since @xmath42 and @xmath43 for ao particles@xcite ) , @xmath44 , and @xmath45 . @xmath46 acts on each colloid independently and takes the form : @xmath47 where @xmath48 is the polymer packing fraction in the reservoir , @xmath49 is the size ratio , and @xmath50 is the heaviside step function ( @xmath51 , @xmath52 ; @xmath53 , @xmath54 ) . @xmath55 is the asakura oosawa depletion@xcite potential between two spheres in a bath of ideal polymers ; defining now @xmath56 , @xmath57 is given by : @xmath58 the effective hamiltonian for the ao model , with @xmath25 restricted to the 0 , 1 and 2body terms in eq [ nterms ] is strictly valid only for size ratios @xmath59 ; for larger size ratios , three and more body effective interactions between colloidal particles come into play @xcite , but explicit calculations of bulk properties show that they do not play a significant role for @xmath60 up to @xmath61 @xcite . subsequent calculations will neglect more than two body interactions . for the ao model , @xmath28 and the bulk part of @xmath30 , @xmath62 , do not affect the interfacial profiles , but do make contributions to the surface tension @xmath63 as will be shown in subsequent sections . the ao pair potential ( eq [ vao ] ) assumes ideal polymers to be spherical , so that the width of the depletion layer is always equal to @xmath64 . however , polymers can wrap " around colloidal spheres , the more so the smaller the radius @xmath18 of the latter . hence , one expects the width of the depletion layer around a colloid to shrink as @xmath18 decreases . this effect can be accounted for by following the prescription of refs @xcite , whereby the ao form ( eq [ vao ] ) of the effective pair potential holds , but with a renormalized size ratio @xmath65 and a renormalized polymer packing fraction @xmath66 : @xmath67 for interacting polymers we can also carry out an expansion of @xmath25 . accurate expressions for @xmath68 , @xmath69 , @xmath70 and @xmath71 are known and have been validated by computer simulations for self avoiding walk ( saw ) chains@xcite , so that @xmath28 , @xmath30 and @xmath31 directly follow from eq ( [ omega012 ] ) . the derjaguin approximation , which is reasonably accurate for an ideal polymer depletant , is expected to remain valid in the case of interacting polymers , at least for sufficiently small @xmath60 , so that the required wall colloid effective depletion potential @xmath72 is given by @xmath73 where the effective potential between two colloids induced by interacting polymers is well approximated by the semi - empirical form @xmath74 ^ 2 \theta(s - d)\ ] ] here @xmath75 and @xmath76 is the range of the depletion potential : @xmath77 because @xmath78 depends on polymer density only through @xmath23 ( i.e. @xmath22 ) , its form does not change when the polymer density is inhomogeneous . in contrast to the ao model , higher order colloid colloid and colloid wall terms are relevant for any size ratio . the effective one component representation of colloid polymer mixtures is thus fully defined , both for ideal and interacting polymers . the next step is to define the density functional appropriate for the description of the inhomogeneous effective one component model . given the effective hamiltonian specified by eqs [ effh ] and [ omega012 ] , one may construct an approximate free energy density functional to investigate the properties of the inhomogeneous effective one component system of colloidal particles . the latter interacts via a hard sphere repulsions ( for @xmath79 ) and a polymer induced depletion attraction that will be described within first order perturbation theory@xcite , which is expected to be accurate for not too small values of @xmath60 ( i.e. for sufficiently long range attractions ) . the intrinsic free energy functional is then conveniently split into ideal , hard sphere and perturbation parts ; for the hard core part we adopt the very accurate white bear `` version@xcite of rosenfeld s fundamental measure '' ( fmt ) functional@xcite @xmath80= f_{id } \left [ \rho_c(\vec{r})\right]+f_{fmt } \left [ \rho_c(\vec{r})\right]+f_1 \left [ \rho_c(\vec{r})\right]\ ] ] the ideal contribution is : @xmath81=k_b t \int d\vec{r}\rho_c(\vec{r})\left [ \ln(\lambda_c^3\rho(\vec{r}))-1 \right]\ ] ] where @xmath82 is an irrelevant colloidal length scale . hard core contribution is of the weighted density " type , namely @xmath83 & = & \int d\vec{r } [ \phi_1\left ( \ { n_j(\vec{r})\ } \right)+\phi_2\left ( \{n_j(\vec{r})\ } \right ) \nonumber \\ & + & \phi_3\left ( \{n_j(\vec{r})\ } \right ) ] \end{aligned}\ ] ] where the @xmath84 are weighted densities of the form @xmath85 the functions @xmath86 and the weight functions @xmath87 are defined in appendix a. finally , the first order perturbation term reads : @xmath88=\int d\vec{r } \rho_c(\vec{r})\psi_{1}(\vec{r})\ ] ] with @xmath89 where @xmath90 or @xmath78 is the depletion potential induced by ideal ( @xmath91 ) or interacting ( @xmath92 ) polymer coils ; @xmath93 is the pair distribution function of the homogeneous reference hard sphere fluid , evaluated at an intermediate density between the two points @xmath94 and @xmath95 : @xmath96 with @xmath97 @xmath98 is a smoothed density profile around @xmath94 ; the radius @xmath99 is of the order of @xmath18 , and results are not expected to be very sensitive to the precise value of @xmath99 . following the earlier experience of ref @xcite we have chosen @xmath100 . the form [ psi1 ] is the generalisation of the standard first order thermodynamic theory @xcite to inhomogeneous fluids . the choices given in eq [ rhocbar ] and [ rhocbarnu ] have proved very adequate in many dft calculations of fluids near hard walls . in the homogeneous limit , where the density profile reduces to the bulk density , the free energy given by eq [ fpdft ] goes over to the helmholtz free energy of the fluid phase calculated within first order thermodynamic perturbation theory@xcite , which leads to reasonable phase diagrams of colloid polymer mixtures@xcite . the familiar generalized van der waals mean field approximation amounts to setting @xmath101 , which leads of course to a considerable simplification of the dft calculations . keeping in mind that the total effective hamiltonian of the colloids is given by eqs [ effh][omega012 ] , with @xmath102 , the grand potential functional to be minimized with respect to the density profile @xmath103 is the sum of the intrinsic free energy functional [ fpdft ] and of the contributions from the external fields : @xmath104 & = & f\left [ \rho_c \right]+\int \rho_c(\vec{r})\left[\varphi_c(\vec{r})-\mu_c^0 \right]d\vec{r } \nonumber \\ & + & \omega_0+\omega_1^{bulk}\end{aligned}\ ] ] where @xmath105 is the bulk chemical potential of the colloids , while @xmath28 and @xmath62 are defined in eq [ omega012 ] . since the latter are constants , they have no influence on the equilibrium profile @xmath103 , but they will contribute to the equilibrium value of the grand potential , and hence to the surface tension . @xmath106 is the sum of the external potential acting directly on the colloidal particles ( @xmath107 ) and of the polymer induced depletion contribution , @xmath108 , given by eq [ varphiao ] or [ varphis ] for ideal and interacting polymers respectively . the euler lagrange equation of the variational problem reads as : @xmath109}{\delta \rho_c(\vec{r})}=\frac{\delta f[\rho_c(\vec{r})]}{\delta \rho_c(\vec{r } ) } + \varphi_c(\vec{r})-\mu_c^0=0\ ] ] @xmath110 is the sum of ideal ( @xmath111 ) and excess ( @xmath112 ) parts ; defining the local excess chemical potential as @xmath113}{\delta \rho_c(\vec{r})}=\frac{\delta f_{fmt}[\rho_c(\vec{r})]}{\delta \rho_c(\vec{r})}+\frac{\delta f_{1}[\rho_c(\vec{r})]}{\delta \rho_c(\vec{r})},\ ] ] the euler lagrange equation may be cast in the form : @xmath114+\mu_c^{ex}(\vec{r})=\mu_c^0-\varphi_c(\vec{r})\ ] ] so that the density profile satisfies the non linear equation : @xmath115 \}\ ] ] where @xmath116 is the the excess part of the bulk chemical potential of the colloids . the coupled equations [ mucex ] ( with @xmath117 and @xmath118 given by eqs [ ffmt ] and [ f1 ] ) and [ rhorho0 ] must be solved numerically by standard iterative procedures . since only planar interfaces will be considered , the external potential , the density profile and local chemical potential all depend only on @xmath39 , the coordinate orthogonal to the plane of the interface . the corresponding simplified expression for the local excess chemical potential @xmath119 @xcite is given in appendix b , together with the weight functions @xmath120 appropriate for the one dimensional problem . once the equilibrium profile @xmath121 has been determined , it can be substituted into the expression of the functional [ omegagrand ] to determine the equilibrium grand potential @xmath25 . subtraction of the bulk contribution then allows the surface tension @xmath63 to be calculated , according to the definition : @xmath122 where @xmath123 is the total bulk osmotic pressure of the mixture and @xmath32 the total area of the planar interface . consider first the case of a colloid polymer mixture near a hard wall placed at @xmath37 . the density profiles were calculated by solving the one dimensional versions of eqs [ mucex ] and [ rhorho0 ] ( see appendix b ) . a systematic comparison is made between profiles for ideal and interacting polymers , over a range of colloid and polymer packing fractions @xmath124 and @xmath125 and for size ratios @xmath126 , 0.5 , 0.67 , 0.85 and 1.05 . figures [ rho1]a , b compare the density profiles calculated for a fixed colloidal density and several polymer concentrations , for interacting and ideal polymers . as expected , the colloid adsorption at contact increases dramatically with increasing polymer concentration , due to the enhanced effective depletion induced attraction to the wall . the effect is stronger for ideal polymers , which also lead to strong layering at the highest packing fraction hinting at a possible layering transition . the enhanced adsorption and layering are easily understood , since the polymer induced attraction is substantially stronger for ideal polymers ( cf . eq [ varphiao ] ) compared to interacting polymers ( eqs [ vs ] and [ varphis ] ) , at the same @xmath21 , @xmath60 and @xmath23@xcite . the structured profile at @xmath127 in figure [ rho1]b is for a thermodynamic state close to the fluid fluid binodal ( on the colloid poor vapour side " ) calculated from the same free energy model ( see ref @xcite ) giving further support to the possibility of a layering transition@xcite . the effect of the range of the depletion attraction is illustrated in figures [ rho2]a , b for interacting and ideal polymers respectively . the trend of the density profiles with increasing @xmath60 is opposite that observed with increasing @xmath125 . the adsorption at contact is now strongest for the smallest size ratio . this is essentially due to the fact that the wall colloid depletion potential at contact , @xmath128 , drops as the polymer density decreases . since @xmath129 , a small increase in the size ratio @xmath60 implies a big reduction in polymer density , and also in @xmath130 . calculations carried out at higher colloid packing fractions show that the effect of polymer induced wall colloid attraction on the density profiles is much reduced as @xmath124 increases , due to the predominance of purely excluded volume effects under high density conditions@xcite once the colloid density profiles have been calculated , the surface tension may be determined by substituting @xmath121 into eq [ omegagrand ] , and then applying relation [ gammap ] . some care has to be taken in treating the bulk zero and one body contribution @xmath28 and @xmath131 . these also contribute to the bulk properties ( calculated by letting @xmath121 go to the bulk value @xmath132 ) , and in particular to the colloid chemical potential @xmath105 and to the osmotic pressure of the mixture . thus , for the chemical potential of the bulk one obtains : @xmath133 where @xmath70 is already defined in eq [ omega012 ] . in a similar fashion , the total osmotic pressure is the sum of the colloid contribution @xmath134 ( calculated by differentiating the homogeneous limit of the intrinsic free energy [ fpdft ] with respect to @xmath132 ) and of the osmotic pressure of the polymer reservoir : @xmath135 hence , @xmath136}{a } -\mu_c^0\int dz \rho_c(z ) \ } + \frac{pv}{a } \nonumber\end{aligned}\ ] ] where @xmath137 $ ] is the colloid contribution to the inhomogeneous free energy , given by eq [ fpdft ] . substituting eqs [ mutot ] and [ ptot ] shows that the bulk contributions to @xmath28 and @xmath30 are exactly cancelled so that the final expression for the surface tension is given by : @xmath138 + \rho_c(z)[\varphi_c(z)-\mu_c(\rho_c^0)]+p_c\ } \nonumber\end{aligned}\ ] ] where @xmath139 is the intrinsic colloid free energy density [ fpdft ] . in other words , the surface tension may be written as the sum of a colloid contribution @xmath140 ( which would be obtained by ignoring @xmath28 and @xmath131 in eq [ omegagrand ] ) and of the contribution of the polymers under reservoir conditions : @xmath141 equation [ gammatot ] is exact within an effective one component representation of a mixture of colloids and polymers where @xmath25 in eq [ nterms ] is truncated at @xmath31 . for @xmath142 of interacting ( saw ) polymers , we use the results of ref @xcite . the resulting total surface tensions for the cases of ideal and interacting polymers are plotted as a function of the polymer reservoir packing fraction in figure [ gammaw9 ] , and compared to the predictions of the two component representation ( with ideal polymers ) , calculated within scaled particle theory@xcite , modified so as to account for the polymer wrapping " effect , according to the prescriptions of eq . [ qetap ] . the agreement between the surface tensions calculated within the effective one and two component representations is seen to be good for low densities and to deteriorate somewhat beyond . the surface tension with interacting polymers is substantially larger ( up to a factor of two at the highest polymer concentrations ) compared to the ideal polymer case . this is because the colloid wall surface tension is higher with interacting polymers , due to the weaker effective wall colloid attraction , and the wall polymer surface tension is also higher for interacting polymers@xcite . figure [ gammaw10 ] illustrates the variation of the surface tension with size ratio @xmath60 . for fixed values of @xmath124 and @xmath125 , the surface tension is seen to decrease rapidly as @xmath60 increases , and to tend to the result for hard spheres when @xmath143 . finally the variation of the surface tension with colloid packing fraction ( for fixed @xmath60 and @xmath125 ) is shown in figure [ gammaw11 ] . the agreement between the effective one and two component representations found at low packing fractions is seen to deteriorate rapidly as @xmath124 increases , thus illustrating the break down of the effective one component model for highly concentrated colloidal suspensions . the depletion potential per unit area induced by a colloid polymer mixture between two hard walls of area @xmath32 separated by @xmath144 is determined by : @xmath145 clearly , @xmath146 as @xmath147 , while @xmath148 , because when the walls come into contact two fluid wall interfaces are destroyed . for arbitrary @xmath144 , the colloid contribution @xmath149 to @xmath150 obtained by momentarily ignoring the bulk contributions @xmath28 and @xmath131 to the total grand potential , reads , by straightforward analogy with expression [ gammadft ] for the surface tension : @xmath151 } \nonumber \\ \ \ \ \ \ & + & \rho_c(z)[\varphi_c(z)-\mu_c(\rho_c^0)]+p_c\ } -2\gamma_{w , c}\end{aligned}\ ] ] figure [ wl1 ] shows the comparison of the depletion potentials @xmath152 calculated for a pure hard sphere depletant ( i.e.@xmath153 ) and for hard sphere colloids and ideal or interacting polymers , within the present effective one component representation . the extra attraction between the walls and colloidal particles forces the latter into the region between the two plates , enhancing the potential barrier of the depletion potential at @xmath154 . the effect is stronger for ideal than for interacting polymers , because effective wall colloid and colloid colloid attractive interactions are enhanced in going from interacting to ideal polymers . for @xmath155 the hard colloids are excluded from the space between the walls , and the depletion potential is entirely controlled by the external , unbalanced osmotic pressure which pushes the walls together , i.e. : @xmath156 to obtain the total depletion potential , the volume terms @xmath28 and @xmath131 must be included in the grand potential . it is easily verified that , within the truncation of @xmath25 at @xmath31 , i.e. ignoring colloid polymer and similar higher order terms , the depletion potential takes the form : @xmath157 where @xmath158 is the osmotic pressure of the polymers in the reservoir , @xmath159 is the corresponding wall polymer surface tension , and @xmath160 is the range of the polymer depletion potential , which takes the value @xmath161 for ao particles . the resulting total depletion potential for ideal polymers is shown in figure [ wl2 ] . it remains continuous at @xmath162 , but the resulting force is discontinuous at that separation . the basic input in the evaluation of surface tensions or depletion forces are the density profiles @xmath121 . in order to check the reliability of the profiles calculated within the present perturbation dft , we have carried out some grand canonical monte carlo ( gcmc ) simulations of profiles , using the same effective colloid colloid and colloid wall interactions as with dft . two typical examples of such a comparison are shown in figure [ sim5]a , b for a mixture of colloids and interacting polymers confined between two hard walls ( slit geometry ) . at the lower polymer concentrations , corresponding to relatively weak colloid colloid and wall colloid attraction , the agreement between dft and simulation is excellent ( figure [ sim5]a ) . at the higher polymer concentration ( figure [ sim5]b ) the attractive perturbation is much stronger and , as expected , the agreement worsens . nevertheless , the perturbation dft is still capable of reproducing the main features of the density profile . figure [ sim5]b also shows the result from the mean field dft , which amounts to neglecting correlations in @xmath163 $ ] ( cf . section [ wst ] ) . the disagreement with the simulated data is now much more severe ( see the inset in figure [ sim5]b ) , stressing the importance of properly including reference system correlations in eq [ psi1 ] . we finally turn to the fluid fluid interface at coexistence between colloid poor ( gas `` ) and colloid rich ( liquid '' ) phases . this is a free " interface , since translational symmetry is broken in the absence of any external potential , i.e. @xmath164 . an accurate and consistent determination of the phase boundary ( binodal ) in the @xmath124 ( colloid packing fraction)@xmath125 ( polymer reservoir packing fraction ) is required . the bulk free energy per unit volume , obtained from eqs [ fpdft][psi1 ] in the homogeneous ( @xmath165 ) limit reads : @xmath166 \\ & + & \frac{{(\rho_c^0)}^2}{2}\int d\vec{r}g_{hs}(r,\rho_c^0)\beta v(r ) . \nonumber \end{aligned}\ ] ] this free energy depends implicitly on the polymer concentration @xmath125 via the effective depletion pair potential @xmath167 , which is given by eq [ vao ] ( @xmath57 ) for ideal polymers and by eq [ vs ] ( @xmath168 ) for interacting polymers . for any fixed value of @xmath125 the colloid packing fractions of the coexisting phases may be determined by applying the standard maxwell double tangent construction to @xmath169 . the resulting binodals for ideal and interacting polymers ( not shown ) are very close to those calculated in ref @xcite , where an estimate of the second order perturbation correction to the free energy was included . the trends of the binodals are according to expectation . qualitatively , the behaviour for ideal and interacting polymers is similar , with critical points at higher @xmath125 as @xmath60 increases , but with considerably flatter " binodals for interacting polymers . there are , however , very significant quantitative differences , since the binodals for interacting polymers are shifted to considerably larger values of @xmath125 for each size ratio @xmath60 , i.e. polymer interactions enhance the miscibility of colloid polymer mixtures . this is easily understood , since the polymer induced depletion attraction between colloids is weaker ( for given @xmath60 and @xmath125 ) for interacting polymers . the colloid density profile at the fluid fluid interface is calculated by minimizing the grand potential ( eq [ omegagrand ] ) , with @xmath170 , which leads back to the expression [ rhorho0 ] ( again with @xmath170 ) . the profiles for ideal and interacting polymers are shown in figures [ ff_lou ] and [ ff_ao ] , under conditions close to the fluid fluid solid triple point , for a size ratio @xmath171 . the profiles are compared to earlier predictions based on a square gradient density functional ( sgt ) @xcite , using the same effective one component description . there are remarkable differences between the profiles corresponding to interacting and ideal polymers . the interface is much sharper in the latter case and exhibits striking oscillations on the high colloid density ( liquid " ) side @xcite . the profile obtained with interacting polymers varies more smoothly , and shows no sign of oscillations . this clear cut difference in behaviour may be partly understood by noting that the jump in colloid density between the two fluid phases is significantly smaller in the case of interacting polymers , for which the triple and critical points are much closer than for ideal polymers . figures [ ff_lou ] and [ ff_ao ] also show the result of our earlier square gradient calculations ( sgt ) @xcite . the corresponding profiles agree reasonably well with the results of the more elaborated density functional used in this paper ; as expected the square gradient functional can not account for the oscillatory structuring on the dense fluid side in figure [ ff_ao ] . in the case of interacting polymers ( figure [ ff_lou ] ) the width of the interface predicted by the present perturbation dft is significantly larger than that obtained from square gradient theory . the interfacial width @xmath172 is conventionally defined as the distance between the two points where the density profile @xmath121 reaches 90% and 10% of the difference between the bulk densities of the two coexisting phases . results for @xmath172 obtained within the perturbation dft are plotted in figure [ ff_w ] as a function of the deviation of the polymer reservoir packing fraction from its value at the critical point , @xmath173 , for ideal and interacting polymers and for three size ratios @xmath60 . as expected , the width increases with @xmath60 and increases sharply as @xmath174 decreases , i.e. upon approaching the critical point . although the widths @xmath172 for ideal and interacting polymers are rather close for given @xmath174 and @xmath60 , polymer interactions tend to reduce the width compared to the ideal case , as found in @xcite . the surface tension @xmath63 of the fluid fluid interface is given by a relation similar to eq [ gammadft ] , and it is easily verified that the bulk terms @xmath28 and @xmath131 in eq [ omegagrand ] do not contribute to @xmath63 . the relation reads : @xmath175 -\rho_c(z)\mu_c^0 + p_c\}\ ] ] where @xmath105 and @xmath176 are the common values of the colloid contribution to the chemical potential and of the pressure in the coexisting bulk phases . figure [ ff_gamma_ao ] compares results obtained from the perturbation and square gradient theories for ideal polymers , at three different size ratios ; @xmath63 is plotted versus the difference between the colloid packing fractions in the liquid `` and gas '' phases . the surface tensions are seen to increase with @xmath60 and @xmath177 . the agreement between the two theories is excellent for @xmath178 , and deteriorates for smaller size ratios . the surface tensions obtained from perturbation dft are systematically larger than their square gradient counterparts and closer to the results of the two component dft of ref @xcite . a comparison between the surface tensions calculated within perturbation dft for ideal and interacting polymers is finally made in figure [ ff_gamma ] . the surface tension is seen to be lowered when polymer interactions are included , a trend which is opposite to that observed for the wall surface tension @xmath179 ( cf . figure [ gammaw10 ] ) . a fluid - fluid interface also implies an inhomogeneous polymer density profile . for ideal polymers at constant @xmath22 this does not cost any additional free - energy , but this is not true for interacting polymers . for the latter depletant , this correction will raise the surface tension compared to the values we calculate within the one - component picture . on the other hand , for ideal polymers , the many - body interactions between the colloids , fully taken into account with the two - component formulation , also result in a larger surface tension . the effect of many - body interactions for interacting polymers is unknown . thus our prediction for the relative strength of the surface tensions should be tempered by the fact that the exact form of the neglected corrections is not know and awaits a full two - component treatment of interacting polymer - colloid mixtures . we have introduced a simple generic density functional description of colloid polymer mixtures within the effective one component picture where polymer degrees of freedom have been traced out . the free energy functional accounts correctly for the colloid excluded volume effects , and treats the polymer induced depletion attraction within first order perturbation theory . the dft formulation is very flexible and can be applied to confined colloid polymer mixtures as well as to the free interface between coexisting fluid phases . although this effective one component description accounts only for pair wise additive depletion interactions , and neglects more than two body effective interactions ( which are automatically included in an effective two component representation ) , the present theory has the advantage of being able to treat the cases of ideal as well as interacting polymers consistently , thus allowing a direct estimate of the effect of polymer interactions on the interfacial properties of colloid polymer mixtures . the present effective one component dft description can be tested against the more fundamental two component dft picture in the case of ideal polymers@xcite . reasonable agreement is found for size ratios up to @xmath180 , giving confidence in the predictions of the simpler one component representation for ideal and interacting polymers alike . the reduction to an effective one component representation leads to the appearance of zero and one body bulk contributions to the total grand potential of the mixture ( terms @xmath28 and @xmath131 in eq [ omegagrand ] ) , which make significant contributions to the wall surface tension @xmath179 and to the depletion interaction between two walls , and must not be overlooked . the key findings of the present investigation may be summarized as follows : * density profiles @xmath121 near a hard wall deviate considerably from pure hard sphere behaviour at low colloid packing fractions . significant differences between the behaviour observed for ideal and interacting polymers may be traced back to the weaker depletion attraction induced by the latter . * when the bulk terms @xmath28 and @xmath131 in the grand potential are properly taken into account , the wall surface tensions @xmath179 calculated with ideal polymers are in good agreement with a recent full two component treatment of the ao model@xcite , for @xmath181 and not too high colloid packing fraction @xmath182 . * the depletion potential induced by colloid polymer mixtures between two walls exhibits structure on both length scales @xmath18 and @xmath21 which opens the possibility of further flexibility in engineering " effective depletion forces . * in general , the wall surface tension @xmath179 induced by mixtures of colloids and interacting polymers is larger than that found for ideal polymers . this trend is opposite to that predicted for the fluid fluid interfacial tension . the present predictions agree at least qualitatively with the experimental data of ref @xcite , and may be understood in terms of the wall surface tension of the pure polymer component . * the present effective one component dft predicts an oscillatory density profile on the high colloid density side of the fluid fluid interface in the case of ideal polymers sufficiently close to the triple point ; this behaviour agrees with the earlier prediction based on the effective two component ( ao model ) representation@xcite . the oscillations are not observed in the case of interacting polymers , presumably due to the smoother variation ( larger width ) of the interfacial profile . * a direct comparison between the results of square gradient analysis@xcite and the present more sophisticated dft shows that the former is surprisingly accurate , even for rather sharp fluid fluid interfaces ( except , of course , as regards the oscillatory behaviour observed for ideal polymers ) . the good agreement validates the predictions of the simple square gradient theory concerning the effect of polymer polymer interactions on the fluid fluid interfacial properties@xcite . the present effective one component description predicts a number of significant differences between interfacial behaviour of mixtures of colloids and ideal versus interacting polymer coils . the corresponding two component representation involving ideal polymers ( i.e. the ao model ) is well established , and confirms many of the predictions of the present effective one component picture . future work should focus on developing a viable effective two component representation in the case of interacting polymers , in order to validate the present predictions based on the effective one component description . a. moncho jord thanks the ministerio de ciencia y tecnologa [ plan nacional de investigacin cientfica , desarrollo e innovacin tecnolgica ( i+d+i ) , project mat 200308356c0401 ] , j. dzubiella acknowledges the epsrc within the portfolio grant rg37352 , and a. a. louis thanks the royal society ( london ) , for financial support . part of this work was carried out while j. p. hansen was on leave at universit degli studi di roma la sapienza " , and support of infm is gratefully acknowledged . in order to model the hard sphere nature of the colloidal particles , we have used the white - bear version of the rosenfeld functional@xcite . this functional improves the one proposed by rosenfeld@xcite in that it leads to the mansoori et al . equation of state for a homogeneous mixture@xcite . the free energy density @xmath183 reads@xcite : @xmath184 where @xmath185 are weighted densities , obtained as convolutions of the colloid density @xmath103 and the weight functions @xmath186 ( see eq [ nj ] ) . the latter are given by : @xmath187 for the case of planar fluid fluid interfaces or infinite planar walls , the calculations simplify to a one - dimensional problem . then , the position dependent excess chemical potential @xmath188 , which can be obtained from the functional derivative of the excess part of our perturbation free energy functional ( eq [ mucex ] ) , depends only on @xmath39 , the distance to the wall ( or to the interface ) . its explicit form for @xmath189 is@xcite : @xmath190}{\partial n_j(z_2)}\frac{\delta n_j(z_2)}{\delta \rho_c(z_1)}dz_2 \\ & + & 2\pi \int_{z_1-r_m}^{z_1-r_m}dz_2\rho_c(z_2 ) \times \nonumber \\ & \times & \int_{|z_1-z_2|}^{r_m}dr_{12}r_{12}\beta v(r_{12})g_{hs}(r_{12},\bar{\rho}_c(z_1,z_2))+ \nonumber \\ & + & \frac{3\pi}{4r_\nu^3}\int_{z_1-r_m}^{z_1-r_m}dz_2\rho_c(z_2)\left [ r_{\nu}^2-(z_1-z_2)^2 \right]\times \nonumber \\ & \times & \int_{z_2-r_m}^{z_2-r_m}dz_3\rho_c(z_3 ) \times \nonumber \\ & \times & \int_{|z_2-z_3|}^{r_m}dr_{23}r_{23}\beta v(r_{12})\frac{\partial g_{hs}(r_{23},\bar{\rho}_c(z_2,z_3))}{\bar{\rho}_c } \nonumber\end{aligned}\ ] ] where @xmath191 is the corresponding colloid - colloid depletion potential , @xmath192 its range and @xmath193 for planar geometry , the weight functions are given by : @xmath194\theta(r_c-|z - z^{\ \prime}| ) \nonumber \\ \vec{\omega}^{(v1)}(z^{\ \prime}-z ) & = & \frac{1}{2r_c}(z - z^{\ \prime})\theta(r_c-|z - z^{\ \prime}|)\vec{k } \nonumber \\ \vec{\omega}^{(v2)}(z^{\ \prime}-z ) & = & 2\pi(z - z^{\ \prime})\theta(r_c-|z - z^{\ \prime}|)\vec{k } \nonumber\end{aligned}\ ] ] for a recent comparison between theoretical predictions and experimental data , see bolhuis , p. g. ; louis , a. a. ; hansen , j. p. _ phys . lett . _ * 2002 * , _ 89 _ , 128302 and ramakrishnan , s. ; fuchs , m. ; schweizer , k. s. ; zukoski , c. f. _ j. chem . phys . _ * 2002 * , _ 116 _ , 2201 .

interfacial properties of colloid polymer mixtures are examined within an effective one component representation , where the polymer degrees of freedom are traced out , leaving a fluid of colloidal particles interacting via polymer induced depletion forces . restriction is made to zero , one and two body effective potentials , and a free energy functional is used which treats colloid excluded volume correlations within rosenfeld s fundamental measure theory , and depletion induced attraction within first order perturbation theory . this functional allows a consistent treatment of both ideal and interacting polymers . the theory is applied to surface properties near a hard wall , to the depletion interaction between two walls , and to the fluid fluid interface of demixed colloid polymer mixtures . the results of the present theory compare well with predictions of a fully two component representation of mixtures of colloids and ideal polymers ( the asakura oosawa model ) , and allow a systematic investigation of the effects of polymer polymer interactions on interfacial properties . in particular , the wall surface tension is found to be significantly larger for interacting than for ideal polymers , while the opposite trend is predicted for the fluid fluid interfacial tension .

WARNING: This audio may not be reproduced. Mel Gibson made up to 30 “terrorizing” phone calls to his ex-lover, Oksana Grigorieva, on the same night she walked out on their volatile three-year relationship, she has told law enforcement investigators. Included in the barrage was eight profanity-laced voicemail messages the clearly irrational Lethal Weapon star left on Oksana’s answering machine at her home. PHOTOS: Celebrity Death Threats RadarOnline.com has exclusively obtained those tapes — which are more evidence in three separate law enforcement investigations. Listen to the blockbuster recordings below. The rantings are a twisted mix of more misogynistic insults and rage as Mel again ripped into the mother of his illegitimate child, at one stage labeling her “f*cking disloyal and f*cking weak” and “such a f*cking sl*t”. PHOTOS: Mel & Oksana’s First Hollywood Appearance In one tirade that lasted just over two minutes, Mel dropped a staggering 23 F-bombs. In another bizarre message, that lasted just 13 seconds, the words coming out of his mouth barely sounded like words. EXCLUSIVE PHOTOS: See The First Photos of Mel and Oksana In a Passionate Embrace On The Beach Oksana has told investigators, who are probing the Oscar-winning actor/director for domestic abuse, that she was “terrorized by a stream of harassing and threatening telephone calls” from Mel after she fled his Malibu mansion, on February 18 this year. “She estimated that from the time she arrived at the Sherman Oaks home, after she escaped from his house, that she received approximately 30 calls from 8pm to 6am,” said a source, familiar with the case. “Mel told her he wanted to keep her up all night.” PHOTOS: Oksana Through The Years As she attempted to care for the couple’s daughter Lucia, who was just three-months-old at the time, Oksana was unable to answer all the calls and allowed to go to her message-bank. “You have f*cked me up,” Mel said, in one message captured on her machine. He went on: “You have f*cked me up. You have f*cked me up. I did nothing but help you. But you f*cking shat on me like a low-life sl*t.” What Oksana recorded will provide investigators an insight into Mel’s state of mind. PHOTOS: Celebrity Racist Rants In another message, he taunted the mother-of-two: “Just making sure you’re awake, if you were trying to sleep. Because I am awake — and you deserve to be.” “Don’t ever sleep again,” he repeated, later. “Don’t sleep as long as I don’t sleep.” In the space of 17 minutes, from 2:29am to 2:46am, a seething and scorned Mel made five calls to Oksana. Seemingly paranoid, he also accused Oksana of wanting to destroy him and “see me die” because “subconsciously that is your whole f*cking aim,” as he claimed. WORLD EXCLUSIVE PHOTOS: Bruised & Battered Oksana Grigorieva After Brawl With Mel Gibson A furious Mel also warned how mean he could be — “have I testified the title mean yet” — and delivered the Russian singer/ pianist his assessment of her musical talents — “it’s ordinary… it’s NOT extraordinary”. He said bluntly, “I’d like to see you play a concert sometime. You make mistakes all over with live performances. You can’t do it. “Haven’t seen you not f*ck it up yet. It’s flawless, you understand. You have to be f*cking flawless. PHOTOS: Timothy Dalton Goes To See Oksana “You are not in that league. So give it up. Do what you’re good at. Whatever the f*ck that is. Oh, I know what that is. Deception!” The messages also provide a window into the events which led to the explosive end to their relationship. As RadarOnline.com revealed as part of our headline-making investigation, Oksana walked out on Mel after a tree-planting ceremony in honor of their daughter Lucia, who was three-months-old at the time. At the event, Mel and Oksana buried their daughter’s placenta in the backyard. PHOTOS: Oksana Shows Off Her Post Baby Body In one message, at 2:31am, Mel told Oksana she was “a sour faced bitch” at the ceremony, at which his one-time love supposedly smiled at a maintenance worker. “Do you think it was tricky to get that f*cking tree in the hole, the placenta and organize that sh*t?” Mel asked. “Do you know how much f*cking time and money went into that? “You were down there looking like a spoiled c*nt.” PHOTOS: Mel’s Ex Oksana Grigorieva Beefs Up Security The first voice message was left at 10:27pm and the last at 3:06am, RadarOnline.com has learned. Here’s how the sequence went down: February 18, 22:27pm MG: Arghhh. Arghhhhhh. Arghhhhh. Argh. Argh. I called. February 19, 12:40am MG: Edith is not to work at your house. If she does, I will fire her. I will not pay her for any hours at your house. OK? She only works at my house. Alright? I don’t want her at your house or I will fire her. You know I will do it. I fire people all the time. You will have to find some other f*cker but you will have to pay for it yourself. She works at my house. She is my employee. Just thought I would mention that right now. If you want to call me back, I think we should discuss the terms of separation, don’t you? Don’t you think? Yes? Yes, let’s do it. I won’t smoke either, just to f*ck with you. I want to really badly. You would love me to. Because you want to destroy me and see me die. I know subconsciously that is your whole f*cking aim, is to ruin me. But I won’t let you. Alright. You selfish bitch. Alright. February 19, 2.29am MG: Whore. Answer the f*cking phone. F*cking bitch. February 19, 2.31am MG: You were a sour faced bitch today. Do you think it was tricky to get that f*cking tree in the hole, the placenta and organize that sh*t? Do you know how much f*cking time and money went into that? Did you thank me? Did you even have a f*cking smile on your face? F*ck no. You were down there looking like a spoilt c*nt. You don’t give f*ck do you. You really a shallow bitch. Everything about you stinks and I am seeing it real, loud and clear. F*ck yeah. Fuck y*ah. February 19, 2.37am MG: Oh. Just making sure you’re awake, if you were trying to sleep. Because I am awake — and you deserve to be. Yeah. February 19, 2.39am MG: Have I testified the title mean yet? I think so. OK, I will stop being mean now. I will stop being mean because that’s me. You call mean, you will get mean. You call me something I’m not you will get it in spades. Remember that and I don’t give a f*ck if you ever call me again or not. February 19, 2.46am MG: See, you can see I am not available for use anymore, you can see the well has dried up and you just take off, you just leave, take off, because I am finished for you right? Because I can’t give anymore, right? To your personal cause. You. I can’t do it anymore. So you’re out of here from the sinking ship. That’s your MO, isn’t it baby? Hmmm? That’s your MO. I will believe that because it seems to be the truth. February 19, 3.06am MG: It is to me. F*cking disloyal and f*cking weak. You’re f*cking blind. F*cking thankless. Such a f*cking slut. F*ck you. F*ck you. Don’t ever sleep again. Don’t sleep as long as I don’t sleep. Don’t sleep. F*cking get sick. You f*ck me up. You have f*cked me up. You have f*cked me up. You have f*cked me up. I did nothing but help you. But you f*cking shat on me like a low-life sl*t. Which is now what I am convinced you are. F*ck I am angry at you. You are a waste of time. I am angry at you. What a waste of my f*cking time. F*ck you. You f*cking ordinary c*nt. You are just f*cking ordinary. That goes for the talent too — it’s ordinary. It’s NOT extraordinary. It’s pretty f*cking common. I’d like to see you play a concert sometime. You make mistakes all over with live performances. You can’t do it. So touring is out of the question for you because you will f*ck it up. You have not yet f*cked up yet live. Haven’t seen you not f*ck it up yet. It’s flawless, you understand. You have to be f*cking flawless. You don’t know how to do that. You are not in that league. So give it up. Do what you’re good at. Whatever the f*ck that is. Oh, I know what that is. Deception! Sheriff’s detectives have opened a criminal probe into Oksana’s claim that Mel punched her twice in the left temple and mouth as she held their infant daughter, Lucia, at his Malibu home on January 6. Mel’s camp has vehemently denied that the volatile actor ever hurt Oksana or little Lucia. The Department of Children and Family Services is also investigating while a judge, in another matter, oversees the former couple’s civil battle over custodial rights. RELATED: ALL OF THE MEL GIBSON TAPES MEL AUDIO TAPE #1: Mel’s Racist Rant MEL AUDIO TAPE #2: Mel Gibson Admits Hitting Oksana, Threatens To Kill Her MEL AUDIO TAPE #3: Another Mel Gibson Slur Caught On Tape In Crazed Rage MEL AUDIO TAPE #4: Out Of Control Mel Gibson Says He’ll Burn Down House After Demanding Sex MEL AUDIO TAPE #5: Mel Gibson Completely Loses It: ‘B*tch, C*nt, Wh*re, Gold Digger!’ MEL AUDIO TAPE #6: The Tape That Could Destroy Mel: “No One Will Believe You”, He Says After She Charges: “You Hit The Baby” MEL AUDIO TAPE #7: Mel Gibson’s Twisted Rant Includes Jealous Rage Over Timothy Dalton ||||| What's Behind Mel Gibson's Pathological Ranting? Email This As we hear more and more expletive-laden crazy-pants rants from Mel Gibson we have to wonder whether Mel has lost that little voice inside his head that tells him he has crossed a line, or whether he ever had that little voice in the first place. Maybe the answer is that he just can't help himself. Experts tell us that Mel's continued verbal diarrhea is pathological and deeply ceded in psychological issues. "Mel is driven by his sexual frustration, fear of abandonment, and disillusionment at the realization that Oksana doesn't love him, but is merely a gold-digger," explains psychiatrist Dr. Carole Lieberman, M.D. As we hear more and more expletive-laden crazy-pants rants from Mel Gibson we have to wonder whether Mel has lost that little voice inside his head that tells him he has crossed a line, or whether he ever had that little voice in the first place.Maybe the answer is that he just can't help himself.Experts tell us that Mel's continued verbal diarrhea is pathological and deeply ceded in psychological issues."Mel is driven by his sexual frustration, fear of abandonment, and disillusionment at the realization that Oksana doesn't love him, but is merely a gold-digger," explains psychiatrist Dr. Carole Lieberman, M.D. The latest Gibson recording released by Radar Online , has Gibson going after his baby mama Oksana Grigorieva's ex boyfriend, none other than James Bond, Timothy Dalton.In the new tape, mad Mel says: "Did you get my last message about me being a bad father, and Tim being a great dad now?"Oksana says "no" and Gibson continues, saying: "You didn't hear that one? Well, you should go and (expletive) him (Dalton), you know, you fickle (expletive), because I don't care."And that's the nice part of the conversation. After hearing seven of mad Mel's recordings, it really does seem like he has no control over what comes out of his mouth and that in some sick and twisted way, he's actually enjoying what he's doing."He seems to be getting some kind of gratification by talk, talk, talking," says life coach and relationship expert Tracey Steinberg . "It seems as though he has a lot of anger and resentment and he doesn't know how to express himself in a constructive and healthy way to people who want to help him. So instead he lashes out at the person who least wants to help him and the angry cycle continues.Steinberg's advice to Mel, to put an end to his viral venting: "He would be better off treating himself to a nice vacation with people who care about him."But psychology expert and "Cult of Celebrity" author Cooper Lawrence sees a darker side to Gibson's gabbing. Se believes he is fulfilling an acquired situational narcissism that has struck the star as he approaches the twilight of his career."No one is kissing his ass anymore. He's not a big star. The anger that comes with that causes his lashing out. This is no different than when Alec Baldwin called his daughter a little pig," Lawrence explains. "Mel can't shut up because he feels the need to constantly validate himself and he is doing that through his anger. These narcissists lash out impulsively and cant stop themselves. He is out of control. A sane person would have stopped before it reached this point." ||||| Click to email this to a friend (Opens in new window) Click to share on Pinterest (Opens in new window) Click to share on Tumblr (Opens in new window) Click to share on Google+ (Opens in new window) Click to share on Twitter (Opens in new window) Mel Gibson is viewed as an excellent father to his 8-month-old daughter Lucia by the Department of Children and Family Services, RadarOnline.com has learned exclusively. DCFS launched an investigation as Mel, 54, and Oksana Grigorieva, 40, trade allegations in their bitter breakup and the Oscar-winning star is accused of punching his ex while she held their daughter. PHOTOS: Mel Gibson’s Greatest Movie Roles But RadarOnline.com has learned that at this point Mel is in no danger of losing access to his daughter, and in fact is viewed as an excellent father who has a strong relationship with Lucia. “The Department of Children and Family Services believes Mel has a wonderful relationship with his infant daughter Lucia,” a source close to the actor told RadarOnline.com. DCFS visited Gibson at his home last week, as RadarOnline.com was first to report. PHOTOS: Mel Gibson & Oksana Grigorieva At Edge Of Darkness Premiere “They have a very healthy father-daughter relationship,” the source said. “He is very involved with her. “Mel is a great father to her and this is why there have been no changes as far as his visits with her are concerned.” It’s good news for Gibson, who is being investigated by the L A. County Sheriff’s Department on domestic violence charges. His ex has produced powerful evidence indicating he hit her on January 6. EXCLUSIVE PHOTOS: See The First Photos of Mel and Oksana In a Passionate Embrace On The Beach Oksana’s mouth was damaged and she suffered a concussion. RadarOnline.com exclusively published photographs of her damaged teeth and bruising on the left side of her head. RadarOnline.com confirmed that Gibson was interviewed by the Sheriff’s department on Sunday but refused to talk about the domestic violence case. His Fifth Amendment right against self incrimination helped his lawyer limit the scope of the interview. EXCLUSIVE PHOTO of Oksana After She Says Mel Punched Her The best news for Gibson so far is that DCFS believes Lucia is safe with him. “Mel has been lamenting that he made a mistake in ending his marriage to Robyn,” the source close to the actor told RadarOnline.com. “Robyn kept him together. As far as DCFS is concerned Mel is an outstanding father. Lucia is safe emotionally and physically with Mel, and that is the only concern for officials.” PHOTOS: Mel & Ex-Wife Robyn Despite some media reports that it was Gibson’s idea to have a volunteer monitor his visitation with Lucia, RadarOnline.com has learned it was the DCFS’s suggestion. “The idea was actually from the social workers as a way to try and help the situation,” the source close to Mel said. “There is such heightened tension surrounding the care of Lucia that if she had an accident… now there will be an independent witness to alleviate any potential issues.” EXCLUSIVE VIDEO: Mel & Oksana Talk To Radar In Happier Times DCFS will continue to monitor the ongoing custody battle, RadarOnline.com has learned. The agency will conduct more interviews with people connected to caring for Lucia. ||||| Mel and Oksana -- The Placenta Factor TMZ has learned that on the day Oksana Grigorieva recorded Mel Gibson 's infamous rant, the two had engaged in a special ceremony that included their daughter's... and a tree.Hours before Mel lost his cool on the phone on February 18, he and Oksana were in the backyard of his Malibu mansion ... watching as a gardener planted a Santa Lucia fir tree in honor of their daughter Lucia.But that's not all that went in the ground that day -- sources close to Oksana tell us the couple also buried the placenta from the birth of their then 3-month-old daughter... a tradition in some parts of Australia ... where Mel grew up.We're told Mel did this placenta ceremony for all of his children.The source also says during the ceremony the gardener made an innocent comment and Oksana smiled at him. We're told that's what set Mel off.As we first reported, Mel then accused Oksana of having an affair with the gardener ... and that's when all hell broke loose. ||||| These are the shocking photos that provide powerful evidence against Mel Gibson. Oksana Grigorieva had deep bruises around her left eye after she claims Mel Gibson punched her in the head twice – and RadarOnline.com has exclusively obtained the blockbuster photographs of her injuries. EXCLUSIVE PHOTOS: Bruised & Battered Oksana These pictures are crucial evidence in the investigation against Gibson on domestic violence charges and provide strong support for Oksana’s accusations that Mel punched her as they argued at his home on January 6. Oksana told authorities she was holding her baby Lucia when Mel struck her in the mouth and the head, near the left temple. RadarOnline.com has learned that the photographs were taken the morning after the brutal confrontation. They show obvious bruising around Oksana’s left eye and also redness. The bruising extends from below Oksana’s left eye to her forehead. The area around her left eye appears to be swollen. These never-before-seen pictures are key components of three separate investigations, RadarOnline.com has confirmed. PHOTOS: Oksana Through The Years RadarOnline.com exclusively obtained the evidence photos which are the second set of photos taken to document Oksana’s injuries in the aftermath of the brutal January 6 brawl at Mel’s Malibu mansion. They form powerful evidence for Oksana’s allegations, especially when coupled with photographs she took of her damaged mouth. Oksana also has photographs of her damaged mouth. Those pictures were taken a day before these new ones and it is clear from the documentation that the bruising and swelling around her eye has become pronounced overnight, which is consistent with this type of injury. The veneer from Oksana’s upper left front tooth was snapped off and the veneer on her upper right tooth was cracked. Dental experts agree that only tremendous force could cause that type of damage. PHOTOS: Celebrity Racist Rants Mel denies hitting Oksana and his lawyers have told cops she tried to extort him. But these new photos provide Oksana with more powerful evidence against the man she dated for three years, especially when coupled with text messages and audio tapes, as revealed on RadarOnline.com. In addition, Oksana, 40, also has a strong affidavit from her dentist about the extent of her injuries. And, as RadarOnline.com reported exclusively, Oksana was diagnosed with a concussion after visiting Dr. Arthur Gordon, who could now be a powerful witness for her. The Los Angeles County Sheriff’s Department has these images as part of its investigation into the actor for domestic violence. PHOTOS: Celebrity Death Threats It was also included in Oksana’s declaration to the court in the estranged couple’s vicious custody battle over their eight-month-old daughter Lucia — and was also presented to the Department of Children and Family Services, RadarOnline.com has learned exclusively. PHOTOS: Mel & Oksana’s First Hollywood Appearance Oksana has told police that after Mel punched her she fell back on the bed, while holding their baby. She says he then choked her with his forearm, pressing it into her throat and putting his free hand over her mouth. EXCLUSIVE PHOTOS: See The First Photos of Mel and Oksana In a Passionate Embrace On The Beach As RadarOnline.com revealed, two days after the brawl, Oksana told a doctor she started experiencing excruciating headaches after the incident. When questioned why she did not seek immediate medical treatment, RadarOnline.com has learned Oksana told authorities: “I was unable to go a hospital that night because I had no one to care for the children.” PHOTOS: Mel & Oksana At Pre-Oscar Bash RELATED: ALL OF THE MEL GIBSON TAPES MEL AUDIO TAPE #1: Mel’s Racist Rant MEL AUDIO TAPE #2: Mel Gibson Admits Hitting Oksana, Threatens To Kill Her MEL AUDIO TAPE #3: Another Mel Gibson Slur Caught On Tape In Crazed Rage MEL AUDIO TAPE #4: Out Of Control Mel Gibson Says He’ll Burn Down House After Demanding Sex MEL AUDIO TAPE #5: Mel Gibson Completely Loses It: ‘B*tch, C*nt, Wh*re, Gold Digger!’ MEL AUDIO TAPE #6: The Tape That Could Destroy Mel: “No One Will Believe You”, He Says After She Charges: “You Hit The Baby”

– Just hours before going off on that taped rant that's emblazoned in our minds, Mel Gibson and Oksana Grigorieva had been enjoying a peaceful ceremony together…planting their daughter’s placenta. It’s an Australian tradition, TMZ reports, and all was well until Grigorieva smiled at the gardener, causing Gibson to flip out and accuse her of having an affair with him. “Do you think it was tricky to get that f*cking tree in the hole, the placenta and organize that sh*t?” Mel said later in one of 30 phone calls he made to Oksana after she walked out, Radar reports. The rest of his phone calls, including eight voicemails, are more of the same: He calls her “such a f*cking sl*t” and the like. In one two-minute message, he dropped 23 F-bombs. Despite the scary rants, Child Protective Services has reportedly deemed Gibson an excellent father, a source tells Radar. The gossip site also has photos it claims are of Grigorieva after Gibson allegedly beat her. Oh, and click here to read about the psychological issues that may be fueling Mel’s rage.

the velocity - density relation is one of the most important characteristics for the transport properties of any traffic system . for pedestrian traffic there is currently no consensus even about the principle shape of this relation which is reflected e.g. in conflicting recommendations in various handbooks and guidelines @xcite . discrepancies occur in particular in the high - density regime which is also the most relevant for applications in safety analysis like evacuations or mass events . at high densities stop - and - go waves occur indicating overcrowding and potentially initiating dangerous situations due to stumbling etc . however , the densities where the flow breaks down due to congestion ranges from densities of @xmath0 m@xmath1 to @xmath2 m@xmath1 @xcite . this large variation in values for @xmath3 reported in the literature is partly due to insufficient methods of data capturing and data analysis . in previous experimental studies , different kinds of measurement methods are used and often a mixture of time and space averages are realized . especially in the case of spatial and temporal inhomogeneities the choice of the measurement method and the type of averaging have a substantial influence on the results @xcite . up to now , congested states in pedestrian dynamics have not been analyzed in much detail . this is in contrast to vehicular traffic where the congested phase is well - investigated , both empirically and theoretically @xcite . in this contribution we show that even improved classical measurement methods using high precision trajectories but basing on mean values of density and velocity fail to resolve important characteristics of congested states . for a thorough analysis of pedestrian congestion we apply a new method enabling measurements on the scale of single pedestrians . for our investigation we use data from experiments performed in 2006 in the wardroom of bergische kaserne dsseldorf with a test group of up to @xmath4 soldiers . the length of the circular system was about 26 m , with a @xmath5 m long measurement section . detailed information about the experimental setup and data capturing providing trajectories of high accuracy ( @xmath6 m ) is given in @xcite . and @xmath7 ( left to right , top to bottom ) . with increasing density the occurrence of stop - and - go waves accumulate.,title="fig:",scaledwidth=45.0% ] and @xmath7 ( left to right , top to bottom ) . with increasing density the occurrence of stop - and - go waves accumulate.,title="fig:",scaledwidth=45.0% ] and @xmath7 ( left to right , top to bottom ) . with increasing density the occurrence of stop - and - go waves accumulate.,title="fig:",scaledwidth=45.0% ] and @xmath7 ( left to right , top to bottom ) . with increasing density the occurrence of stop - and - go waves accumulate.,title="fig:",scaledwidth=45.0% ] in fig . [ fig : traj ] the @xmath8-component of trajectories is plotted against time . for the extraction of the trajectories , the pedestrians heads were marked and tracked . backward movement leading to negative velocities is caused by head movement of the pedestrians during a standstill . inhomogeneities in the trajectories increase with increasing density . as in vehicular traffic , jam waves propagating opposite to the movement direction ( upstream ) occur at higher densities . stopping is first observed during the runs with @xmath9 pedestrians , at @xmath7 pedestrians they can hardly move forward . macroscopically one observes separation into a stopping area and an area where pedestrians walk slowly . in the following we analyze how macroscopic measurements blur this phase separation and apply a technique introduced in @xcite enabling a measurement of the fundamental diagram on a ` microscopic ' scale . speed @xmath10 of pedestrian @xmath11 and the associated density @xmath12 are calculated using the entrance and exit times @xmath13 and @xmath14 into and out of a measurement section of length @xmath15 m , @xmath16 ) occur only at large densities where no moving states ( @xmath17 ) are observable.,scaledwidth=46.0% ] the speed @xmath10 is a mean value over the space - time interval @xmath18 and @xmath19 . by integration over the instantaneous density @xmath20 the density is assigned to the same space - time interval . to reduce the fluctuations of @xmath20 we use the quantity @xmath21 , introduced in @xcite , which measures the fraction of space between pedestrians @xmath11 and @xmath22 that is inside the measurement area . results of the macroscopic measurement method are shown in fig . [ fig : fdmacro ] . in comparison to method b introduced in @xcite ( see fig . 6 of @xcite which uses data based on the same trajectories as this study ) the scatter of the data is reduced due to an improved density definition and a better assignment of density and velocity . however the resulting velocity - density relation does not allow to identify phase - separated states although these are clearly visible in the trajectories . to identify phase separated states we determine the velocity - density relation on the scale of single pedestrians . this can be achieved by the voronoi density method @xcite . in one dimension a voronoi cell is bounded by the midpoints @xmath23 of the pedestrian positions @xmath24 and @xmath25 . with the length @xmath26 of the voronoi cell corresponding to pedestrian @xmath11 and @xmath27 s we define the instantaneous velocity and density by @xmath28 m@xmath29 both stopping and moving states are observable . * right : * probability distribution of the velocities for different density intervals . the double peak structure indicates the coexistence of moving and stopping states . the height of the stopping peak increases with increasing density.,title="fig:",scaledwidth=48.0% ] m@xmath29 both stopping and moving states are observable . * right : * probability distribution of the velocities for different density intervals . the double peak structure indicates the coexistence of moving and stopping states . the height of the stopping peak increases with increasing density.,title="fig:",scaledwidth=48.0% ] the fundamental diagram based on the voronoi method is shown on the left side of fig . [ fig : fdmicro ] . regular stops occur at densities higher than 1.5 m@xmath29 . on the right side of fig . [ fig : fdmicro ] the distribution of the velocities for fixed densities from 1.8 m@xmath29 to 2.6 m@xmath29 are shown . there is a continuous change from a single peak near @xmath30 m/s , to two peaks , to a single peak near @xmath31 m/s . the right peak represents the moving phase , whereas the left peak represents the stopping phase . at densities around 2.2 m@xmath29 these peaks coexist , indicating phase separation into a flowing and a jammed phase . in highway traffic , phase separation into moving and stopping phases typically occurs when the outflow from a jam is reduced compared to maximal possible flow in the system . related phenomena are hysteresis and a non - unique fundamental diagram . at intermediate densities two different flow values can be realized . the larger flow , corresponding to a homogeneous state , is metastable and breaks down due to fluctuations or perturbations ( capacity drop ) . the origin of the reduced jam outflow is usually ascribed to the so - called slow - to - start behaviour ( see @xcite and references therein ) , i.e. an delayed acceleration of stopped vehicles due to the loss of attention of the drivers etc . the structure of the phase - separated states in vehicular traffic is different from the ones observed here . for vehicle traffic the stopping phase corresponds to a jam of maximal density whereas in the moving phase the flow corresponds to the maximal _ stable _ flow , i.e. all vehicles in the moving phase move at their desired speed . this scenario is density - independent as increasing the global density will only increase the length of the stopping region without reducing the average velocity in the free flow regime . the probability distribution of the velocities ( in a periodic system ) shows a similar behaviour to that observed in fig . [ fig : fdmicro ] . the position of the free flow peak in the case of vehicular traffic is independent of the density . the behaviour observed here for pedestrian dynamics differs slightly from that described above . the main difference concerns the properties of the moving regime . here the observed average velocities are much smaller than the free walking speeds . therefore the two regimes observed in the phase separated state are better characterized as stopping " and slow moving " regimes . further empirical studies are necessary to clarify the origin of these differences . one possible reason are the different acceleration properties of vehicles and pedestrians as well as anticipation effects . it also remains to be seen whether in pedestrian systems phenomena like hysteresis can be observed . in this section we introduce the adaptive velocity model , which is based on an event driven approach @xcite . a pedestrian can be in different states which determine the velocity . a change between these states is called _ event_. the model was derived from force - based models , where the dynamics of pedestrians are given by the following system of coupled differential equations @xmath32 where @xmath33 is the force acting on pedestrian @xmath11 . the mass is denoted by @xmath34 , the velocity by @xmath10 and the current position by @xmath24 . @xmath33 is split into a repulsive force @xmath35 and a driving force @xmath36 . the dynamics is regulated by the interrelation between driving and repulsive forces . in our approach the role of repulsive forces are replaced by events . the driving force is defined as @xmath37 where @xmath38 is the desired speed of a pedestrian and @xmath39 the relaxation time of the velocity . by solving the differential equation @xmath40 the velocity function is obtained . this is shown in fig . [ fig : paramodell ] together with the parameters governing the pedestrians movement . , the step length @xmath41 and the safety distance @xmath42 . * right : * the adaptive velocity : acceleration until @xmath43 than deceleration until @xmath44 , again acceleration until @xmath45 and so on.,title="fig:",height=170 ] , the step length @xmath41 and the safety distance @xmath42 . * right : * the adaptive velocity : acceleration until @xmath43 than deceleration until @xmath44 , again acceleration until @xmath45 and so on.,title="fig:",height=170 ] in this model pedestrians are treated as bodies with diameter @xmath46 @xcite . the diameter depends linearly on the current velocity and is equal to the step length @xmath41 in addition to the safety distance @xmath42 step length and safety distance are introduced to define the rules for the dynamics of the system . we determine the model parameters from empirical data which allows to judge the adequacy of the rules . based on @xcite the step length is a linear function of the current velocity with following parameters : @xmath48 \ ; v_i(t).\ ] ] the required quantities for the safety distance can be specified through empirical data of the fundamental diagram @xmath49 , see @xcite . with these experimental results the previous equations can be summarized to @xmath50 with @xmath51 m and @xmath52 s. no free model parameter remain with these specifications . in the following we describe the rules for the movement . a pedestrian accelerates to the desired velocity @xmath38 until the distance @xmath53 to the pedestrian in front is smaller than the safety distance . from this time on , he / she decelerates until the distance is larger than the safety distance . to guarantee a minimal volume exclusion , case `` collision '' is included , in which the pedestrians are too close to each other and have to stop . via @xmath53 , @xmath54 and @xmath55 the velocity function for the states deceleration ( dec . ) , acceleration ( acc . ) and collision ( coll . ) can be defined , see eq . [ eq : vel ] : @xmath56 where @xmath57 is the distance between the centers of both pedestrians . the current velocity @xmath58 of an pedestrian @xmath11 depends on his / her state . @xmath59 denominates the point in time where a change from acceleration to deceleration takes place . conversely @xmath60 is the change from deceleration to acceleration . @xmath61 and @xmath62 are defined accordingly . at the beginning @xmath63 s with a change from acceleration to deceleration a new calculation of @xmath64 is necessary : @xmath65 the discreteness of the time step could lead to configurations where overlapping occurs . to ensure good computational performance for high densities , no events are explicitly calculated . instead in each time step , it is checked whether an event has taken place and @xmath59 , @xmath60 or @xmath66 are set to @xmath67 accordingly . to avoid too large interpenetration of pedestrians and to implement a reaction time in a realistic size we choose @xmath68 s. to guarantee a parallel update a recursive procedure is necessary : each person is advanced one time step according to eq . [ eq : vel ] . if after this step a pedestrian is in a different state because of the new distance to the pedestrian in front , the velocity is set according to this state . then the state of the next following person is reexamined . if the state is still valid the update is completed . otherwise , the velocity is calculated again . in the following we face model results with experimental data and study how the distribution of individual parameter influences the phase separation . for all simulations the desired velocity is normal distributed @xmath69 with average @xmath70 m / s and variance @xmath71 . [ fig : simohne ] and fig . [ fig : simmit ] show the simulation results for two different choices of parameter distributions . , @xmath72 and @xmath73 for all pedestrians * left : * comparison of fundamental diagrams of modeled and empirical data . * middle : * trajectories for @xmath74 ( model ) . * right : * trajectories for @xmath4 ( model).,title="fig:",scaledwidth=32.0% ] , @xmath72 and @xmath73 for all pedestrians * left : * comparison of fundamental diagrams of modeled and empirical data . * middle : * trajectories for @xmath74 ( model ) . * right : * trajectories for @xmath4 ( model).,title="fig:",scaledwidth=32.0% ] , @xmath72 and @xmath73 for all pedestrians * left : * comparison of fundamental diagrams of modeled and empirical data . * middle : * trajectories for @xmath74 ( model ) . * right : * trajectories for @xmath4 ( model).,title="fig:",scaledwidth=32.0% ] ( model ) . * right : * trajectories for @xmath4 ( model).,title="fig:",scaledwidth=32.0% ] ( model ) . * right : * trajectories for @xmath4 ( model).,title="fig:",scaledwidth=32.0% ] ( model ) . * right : * trajectories for @xmath4 ( model).,title="fig:",scaledwidth=32.0% ] the model yields the right macroscopic relation between velocity and density even if @xmath75 and @xmath73 are the same for all pedestrians , see fig . [ fig : simohne ] ( left ) . the trajectories display that phase separation does not appear . even at high densities the movement is ordered and no stops occur . for further simulations we incorporate a certain disorder by choosing the following individual parameter normal distributed : @xmath76 , @xmath77 and @xmath78 . variation of the personal parameters affects the scatter of the fundamental diagram , see fig . [ fig : simmit ] , left . phase separation appears in the modeled trajectories as in the experiment , see fig . [ fig : simmit ] middle and right . it is clearly visible that long stop phases occur by introducing distributed individual parameters . then the pattern as well as the change of the pattern from @xmath79 to @xmath80 are in good agreement with the experimental results , see fig . [ fig : traj ] . even the phase separated regimes match qualitatively . however , the regimes appear more regular in the modeled trajectories . in fig . [ fig : fdmicmod ] microscopic measurements of fundamental diagram and the related velocity distributions are shown . separation of phases is reproduced well . but the position of the peak attributed to the moving phase is not in conformance with the experimental data , compare fig . [ fig : fdmicro ] ( right ) . the experimental data show that the peak position is independent from the density at @xmath81 around @xmath82 m / s . at the model data the position of the peak changes with increasing density . measurements with different time steps show that the size of the time step influences the length and shape of the stop phase at high densities . but the density where first stops occur seems independent from the size of the time step . further model analysis is necessary to study the role of the reaction time implemented by discrete time steps in this special type of update . furthermore we will study how the change of the peak could be influenced by including a distribution for the step length and other variations of the distribution for the safety distance . at fixed densities.,title="fig:",scaledwidth=48.0% ] at fixed densities.,title="fig:",scaledwidth=48.0% ] we have investigated the congested regime of pedestrian traffic using high - quality empirical data based on individual trajectories . strong evidence for phase separation into standing and slow moving regimes is found . the corresponding velocity distributions show a typical two - peak structure . the structure of the trajectories is well reproduced by an adaptive velocity model which is a variant of force - based models in continuous space . future studies should clarify the origin of the differences to the phase separated states observed in vehicular traffic . here phase separation into a stopping and a moving phase occurs such that the average velocity in the moving regime is independent of the total density . schadschneider , a. , klingsch , w. , klpfel , h. , kretz , t. , rogsch , c. , seyfried , a. : evacuation dynamics : empirical results , modeling and applications , in : meyers r. a. ( ed . ) , encyclopedia of complexity and system science , pp . 3142 - 3176 . springer ( 2009 ) seyfried , a. , boltes , m. , khler , j. , klingsch , w. , portz , a. , schadschneider a. , steffen , b. , winkens , a. : enhanced empirical data for the fundamental diagram and the flow through bottlenecks . in : klingsch , , rogsch , c. , schadschneider , a. and m. schreckenberg ( eds . ) , pedestrian and evacuation dynamics 2008 , pp . 145 - 156 , springer ( 2010 ) boltes , m. , seyfried , a. , steffen , b. and schadschneider , a. : automatic extraction of pedestrian trajectories from video recordings . in : klingsch , , rogsch c. , schadschneider a. and m. schreckenberg ( eds . ) , pedestrian and evacuation dynamics 2008 , pp . 43 - 54 , springer ( 2010 )

experimental results for congested pedestrian traffic are presented . for data analysis we apply a method providing measurements on an individual scale . the resulting velocity - density relation shows a coexistence of moving and stopping states revealing the complex structure of pedestrian fundamental diagrams and supporting new insights into the characteristics of pedestrian congestions . furthermore we introduce a model similar to event driven approaches . the velocity - density relation as well as the phase separation is reproduced . variation of the parameter distribution indicates that the diversity of pedestrians is crucial for phase separation . dynamics , velocity - density relation

the institutional review board approved the research , and the patients provided informed consent ( irb - rok - mnd-2014-kmmrp-019 ) . all patients underwent a complete ophthalmic examination including visual acuity , iop , refraction , slit lamp biomicroscopy , and fundus examination . in the non - surgical group , subjects with non - refractive ocular abnormalities , including ocular or systemic diseases that may affect the cornea , and those with a history of ocular surgery or trauma were excluded . in the post - prk group , 108 participants who had undergone advanced surface ablation prk to correct myopia at least 6 months before enrollment were enrolled . subjects with any ocular pathology such as keratectasia , cataract , and glaucoma and those with any post - surgical complications were excluded . measurements were randomly performed by tono - pachymetry ( tx-20p ; canon , tokyo , japan ) , us pachymetry ( us-4000 ; nidek , gamagori , japan ) , or gat ( at-900 ; haag - streit , bern , switzerland ) . all measurements were made on both eyes of the participants ; however , only one eye of each participant was randomly selected for analyses . for each individual , all measurements were performed within a 10-minute period by a single experienced examiner . measurement using tono - pachymetry was conducted with the patient seated using a chin rest and head rest . the cct - corrected iop was calculated automatically using the following compensation formula : corrected iop = measured iop + ( 550 cct ) 0.040 assessment of cct using us pachymetry was made after corneal anesthesia with topical application of 0.5% proparacaine with the patient in the sitting position . briefly , the cornea was anesthetized with a topical preparation of 0.5% proparacaine , and the tear film was stained with a fluorescein strip . with the cornea and biprism illuminated by a cobalt blue light from the slit lamp , the biprism is brought into gentle contact with the apex of the cornea . the fluorescent semicircles were viewed through the biprism , and the force against the cornea was adjusted until the inner edges overlapped . calibration error testing was performed for every 10 consecutive measurements , as recommended by the manufacturer using the standard calibration error check weight bar . the corrected iop that corresponded to measurements by us pachymetry and gat was calculated with the aforementioned formula . repeatability of cct measurement with each instrument was established by the intraclass correlation coefficient ( icc ) and the coefficient of variation ( cov ) . differences in cct , iop , and corrected iop measurements between instruments were evaluated by the paired sample t - test . additionally , correlation analysis was conducted between the refractive error and the differences in corrected iop between the two devices . one hundred eight eyes of 108 healthy participants and 108 eyes of 108 post - prk subjects were evaluated . the mean age was 22.38 3.23 years in non - surgical eyes and 25.12 3.75 years in post - prk eyes . the sex ratio ( male / female ) was 2.63 in non - surgical eyes and 1.92 in post - prk eyes . the average spherical equivalent refractive error was 2.34 2.64 diopter in non - surgical eyes and 0.07 0.36 diopter in post - prk eyes . tono - pachymetry yielded an icc of 0.984 ( 95% confidence interval [ ci ] , 0.9810.987 ) and a cov of 0.69% in non - surgical eyes ; an icc of 0.981 ( 95% ci , 0.9750.987 ) and a cov of 0.70% in post - prk eyes . us pachymetry yielded an icc of 0.976 ( 95% ci , 0.9710.981 ) and a cov of 0.71% in non - surgical eyes ; an icc of 0.967 ( 95% ci , 0.9570.977 ) and a cov of 0.73% in post - prk eyes . both devices demonstrated an icc > 0.9 , which is sufficient to ensure reasonable validity . tono - pachymetry yielded slightly higher icc and lower cov values compared to us pachymetry , which indicated a higher degree of repeatability ( table 1 ) . tono - pachymetry yielded an icc of 0.967 ( 95% ci , 0.9390.984 ) and a cov of 2.84 % in non - surgical eyes ; an icc of 0.972 ( 95% ci , 0.9570.987 ) and a cov of 2.33% in post - prk eyes . gat yielded an icc of 0.943 ( 95% ci , 0.8890.973 ) and a cov of 4.78% in non - surgical eyes ; an icc of 0.949 ( 95% ci , 0.9140.974 ) and a cov of 4.25% in post - prk eyes . tono - pachymetry yielded a slightly higher icc and lower cov values compared to gat , which indicated a higher degree of repeatability ( table 2 ) . the average cct measurement by tono - pachymetry and us pachymetry was 549.40 31.10 m and 542.05 35.58 m in non - surgical eyes , respectively , and 495.73 46.03 m and 477.96 48.77 m in post - prk eyes . tono - pachymetry yielded cct measurements that were greater by 7.35 11.37 m in non - surgical eyes ( p < 0.001 ) ( fig . 1a ) , and by 17.76 12.09 m in post - prk eyes ( p < 0.001 ) ( fig . the mean iop measurement by tono - pachymetry and gat was 17.24 2.89 mmhg and 17.27 2.83 mmhg in non - surgical eyes , respectively , and 15.12 2.77 mmhg and 15.24 2.79 mmhg in post - prk eyes . the differences were not significant by the paired t - test ( table 3 ) . in bland - altman plot , iop obtained by tono - pachymetry and us pachymetry showed close agreement , with the mean difference centered around zero , and 95% of the points were accurately located between the predicted 95% limits of agreement in both non - surgical eyes ( fig . the parameters of slope and intercept of the regression equation in both non - surgical eyes and post - prk eyes were not significant . the average corrected iop value obtained by tono - pachymetry and calculated from measurements by us pachymetry and gat was 17.26 3.37 mmhg and 17.59 3.43 mmhg in non - surgical eyes and 17.37 3.79 mmhg and 17.93 3.76 mmhg in post - prk eyes , respectively . the mean difference was 0.33 0.87 mmhg in non - surgical eyes ( p < 0.001 ) and 0.57 1.08 mmhg in post - prk eyes ( p < 0.001 ) . differences were significant by the paired t - test ( table 3 ) . in the bland - altman plot , corrected iop obtained by tono - pachymetry and us pachymetry - gat showed close agreement , with the mean difference centered around zero , and 95% of the points were accurately located between the predicted 95% limits of agreement in both non - surgical eyes ( fig . the parameters of slope and intercept of the regression equation in both non - surgical eyes and post - prk eyes were not significant . in correlation analyses , there were no significant correlations between spherical equivalent refractive error and differences in corrected iop between the two devices in either non - surgical eyes ( p = 0.983 ) or post - prk eyes ( p = 0.875 ) ( fig . 4a and 4b ) . tono - pachymetry yielded an icc of 0.984 ( 95% confidence interval [ ci ] , 0.9810.987 ) and a cov of 0.69% in non - surgical eyes ; an icc of 0.981 ( 95% ci , 0.9750.987 ) and a cov of 0.70% in post - prk eyes . us pachymetry yielded an icc of 0.976 ( 95% ci , 0.9710.981 ) and a cov of 0.71% in non - surgical eyes ; an icc of 0.967 ( 95% ci , 0.9570.977 ) and a cov of 0.73% in post - prk eyes . both devices demonstrated an icc > 0.9 , which is sufficient to ensure reasonable validity . tono - pachymetry yielded slightly higher icc and lower cov values compared to us pachymetry , which indicated a higher degree of repeatability ( table 1 ) . tono - pachymetry yielded an icc of 0.967 ( 95% ci , 0.9390.984 ) and a cov of 2.84 % in non - surgical eyes ; an icc of 0.972 ( 95% ci , 0.9570.987 ) and a cov of 2.33% in post - prk eyes . gat yielded an icc of 0.943 ( 95% ci , 0.8890.973 ) and a cov of 4.78% in non - surgical eyes ; an icc of 0.949 ( 95% ci , 0.9140.974 ) and a cov of 4.25% in post - prk eyes . tono - pachymetry yielded a slightly higher icc and lower cov values compared to gat , which indicated a higher degree of repeatability ( table 2 ) . the average cct measurement by tono - pachymetry and us pachymetry was 549.40 31.10 m and 542.05 35.58 m in non - surgical eyes , respectively , and 495.73 46.03 m and 477.96 48.77 m in post - prk eyes . tono - pachymetry yielded cct measurements that were greater by 7.35 11.37 m in non - surgical eyes ( p < 0.001 ) ( fig . 1a ) , and by 17.76 12.09 m in post - prk eyes ( p < 0.001 ) ( fig . the mean iop measurement by tono - pachymetry and gat was 17.24 2.89 mmhg and 17.27 2.83 mmhg in non - surgical eyes , respectively , and 15.12 2.77 mmhg and 15.24 2.79 mmhg in post - prk eyes . the differences were not significant by the paired t - test ( table 3 ) . in bland - altman plot , iop obtained by tono - pachymetry and us pachymetry showed close agreement , with the mean difference centered around zero , and 95% of the points were accurately located between the predicted 95% limits of agreement in both non - surgical eyes ( fig . the parameters of slope and intercept of the regression equation in both non - surgical eyes and post - prk eyes were not significant . the average corrected iop value obtained by tono - pachymetry and calculated from measurements by us pachymetry and gat was 17.26 3.37 mmhg and 17.59 3.43 mmhg in non - surgical eyes and 17.37 3.79 mmhg and 17.93 3.76 mmhg in post - prk eyes , respectively . the mean difference was 0.33 0.87 mmhg in non - surgical eyes ( p < 0.001 ) and 0.57 1.08 mmhg in post - prk eyes ( p < 0.001 ) . differences were significant by the paired t - test ( table 3 ) . in the bland - altman plot , corrected iop obtained by tono - pachymetry and us pachymetry - gat showed close agreement , with the mean difference centered around zero , and 95% of the points were accurately located between the predicted 95% limits of agreement in both non - surgical eyes ( fig . the parameters of slope and intercept of the regression equation in both non - surgical eyes and post - prk eyes were not significant . in correlation analyses , there were no significant correlations between spherical equivalent refractive error and differences in corrected iop between the two devices in either non - surgical eyes ( p = 0.983 ) or post - prk eyes ( p = 0.875 ) ( fig . 4a and 4b ) . newly introduced instruments should be evaluated for repeatability and should be compared with former instruments to determine the interchangeability of methods before they are widely applied in clinical practice . the combination unit of non - contact tonometry and pachymetry is a recently developed instrument . there are few previous studies that evaluated this device , and the results are inconsistent . . demonstrated that tono - pachymetry ( nt-530p , nidek ) offered high repeatability and reproducibility in both iop and cct measurements . . showed that uncorrected iop measurement by tono - pachymetry ( nt-530p ) did not differ significantly from that obtained by another non - contact tonometer ( tx-10 , canon ) and gat readings . examined iop and cct measurements with tono - pachymetry ( nt-530p ) and assessed agreement of the device with gat and us pachymetry in 62 eyes of normal subjects . on average , tono - pachymetry overestimated the iop by 1.3 mmhg compared with gat . cct readings with tono - pachymetry were on average 13 m thinner than the readings obtained with us pachymetry . compared the iop values measured using tono - pachymetry ( nt-530p ) and gat in the same eyes of 26 patients before and after laser - assisted subepithelial keratectomy . cct was also measured by tono - pachymetry and us pachymetry before and after surgery . differences in iop measurement between tono - pachymetry and gat were not significant in the paired t - test before and after laser - assisted subepithelial keratectomy . tono - pachymetry overestimated cct measurements by 3.37 m before surgery and by 6.27 m after surgery compared with us pachymetry . in the present study , the mean cct measurement using tono - pachymetry was significantly thicker than that obtained using us pachymetry , by 7.35 11.37 m in non - surgical eyes and 17.76 12.09 m in post - prk eyes . the extent of overestimation of cct was greater in post - prk eyes than innon - surgical eyes . probe - corneal contact can yield thinner cct readings as a result of tissue indentation and displacement of the tear film . this effect can be greater in athinner cornea , including post - prk eyes . in the bland - altman plot , cct measurement by tono - pachymetry and us pachymetry showed close agreement with the clinically acceptable range of limits of agreement . however , regression equations of the bland - altman plot were significant in both non - control eyes and post - prk eyes . when bland - altman plots of non - surgical eyes and post - prk eyes were merged , the average difference in cct measurement between tono - pachymetry and us pachymetry was 12.8 m ( fig . additionally , the regression analysis showed that tono - pachymetry tended to underestimate cct for thicknesses greater than 514 m and tended to overestimate cct for thicknesses less than 514 m when compared to the us pachymetry measurement . the exact reason for this result is unclear ; however , methodological properties inherent to the device may have partly contributed to this tendency . the iop measurement by tono - pachymetry showed a reasonable agreement with that obtained by gat in both non - surgical eyes and post - prk eyes . the difference of iop value between tono - pachymetry and gat was not significant in paired t - test . the bland - altman plot demonstrated a very close agreement between the iop measurement by tono - pachymetry and us pachymetry . the mean difference in iop measurement was 0.0 mmhg in non - surgical eyes and 0.2 mmhg in post - prk eyes . the corrected iop value obtained by tono - pachymetry showed a reasonable agreement with that calculated from us pachymetry and gat measurements . the difference in corrected iop value between tono - pachymetry and us pachymetry and gat was significant by the paired t - test . however , the mean discrepancy was 0.33 mmhg in non - surgical eyes and 0.57 mmhg in post - prk eyes , which is too small to produce any clinical effect . the bland - altman plot demonstrated very close agreement between the corrected iop obtained by tono - pachymetry and us pachymetry . the gat examiner was not masked to the iop readings using tono - pachymetry , eyes with high or low iop were not included , and only very young subjects were included . in conclusion , the cct and iop measurements by tono - pachymetry had a high level of repeatability . cct measurement obtained using tono - pachymetry was significantly thicker than that obtained using us pachymetry , and the difference in cct was greater in post - prk eyes than non - surgical eyes . the corrected iop value obtained by tono - pachymetry showed reasonable agreement with that calculated from us pachymetry and gat measurements .

purposeto assess the validity of central corneal thickness ( cct ) and corrected intraocular pressure ( iop ) values obtained by tono - pachymetry in non - surgical and post - photorefractive keratectomy ( prk ) eyes.methodsfor the study , 108 young healthy participants and 108 patients who had prk were enrolled . measurements were randomly performed by tono - pachymetry , ultrasonic ( us ) pachymetry , and goldmann applanation tonometry ( gat ) . cct measurement by tono - pachymetry was compared to that of us pachymetry . the corrected iop value obtained by tono - pachymetry was compared to that obtained by us pachymetry and gat . the corrected iop from us pachymetry and gat was calculated using the identical compensation formula built into the tono - pachymetry . bland - altman plot and paired t - test were conducted to evaluate the between - method agreements.resultsthe mean cct measurement using tono - pachymetry was significantly greater by 7.3 m in non - surgical eyes ( p < 0.001 ) and 17.8 m in post - prk eyes ( p < 0.001 ) compared with us pachymetry . differences were significant in both bland - altman plotand paired t - test . the mean difference of corrected iop values obtained by tono - pachymetry and calculated from measurements by us pachymetry and gat was 0.33 0.87 mmhg in non - surgical eyes and 0.57 1.08 mmhg in post - prk eyes . the differences in the bland - altman plot were not significant.conclusionsthe cct measurement determined using tono - pachymetrywas significantly thicker than that of us pachymetry . the difference in cct was greater in post - prk eyes than in non - surgical eyes . however , the corrected iop value obtained by tono - pachymetry showed reasonable agreement with that calculated from us pachymetry and gat measurements .

jacob arthur in dublin in 1827 first coined the term rodent ulcer to describe what we now know as a basal cell carcinoma ( bcc ) . it takes its name from the resemblance of the epithelial tumor cells to normal basal cells of the skin . basal cell carcinoma is a locally invasive , slow growing malignancy that arises from the basal layer of the epidermis and its appendages and is considered to be most common skin malignancy in adults of fair - complexion [ 2 , 3 ] . recent studies have shown that two thirds of the tumors are located in the head and neck region as these are the most sun exposed regions of the body . the incidence of bcc has increased substantially in the last decade or so and it shows geographical variations . other predisposing factors include exposure to radiotherapy , arsenic , albinism , burns , scars , immunosuppression , bazex , and gorlin syndromes [ 710 ] . clinically , bcc in the head and neck usually presents as a slow growing well defined papule or nodule with telangiectasias located above the line connecting the angle of the mouth and ear lobe . it is a locally destructive lesion and can cause serious disfigurement but metastasizes rarely . according to clinical appearance and aggressiveness there are several variants including nodular ( with or without ulceration ) , pigmented , sclerosing , superficial , and baso - squamous [ 11 , 12 ] . histologically , bcc exhibits uniform , extremely dark basaloid cells with little cytoplasm and oval nuclei . some lesions produce keratin with pearl formation and in others benign melanocytes give the lesion a black color [ 7 , 13 ] . surgical resection with an adequate margin of normal tissue is the accepted standard of practice . reported recurrence rates are around 10% when a bcc is completely excised as compared to recurrence rates of over 30% when a bcc is incompletely excised . clinicians usually employ the technique of moh 's micrographic surgery to achieve margin clearance in bcc [ 14 , 15 ] . the rationale for the study was to evaluate the pattern and presentation of basal cell carcinomas of head and neck areas in northern pakistan along with the evaluation of frequency of specimens where margin clearance was obtained . data of all the malignant skin tumors which presented to the pathology department from january 2009 through december 2011 were analyzed retrospectively . out of these records , tumors with a diagnosis of basal cell carcinoma were retrieved . hematoxylin and eosin stained slides were examined under the microscope and histopathological pattern was reconfirmed on these slides . the age , gender of the patient , and anatomic location and pattern of tumor were noted as described in the records . the samples with incomplete record or with necrosed , scanty , and autolysed tissues were excluded from the study as it was difficult to identify the clinical parameters and histopathological pattern in these samples . the tumor was labeled as nodular bcc if it comprised of well demarcated islands and strands which arose from basal cells of the epithelium and contained uniform ovoid , dark staining basaloid cells with moderate sized nuclei and relatively little cytoplasm . if the sample consisted of tumor islands containing dendritic melanocytes and melanophages , it was labeled as pigmented bcc . when strands of basaloid tumor cells were present with a densely collagenous background , it was classified as sclerosing variety . if lobules of tumor cells that dropped from epidermis in a multifocal pattern were present , the lesion was termed as superficial bcc . when bcc was admixed with squamous cell carcinoma of the skin we labeled it as baso - squamous variety . in order to assess the margins status of the excised specimens , margins were considered clear when no tumor was present within 35 mm of the resection margin , close when tumor existed within 1 mm and involved when the tumor encroached on the resection margins and the distance was either less than 1 mm or there was a cut through the tumor . all data was recorded on specially designed forms developed for the data collection and analyzed using spss version 17.0 . mean and standard deviation was calculated for age of presentation and size of the lesion . frequency and percentages were calculated for gender , pattern of presentation , and margin status . a total of 171 cases of bcc from various sites of head and neck were retrieved . out of these , 100 ( 58.5% ) patients were male and 71 ( 41.5% ) were female with an overall male to female ratio of 1.4 : 1 . seventy six of the cases were located on the right side of face , 79 on left side while 16 were in the midline . the most common anatomical site was the nose where tumor occurred in 53 ( 31.5% ) cases followed by the cheek which was involved in 46 ( 26.9% ) cases . regarding pattern of presentation , nodular lesions were the most common , seen in 79 ( 46.2% ) cases followed by pigmented ( 32 cases , 18.7% ) and superficial ( 31 cases , 18.1% ) varieties , respectively . the size of the tumor specimens was also analyzed from the records of the gross specimen and ranged from 0.2 cm to 9.0 cm ( mean 2.2 1.4 cm ) . we also assessed margin clearance in the excised specimens and it was seen that in 77 ( 45.1% ) cases margins were clear , in 37 ( 21.6% ) cases one of the margin was involved , in 49 ( 28.6% ) cases more than one margin was found involved while in 8 ( 4.7% ) cases margins were found to be close ( figure 1 ) . ear , nose and eyelids were the sites that showed maximum involvement of margins in the resected specimens respectively . chi square test was used to determine the effect of site on margin clearance but the results obtained were statistically insignificant . basal cell carcinoma ( bcc ) is considered to be the most common skin malignancy and its incidence is on the rise worldwide because of increased exposure to uv light and ozone depletion in various parts of the world due to environmental and industrial pollution . exposure to uv light results in dna damage that leads to development of skin cancer . bcc has been linked with various syndromes also like bazex , rombo , nevoid basal cell carcinoma syndrome , rasmussen , and darier 's disease because of mutations in sonic hedgehog pathway [ 3 , 18 ] . in our study , bcc was slightly more common in male patients ( m : f = 1.4 : 1 ) . this could be because of the fact that males are more exposed to sun light because of their outdoor occupations . these results are similar to what is reported by aandani and ganatra and cigna et al . while on the other hand chow et al . bcc was most prevalent in 6th and 7th decade in our study group and mean age of presentation was 61 years . similar results were reported by cigna et al . while aandani and ganatra reports bcc to be more prevalent in 5th decade in their study . when we analyzed the anatomical site for occurrence of bcc , we found that the nose was the most common location followed by cheek . these results are in harmony with those reported by chow et al . and aandani and ganatra who also report the nose and the cheek to be the most commonly involved site for bcc . another factor that we assessed in our study was the histopathological pattern of the tumor and in this regard , we found that nodular variety was the most frequent in our study sample followed by the pigmented variety . also report ulcerative and nodular variety to be the most common type of pattern . from our records we extracted the information about the size the lesions and it was seen that the mean size at the time of excision was approximately 2 cm ranging from 0.2 cm to 9 cm . cigna et al . from italy , reports a slightly smaller size of lesion at the time of presentation , around 12 mm . late presentations for malignancy are a common finding in patients of third world countries . one of the fundamental requirements for treating bccs or for that matter any malignancy is attainment of clear surgical margins after complete excision . so we assessed our samples for margin clearance and it was found out that we could achieve margin clearance in only 45 percent of the cases while in around 50 percent cases either one of more than one margin was involved by the tumor . studies report frequency of incomplete excision ranging from 320% [ 1 , 14 , 15 , 21 ] . a four millimeter excision margin is currently recommended for small , well demarcated bcc 's as this gives a complete excision rate of approximately 95% . ear , nose , and eyelids were the sites where involvement of margins was seen most of the time in our cases . possible reasons for that could be unavailability of mohs micrographic surgery in most of the plastic and maxillofacial units , and in these areas anatomical landmarks are pressing and surgeons tend to go less aggressive while excising tumors . another possibility could be larger sized tumors at the time of presentation . for cases with involved margins either reexcision or radiotherapy re excision was done mostly in cases where site was closed primarily and in cases where some flap was used , the patients were referred for radiotherapy . bcc is quite common in our society . the nose was the most common site followed by the cheek . nodular and pigmented varieties were the most frequent . margin clearance could not be achieved in more than fifty percent of the cases . all effort should be directed towards achievement of clear margins in order to decrease the chances of recurrence and improve survival . attempts should be made to utilize moh 's micrographic surgery whenever available or one can attempt staged excision .

objective . to analyze the pattern of presentation of basal cell carcinoma ( bcc ) and margin status for excised specimens in the head and neck region . study design . retrospective cross - sectional . duration of study . january 2009 to december 2011 . methodology . the database of the pathology department was searched to identify records of all malignant skin tumors that underwent standard excision with margins . out of these records , tumors with a diagnosis of bcc in the head and neck region were retrieved and separated . age , gender , anatomic location , pattern of tumor , and margin status were noted . results . a total of 171 cases of bcc from various sites of head and neck were retrieved . male to female ratio was 1.4 : 1 . the age ranged from 22 to 90 years . seventy - six cases presented on right side , 79 on left , and 16 were in the midline . most common anatomical site was the nose followed by the cheek . nodular lesions were the most common ( 46.2% ) followed by pigmented variety ( 18.7% ) . margins were clear in 77 ( 45.1% ) cases , involved in 86 ( 50.2% ) cases , and close in 8 ( 4.7% ) cases . conclusion . nose was the most common site followed by the cheek . nodular and pigmented varieties were the most frequent and margins were involved in more than fifty percent of the cases .

the system response to surgical trauma includes activation of the sympathetic nervous system , the endocrine stress response , and immunological and hematological changes .various kinds of stress cause an increase in the secretion of acth from the adenohypophysis , and ( within a few minutes ) an increase in secretion of cortisol from the adrenal cortex . many different , non - specific stimuli can cause a noticeable increase in secretion of cortisol from the adrenal cortex ( e.g. , trauma , surgery , infection , strong heat or cold , and almost any debilitating disease ) . generally , the level and duration of increase in intra - and postoperative concentrations of cortisol are in proportion with the degree of surgical trauma . the etiology of hyperglycemia in stress is multi - factorial , but is thought primarily to be the result of activation of the sympathoadrenal system , with contributions from the hypothalamus and adenohypophysis . the stress response triggers an increase in levels of plasma catecholamines and glucocorticoids , which in turn lead to hyperglycemia . cortisol also has a huge impact on the glucose metabolism in stress , because by increasing glycogenolysis and glucogenesis it can lead to hyperglycemia . clinical implications of stress response involve hypertension , tachycardia , arrhythmia , myocardial ischemia , protein catabolism , suppression of the immune response , and loss of the excretory renal function with retention of electrolytes and water . stress response is a significant risk factor for an unsatisfactory outcome in patients with cardiovascular disease , in patients with known endocrine , metabolic and immune disorders , as well as in patients with infection and immunosuppression . thus , the reduction and modulation of stress response during the operation can significantly reduce the incidence of post - operative complications and morbidity . the choice of anesthesia technique depends on the surgical disease , the general condition of the patient , the level and extent of the surgical operation , as well as the availability of resources required for anesthesia . many surgical procedures can be done under spinal anesthesia , which has been used in clinical practice for more than a hundred years . the advantages of regional anesthesia over general anesthesia are documented in many studies ( e.g. , inhibition of metabolic and hormonal responses to stress , reducing the incidence of post - operative pain , speeding peristalsis after abdominal operations , reducing the incidence of deep vein thrombosis , and shorter hospital stay ) . the potential lack of regional anesthesia is that its limited duration has an impact on the management of surgery . the advantages of general anesthesia are its simple and easy method of application , rapid sedation of the patient , and increased comfort of surgeons and anesthesiologists when the surgery has to last longer . the disadvantages of general anesthesia are poor control of anesthetics ( depends on the individual ability of the organism to degrade and eliminate them ) and postoperative adverse effects ( e.g. , sickness , nausea , vomiting , and pain ) . the aim of the study was to determine the significance of spinal anesthesia in suppressing the metabolic , hormonal , and hemodynamic response to surgical stress during and after elective operations in abdominal , urological , and orthopedics surgery compared with the technique of general anesthesia . to monitor the metabolic and hormonal responses to stress , we measured the serum cortisol levels and glycemia , which are most easily detectable and are closely correlated with the intensity of stress . the secondary objective was to investigate the suppression of the adrenergic response by monitoring hemodynamic parameters : systolic and diastolic arterial pressure ( ap ) and heart rate ( hr ) . the research was conducted at the kosovska mitrovica health center from september 2013 to march 2014 . the patients were divided into 2 groups , depending on the anesthetic technique . in the spinal anesthesia group there were 38 patients and in the general anesthesia group were 37 patients undergoing the same surgical procedure . depending on the performed surgical procedure , patients were classified into several subgroups : general surgery ( herniotomy and thrombosaphenectomy ) , orthopedics ( osteosynthesis ) , and urology ( prostatectomy ) . the choice of anesthesia technique was made by the anesthesiologist , based on preanesthetic parameters ( clinical examination of the patient , laboratory analysis ) , the type of surgery , and on the patient s preference . to assess the operational risk , we used a classification adopted by the american society of anesthesiologists ( asa ) . the study included patients of asa 1 ( patients with no organic pathology or patients in whom the pathological process is localized and does not cause any systemic disturbance or abnormality ; excludes very young and very old patients ) and asa 2 ( patients with no functional limitations , with well - controlled disease of 1 body system ) . the study did not include patients with severe and extreme systemic disorders ( asa 36 ) . serum cortisol levels were measured using the eleksys 2010 chemiluminescence apparatus and glycemia was measured on the hitachi 902 biochemical analyzer in the laboratory of the kosovska mitrovica health center . hemodynamic parameters systolic and diastolic ap , heart rate ( hr ) , arterial oxygen saturation ( spo2 ) were monitored in all patients . serum cortisol levels , glycemia and hemodynamic parameters were measured at the following time points : before induction on anesthesia ( t1 ) , 30 min after the surgical incisions ( t2 ) , 1 h postoperatively ( t3 ) , and 24 h after surgery ( t4 ) . 30 min prior to surgery . in the general anesthesia group , for the induction of anesthesia we used propofol ( 2.5 mg / kg b.w . ) and for endotracheal intubation we used succinyl - choline ( 1.5 mg / kg b.w . ) . to maintain anesthesia , we used propofol boluses with a 2 : 1 nitrous oxide : oxygen ( n2o - to - o2 ) ratio . analgesia was achieved with fentanyl ( 0.05 mg / kg b.w . ) and muscle relaxation with rocuronium bromide ( 0.6 mg / kg b.w . ) . for the reversal of neuromuscular blockade , we used 1.5 mg prostigmin and 0.5 mg atropine . in the spinal anesthesia group , we used a 2226 g spinal needle , local anesthetic ( bupivacaine 15 mg 0.5% ) , and opioids ( fentanyl 0.05 mcg ) . for the analysis of primary data , descriptive statistical methods and hypothesis testing methods were used . we used the following descriptive statistical methods : measures of central tendency ( arithmetic mean ) , measures of variability ( standard deviation ) , and relative numbers . to test hypotheses about the difference in frequency the t - test was used for testing hypothesis about difference of arithmetic means between the 2 groups . anova for repeated measures was used to identify differences between groups in which the data were parametric and normally distributed . to assess correlations between continuous variables , there was no statistically significant difference between the spinal and the general anesthesia groups regarding age , duration of surgery , asa categories , and type of surgery . for comorbidity and the type of surgery , the frequency is shown by category ( table 1 ) . intraoperatively ( t2 ) , serum cortisol level ( 694.7140.8 vs. 478.791.9 ) increases in both groups , but significantly more in the general anesthesia group . serum cortisol levels in the general anesthesia group at 1 h after surgery ( t3 ) and 24 h postoperatively ( t4 ) were significantly higher than in the spinal anesthesia group ( figure 1 ) . glycemia values were statistically significantly increases 30 min after surgical incision ( t2 ) in both groups , but at t3 and t4 glycemia decreased ( figure 2 ) . there was a statistically significant , positive correlation between serum cortisol levels and glycemia at all times observed . at time t1 , there was a statistically significant , weak negative correlation between serum cortisol level and systolic ap , and between serum cortisol level and diastolic ap . during the same period , there was a statistically significant , positive correlation between serum cortisol level and hr . at time t4 there was a statistically significant , weak positive correlation between serum cortisol levels and spo2 ( table 2 ) . systolic and diastolic ap did not differ significantly between the groups . in the observed period , systolic and diastolic ap were significantly different , with a significant linear trend of decreasing ap values , but there was no significant difference in the fluctuations at the points of measurement , of the values for systolic and diastolic ap ( figure 3 ) . the hr was significantly higher in the general anesthesia group compared to the spinal anesthesia group ( p<0.01 ) ( figure 4 ) . measurements of the parameters at t3 determined that there was no statistically significant correlation between the duration of surgery and serum cortisol levels or between the duration of surgery and glycemia . measurements of the parameters at t4 determined that there was no statistically significant correlation between the duration of surgery and serum cortisol levels or between the duration of surgery and glycemia ( table 3 ) . serum cortisol levels are correlated with the intensity , duration , and type of stress that caused them ; therefore , plasma cortisol concentration is the most commonly used marker for perioperative examination of stress induced by surgical trauma . many studies have examined the effect of different anesthesia techniques on the concentration of serum cortisol levels . in general , the results of previous studies have shown that the choice of anesthesia technique affects intraoperative stress response , and thus significantly affects the outcome and morbidity of surgical patients and the reduction of postoperative pain . attenuation of the endocrine metabolic response may reduce the frequency of postoperative complications . in our study , basal serum cortisol levels , which we measured before the start of surgery , were in the range of reference values . thirty minutes after surgical incision , there was a significant rise in serum cortisol levels in both groups of patients , but significantly higher in the general anesthesia group . perioperative serum cortisol levels in the spinal anesthesia group were significantly lower compared to those in the general anesthesia group . postoperative serum cortisol levels were also significantly lower in the spinal anesthesia group , as previously described . this difference can be attributed to spinal anesthesia blocking the sensory afferent nerve impulses originating from the surgical trauma . it is known that blocking the efferent and afferent pathways of the sympathetic and somatic nervous system inhibits activation of the neuroendocrine axis during surgical procedures . in our study , we researched the following procedures : prostatectomy , osteosynthesis , herniotomy , and thrombosaphenectomy . these types of surgeries are procedures of intermediate severity and can potentially cause an increase in cortisol secretion in response to surgical stimulation . increased levels of stress hormones are considered undesirable because they lead to intraoperative and postoperative metabolic catabolism and to hemodynamic instability . clinical evidence has shown that spinal anesthesia has an effect in modification of stress response by means of modulation or inhibition of the nociceptive afferent signals from the area of surgical trauma . the changes include alterations in metabolic , hormonal , inflammatory , and immune systems , which can be collectively termed the stress response . integral to stress responses are the effects of nociceptive afferent stimuli on systemic and pulmonary vascular resistance , heart rate , and blood pressure , which are a combination of efferent autonomic response and catecholamine release via adrenal medulla . the magnitude of the response is broadly related to the site of injury ( greater in regions with visceral pain afferents , such as the abdomen and thorax ) and extent of the trauma . conducted a comparative study in which they compared the effects of general and spinal anesthesia on serum cortisol levels in anorectal surgery . the results showed that serum cortisol levels were significantly lower in the spinal anesthesia group compared to the general anesthesia group . davis et al . concluded that unilateral spinal anesthesia more effectively suppresses the metabolic stress response in orthopedic patients undergoing total hip arthroplasty compared with general anesthesia . in our study , we found a suppression of the hyperglycemic response in both groups . lower glycemia were observed in the spinal anesthesia group at 1 h and 24 h postoperatively . there was a statistically significant positive correlation between serum cortisol levels and glycemia at all points of measurement , which means that an increase in serum cortisol levels has a direct impact on the increase of glycemia . surgery - related metabolic and endocrine derangements lead to adverse effects , including increased oxygen consumption , hypertension , tachycardia , arrhythmia , myocardial ischemia , hemodynamic instability , catabolism , and impaired immune function . these derangements have been associated with poor postoperative course and clinical outcome [ 2224 ] . anesthesia is performed adequately if the ap and hr do not exceed 20% of the values before induction . in our study , hemodynamic parameters showed that the suppression of the adrenergic response was adequate in both investigated groups . in the general anesthesia group , systolic ap was significantly higher 30 min after the surgical incision , 1 h postoperatively , and 24 h after surgery , but with no substantial oscillation of the values . the diastolic ap was significantly lower in the spinal anesthesia group 30 min after the surgical incision and 1 h postoperatively , but there were no differences in their dynamics . the values of hr were significantly higher in the general anesthesia group , but without significant fluctuations at the different points of measurement , which indicates a satisfactory depth of anesthesia . wolf reported that the sympathetic block induced by regional anesthesia resulted in a profound suppression of hemodynamic and stress response to pediatric surgery . the systolic and diastolic ap was significantly higher in the general anesthesia group intraoperatively and immediately postoperatively . however , we noted no significant fluctuations in the dynamics of changes in the studied groups . due to the reduced sensitivity to norepinephrine in patients under stress , despite its elevated levels in plasma , there were no significant changes in ap . changes in hr during the period did not differ significantly between the groups , although significantly higher values of hr were recorded in the general anesthesia group . attari et al . conducted a study in which they compared the effects of spinal and general anesthesia on the hemodynamic stability of patients and the need for postoperative analgesia in elective surgery of the lumbar spine . they concluded that spinal anesthesia is superior in terms of hemodynamic stability and postoperative analgesia compared with general anesthesia . concluded that the vast majority of patients who have undergone both general and local anesthesia for dacryocystorhinostomy would choose local anesthesia again . our findings are in agreement with other reports in the literature suggesting that regional anesthesia could produce an attenuation of the stress response to surgical trauma . in our study , the number of patients is too small to reach conclusion regarding different types of surgery . another limitation is that stress response to surgical trauma measured by serum cortisol levels and glycemia could be due to other factors besides type of anesthesia , such as type of surgery , magnitude of surgical injury , duration of operation , and degree of postoperative pain . different techniques of anesthesia have not been shown to affect clinical outcome , so studies with more sensitive methods should be carried out to further investigate this issue . spinal anesthesia showed better efficacy in suppressing cortisol response as compared to the technique of general anesthesia . in the suppression of the hyperglycemic response , both types of anesthesia proved equally effective , although slightly lower glycemia were recorded in patients who underwent spinal anesthesia . hemodynamic parameters showed that the suppression of the adrenergic response was adequate in both groups , but hemodynamic stability was better in the spinal anesthesia group . based on metabolic , hormonal , and hemodynamic responses , spinal anesthesia proved more effective than general anesthesia in suppressing stress response during elective procedures in abdominal , urological , and orthopedic surgery .

backgroundthe aim of the study was to determine the significance of spinal anesthesia in the suppression of the metabolic , hormonal , and hemodynamic response to surgical stress in elective surgical patients compared to general anesthesia.material/methodsthe study was clinical , prospective , and controlled and it involved 2 groups of patients ( the spinal and the general anesthesia group ) who underwent the same surgery . we monitored the metabolic and hormonal response to perioperative stress based on serum cortisol level and glycemia . we also examined how the different techniques of anesthesia affect these hemodynamic parameters : systolic arterial pressure ( ap ) , diastolic ap , heart rate ( hr ) , and arterial oxygen saturation ( spo2 ) . these parameters were measured before induction on anesthesia ( t1 ) , 30 min after the surgical incisions ( t2 ) , 1 h postoperatively ( t3 ) and 24 h after surgery ( t4).resultsserum cortisol levels were significantly higher in the general anesthesia group compared to the spinal anesthesia group ( p<0.01 ) . glycemia was significantly higher in the general anesthesia group ( p<0.05 ) . there was a statistically significant , positive correlation between serum cortisol levels and glycemia at all times observed ( p<0.01 ) . systolic and diastolic ap did not differ significantly between the groups ( p=0.191 , p=0.101 ) . the hr was significantly higher in the general anesthesia group ( p<0.01 ) . spo2 values did not differ significantly between the groups ( p=0.081).conclusionsbased on metabolic , hormonal , and hemodynamic responses , spinal anesthesia proved more effective than general anesthesia in suppressing stress response in elective surgical patients .

Michael Buckner/Getty Their subtle rings appeared to be a quiet way of announcing their marriage at the Oscars on Sunday. And adding fuel to the fire, jeweler Jamie Wolf confirmed today that she designed Natalie Portman and Benjamin Millepied’s “wedding rings,” she shares in a release. Wolf created two diamond rings for Portman, made to fit on either side of her engagement ring, and a platinum band for Millepied. Both baubles are eco-friendly, made with recycled metals and conflict-free diamonds. Wolf, one of Millepied’s dancer pals, designed Portman’s engagement ring, as well. “Ben was exceptionally thoughtful and dedicated and patient to make sure we had everything right,” she said shortly after the actress debuted the sparkler last year. That ring, made of recycled platinum and featuring an antique diamond surrounded by certified conflict-free stones, was designed to fit in with Portman’s earth-friendly lifestyle. Said Wolf, “We wanted everything about the ring to speak to things that are important to Natalie.” SEE THE BEST AND BRIGHTEST STAR ENGAGEMENT RINGS ||||| Natalie Portman, Benjamin Millepied secretly married, confirms jeweler who designed couple’s wedding bands The actress and the dancer-choreographer are parents to an 8-month-old son named Aleph Natalie Portman and Benjamin Millepied were all smiles at Sunday night's Academy Awards. There’s a reason why Natalie Portman couldn’t stop smiling at the Academy Awards. Instead of making a public announcement via a press release or televised interview, the actress subtly revealed her marital status when she and dancer-choreographer Benjamin Millepied attended Sunday night’s star-studded event wearing wedding bands. PHOTOS: SECRET CELEBRITY MARRIAGES Jeweler Jamie Wolf confirmed Tuesday that she designed the couple’s new accessories: two diamond rings made to be worn on either side of Portman’s engagement ring, and a platinum band for Millepied. "They were made with recycled platinum and conflict free diamonds," Wolf said in a statement. Portman showed off her new ring while presenting at Sunday's Oscars. (Kevin Winter/Getty Images) Portman showed off her new ring while presenting at Sunday's Oscars. (Kevin Winter/Getty Images) Wolf, one of Millepied’s dancer friends, also designed Portman’s engagement ring: an antique diamond surrounded by certified conflict-free stones and made of recycled platinum. “Ben was exceptionally thoughtful and dedicated and patient to make sure we had everything right,” the jeweler told InStyle last year. “We wanted everything about the ring to speak to things that are important to Natalie.” Portman, 30, and Millepied, 34, who first met on the set of “Black Swan,” announced their engagement in December 2010. They welcomed a son, Aleph, last June. The actress’ rep has yet to respond to the Daily News' requests for comment.

– Yes, those were wedding bands worn by Natalie Portman and her guy, Benjamin Millepied, that lit a buzz at the Oscars. They're made with "recycled platinum and conflict-free diamonds," spilled jeweler Jamie Wolf, who designed the wedding rings for the 30-year-old actress and choreographer, 34. The platinum band is for Millepied, and Portman sports two diamond rings on either side of her engagement ring, notes People. Wolf, a dancer pal of Millepied, also designed Portman's engagement ring. The couple met on the set of the Black Swan, and announced late last year that they would marry. They have an eight-month-old son, Aleph.

humans are exposed to toxins by consuming foods contaminated with products of fungal growth throughout life time . since prevention of fungal growth in foods is difficult , such exposures are not easy to be avoided . mycotoxins have received considerable attention due to their significance in agricultural loss and human health . amongst the mycotoxins that are known to cause human diseases , aflatoxins are a group of mycotoxins produced by strains of aspergillus , especially a. flavus and a. parasiticus . aflatoxin has been found as contaminats in agricultural and food products especially in cereals and cereal products ( 3 , 4 ) . in numerous studies , caldas in 2002 analyzed 366 food samples including cereals , peanuts and rice , and reported that 19.6% of the samples were contaminated with aflatoxins ( 5 ) . aflatoxin b1 ( afb1 ) is the most potent hepatocarcinogen known in mammals and is classified by the international agency of research on cancer ( iarc ) as group 1 carcinogen ( 6 ) . halt detect afb1 in a mean level of 16.3 ng / g in wheat samples ( 8) . 63.7% and 2.54% of the samples were contaminated with aspergillus , and aflatoxin respectively ( 9 ) . due to the toxicity of aflatoxin , its presence in flour and flour products and its effect in public health , this study was conducted to determine the level of aflatoxin and factors affecting aflatoxin formation in wheat flour in golestan province . this cross - sectional study was conducted in 2010 in golestan province , northern iran . according to the institute standard and industrial research of iran no : 2836 ( sampling of agricultural products ) , a total of 200 samples obtained from 25 wheat flour manufactures in the province . to determine the seasonal effects on aflatoxin contamination , sampling was conducted in two stages , the warm season ( mid - summer ) ( 100 samples ) , and the cold season ( mid - winter ) ( 100 samples ) . to determine the effect of environmental factors in aflatoxin formation , characteristics of silos including temperature , humidity , and storage duration of wheat and flour were recorded . storage duration of wheat was defined as the time between delivery of wheat to silos and the time of flour production . storage duration of flour was defined as the time between flour production and the time of sampling . all samples were stored in plastic bags , taken to the laboratory of biochemistry of the golestan medical university and kept in the refrigerator for maximum three months after sampling . hplc ( high - performance liquid chromatography ) , and immunoaffinity chromatography were used for aflatoxin detection . aflatoxins were extracted from 50 g of sample using methanol : water ( 80:20 v / v ) . 20 ml of filtered solution was diluted , centrifuged , and filtered , then the mixture of the filtered diluted extract ( 50 ml ) was applied to the immunoaffinity column ( lctech , germany ) and allowed to flow at rate of 1 ml per min . washing with deionoised water was done to remove unbound materials . in the next step sample was injected into hplc for quantitative determination of aflatoxin b1 , b2 , g1 , and g2 . then the samples were passed through affinity columns and extracted samples were measured by hplc with c18 column , with a mobile phase consisting of water / meoh / acetonitrile ( 60:30:15 , v /v/ v ) and the detector wavelength 440 nm ( emission ) and 365 nm ( excitation ) . only aflatoxin b2 and g2 were fluorescent . photochemical reactor was used to convert the wavelength of the absorption of aflatoxin b1 and g1 in the wavelength 254 nm for detection with fluorescence detector to derive quantifiable . worldwide regulations for mycotoxins in food and feed ( total aflatoxin : 4ng / g and aflatoxin b1 : 2ng / g ) ( 10 ) and the regulation of institute of standards and industrial research of iran ( isri ) no:6872 ( 15 ng / g for total aflatoxin , 5 ng / g for aflatoxin b1 ) ( 11 ) were used to determine the permissible limits of aflatoxins in wheat flour . pearson correlation test was used in order to examine the relationship between quantitative variables and for study the relationship between qualitative and quantitative variables the student t - test was used . considering that aflatoxin b1 was the most important and toxic aflatoxin of wheat , multivariate regression analysis was used for study the effect of different variables on this type of aflatoxin . variables with p - value less than 0.2 in univariate analysis were entered into the multivariate analysis . a total of 200 samples were taken from 25 wheat flour manufactures in golestan province ( 100 in summer 100 in winter ) . results showed that the incidences of aflatoxin in wheat flour in summer and winter were about 99% and 70% , respectively . the levels of total aflatoxin and aflatoxin b1 in all wheat flour samples were within permissible limits by the regulation of institute of standards and industrial research of iran ( isri ) no:6872 ( 15 ng / g for total aflatoxin , 5 ng / g for aflatoxin b1 ) ( 11 ) . mean and proportion of contamination of wheat flour samples with different types of aflatoxins in two seasons are shown in table 2 . mean ( sd ) of total aflatoxin in samples in winter and summer were 0.99 ( 1.96 ) ng / g and 0.82 ( 3.05 ) ng /g , respectively ( table 2 ) . aflatoxin b1 levels were detected in 3.1% , 7.4% and 5.2% over permissible limits by worldwide regulations ( 2ng / g ) ( 9 ) in samples collected in summer , winter and total samples , respectively . these values for total aflatoxins were 3.1% , 12.6% and 7.9% ( regarding the permissible limits by worldwide regulations of 4 ng / g ) , respectively . the relationships between aflatoxin levels and humidity , storage temperature and storage duration of wheat and flour in two seasons are shown in table 3 . we found significant relationship between the levels of aflatoxin g1 , g2 , b1 , b2 and total aflatoxin with the temperature and humidity of silos in summer ( table 3 ) . in winter the results of multivariate regression showed that humidity of silos had the strongest relationship with levels of aflatoxin b1 in flour samples ( standardized beta coefficient=0.25 ; p=0.04 ) . the results showed that the incidences of aflatoxin in wheat flour in winter and summer were respectively about 99% and 70% . aflatoxin b1 contamination levels in the winter has seen higher than the summer ( 77% vs. 33% ) . the level of aflatoxin contamination in milk in 14 states in iran in winter was significantly higher than in summer ( 12 ) . the mean levels for total aflatoxins in samples in winter and summer were 0.99 ng /g and 0.82 ng / g , respectively . the levels of aflatoxins were in isir s recommended range for aflatoxin levels ( 11 ) . in a study wheat flour samples were analyzed by using elisa , the mean level of aflatoxin b1 was 0.93 ng / g and 6.5% of samples were higher than the maximum limits set by the worldwide regulations for aflatoxin b1 ( 13 ) . in another study , 2.54% of samples were contaminated with aflatoxin , and afalatoxin b1 , g1 detected in 2.54 and 3.39% of samples , respectively . total aflatoxin and aflatoxin b1 levels in samples ranged between ( 1.3 7.1 ng / g ) and ( 1.361.78 ng / g ) , respectively ( 9 ) . reported the mean level of total aflatoxin and aflatoxin b1 in wheat flour as 0.07 ng / gr and 0.07 ng / g , respectively , and did not found aflatoxin b2 , g1 , g2 in any sample ( 14 ) . in malaysia , 21.7% of samples were contaminated with aflatoxin and aflatoxin g2 , g1 , b2 , b1 detected in 1.2 % , 4.8 % , 4.8 % , 13.3 % of samples , respectively ( 15 ) . in another study , 41 samples of wheat were analyzed and 59% of samples was contaminated with aflatoxin and the incidence of aflatoxin g2 , g1 , b2 , b1 were 42% , 12% , 37% and 12% , respectively ( 16 ) . in the study of halt et al . the mean level of aflatoxin b1 was 16.3 ng / g ( 8) . despite the level of aflatoxins in flour samples was not higher than the limits set by iran standard institute but regarding worldwide regulations and the results of many other studies , there were impermissible high aflatoxin level in a considerable number of our samples ( 10 , 14 , 17 ) . geographical location and climatic characteristics and favorable conditions of temperature and humidity , close to the caspian sea , agricultural practices , soil characteristics , type of wheat , sampling method and wheat and flour storage condition can affect the contamination level of flour . baliukoniene et al . showed that storage conditions have very significant impact on levels of aflatoxin ( 18 ) . in the summer temperature and humidity are higher and very favorable to mycotoxin production but as can be seen in table 2 aflatoxin levels in winter was higher than summer . storage duration of wheat is an important factor in level of aflatoxin contamination in the winter . because of the wheat harvest was in the first half of year and kept in stocks for months , this storage duration can be a considerable result on high aflatoxin contamination in the winter of the year . our results also showed that the relationship between humidity and the rate of total aflatoxin was significant . basilico showed that fungal growth and toxin production were interaction between fungi , host and environment that can influence the types and quantity of toxin produced by the fungus ( 19 ) . it is known that the crop varies , weather pattern , temperature , humidity , water activity , level of oxygen , poor storage condition , inadequate drying , activity of insects or rodents and other problems affect aspergillus growth and aflatoxin production in storage products stored ( 20 , 21 ) . we found that the level of aflatoxins in flour samples was not higher than the limits set by iran standard institute . but , regarding worldwide regulations and the results of many other studies , a considerable number of our samples were contaminated with impermissible high levels of aflatoxins , especially aflatoxin b1 . in our study humidity , was the most important factor associated with aflatoxin contamination of flour . due to the important role of aflatoxin contamination , especially negative effect of aflatoxin b1 on public health , efforts should be conduct to prevent the contamination , since prevention is the most economical and practical approach . controlling environmental factors such as storage duration , temperature and humidity can help us with achieving this goal . ethical issues ( including plagiarism , informed consent , misconduct , data fabrication and/or falsification , double publication and/or submission , redundancy , etc ) have been completely observed by the authors .

background : due to the high toxicity of aflatoxin and its effects on public health , determination of aflatoxin level in wheat flour samples in the golestan province , north of iran was investigated . to examine the effect of seasonal changes , summer and winter sampling was performed with standard sampling methods.methods:a total of 200 flour samples were collected from 25 factories . hplc method with immunoaffinity chromatography was used to measure aflatoxin types ( g2 , g1 , b2 and b1 ) . statistical analysis was performed by the pearson correlation test , one - way anova and multivariate regression analysis.results:mean total aflatoxin levels of samples were 0.82 and 1.99 ng / g in summer and winter , respectively . aflatoxin b1 levels were detected in 3.1% , 7.4% over permissible limits by worldwide regulations in samples collected in summer and winter , respectively . aflatoxins in winter were higher than summer . the highest frequency of aflatoxin contamination in winter was b2 ( 98% ) and in summer g1 ( 51% ) . the relationship between humidity and rate of aflatoxin b1 and total aflatoxin was significant in winter . results of multivariate regression were showed the strongest relationship with humidity and aflatoxin level . despite the contamination of flour samples , there was no contamination higher than the standard limit of iran standard institute . but it was significantly higher than similar studies from other regions.conclusions:therefore , with regard to negative impacts of aflatoxin on health , aflatoxin contamination should be considered in future programs . decrease of aflatoxin contamination may be made practical through reducing wheat storage duration and controlling humidity .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Federal Real Property Disposal Enhancement Act of 2009''. SEC. 2. DUTIES OF THE GENERAL SERVICES ADMINISTRATION AND EXECUTIVE AGENCIES. (a) In General.--Section 524 of title 40, United States Code, is amended to read as follows: ``Sec. 524. Duties of the General Services Administration and executive agencies ``(a) Duties of the General Services Administration.-- ``(1) Guidance.--The Administrator shall issue guidance for the development and implementation of agency real property plans. Such guidance shall include recommendations on-- ``(A) how to identify excess properties; ``(B) how to evaluate the costs and benefits involved with disposing of real property; ``(C) how to prioritize disposal decisions based on agency missions and anticipated future need for holdings; and ``(D) how best to dispose of those properties identified as excess to the needs of the agency. ``(2) Annual report.--(A) The Administrator shall submit an annual report, for each of the first 5 years after 2009, to the congressional committees listed in subparagraph (C) based on data submitted from all executive agencies, detailing executive agency efforts to reduce their real property assets and the additional information described in subparagraph (B). ``(B) The report shall contain the following information for the year covered by the report: ``(i) The aggregated estimated market value and number of real property assets under the custody and control of all executive agencies, set forth government-wide and by agency, and for each at the constructed asset level and at the facility/ installation level. ``(ii) The aggregated estimated market value and number of surplus real property assets under the custody and control of all executive agencies, set forth government-wide and by agency, and for each at the constructed asset level and at the facility/ installation level. ``(iii)(I) The aggregated cost for maintaining all surplus real property under the custody and control of all executive agencies, set forth government-wide and by agency, and for each at the constructed asset level and at the facility/installation level. ``(II) For purposes of subclause (I), costs for real properties owned by the Federal Government shall include recurring maintenance and repair costs, utilities, cleaning and janitorial costs, and roads and grounds expenses. ``(III) For purposes of subclause (I), costs for real properties leased by the Federal Government shall include lease costs, including base and operating rent and any other relevant costs listed in subclause (II) not covered in the lease contract. ``(iv) The aggregated estimated deferred maintenance costs of all real property under the custody and control of all executive agencies, set forth government-wide and by agency, and for each at the constructed asset level and at the facility/ installation level. ``(v) For each surplus real property facility/ installation disposed of, an indication of-- ``(I) its geographic location with address and description; ``(II) its size, including square footage and acreage; ``(III) the date and method of disposal; and ``(IV) its estimated market value. ``(vi) Such other information as the Administrator considers appropriate. ``(C) The congressional committees listed in this subparagraph are as follows: ``(i) The Committee on Oversight and Government Reform and the Committee on Transportation and Infrastructure of the House of Representatives. ``(ii) The Committee on Homeland Security and Governmental Affairs and the Committee on Environment and Public Works of the Senate. ``(3) Assistance.--The Administrator shall assist executive agencies in the identification and disposal of excess real property. ``(b) Duties of Executive Agencies.-- ``(1) In general.--Each executive agency shall-- ``(A) maintain adequate inventory controls and accountability systems for property under its control; ``(B) continuously survey property under its control to identify excess property; ``(C) promptly report excess property to the Administrator; ``(D) perform the care and handling of excess property; and ``(E) transfer or dispose of excess property as promptly as possible in accordance with authority delegated and regulations prescribed by the Administrator. ``(2) Specific requirements with respect to real property.--With respect to real property, each executive agency shall-- ``(A) develop and implement a real property plan in order to identify properties to declare as excess using the guidance issued under subsection (a)(1); ``(B) identify and categorize all real property owned, leased, or otherwise managed by the agency; ``(C) establish adequate goals and incentives that lead the agency to reduce excess real property in its inventory; ``(D) when appropriate, use the authorities in section 572(a)(2)(B) of this title in order to identify and prepare real property to be reported as excess. ``(3) Additional requirements.--Each executive agency, as far as practicable, shall-- ``(A) reassign property to another activity within the agency when the property is no longer required for the purposes of the appropriation used to make the purchase; ``(B) transfer excess property under its control to other Federal agencies and to organizations specified in section 321(c)(2) of this title; and ``(C) obtain excess properties from other Federal agencies to meet mission needs before acquiring non- Federal property.''. (b) Clerical Amendment.--The item relating to section 524 in the table of sections at the beginning of chapter 5 of such title is amended to read as follows: ``524. Duties of the General Services Administration and executive agencies.''. SEC. 3. ENHANCED AUTHORITIES WITH REGARD TO PREPARING PROPERTIES TO BE REPORTED AS EXCESS. Section 572(a)(2) of title 40, United States Code, is amended-- (1) by redesignating subparagraphs (B) and (C) as subparagraphs (C) and (D), respectively; and (2) by inserting after subparagraph (A) the following new subparagraph: ``(B) Additional authority.--(i) From the fund described in paragraph (1), subject to clause (iv), the Administrator may obligate an amount to pay the direct and indirect costs related to identifying and preparing properties to be reported excess by another agency. ``(ii) The General Services Administration shall be reimbursed from the proceeds of the sale of such properties for such costs. ``(iii) Net proceeds shall be dispersed pursuant to section 571 of this title. ``(iv) The authority under clause (i) to obligate funds to prepare properties to be reported excess does not include the authority to convey such properties by use, sale, lease, exchange, or otherwise, including through leaseback arrangements or service agreements. ``(v) Nothing in this subparagraph is intended to affect subparagraph (D).''. SEC. 4. ENHANCED AUTHORITIES WITH REGARD TO REVERTED REAL PROPERTY. (a) Authority To Pay Expenses Related to Reverted Real Property.-- Section 572(a)(2)(A) of title 40, United States Code, is amended by adding at the end the following: ``(iv) The direct and indirect costs associated with the reversion, custody, and disposal of reverted real property.''. (b) Requirements Related to Sales of Reverted Property Under Section 550.--Section 550(b)(1) of title 40, United States Code, is amended-- (1) by inserting ``(A)'' after ``(1) In general.--''; and (2) by adding at the end the following: ``If the official, in consultation with the Administrator, recommends reversion of the property, the Administrator shall take control of such property, and, subject to subparagraph (B), sell it at or above appraised fair market value for cash and not by lease, exchange, leaseback arrangements, or service agreements. ``(B) Prior to sale, the Administrator shall make such property available to State and local governments and certain non-profit institutions or organizations pursuant to this section and sections 553 and 554 of this title.''. (c) Requirements Related to Sales of Reverted Property Under Section 553.--Section 553(e) of title 40, United States Code, is amended-- (1) by inserting ``(1)'' after ``This Section.--''; and (2) by adding at the end the following: ``If the Administrator determines that reversion of the property is necessary to enforce compliance with the terms of the conveyance, the Administrator shall take control of such property and, subject to paragraph (2), sell it at or above appraised fair market value for cash and not by lease, exchange, leaseback arrangements, or service agreements. ``(2) Prior to sale, the Administrator shall make such property available to State and local governments and certain non-profit institutions or organizations pursuant to this section and sections 550 and 554 of this title.''. (d) Requirements Related to Sales of Reverted Property Under Section 554.--Section 554(f) of title 40, United States Code, is amended-- (1) by inserting ``(1)'' after ``This Section.--''; and (2) by adding at the end the following: ``If the Secretary, in consultation with the Administrator, recommends reversion of the property, the Administrator shall take control of such property and, subject to paragraph (2), sell it at or above appraised fair market value for cash and not by lease, exchange, leaseback arrangements, or service agreements. ``(b) Prior to sale, the Administrator shall make such property available to State and local governments and certain non-profit institutions or organizations pursuant to this section and sections 550 and 553 of this title.''. SEC. 5. AGENCY RETENTION OF PROCEEDS. The text of section 571 of title 40, United States Code, is amended to read as follows: ``(a) Proceeds From Transfer or Sale of Real Property.--Net proceeds described in subsection (d) shall be deposited into the appropriate real property account of the agency that had custody and accountability for the real property at the time the real property is determined to be excess. Such funds shall be expended only as authorized in annual appropriations Acts and only for activities as described in section 524(b) of this title and disposal activities, including paying costs incurred by the General Services Administration for any disposal-related activity authorized by this title. Proceeds may also be expended by the agency for maintenance and repairs of the agency's real property necessary for its disposal or for the repair or alteration of the agency's other real property, provided that proceeds shall not be authorized for expenditure in an appropriations Act for any repair or alteration project that is subject to the requirements of section 3307 of this title without a prospectus submitted by the General Services Administration and approved by the Committee on Transportation and Infrastructure of the House of Representatives and the Committee on Environment and Public Works of the Senate. ``(b) Effect on Other Sections.--Nothing in this section is intended to affect section 572(b), 573, or 574 of this title. ``(c) Disposal Agency for Reverted Property.--For the purposes of this section, for any real property that reverts to the United States under sections 550, 553, and 554 of this title, the General Services Administration, as the disposal agency, shall be treated as the agency with custody and accountability for the real property at the time the real property is determined to be excess. ``(d) Net Proceeds.--The net proceeds referred to in subsection (a) are proceeds under this chapter, less expenses of the transfer or disposition as provided in section 572(a) of this title, from a-- ``(1) transfer of excess real property to a Federal agency for agency use; or ``(2) sale, lease, or other disposition of surplus real property. ``(e) Proceeds From Transfer or Sale of Personal Property.--(1) Except as otherwise provided in this subchapter, proceeds described in paragraph (2) shall be deposited in the Treasury as miscellaneous receipts. ``(2) The proceeds described in this paragraph are proceeds under this chapter from-- ``(A) a transfer of excess personal property to a Federal agency for agency use; or ``(B) a sale, lease, or other disposition of surplus personal property. ``(3) Subject to regulations under this subtitle, the expenses of the sale of personal property may be paid from the proceeds of sale so that only the net proceeds are deposited in the Treasury. This paragraph applies whether proceeds are deposited as miscellaneous receipts or to the credit of an appropriation as authorized by law.''. SEC. 6. DEMONSTRATION AUTHORITY. (a) In General.--Subchapter II of chapter 5 of title 40, United States Code, is amended by adding at the end the following new section: ``Sec. 530. Demonstration program of inapplicability of certain requirements of law ``(a) Authority.--Effective for fiscal years 2009 and 2010, the requirements of section 501(a) of the McKinney Vento Homeless Assistance Act (42 U.S.C. 11411(a)) shall not apply to eligible properties. ``(b) Eligible Properties.--A property is eligible for purposes of subsection (a) if it meets both of the following requirements: ``(1) The property is selected for demolition by an agency and is a Federal building or other Federal real property located on land not determined to be excess, for which there is an ongoing Federal need, and not to be used in any lease, exchange, leaseback arrangement, or service agreement. ``(2) The property is-- ``(A) located in an area to which the general public is denied access in the interest of national security and where alternative access cannot be provided for the public without compromising national security; or ``(B) the property is-- ``(i) uninhabitable; ``(ii) not a housing unit; and ``(iii) selected for demolition by an agency because either-- ``(I) the demolition is necessary to further an identified Federal need for which funds have been authorized and appropriated; or ``(II) the property poses risk to human health and safety or has become an attractive nuisance. ``(c) Limitations.-- ``(1) No property of the Department of Veterans Affairs may be considered an eligible property for purposes of subsection (a). ``(2) With respect to an eligible property described in subsection (b), the land underlying the property remains subject to all public benefit requirements and notifications for disposal. ``(d) Notification to Congress.--(1) A list of each eligible property described in subsection (b) that is demolished or scheduled for demolition, by date of demolition or projected demolition date, shall be sent to the congressional committees listed in paragraph (2) and published on the Web site of the General Services Administration biannually beginning 6 months after the date of the enactment of this section. ``(2) The congressional committees listed in this paragraph are as follows: ``(A) The Committee on Oversight and Government Reform and the Committee on Transportation and Infrastructure of the House of Representatives. ``(B) The Committee on Homeland Security and Governmental Affairs and the Committee on Environment and Public Works of the Senate. ``(e) Relationship to Other Provisions of Law.--Nothing in this section may be construed as interfering with the requirement for the submission of a prospectus to Congress as established by section 3307 of this title or for all demolitions to be carried out pursuant to section 527 of this title.''. (b) Clerical Amendment.--The table of sections at the beginning of chapter 5 of title 40, United States Code, is amended by inserting after the item relating to section 529 the following new item: ``530. Demonstration program of inapplicability of certain requirements of law.''.

Federal Real Property Disposal Enhancement Act of 2009 - Requires the Administrator of the General Services Administration (GSA) to: (1) issue guidance for federal agency real property plans, including recommendations on how to identify and dispose of excess properties, evaluate disposal costs and benefits, and prioritize disposal decisions based on agency missions and anticipated future need for holdings; (2) report to specified congressional committees annually for five years on agency efforts to reduce their real property assets; and (3) assist agencies in the identification and disposal of excess real property. Includes among the amounts the Administrator is authorized to obligate from proceeds from the disposition of excess real property: (1) amounts to pay the costs related to identifying and preparing properties to be reported excess by another agency; and (2) amounts to pay the costs associated with the reversion, custody, and disposal of reverted real property. Revises requirements for federal agency retention of proceeds from the transfer or sale of excess real property. Provides that requirements under the McKinney Vento Homeless Assistance Act for the use of public buildings and real property to assist the homeless shall not apply to certain non-excess federal buildings or real property selected for demolition.

infrared ( ir ) radiation , due to thermal emission from dust grains , is a key feature of star - forming regions . these grains play an important role in the chemistry , thermal balance , and evolution of these regions . this role , coupled with the ability for ir radiation to escape from areas of high optical depth , makes the determination of source parameters through the study of ir observations of great importance . the problem of obtaining source parameters from the ir observations is a difficult one . as a result , it is important to study and evaluate the analysis methods used to judge their value and regimes of validity . in general , the analysis of ir observations can be broadly broken into two groups . the first approach relies upon the use of relatively simple , semi - analytic expressions which are derived from idealized and simplified approximations and assumptions ( see e.g. hildebrand 1983 ) . it has been shown previously that the strict use of this approach may lead to interpretations which are ambiguous or erroneous ( see e.g. , schmid - bergk & scholz 1976 ; butner et al . 1991 ; doty & leung 1994 ; menshcikov & henning 1997 ; shirley , et al . the second approach involves the construction ( usually a grid ) of detailed , self - consistent radiative transfer models for the computation of model spectra and comparison with observations . while such codes are available for use by the general community ( e.g. csdust3 by egan , leung , & spagna 1983 ; dusty by ivezic , nenkova , & elitzur 1999 ) , constructing such models requires substantial time and effort . as a result , the first approach remains a common choice . in this paper we critically evaluate semi - analytic methods of analysis of ir observations of star - forming regions . here we consider internal and externally heated dust clouds as analogues of early - type star - forming regions . in particular , we examine the usual assumptions of homogeneities in density and temperature , as well as the neglect of opacity effects when applied to externally heated ir sources . we do this by constructing a series of realistic models of these regions , treating the model output as simulated observations . we then apply common semi - analytic methods to infer the source properties , and compare them to those used in constructing the models . the discrepancies between the input and inferred source properties yield a measure of the limitations of the semi - analytic methods used . the outline of this paper is as follows . in section 2 we summarize the problem and current methods of analysis . we describe the models run and testing procedure in section 3 . in section 4 , we discuss the role and determination of the dust temperature . we consider the dust mass in section 5 . in section 6 we discuss the determination of the dust opacity function . we consider the determination of the dust density distribution in section 7 . finally , in section 8 , we summarize and draw conclusions from this study . for a spherically symmetric dust shell , the specific luminosity , defined to be the amount of energy emitted per unit frequency per unit time can be written as @xmath3 e^{-\tau ( \nu , r ) } n(r)4 \pi r^2 ~ \mathrm{d}r}.\ ] ] here @xmath4 $ ] is the planck function at the dust temperature , @xmath5 , and @xmath6 , @xmath7 , and @xmath8 are the optical depth , grain absorption coefficient , and density distribution respectively as defined below . the density distribution and the grain absorption cross section are both assumed to be power laws with indices @xmath9 and @xmath10 , given by @xmath11 and @xmath12 respectively . the optical depth , @xmath6 , at a radius @xmath13 is defined as @xmath14 for convenience , we define the optical depth in the visible to be @xmath15 . in order to evaluate the specific luminosity explicitly , the temperature distribution , @xmath5 , density distribution , and grain properties need to be known . for this reason , it is common to assume that sources are isothermal and optically thin . in this limit , equation ( 1 ) simplifies to @xmath16 and can then be solved analytically if the density distribution is known or assumed to be known . from equation ( 5 ) we can derive semi - analytic expressions for many of the source parameters , as discussed below . as stated above , it is common to assume that sources are isothermal ( see , e.g. , launhardt et al . 1996 ) . in order to determine the temperature of such a source , wiens law denoting the peak of an unmodified blackbody spectrum ( @xmath17 ) is often used ( assuming an isothermal source as in eq . [ 5 ] ) , @xmath18 it is also possible to find the temperature by fitting the flux spectrum ( see sect 2.4 ) . in practice this takes many forms , depending upon the quantity and quality of data available for a given source . these approaches range from fitting the observed flux at a single wavelength point to find a single equivalent brightness temperature ( e.g. henning et al . 2000 ) , to using a two - wavelength effective color temperature ( e.g. grady et al . 2001 ) to fitting the flux spectrum with a single temperature greybody ( e.g. , siebenmorgen , krgel , & chini 1999 ) , to using two temperature components ( e.g. , krgel et al . 1998 ; ward - thompson et al . 2000 ) . in many cases , the dust properties are assumed to be known _ a priori _ ( e.g. , krgel et al . 1998 ; henning et al . 2000 ) , though they are sometimes determined directly from the observations ( see e.g. , launhardt , ward - thompson , & henning 1997 ; voshchinnikov & krgel 1999 ; abraham et al . 2000 ; and sect 2.4 ) . assuming a dust grain mass @xmath19 , the total dust mass of the source is @xmath20 in the optically thin and isothermal limits , the dust mass can be expressed in terms of the specific luminosity ( see eq . [ 5 ] ) by @xmath21 by expressing the specific luminosity in terms of the observed flux , @xmath22 , and the distance to the source , @xmath23 , the mass can be written as @xmath24 ( hildebrand 1983 ; in various forms by , e.g , beichman et al . 1990 , launhardt et al . 1996 ; siebenmorgen , krgel , & chini 1999 ) . as can be seen , the dust mass can be determined from the observed flux and an estimate of the distance to the source . unfortunately , this requires a good estimate of both the dust temperature ( see sect . 4 ) and grain opacity function ( see sect . 6 ) for an accurate dust mass estimate . the mass of the dust can also be determined by the spectral energy distribution ( doty and leung 1994 ) . the energy emitted from the dust is simply a reprocessing of the energy that the dust has absorbed . as a result , in an optically thin source the total emission is related to the total amount absorbed , which varies with optical depth or dust mass . @xmath25 assuming that the temperature is not a function of the dust mass . for an optically thin source and when the rayleigh jeans approximation ( @xmath26 ; rja ) holds , the specific luminosity becomes @xmath27 by taking the ratio of luminosities at two different frequencies , the opacity index , @xmath10 can be determined ( helou 1989 ) as @xmath28 - 2.\ ] ] an interesting predictor - corrector - like iteration method was utilized by siebenmorgen , krgel , & chini ( 1999 ) . in this approach , previous greybody models of similar sources were used to guess a single dust temperature . this was used to infer a dust opacity index , @xmath10 . given this value of @xmath10 the data were fit to find @xmath29 . finally , the corrected value dust temperature was used to find a final value for @xmath10 . while each step of the iteration used methods / assumptions described elsewhere here , the iterative approach helped to break the degeneracy between temperature and dust opacity . on the other hand , given the power of modern computers , and the large amounts of high quality far - infrared and submillimeter data becoming available for many sources , it is possible to consider the coupled problem and determine the temperature and the opacity index by fitting the observed spectrum ( see , e.g. , krugel et . al . 1998 ; ward - thompson et al . 2000 ; abraham et al . 2000 ) . for an isothermal , optically thin source , the specific luminosity can be written as @xmath30 where @xmath31 , @xmath32 , and @xmath33 become fitting parameters . here , the density distribution is incorporated into @xmath31 , the temperature is @xmath32 , and the opacity index , @xmath10 , is @xmath33 . to compute values for the fitting parameters , the chi - squared @xmath34 ^ 2/\sigma^2(i),\ ] ] is minimized for a given set of frequencies . the uncertainty in the measure of luminosity ( @xmath35 ) is defined by the parameter @xmath36 . we have only considered the case where the uncertainty is equal to a small fraction of @xmath35 ( doty and leung 1994 ) . this has the effect of equally weighting each point in the spectrum . if a resolved source is assumed to be isothermal along any line of sight , the mean intensity can be written as @xmath37 adopting a power law form for the optical depth , @xmath38 , and taking the ratio at two different frequencies , equation ( 15 ) is then @xmath39 assuming that the optical index , @xmath10 , is known ( see sect . 6 ) , a temperature can be found given a ratio of intensities . using this temperature in equation ( 15 ) will yield the optical depth for that frequency and line of sight . the optical depth at a given impact parameter is related to the column density , @xmath40 , along that line of sight . therefore , the form of the optical depth map will be the same form as a column density map for the same source . finally , the power law form for the column density , @xmath41 , can be related to the power law form of the density distribution , @xmath42 ( tomita et al . 1979 ) where @xmath43 . as yun and clemens ( 1991 ) point out , however , this is only appropriate for an infinite source . as one probes closer to the edge of a finite source , the column density along each line of sight approaches zero . thus , when fitting these outer radii , @xmath44 is artificially increased . it is possible to relate the theoretical column density to the density power index by @xmath45 where @xmath46 is an impact parameter and @xmath47 is the distance along the line of sight . for different values of the density distribution index , a column denisty map is formed . following yun and clemens ( 1991 ) , by matching the derived column density map with the calculated map , a value of @xmath9 can be found . in order to evaluate the reliability of current semianalytic methods of analysis one must compare the derived source parameters with their true values . as the source parameters for actual observations are not known , we have created simulated observations using a modified version of the 1d radiative transfer code of egan , leung @xmath48 spagna ( 1988 ) . the output of these models are treated as observational data and analysed using current techniques to derive the source parameters . these derived results can then be compared with the original model parameters . any differences between the two sets of data can be attributed to the method of analysis . we model sources in the interstellar medium that are predominantly heated extenally by the interstellar radiation field . regions of star formation , such as many dark clouds or bok globules , are the primary motivation . the processes involved in low - mass star formation are relatively well understood ( see e.g. review by shu , adams , & lizano 1987 ) . on the other hand , while the picture is not as complete in the high - mass case ( see e.g. churchwell 1993 , 1999 ) , recent work ( van der tak et al . 2000 ; doty et al . 2002a ) seems to suggest that in general similar scalings may be at least potentially reasonable . in both situations , an understanding of the source parameters ( dust properties , material distribution , existence / nature of an embedded star ) are important ( see e.g. , andre , ward - thompson , & barsony 2000 ) . typical model parameters are given in table 1 . .model parameters [ cols="<,<",options="header " , ] + in our models , we consider both internal and external heat sources . externally we use the interstellar radiation field ( isrf ) of mathis , mezger , @xmath48 panagia ( 1983 ) as the primary source of heating of the dust grains . we have also considered the effects of an updated isrf compiled by evans ( 2001 ) for comparison . this results in no significant qualitative difference in our results . to study the effects of young stellar objects ( ysos ) , protostars , and other embedded sources , we have also considered embedded sources with luminosities ranging from @xmath49 . the distribution of material in a star forming region is a topic of continuing study . both theoretical ( e.g. , larson 1969 ; shu 1977 ) and observational ( e.g. , fuller & myers 1993 ; van der tak et al . 1999 ; evans et al . 2001 ) studies suggest that the density distribution can be well fit by a power law . on the other hand , recent work ( e.g. , henriksen , andre , & bontemps 1997 ; alves , lada , & lada 2001 ; whitworth & ward - thompson 2001 ) predict / infer more realistic density profiles , including multiple power laws and bonner - ebert spheres . observations and detailed modeling by evans et al . ( 2001 ) for a number of star - forming sources suggest that it may not always yet be possible to observationally distinguish between power - laws and bonner - ebert spheres . as a result , and as we wish to provide a simple yet somewhat realistic parameterization , we restrict our study here to power laws as given in equation ( 2 ) . based upon models for cloud collapse and observations of star - forming regions ( e.g. , shu 1977 ; whitworth & summers 1985 ; foster & chevalier 1993 ; chandler & sargent 1993 ; ward - thompson et al . 1994 ; andre et al . 1993 ) , we model sources with density distribution indices in the range @xmath50 , namely @xmath51 , @xmath52 , and @xmath53 . we arbitrarily take the outer shell radius to be @xmath54 pc , and the ratio of the inner and outer radii to be @xmath55 . this choice of inner radius is chosen to usually yield dust temperatures of @xmath56 . we find that the choice of outer radius has little effect on the resulting spectra . we take the grain opacity function to be a power law of frequency as given in equation ( 3 ) . laboratory experiments show that for crystalline grain material , @xmath57 and for amorphous grain material , @xmath58 ( see e.g. , tielens @xmath48 allamandola 1987 ; henning , michel , stognienko 1995 ; agladze et al . 1996 ; jager , mutschke , & henning 1998 ; fabian et al . cox and mezger ( 1989 ) have shown that for @xmath59 , the general behavior of the opacity function should be covered in our models . consequently , we take a value of @xmath60 . we normalized our opacity function to draine s ( 1985 ) values at 2.2@xmath61 for the scattering component and at 190@xmath61 for the absorption component . these grain properties not only generally represent laboratory data , but they also have the advantage that they reproduce observations of at least orion quite well ( doty & neufeld 1997 ) . typical flux spectra for sources of varying luminosity and density distributions are shown in fig . 1 . in fig . 2 we show typical temperature distribution for sources of varying luminosity and density distributions . upon integrating equation ( 5 ) over all frequencies , it can be seen that the thermal energy density varies as @xmath62 . as a result , a small change in temperature translates into a large change in the emergent spectrum . therefore , it is very important to determine the temperature distribution ( doty and leung 1994 ; shirley et al . 2000 ) . the effect of different temperature distributions can be seen in figs . 1 and 2 . the peak wavelength of emission as well as the width of the spectra are affected by the dust temperature distribution . for the low luminosity embedded sources , the spectrum for the @xmath63 density distribution peaks at shorter wavelengths than the spectra for models with @xmath64 and @xmath65 . this is consistent with the corresponding temperature distributions in fig . 2 , where the @xmath63 models are generally warmer . on the other hand , for the low luminosity embedded sources , the more uniform sources having @xmath65 and @xmath64 have a greater range of temperatures , and in general have cooler dust . the range in temperatures results in a wider spectrum in fig . 1 . this effect is also seen when comparing the models with @xmath66 with those of lower luminosity . in this case , the central source heats the dust to 800 - 1000k on the inner edge , producing a very large range of dust temperatures in the envelope . the highest temperatures occur with increasing optical depth and density distribution index , @xmath9 , due to radiation trapping in the interior . conversely , the inner dust temperature for a source with either no or a low luminosty central source is between 5 - 15 k with the higher temperatures resulting from a lower optical depth and a higher density distribution index , @xmath9 . these temperatures are not seen in fig . 2 due to the axes chosen for the plot . the corresponding emission spectra of the high luminosity cases both peak at a higher flux and have emission over a broader range of wavelengths . as the intensity along a ray depends upon the temperature - dependent emissivity integrated along the line of sight , it is difficult to determine the temperature distribution in regions of star formation . as a result , it is easiest to assume the source is isothermal . this assumption is best suited for sources which have either no embedded source , or only a very low luminoity central source . as seen in fig . 2 , the temperature distribution is about constant for more than @xmath67 per cent of the source for such cases . when the distribution is not constant , it only changes by 2 - 5 k. on the other hand , for higher luminosity central sources the range of temperatures is 800 - 1000 k. in order to determine the appropriate isothermal temperature to assign to a given source , it is often easiest to consider the peak of the spectrum . we accomplish this using a wiens law modified to account for the wavelength dependance of the absorption coefficient , @xmath68 . in general , the peak of the emergent spectrum ( @xmath69 ) for an opacity index @xmath10 can be given by @xmath70 here @xmath71 is determined numerically , with results shown in fig . 3 . as can be seen , the results are well - fit by @xmath72 with a correlation coefficient of @xmath73 for the range @xmath74 . in the case that @xmath75 ( see sect . 6 below ) , we find that @xmath76 . this temperature can then be compared to other physical temperatures associated with the source . in this way it is possible to know what meaning , if any , can be assigned to this forced isothermal temperature . one temperature used for comparison is the number - weighted grain average temperature defined as @xmath77 this temperature is the average grain temperature . another comparison may be made with the energy - weighted temperature defined as @xmath78^{4+\beta}n(r)4 \pi r^2 ~ \mathrm{d}r } } { \int{n(r)4 \pi r^2 ~\mathrm{d}r}}\right)^{1/(4+\beta)}.\ ] ] physically , this temperature represents the average energy emitted by a grain . in all models tested , except @xmath63 , @xmath66 as discussed below , the peak temperature inferred from equation ( 18 ) does not vary more than 0.5 k from @xmath79 . this can be understood as due to the fact that most of the energy is radiated at a wavelength corresponding to the peak emission and so the corresponding temperature should be about the energy - weighted temperature . also , the temperature agrees well with @xmath80 . in fig . 4 , we plot @xmath81 as a function of the optical depth of the model for cases of different central luminosity . the one outlying result is the @xmath63 case with a highly luminous embedded source having @xmath82 . in this case , the average difference between the inferred and number - weighted dust temperature is about 50k . this difference can be understood by the fact that in a centrally condensed source more dust will be affected by a central heat source . consequently , the peak of the spectrum is shifted to shorter wavelengths , and is due to the central source rather than by the isrf . as a result , the inferred temperature from the peak of the flux spectrum is considerably too high and inapplicable to the problem at hand . in all other cases in fig . 4 , the isrf dominates the majority of the dust heating , and a few trends are immediately obvious . as optical depth increases , so does @xmath83 , although the largest difference is 1 k. for @xmath84 the difference is at most 0.6 k. in conclusion , deriving the dust temperature using a modified wiens law will give a temperature that closely relates both the average energy and the average grain temperature . in order to see the effect of using an isothermal temperature on the emergent spectra , in fig . 5 we plot both the output spectra and a blackbody modified by the absorption coefficient , normalized at the peak in the left panels . in the right panels we plot the fractional difference between the blackbody spectrum and the actual emergent spectrum . for the longer wavelength portion of the spectrum , the derived blackbody spectrum is at most about @xmath85 per cent in error , with larger discrepancies occuring at a smaller density distribution index , @xmath9 . the @xmath86 case is within @xmath87 per cent , and the @xmath88 case is within @xmath89 per cent . for wavelengths shorter than the peak , the errors tend to get worse . in the @xmath63 case , the errors reach only about @xmath90 per cent , while for the @xmath88 and @xmath65 cases , the errors can reach over @xmath91 per cent . as the luminosity of an embedded source increases , stellar emission makes it difficult to fit the spectrum with a single temperature blackbody . it should be noted that fig . 5 shows the most favorable case for a single temperature fit , since the lack of any internal heat source makes this the most isothermal of all the models . as a result the other ( @xmath92 ) cases will be even more poorly fit by a single temperature . although the peak of the output spectrum is a reasonable estimate for either the number- or energy - weighted average dust temperature for regions without strong internal sources , these single temperatures do not represent the actual temperature distribution in the region . as a result , isothermal fits do not generally duplicate the output spectra to better than @xmath87 per cent . consequently , probes that may be sensitive to the range of dust temperatures in a region may require self - consistent radiative transfer modeling . if the mass of a single grain is @xmath93 , then the total dust mass is given by @xmath94 knowledge of the density distribution , @xmath8 , is necessary to determine the dust mass exactly , without assumptions . although the form can be approximated by a power law , its evaluation requires knowledge of both @xmath95 and @xmath96 , which are the inner radius and the amount of dust at the inner radius respectively . these quantities are unknown , suggesting the use of more approximate methods based upon dust emission . the total integrated luminosity measures the total energy emitted per unit time and is given by @xmath97 since dust grains can only emit what they absorb , the total energy emitted should be proportional to the optical depth , or dust mass , of the source . a relative mass can therefore be determined by taking the ratio of luminosities of two different sources . the two basic underlying assumptions here is that the sources are optically thin to the radiation of interest and that the two sources being compared share the same temperature distribution . only then will the dust mass be proportional to the total emitted energy . we test this method by calculating the dust mass for a series of models of increasing optical depth and different central luminosities . we normalize the models to the value at @xmath98 . in fig . 6 , we plot the normalized fractional difference in mass , @xmath99 , defined as @xmath100 for varying optical depths . the dust masses inferred by this method are consistenly lower than the actual dust masses for the same sources . the median error is about @xmath67 per cent with errors as great as @xmath101 per cent ( i.e. a factor of @xmath102 ) . the discrepancy increases with the optical depth , and plateaus at higher optical depths regardless of the luminosity . the plateau for @xmath103 is due to the fact that the sources are no longer transparent to most ir radiation . as the optical depth increases a greater percentage of incident energy from the isrf is absorbed . eventually , at high enough optical depths , all of the possible radiation will be absorbed leading to a constant total luminosity and hence an inferred mass independent of @xmath104 . this effect is less dramatic in the @xmath86 case because most of the mass is centrally condensed , and therefore only radiation that penetrates to the center of the source will be absorbed . the consistently lower results can be understood in the following way . the luminosity is proportional to the density distribution times the energy emitted per grain , which is the blackbody function modified by the absorption coefficient . in order for the luminosity to be truly proportional to the optical depth the energy emitted per grain needs to be the same for the two sources being ratioed . however , as the optical depth increases , the ability for radiation to heat the inside of the source attenuates as @xmath105 , and so the temperature distribution between sources of different optical depths are no longer going to be the same . therefore , the actual luminosity does not increase as quickly as the luminosities predicted using this method and hence , the results are consistently lower . for the @xmath63 case , the differences in the cases with different luminosities can be explained as follows . most of the mass is located to the inside , and therefore most of the optical depth is located there as well . therefore , a majority of the source will be optically thin and so the same majority of the source will be heated to a constant temperature . this helps explain why the results for these cases are better than for the @xmath64 and @xmath65 cases . hildebrand ( 1983 ) proposed that the dust mass of an optically thin and isothermal source can be related to the observed flux of a given frequency and distance to the source via equation ( 9 ) . in order to calculate the total dust mass , the mass of a grain , isothermal temperature , and @xmath106 need to be calculated or estimated . to alleviate this problem , we take the ratio of dust mass for similar sources . in this way , the only parameter that needs to be estimated is the temperature , which we calculate using the modified wiens law in equation ( 18 ) . we use the wavelength of peak emission as the wavelength in equation ( 9 ) . to evaluate this method we calculate the dust mass for a series of models of increasing optical depths and different central luminosities , and compare them to the actual values . we plot the fractional difference as a function of optical depth in fig . 7 . the results are quite good . a median error of about @xmath107 per cent is found for @xmath65 , with errors between @xmath108 per cent depending on the central luminosity for @xmath64 , and approximately @xmath87 per cent errors for @xmath63 . as the optical depth increases , the differences also tend to increase . as was the case for calculating temperature , the mass inferred in the @xmath63 , @xmath109 @xmath110 model is a factor of 50 times higher than the actual mass . the error is due to the inability to determine accurately an average temperature of the source . in most cases , as the luminosity increases , the error increases as well . however , in the case of @xmath64 , @xmath111 we find that the errors are less than without an embedded star . with a constant density distribution , a larger proportion of the mass is found to the outside of the source and so there is a larger change in temperature to the outside of the source ( see fig . however , when there is an embedded star with a high luminosity , the rest of the source is heated and it causes a smaller change in temperature to the outside of the source , giving the appearance of a more isothermal source ( see figs 2 and 4 ) . the grain opacity index , @xmath10 , defines the form of the opacity function . the effects are also evident in the flux spectrum . a lower @xmath10 has the effect of increasing the amount of emission at wavelengths longer than the visible range relative to the emission in the visible . therefore , a lower optical index will broaden the spectrum . conversely , a higher @xmath10 has the effect of narrowing the spectrum . a more common , and potentially easier method for determining @xmath10 is to use the ratios of luminosities from two different wavelengths , as shown in equation ( 12 ) . this method relies on two assumptions : that the rja holds , and that the source is optically thin . again , we have evaluated this technique for models of increasing optical depths and different luminosities . 8 shows the opacity index derived between a reference wavelength , denoted by the various symbols , and a variety of longer wavelengths . our results are consistently lower that the actual value but asymptotically approach it for longer wavelengths . the source is still optically thin over the wavelength range we are looking ( at @xmath112 , @xmath113 ) and so the deviations are due to the rja . the presence of a temperature distribution has the effect of adding up multiple blackbodies . the rja will only hold true if we are on the long wavelength end of a blackbody corresponding to the coolest dust . for the coolest dust in our models ( @xmath114 k ) , the shortest wavelength that satisfies the rja is @xmath115 . as can be clearly seen in fig . 8 , there is some wavelength short of which the inferred opacity indicies are inapplicable . we call this wavelength the cutoff wavelength , and define it to be the shortest wavelength in the pair used in equation ( 12 ) for which @xmath10 is determined to within @xmath85 per cent . in fig . 9 , we plot @xmath116 as a function of optical depth for the models considered . we see that in general , wavelengths greater than @xmath117 should be used in determining @xmath10 from the slope of the fir spectrum , so long as the dust continuum dominates the free - free emission a significant problem in some sources . these results can be considered a means of inferring the validity of the rja . the opacity index may also be determined by treating it as a fitting parameter while fitting the spectrum . it is easiest and somewhat common ( see e.g. , mccarthy , forrest , & houck 1978 ; sopka et al . 1985 ) to assume an isothermal source in making these fits . while this makes the fitting easier , it also removes the effect that the temperature distribution has on the width of the spectrum . consequently , the derived opacity indices are artificially raised to compensate . to try and alleviate this problem , we have only fit the longer wavelength end of the spectrum as it should be more optically thin , as well as sample the cooler ( and hence more isothermal ) dust . this can be seen in fig . 1 where we see that a star does not have a significant effect on the presence of the spectrum at longer wavelengths . based upon this reasoning , and with the advent of recent and upcoming far ir / submm observational data ( e.g. scuba , sirtf , herschel , etc . ) we fit the wavelength range @xmath118 for models of different density distributions and increasing optical depth shown in table 1 . our results are shown in fig . 10 . the errors in this method range from @xmath119 to @xmath120 per cent . in the case of @xmath88 and @xmath53 , the derived indices are too high , with slightly better results as the optical depth increases . for the @xmath65 case , the derived indices are too high by about @xmath121 per cent for optical depths @xmath84 , and at an optical depth of @xmath122 the derived indices are too low by @xmath89 per cent . for luminosities @xmath123 , the derived opacities follow the same trend as the starless core models . but for luminosities @xmath124 , the derived opacity indices tend to be lower , and more accurate by an average of @xmath67 per cent . even at @xmath125 , the star affects the spectrum noticeably ( see fig . 1 ) . the spectrum is artificially broadened by the star , and thus the derived opacities are lowered . in effect , the errors caused by the isothermal assumption are counteracted by the extra luminosity from an embedded star . in order to account for the non - isothermal nature of the sources , we also fit the spectrum with two blackbodies . this simulates a two - temperature core - halo model , with a warm exterior shell heated by the isrf , and a cool interior shell . these fits reduced our error to a maximum of @xmath121 per cent . however , the five fitting parameters make it more difficult to obtain reasonable results due to the presence of local minima , with the accuracy of the fitting depending more significantly on the initial guess for the parameters . in this case , the fits have a maximum error of 0.1 in @xmath10 , with most having errors of 0.05 or less , representing a median error of @xmath126 per cent . we also considered the use of different wavelength ranges on the derived opacity indices . we did not test the use of shorter wavelengths , due to contamination of the spectrum by the embedded sources . using the range from @xmath127 to the end of the spectrum ( about @xmath128 ) , the derived indices are uniformly low for a single blackbody fit , with an average @xmath129 . this effect is due to the addition of emission from the coolest dust , which causes the spectrum to broaden past @xmath130 . therefore , even when longer wavelengths are chosen , the results are not appreciably better , as multiple tempertures are still sampled . the density distribution is crucial to our understanding of the processes and regions of star formation . both observations and theory indicate that typical distributions can be well - described by a power law . as a result we assume a power law distribution in all of our models . the density index , @xmath9 , helps to determine the emergent radiation of a source . a centrally condensed source ( @xmath86 ) is less affected by the isrf and more affected by embedded sources . in contrast , a constant distribution ( @xmath65 ) is affected by the isrf more than by an embedded star ( see fig . 1 ) . yun and clemens ( 1991 ) extended a note by tomita et al . ( 1979 ) regarding the relationship of the column density power index to the density distribution power index . using equation ( 17 ) , a column density map can be formed from the density distribution index . by matching the derived and calculated column density profiles @xmath9 can be constrained . to test the reliability of this method we have calculated the density distribution index for a series of models with different density distributions , optical depths , and central luminosities . we consider the wavelengths of @xmath131 and @xmath132 , as they should be near the peak of emission . as the effects of beamsize are instrument - dependent , and may potentially confuse the analysis , we consider an infinitely small pencil beam for most of this work in order to keep the possible sources of uncertainty to a minimum . based upon the difficulty in determining an edge to the source , and based upon our experience in these fits , we find that choosing impact parameters in the range @xmath133 provide the optimal fits over a wide range of source parameters . we also tested different impact parameters , both closer to the center , and out towards the edge . we found that both of these cases gave poor results . as the beam probes closer to the edge , part of the beam is off the source . as a result there is an artificial lowering in the calculation of the column density . as the beam probes toward the center , the contamination of the spectrum by the embedded source yields poor results . in fig . 11 , we plot @xmath134 for the conditions discussed above . we find that the results are moderate at best . we find a median @xmath135 of @xmath136 , which corresponds to a difference from as low as @xmath90 per cent to over @xmath91 per cent . the maximum deviations range between 0.5 and 0.8 , corresponding to fractional differences between @xmath107 per cent to over @xmath91 per cent . in the @xmath86 case , we see that the results are good for the low luminosities and optical depths . this is due to the fact that the source is fairly isothermal in these cases . as the optical depth increases , the inferred density distribution index also tends to worsen . this is because at higher optical depths , the temperature gradient is larger . the problem is not due to the optical depth because the source is transparent at these wavelengths . for the high luminosity case , we find that the values are not as good as the low luminosity cases at low optical depths , but tend to be slightly better as optical depth increases . we find that generally @xmath137 , meaning that the inferred index is greater than the actual index . this is because we see a slight increase in temperature towards the center and so we get more emission at smaller radii . as a result , we infer more mass towards the center , giving us a larger distribution index . we find that the @xmath88 case is harder to understand . we find that for no embedded star that there is a monatomic decrease in temperature . as a result we have more inferred mass towards the outside , artificially lowering the index . in the @xmath65 case , the results are uniformly too high with a median difference of 0.4 . the high luminosity case did not produce any results . for comparison , we have also tested the effects of using longer wavelengths of @xmath138 and @xmath139 , for comparison with general wavelength ranges probed by scuba and other recent observations . we find that using these wavelengths results in somewhat worse results . in particular , the resulting mean differences between the density distribution indicies inferred at these longer wavelengths and those inferred near the peak of the spectrum are @xmath140 , @xmath89 , and @xmath85 per cent for @xmath141 respectively . in all cases , the indicies inferred near the peak of the flux spectrum provide more accurate results . we also tested the effects of different beam sizes by varying the beam size from 15 arcsec to 4 arcmin ( roughly from scuba to iras beam sizes ) , corresponding to roughly 60 and 4 beams across the source respectively at an assumed distance of 500 pc . we find that the effect of beam size is relatively small for smaller beams . in particular , for beams approximately appropriate for sofia ( @xmath142 arcsec ) and scuba ( @xmath143 arcsec ) , the inferred density distribution has a median variation from the infinitesimal beamsize of only @xmath114 per cent . larger beams , such as @xmath144 similar to iras produce results with at least a @xmath145 per cent difference . in both cases , these results are due to the ability to resolve the source , and the effect of the source only partially filling the beam for pointings near the edge . as a result , it appears that for regions with small temperature gradients , relatively well - resolved observations provide results that are rather insensitive to the beam size . another approach to try and help determine the density distribution is to model the flux spectrum . in order to test this method we produced artificial observations for a base model similar to that described in sect . 3 , but having @xmath146 to simulate a more intermediate value . in order to more closely resemble actual observations , we randomly added noise to the simulated spectra . the noise amplitude was as large as @xmath107 per cent of the simulated observations , with a median noise of @xmath147 per cent over the entire spectrum . we then ran over 2000 models that bracketed this base model in two parameters , optical depth and density distribution index . based upon the results of sect . 6 , we assume that the grain properties could be determined relatively accurately , and thus treat @xmath10 as known . we evaluated the models by calculating the chi - squared difference between the flux spectrum of the test models with the simulated observations . in fig . 12 , we plot the @xmath148 per cent confidence interval for this result . we can see that for any reasonably constrained optical depth , the density distribution index , @xmath9 , is constrained to the range @xmath149 , which is a difference of @xmath85 per cent from the value of @xmath146 adopted in the model . however , if the optical depth can be determined to within @xmath87 per cent , the error in determining the density index , @xmath9 , becomes @xmath150 per cent . uncertainties of a similar magnitude in @xmath9 ( i.e. @xmath151 ) can also result from uncertainties in the isrf ( young & evans 2002 ) , the source geometry ( doty et al . 2002b ) , and the assumed value of @xmath10 . however , it may be possible to constrain these parameters by other data ( e.g. , bolometric luminosity for pre - protostellar cores , source morphology , and the results of sect . 6 ) . it is interesting to note that even when these parameters are not well constrained , the uncertainties in @xmath9 are on the order of the uncertainties implied by the optical depth alone , and smaller otherwise . finally , as the smaller beamsizes of recent and upcoming instruments make it increasingly possible to spatially resolve star - forming regions ( see e.g. , evans et al . 2001 ) it is interesting to consider the implications of the expected surface brightness across the source . shirley et al . ( 2000 ) presented models of the normalized intensity profile as a function of impact parameter for semi - analytic cases similar to equation ( 17 ) with various assumptions regarding the temperature profile in the dust envelope . they found that the assumptions of isothermality and the rja could be important . for comparison , in fig . 13 we plot the expected surface brightness at @xmath152 as a function of impact parameter for @xmath153 , and @xmath154 . this wavelength is chosen as it should be near the peak of the source spectrum , and is observable by scuba . these results are based upon detailed modeling as decribed earlier . in this case the dust temperature distribution is determined self - consistently , and the rja is not applied . from these results , some conclusions may be drawn . first , for well- resolved sources , it appears that it is possible to infer the dust density distribution index , @xmath9 . this is especially true if the source luminosity is somewhat constrained , and more importantly if good signal - to - noise data exist near the source edge without contamination from beam dilution , etc . second , it may be possible to infer the existence of an internal heat source from the surface brightness distribution . this is a problem which is the subject of an upcoming paper ( doty & moore 2002 ) . finally , these results show an apparently wider variation in surface brightness across the source than those from approximate methods ( see e.g. , fig . 13 of shirley et al . 2000 ) . the differences are due to the discrepancies between the assumed dust temperature distribution in the approximate methods , and the self - consistent distribution determined through the modeling . this underscores the importance of detailed modeling of emergent radiation for these and any other but the most simple star - forming regions . we have critically evaluated current semi - analytical methods in analysing regions of low - mass star - formation . in particular , we have investigated the validity of the underlying assumptions for the methods and determined the conditions under which these methods are reliable . based upon this work , we find that : \1 . the temperature distribution plays a significant role in determining the spectrum of a source . as there are no current semi - analytic methods for determining the temperature distribution explicitly , a common assumption is that these sources are isothermal . although an isothermal temperature with some physical basis can be found using a modified wiens law ( fig . 3 and equation [ 18 ] ) , using this temperature does not accurately determine the other source parameters ( see sections 4 , 5 , and 6 ) . it is difficult to reliably determine the total dust mass without an accurate estimate of grain properties , density distribution , and the distance to the source ( section 5 ) . however , a ratio of mass from two similar sources can be determined using the observed flux at a given frequency . the dust masses determined by this method are accurate to within @xmath67 per cent for all cases where the estimated temperature is in reasonable agreement ( 5 k ) with the average grain temperature namely for regions with no or weak internal sources . it is also possible to determine a ratio of dust masses using the integrated luminosity . this method is only applicable for low optical depths , as errors approach @xmath91 per cent for @xmath155 . \3 . for an optically thin source and in a region of frequencies where the rayleigh jeans approximation holds , the opacity index , @xmath10 , can be determined using the ratio of two different frequencies as in equation ( 12 ) . in order to determine the opacity index to within @xmath85 per cent for all optical depths , the pair of wavelengths used need to be longer than about @xmath156 , due to the failure of the rja and the lack of isothermality of the source . this may be problematic due to the existence of free - free emission which may dominate the thermal dust continuum for some sources . another method for determining the opacity index is by fitting the spectrum . with a single blackbody fit , @xmath10 can be determined to within @xmath120 per cent for all cases . if , instead , a two temperature fit is used , the results for @xmath10 are improved considerably , with a maximum error of only @xmath121 per cent . \4 . the density distribution index , @xmath9 , can be determined for a resolved source that is isothermal along any line of sight by using the ratio of intensities at two different wavelengths . for a theoretically small pencil beam , the results have an error of up to @xmath91 per cent . errors increase as the beam size gets larger , growing dramatically for pointings in which the source does not fill the beam . the errors also increase somewhat as the wavelengths used decrease . finally , due to the isothermal assumption , it is important to probe impact parameters that are neither too close to the edge of the source nor too close to the core . we find @xmath157 works well in the cases studied here . it should be possible to infer the dust density distribution , @xmath9 , from the surface brightness distribution across the source . this , however , requires good signal - to - noise data toward the source edge . the range in surface brightness distributions is due to the differences in the actual temperature distributions in the sources , highlighting the need for self - consistent modeling to ensure proper interpretation of observational data . we are grateful to the referee , derek ward - thompson , for helpful suggestions , and to neal evans for discussions and useful comments . we thank ewine van dishoeck for hospitality at leiden university where the work was initially begun . this work was partially supported under a grant from the research corporation , a bezoekerbeurs from the netherlands organization for scientific research ( nwo ) , and supplementary support from the battelle corporation through denison university .

we present an evaluative study of some current methods utilized in the analysis of infrared ( ir ) observations of star - forming regions . a series of self - consistent radiative transfer models are constructed , with the outputs analysed using these methods to infer source properties such as dust tempertaure , mass , opacity function , and density distribution . any discrepancies between the inferred and model quantities can be attributed to the analysis methods . the range of validity of most methods is smaller than expected , due to two effects : ( 1 ) limited applicability of the rayleigh - jeans limit except to very long wavelengths , and ( 2 ) significant errors in the isothermal approximation , even when @xmath0 over 90 per cent of a region . still , an accurate mean @xmath1 can be found using a modified wiens law . this temperature can yield dust masses to within 10 - 25 per cent much better than masses inferred from the integrated luminosity . using long wavelengths ( @xmath2 ) , the opacity index can be determined from the far - ir spectrum to within 20 per cent . fitting the spectrum yields better results . the density distribution can be somewhat constrained by fitting the surface brightness , for well - resolved sources . better results are found by fitting the flux spectrum with detailed models . [ firstpage ] stars : formation infrared : stars ism : clouds .

this retrospective study included 40 dogs that were diagnosed with biliary sludge and gallbladder mucoceles , and had their gallbladder contents collected during surgery or autopsy at the university of miyazaki veterinary teaching hospital , miyazaki , japan , between may 2012 and july 2016 . component analysis was performed using 43 samples of gallbladder contents from 40 dogs diagnosed with biliary sludge or gallbladder mucoceles for three samples , the same animal was re - examined over the course of follow - up . samples that were diagnosed by autopsy were from dogs that either died of natural causes or were euthanized for reasons other than gallbladder diseases . euthanization was conducted as below : first , dogs were administered with pentobarbital sodium ( 50 mg / kg , iv ; somnopentyl , kyoritsu seiyaku corp . , five min later , potassium chloride ( 2 meq / kg , iv ; kcl corrective injection 1 meq / ml , otsuka pharmaceutical factory , inc . biliary sludge and gallbladder mucoceles were diagnosed by gross examination during surgery or autopsy . biliary sludge was diagnosed when the gallbladder contents presented a sludge - like appearance . gallbladder mucoceles were diagnosed when the gallbladder appeared to be completely filled with a jelly - like substance ( figs . biliary sludge presents as hyperechogenic accumulated matter in the direction of gravity on ultrasonography images mild * ( a ) , moderate * ( b ) and severe * ( c ) . gallbladder contents in moderate biliary sludge ( d ) have a black sand - like appearance , while those in severe biliary sludge ( e ) have a black sludge - like appearance . biliary sludge was classified according to its rate of retention within the gallbladder as mild ( 25% ) , moderate ( 2575% ) or severe ( 75% ) . and 2fig . . however , gallbladder contents in gallbladder mucoceles present varied appearances ; in the present study , while gallbladder contents in a few mucoceles presented a black and jelly - like appearance ( c ) , those in other mucoceles presented as an indurated , jelly - like material radiating to the margin ( d ) . ) . biliary sludge was classified according to severity based on the content retention rate relative to size of the gallbladder determined by ultrasonography , as follows : mild ( 25% retention ) , moderate ( 2575% retention ) or severe ( 75% retention ; fig . biliary sludge presents as hyperechogenic accumulated matter in the direction of gravity on ultrasonography images mild * ( a ) , moderate * ( b ) and severe * ( c ) . gallbladder contents in moderate biliary sludge ( d ) have a black sand - like appearance , while those in severe biliary sludge ( e ) have a black sludge - like appearance . * biliary sludge was classified according to its rate of retention within the gallbladder as mild ( 25% ) , moderate ( 2575% ) or severe ( 75% ) . ultrasonography images and gallbladder content findings of gallbladder mucoceles . pattern within the gallbladder on abdominal ultrasonography images ( a and b ) . however , gallbladder contents in gallbladder mucoceles present varied appearances ; in the present study , while gallbladder contents in a few mucoceles presented a black and jelly - like appearance ( c ) , those in other mucoceles presented as an indurated , jelly - like material radiating to the margin ( d ) . of the 40 dogs included in the present study , 18 ( 21 samples ) exhibited biliary sludge , and 22 ( 22 samples ) exhibited gallbladder mucoceles . dogs included in this study were of the following breeds : miniature dachshund , chihuahua and toy poodle ( n=6 , each ) ; miniature schnauzer ( n=4 ) ; pug and mixed breed ( n=3 , each ) ; american cocker spaniel , shetland sheepdog , yorkshire terrier , beagle , french bulldog and doberman ( n=2 , each ) and pomeranian , shiba inu and papillon ( n=1 , each ) . the median age of the 40 dogs ( 43 samples ) included in the present study ( male , 5 ; castrated male , 11 ; female , 7 ; and spayed female , 20 ) was 9 years ( range , 115 years , including one dog of unknown age ) , and the median weight was 5.2 kg ( range , 1.929.0 kg ) . all dogs were examined with the owners consent having been obtained prior to surgical treatment ( cholecystectomy , 25 dogs and gallbladder irrigation , 15 dogs ) or autopsy ( 3 dogs ) . gallbladder irrigation was performed by making a small incision on the gallbladder wall , followed by aspiration of contents in the lumen of the gallbladder and irrigation and cleaning up of the inside of the gallbladder with saline . for component analysis , 43 canine gallbladder content samples with bile ( biliary sludge , 21 and gallbladder mucoceles , 22 ) were first dried well and then prepared as potassium bromide ( kbr ) pellets for evaluation by ir spectroscopy ( ir spectroscopy ft / ir-410 , jasco corp . , tokyo , japan . ) . in a previous study on the ir spectroscopy of ovary - derived mucins therefore , mucins derived from swine stomach ( swine mucin ; purity 80% , wako pure chemical industries , ltd . , tokyo , japan . ) were used to establish the reference ir spectrum for mucins in this study . the ir spectra of biliary sludge and gallbladder mucoceles contents were compared with that of swine mucin in order to determine the composition of the former . of the 43 canine gallbladder content samples , 41 ( biliary sludge , 20 and gallbladder mucoceles , 21 ) were evaluated by bacterial culture . the animals were administered antimicrobials after collection of gallbladder contents , but not within 12 hr prior to collection . bacterial cultures of gallbladder contents were established by aseptically swabbing the inside of the gallbladder with a sterile cotton swab and inoculating the samples onto bacterial media for aerobic and anaerobic culture , followed by bacterial identification . as determined by ultrasonographic findings , there was no mild case , moderate was 10 cases , with all samples exhibiting biliary sludge retention rates 50% , and severe was 11 cases . the ir spectrum of swine mucin corresponded to proteins , with amide bands near 1,650 and 1,550 cm , and polysaccharides , with spectral characteristics of sugar chains ( glycosylation bands ) near 1,070 and 1,050 cm(fig . swine mucin exhibits characteristic absorption bands of proteins ( amide bands near 1,650 and 1,550 cm ; indicated by arrowheads ) and sugar chains ( glycosylation bands near 1,070 and 1,050 cm ; indicated by arrows ) . ) . this ir spectrum was used as the reference for identification of mucins in gallbladder contents . swine mucin exhibits characteristic absorption bands of proteins ( amide bands near 1,650 and 1,550 cm ; indicated by arrowheads ) and sugar chains ( glycosylation bands near 1,070 and 1,050 cm ; indicated by arrows ) . of the 21 samples of gallbladder contents of dogs with biliary sludge , 20 ( 95.2%)ten samples each of moderate and severe biliary sludge exhibited ir spectra coinciding with amide and glycosylation bands similar to those observed with swine mucin and were thus identified as being composed of mucins ( fig . ir spectra of swine mucin ( a ; dotted line ) and severe ( b ; solid line ) and moderate ( c ; solid line ) biliary sludge*. ir spectra of severe biliary sludge that was identified as proteins ( d ; solid line ) . moderate ( b ) and severe ( c ) biliary sludge both exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) , with the exception of one sample ( d ) of severe biliary sludge , where only amide bands were observed . * ir spectra of only representative samples are presented in b and c ; b ( n=9 ) and c ( n=10 ) exhibited similar spectra . ) . the ir spectrum of the one remaining sample ( 4.8% ) , which was from a dog with severe biliary sludge , did not exhibit clear glycosylation bands and instead presented only amide bands ; this sample was , therefore , identified as being composed of proteins ( fig . ir spectra of swine mucin ( a ; dotted line ) and severe ( b ; solid line ) and moderate ( c ; solid line ) biliary sludge*. ir spectra of severe biliary sludge that was identified as proteins ( d ; solid line ) . moderate ( b ) and severe ( c ) biliary sludge both exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) , with the exception of one sample ( d ) of severe biliary sludge , where only amide bands were observed . * ir spectra of only representative samples are presented in b and c ; b ( n=9 ) and c ( n=10 ) exhibited similar spectra . all 22 samples of gallbladder contents of dogs with gallbladder mucoceles exhibited ir spectra coinciding with amide and glycosylation bands similar to those observed with swine mucin and were thus identified as mucins ( fig . 5fig . ir spectra of swine mucin ( a ; dotted line ) and gallbladder mucoceles * ( b ; solid line ) . gallbladder mucoceles ( b ) exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) . * ir spectrum of only a representative sample is presented in b. the gallbladder contents of all gallbladder mucoceles ( n=21 ) exhibited similar spectra . ) . the ir spectra of biliary sludge and gallbladder mucoceles contents were found to be similar . ir spectra of swine mucin ( a ; dotted line ) and gallbladder mucoceles * ( b ; solid line ) . gallbladder mucoceles ( b ) exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) . * ir spectrum of only a representative sample is presented in b. the gallbladder contents of all gallbladder mucoceles ( n=21 ) exhibited similar spectra . three of the dogs with biliary sludge received gallbladder irrigation , followed by 12 years of follow - up , at the end of which , progressively accumulated gallbladder contents were again collected by gallbladder irrigation . of the three dogs , one underwent cholecystectomy for extrahepatic bile duct obstruction due to re - accumulation of gallbladder contents about 1 year and 8 months after the second gallbladder irrigation . unlike the other two dogs , the gallbladder contents of this dog at the time of the cholecystectomy had clearly transitioned from sludge - like to jelly - like appearance . therefore , the dog was diagnosed with a gallbladder mucocele rather than biliary sludge based on the findings of analysis of gallbladder contents from the third collection ( fig . ultrasonography findings at 1 year and 7 months after first collection ( a ) and 10 days after second collection ( b ) indicated biliary sludge . gallbladder contents of both first and second collections were similar and determined to be biliary sludge ( c ) . ultrasonography findings at 1 year and 8 months after second collection when extrahepatic duct obstruction occurred ( d ) . gallbladder content findings at third collection indicated a gallbladder mucocele ( f ) . for treatment of biliary sludge , the inside of the gallbladder was cleaned with saline , and all of the sludge - like content ( c ) was collected ( b ) . however , biliary sludge recurred and accumulated progressively ( d ) . during the interval of 1 year and 7 months between the initial collection of biliary sludge and second collection of gallbladder contents , the dog exhibited no clinical symptoms of extrahepatic bile duct obstruction , and its recovery was uneventful . however , upon recurrence of biliary sludge , the patient received additional follow - up for 1 year and 8 months . to resolve the extrahepatic bile duct obstruction observed during follow - up ( d ) , the contents of the excised gallbladder had changed in appearance from sludge ( c ) to jelly - like consistency ( f ) , leading to the diagnosis of gallbladder mucocele . ) . the gallbladder contents of this dog exhibited nearly similar ir spectra at all three collections and were thus identified each time as being composed of mucins ( fig . 7fig . ( b ) collections , both of which were determined to be biliary sludge . ir spectra of gallbladder contents from the third collection ( c ) , which was determined to be from a gallbladder mucocele . gallbladder contents from the first , second and third collections exhibited similar ir spectra ; both amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) were observed , and the contents were identified as mucins . ) . the gallbladder contents of the remaining two dogs presented a sludge - like appearance at the first and second collections , based on which the dogs were diagnosed with biliary sludge . the gallbladder contents were identified as being composed of mucins based on their ir spectroscopic findings . ultrasonography and gallbladder content ultrasonography findings at 1 year and 7 months after first collection ( a ) and 10 days after second collection ( b ) indicated biliary sludge . gallbladder contents of both first and second collections were similar and determined to be biliary sludge ( c ) . ultrasonography findings at 1 year and 8 months after second collection when extrahepatic duct obstruction occurred ( d ) . gallbladder content findings at third collection indicated a gallbladder mucocele ( f ) . for treatment of biliary sludge , the inside of the gallbladder was cleaned with saline , and all of the sludge - like content ( c ) was collected ( b ) . however , biliary sludge recurred and accumulated progressively ( d ) . during the interval of 1 year and 7 months between the initial collection of biliary sludge and second collection of gallbladder contents , the dog exhibited no clinical symptoms of extrahepatic bile duct obstruction , and its recovery was uneventful . however , upon recurrence of biliary sludge , the patient received additional follow - up for 1 year and 8 months . to resolve the extrahepatic bile duct obstruction observed during follow - up ( d ) , the patient underwent cholecystectomy ( e ) . the contents of the excised gallbladder had changed in appearance from sludge ( c ) to jelly - like consistency ( f ) , leading to the diagnosis of gallbladder mucocele . second ( b ) collections , both of which were determined to be biliary sludge . ir spectra of gallbladder contents from the third collection ( c ) , which was determined to be from a gallbladder mucocele . gallbladder contents from the first , second and third collections exhibited similar ir spectra ; both amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) were observed , and the contents were identified as mucins . the infective bacterial species were identified to be escherichia coli and serratia marcescens in one sample each . of the 21 gallbladder mucocele samples , 3 ( 14.3% ) exhibited bacterial infection . the infective bacterial species were identified to be escherichia coli in two samples and enterococcus spp . in one sample . as determined by ultrasonographic findings , there was no mild case , moderate was 10 cases , with all samples exhibiting biliary sludge retention rates 50% , and severe was 11 cases . the ir spectrum of swine mucin corresponded to proteins , with amide bands near 1,650 and 1,550 cm , and polysaccharides , with spectral characteristics of sugar chains ( glycosylation bands ) near 1,070 and 1,050 cm(fig . swine mucin exhibits characteristic absorption bands of proteins ( amide bands near 1,650 and 1,550 cm ; indicated by arrowheads ) and sugar chains ( glycosylation bands near 1,070 and 1,050 cm ; indicated by arrows ) . ) . this ir spectrum was used as the reference for identification of mucins in gallbladder contents . swine mucin exhibits characteristic absorption bands of proteins ( amide bands near 1,650 and 1,550 cm ; indicated by arrowheads ) and sugar chains ( glycosylation bands near 1,070 and 1,050 cm ; indicated by arrows ) . of the 21 samples of gallbladder contents of dogs with biliary sludge , 20 ( 95.2%)ten samples each of moderate and severe biliary sludge exhibited ir spectra coinciding with amide and glycosylation bands similar to those observed with swine mucin and were thus identified as being composed of mucins ( fig . ir spectra of swine mucin ( a ; dotted line ) and severe ( b ; solid line ) and moderate ( c ; solid line ) biliary sludge*. ir spectra of severe biliary sludge that was identified as proteins ( d ; solid line ) . moderate ( b ) and severe ( c ) biliary sludge both exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) , with the exception of one sample ( d ) of severe biliary sludge , where only amide bands were observed . * ir spectra of only representative samples are presented in b and c ; b ( n=9 ) and c ( n=10 ) exhibited similar spectra . ) . the ir spectrum of the one remaining sample ( 4.8% ) , which was from a dog with severe biliary sludge , did not exhibit clear glycosylation bands and instead presented only amide bands ; this sample was , therefore , identified as being composed of proteins ( fig . ir spectra of swine mucin ( a ; dotted line ) and severe ( b ; solid line ) and moderate ( c ; solid line ) biliary sludge*. ir spectra of severe biliary sludge that was identified as proteins ( d ; solid line ) . moderate ( b ) and severe ( c ) biliary sludge both exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) , with the exception of one sample ( d ) of severe biliary sludge , where only amide bands were observed . * ir spectra of only representative samples are presented in b and c ; b ( n=9 ) and c ( n=10 ) exhibited similar spectra . all 22 samples of gallbladder contents of dogs with gallbladder mucoceles exhibited ir spectra coinciding with amide and glycosylation bands similar to those observed with swine mucin and were thus identified as mucins ( fig . ir spectra of swine mucin ( a ; dotted line ) and gallbladder mucoceles * ( b ; solid line ) . gallbladder mucoceles ( b ) exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) . * ir spectrum of only a representative sample is presented in b. the gallbladder contents of all gallbladder mucoceles ( n=21 ) exhibited similar spectra . ) . the ir spectra of biliary sludge and gallbladder mucoceles contents were found to be similar . ir spectra of swine mucin ( a ; dotted line ) and gallbladder mucoceles * ( b ; solid line ) . gallbladder mucoceles ( b ) exhibited amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) . * ir spectrum of only a representative sample is presented in b. the gallbladder contents of all gallbladder mucoceles ( n=21 ) exhibited similar spectra . three of the dogs with biliary sludge received gallbladder irrigation , followed by 12 years of follow - up , at the end of which , progressively accumulated gallbladder contents were again collected by gallbladder irrigation . of the three dogs , one underwent cholecystectomy for extrahepatic bile duct obstruction due to re - accumulation of gallbladder contents about 1 year and 8 months after the second gallbladder irrigation . unlike the other two dogs , the gallbladder contents of this dog at the time of the cholecystectomy had clearly transitioned from sludge - like to jelly - like appearance . therefore , the dog was diagnosed with a gallbladder mucocele rather than biliary sludge based on the findings of analysis of gallbladder contents from the third collection ( fig . ultrasonography findings at 1 year and 7 months after first collection ( a ) and 10 days after second collection ( b ) indicated biliary sludge . gallbladder contents of both first and second collections were similar and determined to be biliary sludge ( c ) . ultrasonography findings at 1 year and 8 months after second collection when extrahepatic duct obstruction occurred ( d ) . gallbladder content findings at third collection indicated a gallbladder mucocele ( f ) . for treatment of biliary sludge , the inside of the gallbladder was cleaned with saline , and all of the sludge - like content ( c ) was collected ( b ) . however , biliary sludge recurred and accumulated progressively ( d ) . during the interval of 1 year and 7 months between the initial collection of biliary sludge and second collection of gallbladder contents , the dog exhibited no clinical symptoms of extrahepatic bile duct obstruction , and its recovery was uneventful . however , upon recurrence of biliary sludge , the patient received additional follow - up for 1 year and 8 months . to resolve the extrahepatic bile duct obstruction observed during follow - up ( d ) , the contents of the excised gallbladder had changed in appearance from sludge ( c ) to jelly - like consistency ( f ) , leading to the diagnosis of gallbladder mucocele . ) . the gallbladder contents of this dog exhibited nearly similar ir spectra at all three collections and were thus identified each time as being composed of mucins ( fig . 7fig . ( b ) collections , both of which were determined to be biliary sludge . ir spectra of gallbladder contents from the third collection ( c ) , which was determined to be from a gallbladder mucocele . gallbladder contents from the first , second and third collections exhibited similar ir spectra ; both amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) were observed , and the contents were identified as mucins . ) . the gallbladder contents of the remaining two dogs presented a sludge - like appearance at the first and second collections , based on which the dogs were diagnosed with biliary sludge . the gallbladder contents were identified as being composed of mucins based on their ir spectroscopic findings . ultrasonography findings at 1 year and 7 months after first collection ( a ) and 10 days after second collection ( b ) indicated biliary sludge . gallbladder contents of both first and second collections were similar and determined to be biliary sludge ( c ) . ultrasonography findings at 1 year and 8 months after second collection when extrahepatic duct obstruction occurred ( d ) . gallbladder content findings at third collection indicated a gallbladder mucocele ( f ) . for treatment of biliary sludge , the inside of the gallbladder was cleaned with saline , and all of the sludge - like content ( c ) was collected ( b ) . however , biliary sludge recurred and accumulated progressively ( d ) . during the interval of 1 year and 7 months between the initial collection of biliary sludge and second collection of gallbladder contents , the dog exhibited no clinical symptoms of extrahepatic bile duct obstruction , and its recovery was uneventful . however , upon recurrence of biliary sludge , the patient received additional follow - up for 1 year and 8 months . to resolve the extrahepatic bile duct obstruction observed during follow - up ( d ) , the contents of the excised gallbladder had changed in appearance from sludge ( c ) to jelly - like consistency ( f ) , leading to the diagnosis of gallbladder mucocele . ir spectra of gallbladder contents from the first ( a ) and second ( b ) collections , both of which were determined to be biliary sludge . ir spectra of gallbladder contents from the third collection ( c ) , which was determined to be from a gallbladder mucocele . gallbladder contents from the first , second and third collections exhibited similar ir spectra ; both amide bands ( near 1,650 and 1,550 cm ; indicated by arrowheads ) and glycosylation bands ( near 1,070 and 1,050 cm ; indicated by arrows ) were observed , and the contents were identified as mucins . the infective bacterial species were identified to be escherichia coli and serratia marcescens in one sample each . of the 21 gallbladder mucocele samples , 3 ( 14.3% ) exhibited bacterial infection . the infective bacterial species were identified to be escherichia coli in two samples and enterococcus spp . in one sample . canine gallbladder diseases especially gallbladder mucoceles are caused by excessive mucin secretion . however , to our knowledge , there are no reports regarding component analysis of actual contents from gallbladder mucoceles . a previous study performed ir spectroscopic analysis of human ovary - derived mucins with the ir spectrum of bovine submaxillary gland - derived mucins as reference . therefore , in the present study , the ir spectrum of swine mucin was employed as the reference for comparative evaluation of ir spectra of biliary sludge and gallbladder mucocele samples . nearly all of the gallbladder content samples of dogs with biliary sludge ( 95.2% ) exhibited similar ir spectra as swine mucin , irrespective of the severity of biliary sludge , which ranged from moderate ( 5075% biliary sludge ) to severe ( fig . 4 ) . in case of gallbladder mucocele contents , all samples exhibited similar ir spectra as swine mucin ( fig . 5 ) . these findings indicated that the principal components of gallbladder contents in both biliary sludge and gallbladder mucoceles were mucins , which suggested the possibility that mucins were involved in the pathogenesis of not only gallbladder mucoceles but also biliary sludge . 7 , it was observed that there were some changes between biliary sludge ( a and b ) and gallbladder mucocele ( c ) . in particular , these changes were observed near 1,460 , 1,375 and 1,055 cm in fig . 7 ( c ) . these were characteristic ir spectra showing cholesterol . it was suggested that these ir spectra were possible to have been affected by cholesterol because cholesterol was contained in the bile . therefore , it was possible that amount of cholesterol in the gallbladder content was increased with varying from biliary sludge to gallbladder mucocele in this case . although these characteristic ir spectra showing cholesterol were observed in some of gallbladder mucocele cases , not in all gallbladder mucocele cases . therefore , since all gallbladder mucocele samples in this study showed amide bands and glycosylation bands , it was considered that the principal component of gallbladder mucocele was mucin . in present study , the gallbladder contents of one of the dogs with biliary sludge were identified as being composed of proteins ( fig . the gallbladder in this case had presented extensive bleeding upon histopathological examination , which indicated the possibility that gallbladder bleeding affected the composition of the biliary sludge contents . in order to verify these hypothesis , the ir spectrum of a clot of peripheral venous blood from a healthy dog was compared with that of the gallbladder contents in this case . the ir spectrum of the blood clot exhibited amide bands but no glycosylation bands , and therefore , the blood clot was identified as being composed of proteins . the ir spectrum of the proteinaceous biliary sludge sample was found to be similar to that of the blood clot ( fig . ir spectra of swine mucin ( a ; dotted line ) and a blood clot from a healthy dog ( b ; dashed line ) . gallbladder contents of biliary sludge determined as being composed of proteins ( c ; solid line ) . the blood clot exhibited only amide bands in its ir spectrum and was , therefore , determined as being composed of proteins . the ir spectra of the blood clot and the biliary sludge determined as being composed of proteins were similar . arrowheads indicate amide bands ( near 1,650 and 1,550 cm ) ; arrows indicate glycosylation bands ( near 1,070 and 1,050 cm ) . ) , which may be attributable to the mixing of biliary sludge with plasma proteins from blood because of gallbladder bleeding . these findings suggest that , in cases where histopathological findings reveal gallbladder bleeding , the composition of gallbladder contents might be different from mucin . ir spectra of swine mucin ( a ; dotted line ) and a blood clot from a healthy dog ( b ; dashed line ) . gallbladder contents of biliary sludge determined as being composed of proteins ( c ; solid line ) . the blood clot exhibited only amide bands in its ir spectrum and was , therefore , determined as being composed of proteins . the ir spectra of the blood clot and the biliary sludge determined as being composed of proteins were similar . arrowheads indicate amide bands ( near 1,650 and 1,550 cm ) ; arrows indicate glycosylation bands ( near 1,070 and 1,050 cm ) . both biliary sludge and gallbladder mucocele samples exhibited a low incidence of bacterial infection ( 10.0 and 14.3% , respectively ) . a previous study reported a 13.5% rate of bacterial infection in gallbladder mucoceles , which corresponds with the findings of the present study . several bacterial species identified in gallbladder infections are among those that constitute normal intestinal flora . therefore , it is possible that the cases of gallbladder infection observed in the present study were due to ascending infection from the duodenum . the findings of component analysis of gallbladder contents from canine biliary sludge and gallbladder mucoceles in the present study have demonstrated the previously unreported fact that mucins are the principle components of gallbladder content in both pathophysiologies . there were no differences in gallbladder composition among biliary sludge samples of various severities . additionally , the low rates of bacterial infection in both biliary sludge and gallbladder mucocele samples indicated that these two disease differ in pathophysiology from gallstones . from the results of this study , it was considered that the pathophysiology of canine biliary sludge may be occurred by progressive accumulation of mucin in the gallbladder . in one of the dogs included in the present study , gallbladder disease progressed from biliary sludge to gallbladder mucocele ( fig . these findings suggest not only that biliary sludge and gallbladder mucoceles share a pathophysiology involving the progressive accumulation of mucins , but also that biliary sludge possibly represents the stage preceding gallbladder mucoceles . however , the factors responsible for the transition of gallbladder contents from sludge to jelly - like appearance in the present study are not clear . as a criterion for differentiating between the sludge and jelly - like appearances of gallbladder contents , in the present study , a resected gallbladder with contents that were semisolid , low in liquid content and appeared molded to the gallbladder was diagnosed as a gallbladder mucocele . the water content of gallbladder contents might be one of the factors responsible for the transition of gallbladder contents from sludge to jelly - like appearance . all of gallbladder contents in this study were dried with bile and analyzed by ir spectroscopy . generally , the components contained in bile are bile acid , cholesterol , lecithin , bilirubin and more , and do not contain volatile components . therefore , these analyses by ir spectroscopy were carried out in gallbladder contents which contained liquid components , and it was considered that only the water content of gallbladder contents was changed by drying . moisture in bile is removed by the actions of the na k and cl hco3 pumps of gallbladder epithelial cells [ 19 , 21 ] and / or based on reports in mice aquaporins , which are channels responsible for transporting water into the body [ 18 , 24 ] . these transport channels have been reported to possess the ability to concentrate bile or manipulate the composition of gallbladder bile . therefore , abnormal functioning of bile moisture absorption mechanisms might be involved in the pathophysiology of canine biliary sludge and gallbladder mucoceles . in this study , since the ir spectroscopy was a qualitative analysis method , it is necessary to quantitatively analyze components of gallbladder content , such as amount of mucin and/or cholesterol , in the future study . it is not known whether biliary sludge is similar to gallbladder mucoceles in terms of involvement of excessive mucin secretion from the gallbladder mucosal epithelium . therefore , future studies on histopathological evaluation of gallbladder mucosal epithelium have been planned to investigate whether excessive mucin secretion is involved in the pathophysiology of biliary sludge . additionally , in the case of gallbladder content transition with histological findings of severe gallbladder bleeding observed in the present study , it is necessary to histopathologically investigate the gallbladder and its principal components in detail . to conclude , the present findings have demonstrated that the principle components of both biliary sludge and gallbladder mucoceles are mucins . these findings suggest the possibility that the two diseases are not independent of each other , but in fact , represent one continuous disease . further studies involving extensive data collection of gallbladder contents from biliary sludge and gallbladder mucocele , and histopathological evaluation of these gallbladder will be conducted to elucidate the pathophysiologies of gallbladder mucoceles and biliary sludge .

the pathophysiology of canine gallbladder diseases , including biliary sludge , gallbladder mucoceles and gallstones , is poorly understood . this study aimed to evaluate the component of gallbladder contents and bacterial infection of the gallbladder in order to elucidate the pathophysiology of biliary sludge and gallbladder mucoceles . a total of 43 samples of canine gallbladder contents ( biliary sludge , 21 and gallbladder mucoceles , 22 ) were subjected to component analysis by infrared spectroscopy , and the resultant infrared spectra were compared with that of swine mucin . of the 43 samples , 41 were also evaluated by aerobic and anaerobic bacterial culture . the contents of 20 ( 95.2% ) biliary sludge and 22 ( 100% ) gallbladder mucocele samples exhibited similar infrared spectra as swine mucin . although biliary sludge and gallbladder mucocele contents exhibited similar infrared spectra , one sample of biliary sludge ( 4.8% ) was determined to be composed of proteins . the rate of bacterial infection of the gallbladder was 10.0% for biliary sludge and 14.3% for gallbladder mucoceles . almost all of the identified bacterial species were intestinal flora . these results indicate that the principal components of gallbladder contents in both gallbladder mucoceles and biliary sludge are mucins and that both pathophysiologies exhibit low rates of bacterial infection of the gallbladder . therefore , it is possible that gallbladder mucoceles and biliary sludge have the same pathophysiology , and , rather than being independent diseases , they could possibly represent a continuous disease . thus , biliary sludge could be considered as the stage preceding the appearance of gallbladder mucoceles .

IRS Chief: No Evidence Of 'Intentional Wrongdoing' So Far i i Win McNamee / Getty Images Win McNamee / Getty Images That "be on the lookout list" used to flag Tea Party groups for extra scrutiny of their tax-exemption applications? It turns out it wasn't the only one the Internal Revenue Service had been using. There were also other lists, covering a "broad spectrum" of categories and cases, according to a preliminary IRS report released Monday. "Once we came to that conclusion, we took immediate action to suspend the use of these lists in the Exempt Organizations unit within IRS," said Danny Werfel, the new acting chief of the IRS, in a conference call with reporters. Werfel said he hopes to be able to release more information about the sorts of other groups that were being flagged in the coming days, but that he could not until the documents were scrubbed of details that could identify groups by name, which privacy laws prohibit. Werfel also said that his review so far hasn't found any evidence of unintentional wrongdoing by any IRS employee, nor any influence by entities outside the IRS in the actions of the exempt-organizations office in Cincinnati. "I'm not providing a definitive conclusion that no intentional wrongdoing occurred. What I'm suggesting is that based on the ongoing review to date, no evidence has yet surfaced," he said. Werfel replaced former acting IRS Commissioner Steven Miller last month after revelations that the IRS had pulled aside groups with "Tea Party," "patriot" or "9/12" in their names for extra scrutiny. That, combined with bureaucratic stumbles, forced some groups to wait years to get an answer on their applications. Nonprofits often seek IRS approval to make it easier to solicit donations as well as guarantee those donors that their names will be kept secret from the public. In Monday's half-hour call, Werfel said the manager at every level in the organizational chart having to do with the exempt organizations had been replaced. "We believe that these individuals should no longer hold a position of public trust within IRS, and therefore we've replaced the leadership in those areas," he said. For groups still awaiting an answer on their applications as 501(c)(4) "social welfare" organizations, Werfel said the IRS has created a new, fast-track process. This allows those waiting more than 120 days to fill out a form on which they promise not to engage primarily in politics and then start operating as a tax-exempt group. Groups set up as social welfare organizations have always had that option available, rather than seeking formal approval from the IRS, Werfel pointed out. (Charities seeking 501(c)(3) status, which, unlike social welfare groups, can offer donors a deduction on their federal taxes, are required to seek pre-approval from the IRS.) If a subsequent audit shows too much politics or other legally impermissible activity, the IRS could then revoke that status — just as it can now. Werfel is the sole witness scheduled to appear before the House Ways and Means Committee hearing on the issue on Thursday. Both the House and the Senate have ongoing inquiries into the matter. To date, leaked transcripts from House interviews of IRS Cincinnati employees portray an environment of unclear guidelines and uneven management, rather than a concerted, politically motivated effort. Werfel said that he hopes a planned Treasury Department analysis of how tax-exempt organizations are reviewed will help create standardized guidelines in the future. "Clearly this issue associated with some ambiguity in the regulation that governs this area contributed in part to these problems," he said. Werfel's assurances Monday, though, did not satisfy the IRS's leading inquisitor in the House, California Republican Darrell Issa, chairman of the House Oversight and Governmental Reform Committee. "As investigations by Congress and the Justice Department are still ongoing, Mr. Werfel's assertion that he has found no evidence that anyone at IRS intentionally did anything wrong can only be called premature," Issa said in a statement Monday. "Only through continued cooperation with ongoing Congressional and Justice Department inquiries can IRS make a meaningful claim that it is trying to regain the trust of the American people." ||||| Daniel "Danny" Werfel, acting commissioner of the Internal Revenue Service (IRS), speaks during a House Appropriations subcommittee hearing in Washington, D.C., on June 3, 2013. Daniel "Danny" Werfel, acting commissioner of the Internal Revenue Service (IRS), speaks during a House Appropriations subcommittee hearing in Washington, D.C., on June 3, 2013. Close The Internal Revenue Service used terms such as “progressive” and evidence of advocacy on Israel to flag groups’ tax-exempt applications for extra attention, complicating what had been seen as targeted scrutiny for small-government groups. The IRS’s disclosure yesterday of 15 redacted versions of its Be On the Lookout document, or BOLO, bolstered its contention that delays experienced by Tea Party groups applying for nonprofit status were a symptom of mismanagement and not politically motivated action. “The BOLO list in my mind loses this sinister nature,” said Jeff Trinca, who was chief of staff to the IRS restructuring commission in the 1990s and is now a lobbyist at Van Scoyoc Associates in Washington. “And it becomes another way of creating criteria lists to try to deal with the huge volumes that come through the agency.” The disclosure raised a new set of questions about the IRS, which acknowledged last month that it had given extra attention to Tea Party organizations and other advocates for small government. The documents don’t explain how employees used the BOLO or which groups, if any, received extra scrutiny because of it. Representative Sander Levin of Michigan, the top Democrat on the tax-writing House Ways and Means Committee, said the IRS inspector general, J. Russell George, should explain why his May 14 report didn’t include this information. Photographer: Andrew Harrer/Bloomberg The Internal Revenue Service revealed May 10 that it had given extra attention to Tea Party groups and other small-government advocates. Close The Internal Revenue Service revealed May 10 that it had given extra attention to Tea... Read More Close Open Photographer: Andrew Harrer/Bloomberg The Internal Revenue Service revealed May 10 that it had given extra attention to Tea Party groups and other small-government advocates. ‘Flawed’ Probes “The audit served as the basis and impetus for a wide range of congressional investigations and this new information shows that the foundation of those investigations is flawed in a fundamental way,” Levin said in a statement. Since the IRS apologized for scrutiny of Republican-leaning groups on May 10, six congressional committees have opened inquiries and the Justice Department has begun a criminal probe. President Barack Obama replaced the acting IRS commissioner and Danny Werfel, the agency’s interim leader, has replaced three others with direct responsibility for tax-exempt groups. The documents don’t show that Tea Party groups and progressives were treated equally. In fact, they suggest that the entries on the BOLO derived from separate efforts to police applications for tax-exempt status for political activity. Law Enforcement The IRS is charged with enforcing tax law, which forbids political activity for 501(c)(3) charities that can receive tax-deductible contributions and limits campaign involvement for 501(c)4 social welfare groups that don’t have to disclose their donors. The term “progressive” appeared on a November 2010 document released by House Ways and Means Committee Democrats. It appears to refer to applications for 501(c)(3) status, not the 501(c)(4) status sought by many Tea Party groups. Employees were told to watch for applications that were “partisan and appear as anti-Republican.” On the document released by Democrats, the reference to progressives is in a different section than the Tea Party groups, and it doesn’t direct employees to send the cases to a special unit, unlike the Tea Party cases. Even on the first BOLO document released, from August 2010, progressives are listed under the label of TAG Historical, short for Touch-and-Go Historical, or issues that had been raised in the past. Tea Party is listed under Emerging Issues. 18-Page Surveys The disclosure of the scrutiny of groups working on Israel-related issues confirms what organizations had suspected. Ameinu, which on its website calls itself a “community of progressive Jews,” received its 501(c)(3) tax-exempt status on May 28 -- five years after applying. IRS agents peppered the group with 18-page surveys and lingered for months without follow-up, Hiam Simon, national director of Ameinu, said in a telephone interview. He said he was looking at a 4-inch thick folder of Ameinu’s communications with the IRS. “I think they were painting with a broad brush, with worries about Middle East ties to terrorism,” he said of the IRS. “I don’t think it was caused by malice. Ignorance is too strong a word, too. They simply weren’t nuanced enough or careful enough.” Committee hearings, an inspector general’s report and congressional investigators’ interviews with IRS employees have shown the scrutiny of Tea Party groups started with a single case in February 2010 that an employee flagged to his manager. Werfel said he was suspending the use of BOLOs, which were employed as recently as last month. The final BOLO released, from April, doesn’t include Tea Party or progressive groups specifically, just general language about political involvement. Redacted Information The IRS took several weeks to release yesterday’s documents, because it had to scrub the be-on-the-lookout lists of taxpayer-specific information before making them public. The BOLO mostly consists of redacted information. The prospect that Democratic-friendly groups experienced extra scrutiny wasn’t entirely new. Eight groups with “progress” or “progressive” in their names had appeared on a publicly available list of groups whose applications had been delayed and later approved by the IRS. That list included many small-government groups. Progress Texas, an Austin-based group that typically backs Democratic positions, received an IRS letter with essentially the same questions the agency had asked of some Republican-leaning groups. As with Tea Party groups, the IRS wanted promotional materials, backgrounds of officers, meeting minutes and specifics about activities the organization said it would conduct. Time Consuming Matt Glazer, former executive director, told Bloomberg News in May that the questionnaire was time consuming, though not intrusive. His group was approved. Still, Steven Miller, the former acting IRS commissioner, told the Ways and Means Committee May 17 that progressive groups weren’t targeted. Congressional Republicans said the IRS’s actions against small-government and Republican-leaning groups weren’t limited to extra scrutiny of tax-exempt applications. House committees are also probing gift-tax audits of donors to a group that backed the war in Iraq, disclosures of the confidential information of several groups and IRS requests that anti-abortion groups agree not to protest at Planned Parenthood as a condition of receiving their tax-exempt status. Flagging Groups “It is one thing to flag a group,” Sarah Swinehart, a spokeswoman for Ways and Means Chairman Dave Camp, said in an e-mailed statement. “It is quite another to repeatedly target and abuse conservative groups.” Werfel will testify at a Ways and Means hearing June 27. J. Russell George, the inspector general whose report revealed the Tea Party scrutiny, was asked at a May 22 hearing whether Democratic-leaning groups were targeted. At first, he said he couldn’t give a definitive answer when questioned by Representative Darrell Issa, a California Republican and chairman of the House Oversight and Government Reform Committee. Then, George said that under “the purposes of the audit that we conducted, which was to determine whether they were looked for in the context of political campaign intervention, there were no others.” The inspector general’s office said in a statement that the initial review had been limited to language designed to flag political involvement. New Review “Although these criteria were not used to select cases for review of potential political campaign intervention, we are reviewing whether these criteria led to expanded scrutiny for other reasons,” according to the statement. Dianne Belsom, president of the Laurens County Tea Party in South Carolina, told lawmakers earlier this month her group had been waiting almost three years to hear from the IRS on an application for tax-exempt status after answering repeated and extensive questionnaires. “The IRS needs to be fully investigated and held accountable for its incompetence, harassment and targeting of conservative groups,” Belsom said at a June 4 Ways and Means Committee hearing. The BOLO also has terms related to Israel, looking for applications that “deal with disputed territories in the Middle East” and “may be inflammatory.” Z Street, which describes itself as a Zionist education organization, sued the IRS in federal court over its treatment, which it called discriminatory. “It’s great that they’re finally acknowledging what we’ve known all along,” co-founder Lori Lowenthal Marcus said in a telephone interview. IRS Backlog Marcus said the IRS told Z Street it “froze” their application for 501(c)(3) tax-exempt status when it filed suit. The case is scheduled for hearings next month in U.S. District Court for the District of Columbia. The documents also show that the tax-exempt office was handling issues that had nothing to do with political campaigns or partisanship, such as cases involving medical marijuana, “potentially abusive” pain management clinics and life insurance policies owned by charities. Also yesterday, Werfel released a report outlining his plans for restoring trust in the agency and reducing the backlog of applications for tax-exempt status. ‘Fairness,’ Neutrality Groups stuck in the backlog will have a chance for approval of their applications within two weeks if they promise to limit political spending. The IRS will send letters to about 80 groups. “The administration is committed to making sure the IRS continues to reform itself with the goals of providing the highest quality service and reflecting the principles of fairness and neutrality,” Jay Carney, the White House press secretary, said in a statement. Obama was briefed yesterday by Werfel and Treasury Secretary Jacob J. Lew. Werfel said his review of the agency’s actions hasn’t found evidence of intentional wrongdoing or involvement from outside the IRS. That’s consistent with the findings so far of congressional investigators. “They just let it fester and then they let some folks who didn’t really have the guidance they need go crazy with these questions,” said Trinca, a former Democratic congressional staff member. “The whole thing was just an absolute debacle.” To contact the reporters on this story: Richard Rubin in Washington at [email protected]; Julie Bykowicz in Washington at [email protected] To contact the editor responsible for this story: Jodi Schneider at [email protected]

– Tea Party groups weren't the only ones targeted by the IRS. Documents obtained by Bloomberg reveal the agency also used terms such as "Israel," "progressive," and "occupy" when applying extra scrutiny to groups seeking tax-exempt status. New agency chief Danny Werfel earlier confirmed that there were more "be on the lookout" lists than just the already known Tea Party-related ones—and that some lists were still being used as recently as last month— but did not disclose what words featured on those lists, the AP reports. "There was a wide-ranging set of categories and cases that spanned a broad spectrum" on the lists, Werfel says. He says he will officially release more information soon, once the lists have been censored to protect groups' privacy, NPR reports. However, Werfel still maintains that no evidence of "intentional wrongdoing" has been found. "I'm not providing a definitive conclusion that no intentional wrongdoing occurred," he clarified. "What I'm suggesting is that based on the ongoing review to date, no evidence has yet surfaced."

materials antibodies for eif2 and 4ebp1 proteins , phospho - eif2 , rps6 , and ampk were obtained from cell signaling technology . antibodies for atf4 , gadd34 , and chop were purchased from santa cruz biotechnology , inc . insulin , h2o2 , uridine , n - acetyl cysteine , and thapsigargin were from sigma . dulbecco 's modified eagle 's medium ( glucose - free ) was purchased from invitrogen . cell culture wild - type , perk , perk / gcn2 ( double knock - out ( dko ) ) , and perk / gcn2/pkr ( triple knock - out ( tko ) ) mefs were kind gifts from dr . the mefs carrying knock - in mutations of either eif2 s51s or s51a were kindly provided by dr . hek293 cells and mefs were propagated in dulbecco 's modified eagle 's medium supplemented with 10% fetal bovine serum ( fbs ) ( gemini bioproducts ) and 4.5 g / liter glucose , as described previously ( 13 ) . 55 m -mercaptoethanol ( bme ) was included during passage for various mefs . cytochrome c wild type and null embryonic cells were derived and cultured as described previously ( 41 ) . cells were plated at varying densities to achieve 60 - 80% confluence at the end of treatments . the cells were shifted to bme - free medium and allowed to adhere for 16 h before any treatment . alternatively , cells were exposed to h2o2 for 1 h ( replenished every 30 min ) or 0.8 m thapsigargin for 4 h. one set of cells was pretreated with either 100 m bme or 5 mm n - acetyl cysteine 2 h before exposure to low o2 or h2o2 . expression constructs and transfection the pcmvsport6-catalase ( mouse ) plasmid was purchased from open biosystems . hek293 cells were transfected using lipofectamine 2000 ( invitrogen ) and allowed 48 h for catalase expression . catalase- and gfp - expressing adenoviruses were obtained from the gene transfer vector core ( university of iowa ) and baylor college of medicine vector development laboratory , respectively ( 40 ) . mefs were transduced ( 500 plaque - forming units / cell ) and allowed 30 h for expression . figure 2.perk is required for induction of the integrated stress response and protein synthesis inhibition during hypoxia . a , eif2 phosphorylation in perk and perk mefs exposed to 0 - 20 h 0.5% o2 . quantitative changes in eif2 phosphorylation , compared with 0 h hypoxia based on image j analysis , are indicated . also shown is the accumulation of atf4 and chop proteins in perk and perk mefs . b , protein synthesis in mefs after 48 h 0.5% o2 measured by [ s]methionine incorporation . see experimental procedures for statistical analyses . perk is required for induction of the integrated stress response and protein synthesis inhibition during hypoxia . a , eif2 phosphorylation in perk and perk mefs exposed to 0 - 20 h 0.5% o2 . quantitative changes in eif2 phosphorylation , compared with 0 h hypoxia based on image j analysis , are indicated . also shown is the accumulation of atf4 and chop proteins in perk and perk mefs . b , protein synthesis in mefs after 48 h 0.5% o2 measured by [ s]methionine incorporation . see experimental procedures for statistical analyses . , all cultures were harvested under either normoxia or hypoxia , and western blotting was performed as described previously ( 13 , 31 ) . protein carbonylation in cell lysates was detected using an oxyblot protein oxidation detection kit ( chemicon ) . quantitative real time pcr total rna was isolated using trizol ( invitrogen ) . first strand cdna was synthesized using 2 g of rna , random hexamers , and the superscript ii first - strand synthesis system for rt - pcr ( invitrogen ) . quantitative real time pcr was performed using the applied biosystems 7900ht sequence detection system and sybergreen pcr master mix ( applied biosystems ) . cells seeded in 12-well plates were subjected to 48 h of 0.5% o2 or 1 h of h2o2 ( 20 or 100 m ) . cells were labeled with [ s]methionine for 1 h under low o2 or h2o2 . radioactivity in cell lysates was determined as described previously ( 13 ) and adjusted with protein content in each sample . the eif2 s51s and s51a mefs ( 1000 cells / well in 96-well plates ) were exposed to 21% or 0.5% o2 for 48 h in medium similarly to colony formation assays . the data were expressed as percentiles of normoxic cells grown in the same medium . colony formation assay s51a and s51a mefs were plated at 1000 cells / well in a 6-well plate and allowed to adhere overnight before 2 h of pretreatment with 5 mm n - acetyl cysteine or drug vehicle . the cells were then exposed to 21 or 0.5% o2 for 24 or 48 h in dulbecco 's modified eagle 's medium consisting of full serum and glucose ( 10% fbs , 4.5 g / liter glucose ) , medium deprived of serum ( 0.5% fbs , 4.5 g / liter glucose ) or medium deprived of glucose ( 10% fbs , 0.2 g / liter glucose ) . the cells were shifted back to regular medium and grown for 1 week under normoxia . results are average s.e . of 4 - 6 samples from two independent studies . statistical significance was defined as follows : , # , or , p < 0.05 ; or # # , p < 0.01 . hypoxia inhibits signaling pathways regulating mrna translation among the four mammalian eif2 kinases ( perk , gcn2 ( gcn2 eif2 kinase ) , pkr , and heme - regulated initiation factor 2- kinase ( hri ) ) , perk appears to be the principal regulator of eif2 when o2 levels are 0.02% o2 ( 18 ) . since modest hypoxia ( > 0.2% o2 ) and anoxia ( 0.02% o2 ) exhibit different kinetics of 4ebp1 and eif2 regulation ( 13 , 46 , 47 ) , we examined the effects of perk on eif2 during moderate hypoxia ( 0.5% o2 ) . phosphorylation of eif2 on ser increased 4-fold in perk mefs after 2 h and was maintained over 20 h ( fig . in contrast , eif2 phosphorylation was only increased 2-fold in perk mefs ( fig . therefore , perk is the principal eif2 kinase operating under moderate hypoxia , although other kinases contribute to eif2 inhibition . of note , all western blot assays depicted in figs . 2 , 3 , 4 , 5 , 6 , 7 were repeated 3 - 5 times to allow precise quantitation of phosphorylation changes . perk was also required for the induction of atf4 and chop in o2-deprived cells ( fig . finally , hypoxic perk activation correlated with a significant drop in protein synthesis , as measured by [ s]methionine pulse labeling . exposure of serum - replete mefs to 0.5% o2 for 48 h resulted in a 55% drop in metabolic labeling ( fig . perk deletion restored translation rates to 70% , further indicating that perk is critical for translational inhibition during chronic but moderate hypoxia . ros inhibit signaling for mrna translation to investigate whether increased ros levels mediate hypoxic regulation of mrna translation , we characterized the effects of ros on signaling pathways controlling protein synthesis . we employed mefs and hek293 cells for these studies , since both have been used extensively for the evaluation of mtor and the isr ( 13 , 15 , 18 , 19 ) . initially , we treated cells with exogenous h2o2 , the major form of intracellular ros generated during o2 deprivation ( 40 , 42 ) . higher h2o2 doses ( 100 - 500 m , 1 h ) significantly inhibited mtor in hek293 cells and mefs based on 4ebp1 and rps6 hypophosphorylation ( fig . 3a ) . however , lower h2o2 doses ( 5 - 20 m ) did not appreciably affect mtor activity . moreover , h2o2 inhibited translation elongation with a dose response similar to mtor . high h2o2 concentrations ( 100 - 500 m ) caused significant eef2 phosphorylation ( fig . 3a ) , whereas low h2o2 doses ( 5 - 20 m ) did not . in direct contrast , eif2 phosphorylation was triggered by as low as 5 m h2o2 ( fig . a , hek293 cells and immortalized wild - type mouse embryonic fibroblasts ( mefs ) were exposed to 0 - 500 m h2o2 for 1 h. whole cell extracts were blotted for 4ebp1 , phospho - rps6 , phospho - eif2 , total eif2 , phospho - eef2 , and total eef2 . hypophosphorylated ( ) and phosphorylated ( and ) forms of 4ebp1 are indicated . levels of total eif2 and eef2 proteins were examined for sample loading and protein stability using the same lysates run on separate gels . changes in eif2 phosphorylation ( based on image j analysis ) compared with 0 m h2o2 are shown . b , protein synthesis in h2o2-treated ( 1 h ) mefs with or without 2 h bme ( 100 m ) preconditioning . bme ( 100 m ) was present during the 1-h protein synthesis c , western blotting for total 4ebp1 protein and rps6 phospho - ser in h2o2-treated ( 1 h ) tsc2 and tsc2 mefs . d , protein synthesis in tsc2 and tsc2 mefs treated with 100 m h2o2 ( 1 h ) . [ s]methionine labeling was carried out in the presence of 100 m h2o2 . a , hek293 cells and immortalized wild - type mouse embryonic fibroblasts ( mefs ) were exposed to 0 - 500 m h2o2 for 1 h. whole cell extracts were blotted for 4ebp1 , phospho - rps6 , phospho - eif2 , total eif2 , phospho - eef2 , and total eef2 . hypophosphorylated ( ) and phosphorylated ( and ) forms of 4ebp1 are indicated . levels of total eif2 and eef2 proteins were examined for sample loading and protein stability using the same lysates run on separate gels . changes in eif2 phosphorylation ( based on image j analysis ) compared with 0 m h2o2 are shown . b , protein synthesis in h2o2-treated ( 1 h ) mefs with or without 2 h bme ( 100 m ) preconditioning . c , western blotting for total 4ebp1 protein and rps6 phospho - ser in h2o2-treated ( 1 h ) tsc2 and tsc2 mefs . d , protein synthesis in tsc2 and tsc2 mefs treated with 100 m h2o2 ( 1 h ) . [ s]methionine labeling was carried out in the presence of 100 m h2o2 . a , hek293 cells were exposed to varying concentrations of h2o2 ( 1 h ) or 0.8 m thapsigargin ( 4 h ) . cell lysates were probed for phospho - eif2 , total eif2 , and perk . b , eif2 phosphorylation in hek293 cells exposed to 20 m h2o2 for 0 - 60 min . c , protein synthesis in mefs treated with 0 - 100 m h2o2 ( 1 h ) ( n = 9 - 10 ) . , p < 0.01 ; wild - type ( wt ) versus perk or dko ( perk , gcn2 ) mefs subjected to 100 m h2o2 . # # , p < 0.01 ; tko ( perk , gcn2 , pkr ) mefs showed significantly higher protein synthesis in comparison with perk and dko mefs upon exposure to 100 m h2o2 . a , hek293 cells were exposed to varying concentrations of h2o2 ( 1 h ) or 0.8 m thapsigargin ( 4 h ) . cell lysates were probed for phospho - eif2 , total eif2 , and perk . b , eif2 phosphorylation in hek293 cells exposed to 20 m h2o2 for 0 - 60 min . c , protein synthesis in mefs treated with 0 - 100 m h2o2 ( 1 h ) ( n = 9 - 10 ) . , p < 0.01 ; wild - type ( wt ) versus perk or dko ( perk , gcn2 ) mefs subjected to 100 m h2o2 . # # , p < 0.01 ; tko ( perk , gcn2 , pkr ) mefs showed significantly higher protein synthesis in comparison with perk and dko mefs upon exposure to 100 m h2o2 . repression of eif4e , eif2 , and eef2 activities correlated with a significant drop in protein synthesis . as shown in fig . 3b , 20 - 100 m h2o2 for 1 h inhibited protein synthesis 70 - 90% , respectively , in mefs . furthermore , the antioxidant bme partially blocked the reduction in protein synthesis caused by h2o2 ( fig . 3b ) . to investigate whether attenuated signaling and protein synthesis is a direct consequence of cell death , we assessed the effects of h2o2 on cell viability using trypan blue staining . of note , 90% of cells were viable immediately following treatment with 100 m h2o2 for 1 h ( supplemental fig . 1a ) , indicating that mrna translation inhibition did not result from acute cell death . together , these data indicate that ros inhibit mrna translation and that eif2 phosphorylation is significantly more sensitive to oxidative stress than mtor regulation or eef2 phosphorylation . tsc2 is necessary for acute hypoxic mtor inhibition ( 13 , 19 ) . therefore , we determined if tsc2 is required for mtor regulation by h2o2 . as shown in fig . 3c , tsc2 mefs exhibited a higher basal level of mtor activity in comparison with tsc2 mefs ( indicated by 4ebp1 and rps6 hyperphosphorylation ) . h2o2 ( 40 - 300 m ) gradually suppressed mtor activity in both cell types , regardless of tsc2 status ( fig . furthermore , h2o2 ( 100 m ) inhibited protein synthesis by 90% in both tsc2 and tsc2 cells ( fig . 3d ) , confirming that tsc2 is not essential for mtor regulation by oxidative stress . because tsc2 is required for rapid mtor inhibition by hypoxia ( 13 , 15 , 19 ) , the data indicate that acute hypoxic mtor regulation is unlikely to involve h2o2 . we therefore investigated whether perk plays a role in eif2 regulation during oxidative stress . perk mefs were exposed to 0 - 100 m h2o2 for 1 h , and eif2 phosphorylation and perk protein mobility ( an assay typically used to study perk activation ( 28 , 34 ) ) were examined by western blots . as little as 0.5 m h2o2 elevated eif2 phosphorylation , which was enhanced as h2o2 concentration increased to 100 m ( fig . a time course study using 20 m h2o2 showed significantly increased eif2 phosphorylation after a 20-min exposure ( fig . 4b ) , demonstrating rapid kinetics for eif2 inhibition by oxidative stress . importantly , h2o2 ( 20 and 100 m ) also caused a moderate but reproducibly detectable shift in perk protein mobility ( fig . 4a ) , suggesting a dose - dependent post - translational modification of perk proteins caused by h2o2 . high h2o2 levels resulted in increased perk protein modification , resolved from unmodified perk by a slight mobility shift . however , h2o2-induced perk mobility change was significantly less pronounced than that resulting from thapsigargin , an ionophore disrupting er ca stores . the multifactorial involvement of eif2 kinases in h2o2 responses was supported by examining protein synthesis using mutant mefs . 4c , 100 m h2o2 caused a 75% reduction in metabolic s labeling in wild - type mefs , whereas both perk and perk gcn2 dko cells exhibited 50% inhibition of mrna translation . pkr deletion in addition to perk and gcn2 in tko cells further alleviated the inhibition to 25% of vehicle control . thus , we concluded that ros activate multiple eif2 kinases , including perk and pkr . however , gcn2 does not appear to play a major role in this pathway . hypoxia enhances ros release we evaluated the impact of endogenous cellular ros generated at 0.5% o2 on pathways regulating mrna translation . given difficulties with typical 2,7-dichlorofluorescein diacetate assays of o2-deprived cells ( 40 ) , we tested protein carbonylation as an indicator of oxidative stress . in this assay , whole cell lysates are probed to reveal multiple polypeptides exhibiting carbonyl modifications . here , hek293 cells were treated with h2o2 , hypoxia , or tnf for varying lengths of time . h2o2 ( 20 m , 1 h ) resulted in modest protein carbonylation ( fig . 5a ) , whereas 100 m h2o2 ( 1 h ) generated significant protein carbonylation ( fig . 2 , treatment of cells with 100 m h2o2 is roughly comparable with growth in 0.5% o2 based on 2,7-dichlorofluorescein diacetate fluorescence ( although this assay is imperfect ) . hypoxia for 2 h caused modest but reproducibly detectable increases in protein carbonylation , which was enhanced by extending treatment to 20 h ( fig . 5a ) . of note , tnf , a cytokine augmenting intracellular ros ( 34 ) , and 0.5% o2 ( 20 h ) resulted in similar levels of protein carbonylation . therefore furthermore , o2 deprivation results in intracellular ros levels comparable with or slightly less than tnf treatment and 100 m h2o2 . effects of hypoxic ros on perk activation were examined by measuring perk protein mobility . hypoxia ( 8 - 24 h ) reproducibly induced subtle reductions in perk mobility . importantly , hypoxic alteration of perk mobility was comparable with that of peroxide ( 20 - 100 m ) ( fig . 5b ) . high doses ( 100 m ) caused enhanced perk modification and increased resolution from unmodified perk protein ( fig . mobility changes induced by hypoxia and h2o2 were significantly less than that caused by thapsigargin ( fig . as stated above , the reasons for these distinct effects on perk mobility are currently unknown . hypoxic mtor regulation does not involve ros to examine whether hypoxic mtor inactivation is mediated by ros , mefs were infected with adenoviral catalase or gfp ( negative control ) and exposed to 0.5% o2 or h2o2 . catalase blocked h2o2-induced p70s6k and 4ebp1 hypophosphorylation , demonstrating that catalase is capable of effectively scavenging h2o2 in mefs ( fig . hypoxic p70s6k and 4ebp1 hypophosphorylation was not affected by catalase expression ( fig . 5c ) , implying that hypoxic mtor regulation is independent of redox change . to further evaluate ros involvement in hypoxic mtor and eef2 regulation , hek293 cells were transfected with empty vector or plasmid encoding catalase . as shown in fig 5d , expression of catalase effectively alleviated h2o2-induced rps6 hypophosphorylation but not rps6 hypophosphorylation caused by 20-h hypoxia , confirming that ros do not affect mtor activity during hypoxia . similar to rps6 , catalase had an insignificant effect on eef2 phosphorylation during hypoxia ( fig . collectively , these data demonstrate that although ros suppress mtor and eef2 activities in vitro , hypoxic mtor and eef2 inhibition does not involve ros . ros activate the isr during hypoxia given the similarity of hypoxia and h2o2 in causing subtle perk mobility changes , we studied the effects of oxidative stress on perk activation during hypoxia . of note , eif2 phosphorylation caused by hypoxia ( 20 h ) and peroxide ( 20 m ) was reduced by catalase ( fig . 5d ) , implying that increased h2o2 during hypoxia activates the perk / eif2 pathway . to extend these data , we tested hypoxic induction of atf4 target genes in hek293 cells using quantitative real time pcr . hypoxia treatment induced gadd34 , bip , and chop as well as the hif target phosphoglycerate kinase ( fig . 5e ) , it effectively blocked the induction of all three er stress genes during hypoxia ( fig . similarly , h2o2 ( 20 m , 6 h ) dramatically increased gadd34 , bip , and chop expression in hek293 cells , which was repressed by catalase ( supplemental fig . interestingly , h2o2 moderately enhanced phosphoglycerate kinase expression , and phosphoglycerate kinase induction was also suppressed by catalase ( supplemental fig . 3b ) . h2o2-induced phosphoglycerate kinase probably results from ros - mediated hif-1 protein accumulation ( 40 - 42 ) . overall , our data demonstrate that ros and hypoxia activate the isr , and these responses are abrogated by ros scavengers . we next determined whether catalase blockade of eif2 phosphorylation affects actual protein synthesis during o2 deprivation . this was accomplished using mefs infected with adenoviral gfp or catalase . as shown in fig . 5f , catalase attenuated hypoxia - induced decreases in metabolic labeling from 45 to 25% , verifying that ros play a partial role in regulating mrna translation during hypoxia . the remaining 25% reduction in protein synthesis probably results from ros - independent 4ebp1 , eif4e , and eef2 modulation . in summary , we concluded that oxidative stress during hypoxia induces the isr , resulting in decreased protein synthesis and activation of atf4-regulated stress genes . mitochondrial ros modulate eif2 activity during hypoxia because ros are important for activating the isr during hypoxia , we investigated the source(s ) of ros causing this effect . ros are produced by various cellular processes and organelles , including mitochondria and the er ( 26 , 48 , 49 ) . er ros are largely generated by ero1 ( endoplasmic reticulum oxidase-1 ) to facilitate intramolecular disulfide bond formation and protein folding ( 49 ) . ( 50 ) previously demonstrated that neither ero1 rna interference nor stable interfering ero1 transgenes reproducibly affected er redox in mammalian cells . consequently , we did not attempt to modulate er redox in our assays . instead , we investigated the effects of mtros on the isr and mrna translation under o2 deprivation given that mtros are biologically active ( 40 , 41 ) . loss of cytochrome c , a key component of the mitochondrial electron transport chain , greatly diminishes mtros release during hypoxia ( 41 ) . therefore , we employed wild type and cytochrome c - null embryonic cells ( ecs ) in our studies . figure 5.role of ros during hypoxic regulation of mrna translation . a , hek293 cells were exposed to h2o ( vehicle control ) , h2o2 ( 20 or 100 m , 1 h ) , hypoxia ( hyp ; 0.5% o2 , 2 or 20 h ) , or tnf ( 10 ng / ml , 6 or 16 h ) . b , hek293 cells were exposed to hypoxia ( 0.5% o2 , 8 or 24 h ) , h2o2 ( 20 or 100 m , 1 h ) , or thapsigargin ( t ) ( 0.8 m , 4 h ) . mobility of total perk proteins and phosphorylation of eif2 were determined . c , mefs infected with adenoviral gfp or catalase were exposed to hypoxia ( 0.5% o2 , 0.5 or 6 h ) or h2o2 ( 50 or 200 m , 1 h ) . phosphorylation of p70s6k and 4ebp1 was examined using anti - phospho - p70s6k ( thr ) and total 4ebp1 antibodies . , the p80s6k isoform , which did not change appreciably during any treatments . the status of 4ebp1 is indicated by mobility shift from phosphorylated form to hypophosphorylated form . d , hek293 cells transfected with catalase or empty vector were exposed to 21% ( n ) or 0.5% o2 ( h ) for 20 h , or 50 m h2o2 for 1 h ( r ) . e , expression of mrna for gadd34 , bip , chop , and phosphoglycerate kinase in hek293 cells transfected with catalase ( cat ) or vector ( vec ) following 20 h of 21% or 0.5% o2 . f , protein synthesis in adenoviral gfp- or catalase - expressing mefs after 48 h 0.5% o2 . , p < 0.05 ; , p < 0.01 . role of ros during hypoxic regulation of mrna translation . a , hek293 cells were exposed to h2o ( vehicle control ) , h2o2 ( 20 or 100 m , 1 h ) , hypoxia ( hyp ; 0.5% o2 , 2 or 20 h ) , or tnf ( 10 ng / ml , 6 or 16 h ) . b , hek293 cells were exposed to hypoxia ( 0.5% o2 , 8 or 24 h ) , h2o2 ( 20 or 100 m , 1 h ) , or thapsigargin ( t ) ( 0.8 m , 4 h ) . mobility of total perk proteins and phosphorylation of eif2 were determined . c , mefs infected with adenoviral gfp or catalase were exposed to hypoxia ( 0.5% o2 , 0.5 or 6 h ) or h2o2 ( 50 or 200 m , 1 h ) . phosphorylation of p70s6k and 4ebp1 was examined using anti - phospho - p70s6k ( thr ) and total 4ebp1 antibodies . , the p80s6k isoform , which did not change appreciably during any treatments . the status of 4ebp1 is indicated by mobility shift from phosphorylated form to hypophosphorylated form d , hek293 cells transfected with catalase or empty vector were exposed to 21% ( n ) or 0.5% o2 ( h ) for 20 h , or 50 m h2o2 for 1 h ( r ) . e , expression of mrna for gadd34 , bip , chop , and phosphoglycerate kinase in hek293 cells transfected with catalase ( cat ) or vector ( vec ) following 20 h of 21% or 0.5% o2 . f , protein synthesis in adenoviral gfp- or catalase - expressing mefs after 48 h 0.5% o2 . , ecs were exposed to 0.5% o2 for 0 - 12 h. hif accumulation and phosphorylation of eif2 and the mtor downstream targets rps6 and 4ebp1 were examined . 6a ) , consistent with previous reports that mitochondria are important for hypoxic hif-1 stabilization ( 40 - 42 ) . hypoxia inhibited mtor activity up to 6 h in both wild type and cytochrome c null ecs , as indicated by rps6 and 4ebp1 hypophosphorylation ( fig . interestingly , hypoxic mtor inhibition was significantly alleviated by cytochrome c deletion after 12 h ( fig . this difference probably results from impaired hif - mediated redd1 induction in cytochrome c null ecs and therefore reduced activation of the redd1/tsc2/mtor pathway in hypoxic cells ( 19 ) . a and b , cytochrome c wild type ( ec - wt ) or null ( ec - null ) embryonic cells were exposed to 0.5% o2 for 0 - 12 h. phospho - rps6 , -eef2 , and hif-1 proteins ( a ) and phospho - eif2 and atf4 proteins ( b ) were examined by western blot . levels of total rps6 and eef2 proteins ( a ) and eif2 proteins ( b ) were analyzed for protein stability . n.s . increases in eif2 phosphorylation and atf4 protein levels compared with 0 h hypoxia are indicated . c , effects of cytochrome c mutation on hypoxic induction of catalase and isr genes gadd34 , bip , chop , and catalase in ec cells . cytochrome c wild type and null cells were exposed to 0.5% o2 for 16 h in the presence or absence of bme ( 100 m ) . , p < 0.01 ; cytochrome c wt versus null ec in the absence of bme . # # , p < 0.01 ; wt ec in the presence or absence of bme . a and b , cytochrome c wild type ( ec - wt ) or null ( ec - null ) embryonic cells were exposed to 0.5% o2 for 0 - 12 h. phospho - rps6 , -eef2 , and hif-1 proteins ( a ) and phospho - eif2 and atf4 proteins ( b ) were examined by western blot . levels of total rps6 and eef2 proteins ( a ) and eif2 proteins ( b ) were analyzed for protein stability . n.s . increases in eif2 phosphorylation and atf4 protein levels compared with 0 h hypoxia are indicated . c , effects of cytochrome c mutation on hypoxic induction of catalase and isr genes gadd34 , bip , chop , and catalase in ec cells . cytochrome c wild type and null cells were exposed to 0.5% o2 for 16 h in the presence or absence of bme ( 100 m ) . 0.01 ; cytochrome c wt versus null ec in the absence of bme . # # , p < 0.01 ; wt ec in the presence or absence of bme . of note , cytochrome c mutagenesis suppressed hypoxic eif2 phosphorylation and atf4 protein accumulation after 6 h of 0.5% o2 ( fig . 6b ) as well as the induction of gadd34 , bip , and chop at 16 h ( fig . bme pretreatment effectively decreased er stress gene induction in wild type cells but not in cytochrome c null ecs ( fig . interestingly , hypoxia also enhanced catalase expression , which was effectively blocked by bme and cytochrome c loss ( fig . altogether , our data suggest that ros , especially mtros , play an important role in hypoxic activation of the isr . isr activation protects cells against o2 and growth factor withdrawal previous studies by bi et al . have shown that 0.02% o2 induces apoptosis within 12 h , and the perk / eif2 pathway is an important protective mechanism for cells experiencing anoxia ( 27 ) . since moderate hypoxia ( 0.2% o2 ) has been shown to affect cell survival differently from anoxia ( 17 ) , we evaluated the effects of the isr on cell survival at 0.5% o2 using mefs carrying knock - in alleles of eif2 s51s ( control cells ) or s51a . notably , the s51a mutation abolishes eif2 phosphorylation caused by hypoxia , h2o2 , and thapsigargin ( fig . downstream isr responses , including eif-2-mediated global translation inhibition , selective atf4 translation , and induction of atf4 target genes , are abrogated by the s51a mutation . we exposed s51s and s51a mefs cultured in regular medium ( 10% fbs , 4.5 g / liter glucose ) to 21 or 0.5% o2 for 48 h. cell viability was assessed by colony formation . consistent with a recent report that modest hypoxia alone is not cytotoxic ( 17 ) , s51s and s51a mefs formed comparable numbers of colonies under normoxia and hypoxia ( fig . 7b ) , indicating that hypoxia resulted in only insignificant amounts of cell death ( < 10% ) for both cell types . we then added secondary stresses by reducing glucose or serum concentrations in the culture medium to mimic cells residing in solid tumors , ischemic tissue , and stroke , where they are probably starved for growth factors and/or nutrients in addition to o2 . glucose reduction from 4.5 g / liter to 0.2 g / liter ( 10% fbs ) did not result in any significant cell death following 48 h of normoxia or hypoxia ( fig . growth factor withdrawal significantly attenuated cell survival under 0.5% o2 . approximately 90 and 98% cell death was detected for s51s and s51a mefs , respectively , under low o2 when serum was decreased from 10 to 0.5% , despite high glucose concentrations ( fig . neither 2-day glucose nor serum deprivation altered eif2 phosphorylation in s51s mefs during normoxia ( fig . therefore , in direct contrast to anoxia , hypoxia alone does not cause appreciable cell death . we concluded that growth factor availability is critical for maintaining cell viability during chronic hypoxia . since 48 h o2 and serum starvation resulted in 90% death for both s51s and s51a mefs , we examined the effect of the isr on cellular resistance to hypoxia by limiting treatment to 24 h. as shown in fig . 7 , d and e , cell survival was enhanced by less pronounced stress ( 0.5% o2 , 0.5% fbs , and 4.5 g / liter glucose ) for a shorter period of time . however , the eif2 s51a mutation greatly compromised cell survival to 25% of normoxia under these combined stresses ( fig . 7 , c and d ) , demonstrating that the isr protects cells from low o2 and growth factor withdrawal . intracellular atp levels were lowered to 55% of normoxic levels in s51s cells , and s51a mutation resulted in significantly lower atp levels ( fig . together , our data demonstrate that cells with a compromised isr pathway exhibit elevated sensitivity to o2 and growth factor deprivation . therefore , an intact perk / eif2 pathway facilitates energy maintenance and cell survival during metabolic stress . however , prolonged o2 deprivation ( 48 h ) coupled with growth factor withdrawal results in cell death even if the isr is intact . figure 7.the perk / eif2 pathway is critical for adaptation to low o2 and growth factor conditions . a , eif2 s51s and s51a mefs were exposed to 20 h of 0.5% o2 ( h ) , 1 h 20 m h2o2 ( r ) , or 4 h of 0.8 m thapsigargin ( t ) . b , eif2 s51s or s51a mefs were exposed to 21 or 0.5% o2 for 48 h in medium containing full ( 10% ) or reduced ( 0.5% ) fbs and full ( 4.5 g / liter ) or reduced glucose ( gluc ) ( 0.2 g / liter ) . cell survival was examined by colony formation in regular medium ( 10% fbs/4.5 g / liter glucose ) under normoxia for an additional 7 days . c , eif2 phosphorylation in s51s mefs after growing for 48 h in normoxia in regular medium ( 10/4.5 ) , or medium containing 0.2 g / liter glucose ( 10/0.2 ) or 0.5% fbs ( 0.5/4.5 ) . d and e , survival for s51s or s51a mefs exposed to 21 or 0.5% o2 for 24 h in serum - reduced medium containing 0.5% fbs . shown are representative assays ( d ) and quantification of colonies ( e ) ( n = 4 ) . , f , intracellular atp levels in s51s and s51a mefs after 48 h of 21 or 0.5% o2 in medium containing 0.5% fbs , 4.5 g / liter glucose . g , schematic diagram for hypoxic activation of the isr and biological significance of this regulation . the perk / eif2 pathway is critical for adaptation to low o2 and growth factor conditions . a , eif2 s51s and s51a mefs were exposed to 20 h of 0.5% o2 ( h ) , 1 h 20 m h2o2 ( r ) , or 4 h of 0.8 m thapsigargin ( t ) . b , eif2 s51s or s51a mefs were exposed to 21 or 0.5% o2 for 48 h in medium containing full ( 10% ) or reduced ( 0.5% ) fbs and full ( 4.5 g / liter ) or reduced glucose ( gluc ) ( 0.2 g / liter ) . cell survival was examined by colony formation in regular medium ( 10% fbs/4.5 g / liter glucose ) under normoxia for an additional 7 days . c , eif2 phosphorylation in s51s mefs after growing for 48 h in normoxia in regular medium ( 10/4.5 ) , or medium containing 0.2 g / liter glucose ( 10/0.2 ) or 0.5% fbs ( 0.5/4.5 ) . d and e , survival for s51s or s51a mefs exposed to 21 or 0.5% o2 for 24 h in serum - reduced medium containing 0.5% fbs . shown are representative assays ( d ) and quantification of colonies ( e ) ( n = 4 ) . , f , intracellular atp levels in s51s and s51a mefs after 48 h of 21 or 0.5% o2 in medium containing 0.5% fbs , 4.5 g / liter glucose . g , schematic diagram for hypoxic activation of the isr and biological significance of this regulation . we show here that oxidative stress inhibits mrna translation by modulating the phosphorylation of key regulators , including 4ebp1 , rps6 , eif2 , and eef2 . cells exposed to significant levels of exogenous h2o2 trigger eif2 phosphorylation by multiple kinases and also inhibit mtor in a dose - dependent manner through tsc2-independent mechanisms . in addition , intracellular ros produced under hypoxic conditions play an important role in activating the perk / eif2/atf4 pathway . this response is quite specific , since hypoxic ros do not affect mtor and eef2 activities . finally , the isr induced by perk / eif2/atf4 is adaptive and promotes cell survival during o2 deprivation . the mechanisms by which oxidative stress regulate the eif2 kinases are complex and are not completely understood . xue et al . ( 34 ) reported that ros generated by tnf signaling can activate perk , whereas eif2 phosphorylation induced by arsenate does not involve perk . here , we demonstrate that h2o2 promotes perk - mediated eif2 phosphorylation , thereby inhibiting protein synthesis . direct activation of perk by h2o2 and hypoxia was reflected in the modest but reproducible change in perk protein mobility , which is similar to that reported for cells treated with tnf ( 34 ) . our data also indicate that multiple eif2 kinases , including perk and pkr , regulate eif2 phosphorylation in response to exogenous ros ( fig . gcn2 plays a minor role at most , since h2o2 treatment elicited comparable changes in protein synthesis in perk and perk / gcn2 dko mefs . our data demonstrate that the isr is induced in hypoxic cells through activation of the perk / eif2/atf4 pathway . interestingly , other regulatory pathways known to inhibit mrna translation ( mtor and eef2 ) were not affected by hypoxic ros . these seemingly disparate effects of ros suggest that their concentration in hypoxic cells may be insufficient to activate mtor and eef2 responses . this notion is supported by the observation that relatively high doses of exogenous h2o2 are required to exert effects on mtor and eef2 activity . either the perk / eif2/atf4 pathway has a particularly low threshold for activation by ros , or perk is exposed to high localized ros concentrations in the er of hypoxic cells . many studies have demonstrated that hypoxic ros are generated from the mitochondrial electron transport chain ( 39 - 41 ) . it is also possible that ros produced directly in the er by ero1 contribute to perk activation . oxidative protein folding occurs in the er , which has a relatively low ratio of gsh / gssg ( 1:1 to 3:1 ) compared with a greater than the 50:1 ratio in the cytoplasm ( 49 ) . therefore , the er may be particularly sensitive to changes in intracellular redox status . in addition , most er ros are produced by ero1 through reoxidation of protein - disulfide isomerase ( 26 , 49 ) , and hypoxia is known to induce the expression of ero1 ( 51 ) . interestingly , cytochrome c null cells ( exhibiting decreased mtros production ) partially reduce perk / eif2 activation , suggesting that other ros sources are involved . however , it should be noted that a physical association between the er and mitochondria has been demonstrated , suggesting that mtros are readily available to er kinases ( 52 , 53 ) . in contrast , mtor and eef2 may not be accessible to mtros , although the 2,7-dichlorofluorescein diacetate assays provided in supplemental fig . 2 suggest that h2o2 levels in cells exposed to 0.5% o2 are sufficient to activate these targets . it is noteworthy that several previous reports referred to essentially anoxic conditions ( 0.02% o2 ) as hypoxic , in contrast to the levels of o2 ( 0.5%-1.5% ) typically used to define hypoxia . for instance , anoxia results in rapid eif2 inhibition and a delay in eif4f regulation ( 46 ) , whereas modest hypoxia rapidly inhibits eif4f and gradually increases eif2 phosphorylation ( 13 , 31 , 47 ) . moreover , 24 h of anoxia was sufficient to induce cell death in several reports ( 17 , 27 , 54 ) , whereas moderate hypoxia ( 0.5% o2 , 48 h ) does not affect cell viability ( fig . secondary stresses , such as serum deprivation , were required to induce cell death during 48 h of moderate hypoxia . thus , it is important to consider the severity and the length of o2 deprivation when studying o2 effects on cell metabolism and survival . the ros - induced isr reported here is an important prosurvival mechanism under moderate hypoxia , a situation that occurs in multiple pathophysiological conditions . ros are well recognized for playing dual roles as both deleterious and beneficial factors . character of ros is substantiated by growing evidence that ros can promote er stress , dna , protein and lipid damage , and apoptosis but can also activate adaptive intracellular signaling pathways ( 36 - 38 , 48 ) . the effects of ros on cellular functions are likely to depend on the location and concentration of ros produced ( 26 ) . however , moderate ros levels produced during hypoxia facilitate early hypoxia tolerance by inhibiting global protein translation , conserving atp , and inducing atf4 target genes modulating survival ( chop ) , protein translation ( gadd34 ) , and removal of oxidative stress ( heme oxidase-1 and enzymes involved in glutathione metabolism ) via the isr ( fig . it is noteworthy that nrf2 , another perk substrate ( 48 ) , is activated during hypoxia ( 55 ) , possibly by ros . nrf2 activates the transcription of genes encoding detoxifying enzymes and antioxidants ( 48 ) . together , atf4 and nrf2 target genes form a negative feedback loop to modify mrna translation and modulate energy and redox status during hypoxia ( fig . we also demonstrate that both growth factor availability and isr activation are crucial for preventing hypoxic cell death . the protective response conferred by extrinsic growth factors against o2 deprivation is likely to involve multiple mechanisms . growth factor signals promote nutrient uptake and their intracellular metabolism and the maintenance of mitochondrial homeostasis ( 56 , 57 ) . additionally , the ability of cells to stimulate anaerobic glycolysis in response to hypoxia depends on growth factor receptor - mediated hif signaling ( 6 ) . our data indicate that the isr promotes hypoxia tolerance by inducing stress genes and facilitating cellular energy and redox homeostasis . this model is supported by the demonstration that cells with a compromised isr pathway exhibit significant sensitivity to o2 and growth factor deprivation . many pathologies , such as solid tumors , ischemia , stroke , neurodegerative diseases , and inflammation , result in cellular redox imbalances . as a result , appropriate administration of antioxidants or free radical - generating compounds are potential therapeutic modalities for treating these diseases . for example , antioxidants inhibit tumorigenesis in three different models ( 45 ) . however , proper treatment strategies can only be designed based upon improved understanding of the interactions between hypoxia and ros .

under hypoxic conditions , cells suppress energy - intensive mrna translation by modulating the mammalian target of rapamycin ( mtor ) and pancreatic eif2 kinase ( perk ) pathways . much is known about hypoxic inhibition of mtor activity ; however , the cellular processes activating perk remain unclear . since hypoxia is known to increase intracellular reactive oxygen species ( ros ) , we hypothesized that hypoxic ros regulate mtor and perk to control mrna translation and cell survival . our data indicate that although exogenous ros inhibit mtor , eif2 , and eef2 , mtor and eef2 were largely refractory to ros generated under moderate hypoxia ( 0.5% o2 ) . in direct contrast , the perk / eif2/atf4 integrated stress response ( isr ) was activated by hypoxic ros and contributed to global protein synthesis inhibition and adaptive atf4-mediated gene expression . the isr as well as exogenous growth factors were critical for cell viability during extended hypoxia , since isr inhibition decreased the viability of cells deprived of o2 and growth factors . collectively , our data support an important role for ros in hypoxic cell survival . under conditions of moderate hypoxia , ros induce the isr , thereby promoting energy and redox homeostasis and enhancing cellular survival .

House passes Keystone bill — all eyes shift to Senate As expected, the House easily passed a bill to approve the Keystone XL pipeline on Friday — setting the stage for drama next week in the Senate, where supporters are inching close to the filibuster-proof majority needed to send the measure to President Barack Obama’s desk. The White House hasn’t issued an official statement on the bill but has given every indication that Obama would probably veto it. Story Continued Below Friday’s House vote was 252-161. Supporters included 31 House Democrats — but not Minority Whip Steny Hoyer (D-Md.), who publicly backs the pipeline. Michigan Republican Rep. Justin Amash voted “present.” (Also on POLITICO: GOP rules change may hit Ryan) The Senate on Tuesday will take up identical Keystone legislation, which is being promoted heavily by Sen. Mary Landrieu (D-La.) in advance of her Dec. 6 runoff election. But under a deal with Republicans, the bill that clears the Senate would be the House version sponsored by her runoff opponent, Rep. Bill Cassidy (R-La.). As of Friday afternoon, Keystone supporters could count on backing from 59 senators, including every Republican senator and 14 Democrats. The latest was Sen. Michael Bennet (D-Colo.), whom Landrieu listed as a supporter during a conference call with reporters Friday afternoon. The pro-Keystone side is still waiting for word on whether Sens. Cory Booker (D-N.J.), Jay Rockefeller (D-W.Va.) or Angus King (I-Maine) will come down on their side. Sen. Tim Johnson (D-S.D.), an avowed “no” on the bill as recently as Thursday, is also facing pressure to switch sides. (Also on POLITICO: Bennet brings Senate's pro-Keystone count to 59) One senator previously seen as on the fence, Minnesota Democrat Amy Klobuchar, said Friday that she’s voting no. During a news conference in Myanmar earlier Friday, Obama scoffed at Keystone supporters’ arguments that the Alberta-to-Texas oil pipeline would be a major economic boon. “I have to constantly push back against the idea that Keystone is either a massive jobs bill for the U.S. or is somehow lowering gas prices,” Obama said during his joint appearance with dissident leader Aung San Suu Kyi. The president also seemed to endorse the argument — pushed by Keystone opponents like billionaire Tom Steyer — that the oil moving through the pipeline would end up being exported abroad. “Understand what the project is, it will provide the ability for Canada to pump their oil and send it through their land down to the Gulf where it will be sold everywhere else,” he said. ||||| Please enable cookies on your web browser in order to continue. The new European data protection law requires us to inform you of the following before you use our website: We use cookies and other technologies to customize your experience, perform analytics and deliver personalized advertising on our sites, apps and newsletters and across the Internet based on your interests. By clicking “I agree” below, you consent to the use by us and our third-party partners of cookies and data gathered from your use of our platforms. See our Privacy Policy and Third Party Partners to learn more about the use of data and your rights. You also agree to our Terms of Service.

– The big news out of Congress today is that the House passed a bill to authorize the building of the Keystone XL oil pipeline. In terms of getting the pipeline built, the vote doesn't mean much, observes the New York Times. But in terms of the Senate runoff in Louisiana, it looms large. The House measure approved today (as expected) was sponsored by Republican Bill Cassidy, who faces Democratic Sen. Mary Landrieu in that Dec. 6 runoff, reports the Washington Post. Both favor the pipeline and are trying to impress the voters back home. Landrieu's test comes Tuesday, when the Senate votes. If she can get 60 votes to avoid a filibuster, the measure goes straight to President Obama's desk. As of now, it's uncertain whether she'll succeed, and even if she does, President Obama seems all but certain to veto it, reports Politico. The Hill agrees, citing Obama's "strong signals" that he wants to wait for a federal review to be completed. It adds that a veto "could deal a blow to Landrieu's chances in the runoff." For the record, the House vote was 252-161, with 31 Democrats joining Republicans. Every Republican voted in favor, except for libertarian-leaning Justin Amash of Michigan.

Serialized fiction first gained prominence in Victorian England and first appeared in newspapers. It was practiced by such literary giants as Charles Dickens, Leo Tolstoy and Joseph Conrad. It fell out of favor in the last fifty years, but is now making a rebound thanks to the iPhone. Apple is showcasing two new e-reading apps under their new and notable category on the main App Store homepage. PigeonHole and Serial Reader both deliver classic novels into bite sized snippets that are easy to digest and appeals to readers who only have a few minutes to read each day. Not only are indie app developers getting involved in serializing classic novels, but major publishers such as Simon & Schuster are also getting involved. A few months ago they developed a new iPhone app called Crave, that lets you subscribe to your favorite author and receive bite sized updates of new novels every 24 hours. Crave makes reading e-books more enjoyable for people who are too busy to breeze through a full length novel. Since only bite sized chunks are delivered on a daily basis, it is a great way to kill some time when you are waiting for transit to arrive, on your break or have a few minutes to spare during the day. Not only does this app encourage women to read, but to also discover new authors. Every week a new author is added to the platform and this month there are e-books contributed by Colleen Hoover, Abbi Glines and K.A. Tucker. Rooster is a new company that launched last year and charges users a monthly subscription to access serialized content, instead of charging a fee for each title. The co-founder and editorial director Yael Goldstein Love spoke to Good e-Reader today about the appeal of serialized subscription reading. While much of the content is currently in the public domain or sourced from the company’s other site, Daily Lit, a different model is underway in which classics are paired with contemporary content. “We’ve been working directly with authors to try to create content that is specifically tailored for the Rooster experience.” The shorter length of Rooster content is perfect for smartphone reading during snippets of time, something that speaks to the company’s model. Rather than luring consumers with a model that affords them the ability to read mountains of content for one price, Rooster’s clientele is expected to read serialized and novella-length works for far less than the cost of a typical e-book subscription plan. I think serialized fiction is one of the those segments in publishing that is enjoying a resurgence, thanks to technology. Some companies are simply cutting up classic, royalty free novels into bite sized chunks, while others are taking modern novels, and just delivering a little bit at a time. I don’t think there is a definitive business model yet that will net someone a million dollars, but I like the fact more people are experimenting. ||||| The seed for Wide00014 was: - Slash pages from every domain on the web: -- a ranking of all URLs that have more than one incoming inter-domain link (rank was determined by number of incoming links using Wide00012 inter domain links) -- up to a maximum of 100 most highly ranked URLs per domain - Top ranked pages (up to a max of 100) from every linked-to domain using the Wide00012 inter-domain navigational link graph ||||| Trying to knock some classic books off your bucket list? Try Serial Reader, an app that delivers literature to your phone in daily snippets that you can read in 20 minutes. A bite-size section of the book will be delivered daily to your phone until you’ve made your way through something like “Moby Dick” — 20 minutes at a time. If you’re looking to avoid cliffhangers or you like to read ahead, this app might be frustrating. But if you’re looking for a way to fit more reading into your day, it’s a pretty elegant solution. Users should know that the key word here is “classics” — you’re not going to find modern bestsellers. There’s a small selection now, but the app developer’s notes say the library is expanding daily. For those who are intimidated by thick, leather-bound tomes, Serial Reader is an good way to break it all down. Free, for iOS devices.

– As daunting as it may seem, you can read Crime and Punishment—20 minutes at a time. Serial Reader is a free iOS app that breaks down dozens of the classics into manageable chunks that are sent to your iPhone or iPad each day at a time you choose, Chris Taylor reports at Mashable. At that rate, the aforementioned Dostoyevsky tome will take you 79 days to read. Mary Shelley's Frankenstein comes in at 28 days. And you could finish The Star Lord by Boyd Ellanby in just 10. "This just might be the reading mode of the future," Taylor writes. Good e-Reader points out that serialized fiction first became popular in the newspapers of Victorian England. And after decades on the decline, it "is now making a rebound thanks to the iPhone." Even publisher Simon & Schuster is getting in on the action with an app called Crave, which charges a fee, as do apps Pigeonhole and Rooster. What makes Serial Reader different is that it's free, according to the Washington Post. "Users should know that the key word here is 'classics,'" Hayley Tsukayama writes. "You’re not going to find modern bestsellers." And if you're the type of reader who likes to skip ahead, she notes, Serial Reader can be frustrating. However, it's an "elegant solution" to the problem of finding time to read. Taylor says he found the 20-minute reading time to be an overestimate—it took him, "not a particularly fast reader," about 15 minutes to complete a day's reading. Also, he notes, you can download an entire text if you choose. (Not into reading? This app will give you the "most intense game of solitaire" you've ever played.)

Tucker Carlson Exposes His Own Sexism on Twitter (Updated) Tucker Carlson has done some good work in the past… His site, The Daily Caller, is a frequent stop of mine and many other Conservatives. They were responsible for exposing the Journolist scandal, which highlighted the planning and coordination of many members of the left-wing press. I will always be grateful to Tucker’s team for bringing that story to light. This is also why I am so angered by Tucker’s recent actions. I thought he was better than this. If you haven’t heard by now, Monday evening, Tucker Carlson posted a disturbing tweet about Governor Palin which said: Palin’s popularity falling in Iowa, but maintains lead to become supreme commander of Milfistan Aside from Tucker’s sheep-like response to warped poll numbers, he also failed to take ownership of his sexist comment. He deleted the original (which is why I had to link to a retweet) obviously aware that what he had posted was wrong. Unfortunately for him, many people had already seen it and responded. You can’t put the toothpaste back in the tube, Tucker. Is this the sort of treatment that Conservative women, who want to get involved in the process, are expected to put up with? Is it okay for male columnists (Conservative or otherwise) to continue objectifying women in the world of politics? No it’s not! The best thing Tucker Carlson could do, is admit that what he tweeted was wrong, apologize to Governor Palin, and urge his fellow colleagues to be respectful with their language and written word. What he did was demeaning and offensive, and there is no place for it in Conservative circles. Update: This is a poor attempt at an apology. Tucker Carlson tries to cover his tracks this morning by repeating the same mistakes he made last night. He wrote: Apparently Charlie Sheen got control of my Twitter account last night while I was at dinner. Apologies for his behavior. He didn’t take responsibility for his comment and he fails horribly at humor. Try again, and Tucker… you’re not funny. Update II: Almost a day later, he finally apologizes: I’m sorry for last night’s tweet. I meant absolutely no offense. Not the first dumb thing I’ve said. Hopefully the last. ||||| Tweet with a location You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| I am not down with @karlrove @tuckercarlson misogynist mockery of @sarahpalinusa . Sick of it. ||||| On Monday night, while the rest of the world was watching Charlie Sheen flame out live on CNN, Tucker Carlson took to Twitter to make some impolitic statements of his own. "Palin's popularity falling in Iowa, but maintains lead to become supreme commander of Milfistan," he wrote. By the next morning, the tweet was deleted and he had apologized, writing, “Apparently Charlie Sheen got control of my Twitter account last night while I was at dinner. Apologies for his behavior.” But that wasn’t enough to spare him the ire of conservative women on the blogosphere and Twitter. On Tuesday, before Carlson’s first apology, Stacy Drake, writing on Conservatives4Palin, praised Carlson’s works at The Daily Caller, particularly the leaks of the Journolist emails, saying that’s why his tweet stung so badly. Aside from Tucker’s sheep-like response to warped poll numbers, he also failed to take ownership of his sexist comment. He deleted the original (which is why I had to link to a retweet) obviously aware that what he had posted was wrong. Unfortunately for him, many people had already seen it and responded. You can’t put the toothpaste back in the tube, Tucker. Is this the sort of treatment that Conservative women, who want to get involved in the process, are expected to put up with? Is it okay for male columnists (Conservative or otherwise) to continue objectifying women in the world of politics? No it’s not! She was unimpressed with his first apology, and called for him to apologize to Palin while continuing to denounce him for sexism on her Twitter account. Michelle Malkin joined the calls Tuesday, tweeting: “I am not down with @karlrove @tuckercarlson misogynist mockery of @sarahpalinusa. Sick of it.” Later Tuesday, Carlson obliged: “I’m sorry for last night’s tweet. I meant absolutely no offense. Not the first dumb thing I’ve said. Hopefully the last.” Some bros have come to Carlson's aid. Tuesday, Erick Erickson tweeted, "Maybe my sense of humor needs to be recalibrated, but when I heard @TuckerCarlson's MILFistan comment, I laughed then got out my passport." (Needless to say, Drake was not amused.) But by Wednesday, the thing had escalated into a full-blown war of the sexes within the conservative blogosphere, with Whitney Pitcher taking Carlson's tweet as inspiration for her post on Conservatives4Palin: "MILF–Misogynists (and Elites) I’d Like to Fulminate." Perhaps an additional reason that Governor Palin does not win the respect of the Elite and Establishment is that you cannot be praised for your “perfectly creased pants” if you often wear a skirt, right David Brooks? The continued line of attack from the Establishment and Elite men in the GOP have come as a result of Governor Palin’s genetic makeup. This post has been updated to correct the spelling of Stacy Drake's first name.

– Tucker Carlson is in deep doodoo with conservative women after an ill-advised tweet referencing Sarah Palin that he posted, then removed, Monday night. "Palin's popularity falling in Iowa, but maintains lead to become supreme commander of Milfistan," he tweeted—and we probably don't need to tell you where that is. His first attempt at an apology, which he tweeted the next morning: "Apparently Charlie Sheen got control of my Twitter account last night while I was at dinner. Apologies for his behavior.” That wasn't good enough for many conservative women, Politico notes, rounding up reactions from bloggers to Michelle Malkin calling his behavior sexist and misogynistic. By late Tuesday, Carlson had offered up a more sincere-sounding apology: “I’m sorry for last night’s tweet. I meant absolutely no offense. Not the first dumb thing I’ve said. Hopefully the last.” But at least one man—Erick Erickson, editor of RedState.com—was on Carlson's side, tweeting his reaction to the post in question: "I laughed then got out my passport."

the acid base disturbance in patients suffering cardiac arrest is more complex than previously thought . makino and colleagues have presented a quantitative assessment of the components that create the disturbance . as previously reported , hyperlactatemia is not the sole cause of metabolic acidosis in the patient after arrest . the physico - chemical approach permits the detection of unmeasured ions and the measurement of their effect on the patient . the authors present a concise review of the physico - chemical approach to acid base balance using the stewart figge methodology . this concept is based on the principles of electric neutrality and the conservation of mass . there are three independent variables that determine blood ph : partial pressure of co2 ( pco2 ) , total weak acid concentration ( atot ) and the strong ion difference ( sid ) . the difference between the strong cations , such as sodium , and the strong anions , such as chloride , is sid . weak acids ( atot ) also carry a charge ; these are principally albumin and phosphate . in keeping with the principles of electric neutrality , the difference between the charges will be zero unless there are unmeasured ions present . this difference is known as the strong ion gap ( sig ) . a more in - depth review and this allows a relatively rare opportunity to collect and study unaltered human cardiac arrest data . the authors comment that some intravenous fluid might have been started immediately before blood draw . saline - based intravenous fluids are well known to create an acid base disturbance , in particular a nongap hyperchloremic metabolic acidosis [ 6 - 8 ] . the fluid used during resuscitation was ringer - based , which has a much smaller effect on the acid base balance . the comparison group was composed of 28 patients who suffered minor injuries and were discharged within 2 days . this group was chosen because all of the necessary blood samples were drawn on arrival . given their minor injuries and short hospitalization , they were considered to be baseline ' normal ' . the authors do comment on the fact that the comparison group initially had a mildly elevated lactate level . although not optimal , that , in combination with the large difference in lactate between the study and comparison groups , does permit an adequate comparison . the patients suffered cardiac arrest from a variety of causes , both from physiologic disease and from trauma . presumably because of the small number of patients enrolled they did not evaluate differences between the groups . twelve percent of the patients are listed as ' other ' for the cause of their cardiac arrest . for example , perhaps this group ingested toxic alcohols , which would lead to severe metabolic acidosis . if this group had been evaluated separately , it might have led to a different outcome . it is not surprising that the initial rhythm in more than 50% of the study patients was asystole . unfortunately the authors did not comment on the outcome data for this group . what was the duration of survival ? obviously the numbers are small , only 20 patients . it would be interesting to know whether there was any trend or difference between survivors and nonsurvivors . in a study on vascular injury patients , unmeasured ions determined only by using the sid / sig methodology have been discovered in a variety of patients : critically ill , trauma , pediatric and now after cardiac arrest . recently martin and colleagues reviewed data from more than 400 patients from their trauma intensive care unit . unmeasured ions were found in 92% of patients and were the most common component of metabolic acidosis in these patients . more importantly , 28% of patients had a different clinical interpretation and would have received different therapy if the physico - chemical approach had been used rather than the standard method that was used . previously unrecognized factors contribute to the metabolic acidosis in equal amounts to that of lactate . this study has identified another area that needs further investigation to determine the significance of the presence of unmeasured ions in the post - arrest patient . atot = total weak acid concentration ; pco2 = partial pressure of co2 ; sid = strong ion difference ; sig = strong ion gap .

metabolic acidosis is a common finding after cardiac arrest . until recently this acidosis was mainly attributed to lactate . the physico - chemical approach to acid base balance permits the detection of previously unmeasured ions . these ions have been shown to affect the acid base status of patients .

ROANOKE, Va - The flash flood warning for Lynchburg is now lasting until 2 a.m. Saturday. At 5:48 p.m., Lynchburg Emergency Management reported that water is holding within the shores of College Lake. While the situation continues to remain stable, emergency officials will monitor the dam through the overnight hours and draining will commence Saturday morning. As a result, the National Weather Services has extended the flash flood warning as a precaution. Flash Flood Warning continues for Lynchburg VA until 2:00 AM EDT pic.twitter.com/ECfSUoI8Vt — NWS Blacksburg (@NWSBlacksburg) August 3, 2018 A flash flood warning now remains in effect until 6 p.m. for the city of Lynchburg. CLICK HERE for a list of current road closures. The potential for more heavy rain continues into the morning. A Flash Flood Watch for the potential for more heavy rain later today continues until 8 P.M. for the entire area. A flash flood watch means that conditions are favorable for flash flooding. Turn around don't drown. PHOTOS: Severe flooding causes road closures, forces evacuations **Update from the National Weather Service through emergency management on the College Lake Dam: * AT 1002 AM EDT, EMERGENCY MANAGEMENT REPORTED THAT 4 TO 6 INCHES OF RAIN OVERNIGHT HAS CAUSED COLLEGE LAKE DAM TO REMAIN ABOVE ITS CAPACITY. ALTHOUGH WATER LEVELS HAVE DECREASED, THE THREAT FOR DAM FAILURE CONTINUES. EMERGENCY PERSONNEL WILL CHECK THE DAM FOR SIGNS OF STRUCTURAL FAILURE TODAY. THUS THE FLASH FLOOD WARNING MAY NEED TO BE EXTENDED AGAIN LATER TODAY. * SOME LOCATIONS THAT WILL EXPERIENCE FLOODING INCLUDE... LYNCHBURG.THIS INCLUDES THE FOLLOWING STREAMS AND DRAINAGES...JAMES RIVER...BLACKWATER CREEK...AND IVY CREEK. Copyright 2018 by WSLS 10 - All rights reserved. ||||| 01:18 Tornado Watch, Severe Weather Outbreak in the South A severe weather outbreak packing damaging winds and tornadoes is happening Monday night over a swath of the South, continuing well into the overnight hours. At a Glance A dam in Lynchburg, Virginia, overtopped Friday morning, sending water barreling across a local road. Evacuations were ordered over fears that the dam could fail. By midday, water levels had receded but more rain forecasted could result in more flooding. If the dam were to completely fail, it would send enough water into the area to reach a depth of 17 feet in seven minutes. More than 100 residences were evacuated in Lynchburg, Virginia, amid fears that a dam there could fail as water overtopped the dam and barreled across local roads. The Lynchburg Department of Emergency Services started evacuating more than 100 residences in the Blackwater Creek Trail area in the southwest side of the city Thursday night as water spilled out of College Lake Dam, local news reported. By early Friday afternoon, the National Weather Service said water levels had receded so the water was no longer overtopping the dam. They warned, however, that the potential remains for more heavy rains that could result in more flooding. Should the dam completely fail, enough water levels in the affected part of the city could rise to 17 feet in just 7 minutes , said local media, citing emergency officials. Earlier in the day, up to a foot and a half of water was seen flowing across Lakeside Drive and into Blackwater Creek after spilling out of the dam, NWS Blacksburg said. The dam was above capacity after storms dropped more than 6 inches of rain in just 24 hours upstream from College Lake, weather.com senior meteorologist Jon Erdman said. Lynchburg has seen an exceptional amount of rain so far in 2018. More than 12 inches of rain have fallen on the city since June 1st, bringing the annual year-to-date total to more than 37 inches. That's more than a foot above the average for this time of the year, making this the third wettest year-to-date at Lynchburg Regional Airport since 1945. And it's not over. "Unfortunately, one final round of rain, potentially locally heavy, is expected in the Piedmont area of Virginia Friday before drier weather moves in for the weekend," Erdman said. College Lake Dam was built in the 1930s and is listed among "high hazard dams" in need of repair in Virginia. In Campbell County, about 13 inches of water was spilling over the Timberlake Dam spillway and a motorist had to be rescued from a vehicle trapped in high water.

– Some 124 homes in Lynchburg, Va., are under evacuation orders with intense flooding in the region. The College Lake Dam, whose complete failure could put the downstream city of 80,000 under 17 feet of water in seven minutes, exceeded its capacity Thursday after four to six inches of rain fell, per WSLS and the BBC. The News & Advance reports 12 to 18 inches of water were flowing out of the dam, over a road, and into a creek after three inches of rain fell in a single hour. The dam "is being closely monitored … for any signs of structural failure" as another inch or so of rain is expected Friday near Lynchburg, 50 miles east of Roanoke, according to the National Weather Service. "This remains a dangerous situation." Footage shows only roofs of cars visible on flooded roads. Those whose homes are considered at risk due to flooding have been moved to temporary shelters, per the News & Advance, which notes some 5,200 residents of Lynchburg and Timberlake were without power Friday morning. A flash flood watch remains in effect for much of central and western Virginia, while central Lynchburg is under a flash flood warning. Per Weather.com, the city is battling its third wettest year since 1945 in which more than 12 inches of rain have fallen since June 1. That brings its annual year-to-date total to more than 37 inches, or more than a foot above last year's total as of this date.

for completeness we recall here the graphical representation of the green s function . the details of the diagrammatic method can be found in @xcite . the green s function @xmath92 can be represented as a sum over diagramms : @xmath227{graph1.eps } \label{eq : fgraph}\ ] ] where the @xmath3-type and @xmath5-type indices of @xmath8 are denoted by filled and empty circles , respectively . the matrix @xmath8 is denoted by an ordered pair of neighbouring filled and empty circles , while @xmath7 is drawn as an pair of such circles in the reverse order . a horizontal solid line stands for @xmath228 , a dashed line for @xmath229 , a solid arc for @xmath21 and a dashed arc for @xmath22 . the two point function ( [ ca ] ) is drawn as a double arc . matrices on a line are multiplied in the order of appearance on this line . if a line is closed , the trace is taken . in the thermodynamical limit only planar diagrams give contribution to @xmath230 . in particular the last term in ( [ eq : fgraph ] ) vanishes . the green s function @xmath231 is represented by an identical set of diagrams with dashed and solid lines exchanged . it is convenient to introduce one - line irreducible diagrams and corresponding generating functions @xmath232 and @xmath233 . the green s functions can be expressed in terms of @xmath232 and @xmath233 as follows : @xmath234{gsig.eps}\ ] ] @xmath235{gsigma.eps}\ ] ] in the planar limit there are two additional equations which relate the sums over one - line irreducible diagrams to the green s functions : @xmath236{sg.eps } \qquad , \qquad \psfrag{s}{{\small $ { \mathbf{\sigma_c}}$}}\psfrag{g}{{\small $ { \mathbf{g_{*c}}}$ } } \psfrag{k}{{\small $ \dots$ } } \includegraphics[width=4.5cm]{sg.eps}\ ] ] analogous diagrammatic equations can be written for @xmath237 with the only difference that the solid line shall denote the propagator @xmath238 and the dashed line @xmath239 . we use the equations ( [ zz_ca ] ) and ( [ map ] ) to determine the relations ( [ mcmm ] ) . as for the case @xmath108 we shall do this using @xmath117 expansion . the function @xmath124 is given by the series : @xmath240 let us determine the expansion for the inverse function @xmath131 as a series around zero : @xmath241 the coefficients of the series can be directly calculated from the condition : @xmath242 which gives us : @xmath243 the equation ( [ zz_ca ] ) takes the form : @xmath244 or if written for @xmath117 : @xmath245 where : @xmath246 thus we have expressed @xmath117 as a series of @xmath120 . inserting this series to the equation ( [ map ] ) and comparing coefficients at @xmath247 we eventually obtain ( [ mcmm ] ) . 99 j. wishart , biometrica * a20 * , 32 ( 1928 ) . anderson , _ introduction to multivariate statistical analysis _ ( wiley , 1958 ) . y. demasure , r. a. janik , phys.lett . * b553 * , 105 ( 2003 ) . moustakas , et al . , science * 287 * , 287 ( 2000 ) . a.m. sengupta and p.p . mitra , physics/0010081 . skipetrov , phys . rev . * e67 * , 036621 ( 2003 ) . s. maslov , y.c . zhang phys . lett . * 87 * 248701 ( 2001 ) . l. laloux , p. cizeaux , j .- bouchaud and m. potters , phys . lett . * 83 * 1467 ( 1999 ) . v. plerou , et al . * 83 * 1471 ( 1999 ) . z. burda and j. jurkiewicz , cond - mat/0312496 , to appear in physica * a*. s.h . simon , a.l . moustakas , math - ph/0401038 . because of the multiplicative nature of the price changes instead of the changes : @xmath248 themselves , in the financial analysis one rather uses returns @xmath249 as random variables . j. feinberg , a. zee , _ jour . phys . _ * 87 * 473 ( 1997 ) . a.m. sengupta and p.p . mitra , phys . rev . * e60 * 3389 , ( 1999 ) . z. burda , a. goerlich , a. jarosz , j. jurkiewicz , cond - mat/0305627 , to appear in physica * a*. r.a . janik , m.a . nowak , j.phys . * a36 * 3629 ( 2003 ) .

we present an analytic method to determine spectral properties of the covariance matrices constructed of correlated wishart random matrices . the method gives , in the limit of large matrices , exact analytic relations between the spectral moments and the eigenvalue densities of the covariance matrices and their estimators . the results can be used in practice to extract information about the genuine correlations from the given experimental realization of random matrices . wishart random matrices play an important role in the multivariate statistical analysis @xcite . they are useful in some problems of fundamental physics @xcite , communication and information theory @xcite , internet trading @xcite and quantitative finance @xcite . a wishart ensemble of correlated random matrices is defined by a gaussian probability measure : @xmath0 \prod_{i,\alpha=1}^{n , t } d x_{i\alpha } \ , \label{preal}\ ] ] where @xmath1 is a real rectangular matrix of dimension @xmath2 . it has two types of indices : an @xmath3-type index runnig over the set @xmath4 and a @xmath5-type index over @xmath6 . throughout the paper the @xmath3-type indices will be denoted by latin letters and the @xmath5-type by greek ones . @xmath7 denotes the transpose of @xmath8 . the matrices @xmath9 and @xmath10 are symmetric square matrices of dimensions @xmath11 and @xmath12 , respectively . they are positive definite . @xmath13 is a normalization constant : @xmath14 chosen to have @xmath15 . let @xmath16 be a quantity depending on @xmath8 . the average of @xmath17 over the random matrix ensemble ( [ preal ] ) is defined as : @xmath18 in particular , the two - point correlation function is : @xmath19 as directly follows from the gaussian integration . in this paper we are interested in the spectral behaviour , the eigenvalue distribution and the spectral moments of the following random matrices : @xmath20 these matrices can be used as estimators of the correlation matrices @xmath21 and @xmath22 if some realizations of random matrices @xmath8 are given . we will refer to @xmath23 and @xmath24 as to covariance matrices or statistically dressed correlation matrices . we will present an analytic method to determine the eigenvalue distribution and the spectral moments of @xmath23 and @xmath24 in the limit of large matrix size . another method of calculating the eigenvalue density of correlated wishart matrices has been recently discussed in @xcite . in parallel to ( [ preal ] ) one can define a wishart ensemble of correlated complex matrices : @xmath25 \prod_{i , \alpha } d x^{re}_{i\alpha } d x^{im}_{i\alpha } . \label{pcompl}\ ] ] the matrices @xmath21 and @xmath22 are now hermitean and positive definite . @xmath26 denotes the hermitean conjugate of @xmath8 . the normalization constant is now @xmath27 . in the analysis of the complex ensemble the estimators ( [ ca ] ) of the correlation matrices are replaced correspondingly by @xmath28 notice that the factor one half in front of the trace in the measure for real matrices ( [ preal ] ) is dropped in ( [ pcompl ] ) . with this choice of the measure the two - point correlations take a similar form as for real matrices ( [ ca ] ) : @xmath29 the star stands for the complex conjugation . additionally we also have : @xmath30 as a consequence , as we shall discuss towards the end of the paper , the matrices @xmath23 and @xmath24 ( [ ca ] ) in the real ensemble have an identical large @xmath3 behaviour as the corresponding matrices ( [ cac ] ) in the complex ensemble . since we are interested here only in the large @xmath3 behaviour it is sufficient to consider one of the two ensembles and draw conclusions for the other . we will focus the presentation on the ensemble of real matrices . an example of a problem which can be formulated in terms of wishart random matrices ( [ preal ] ) is the following . imagine that we probe a statistical system of @xmath3 correlated degrees of freedom by doing @xmath5 measurements . we store the measured values of the @xmath31-th degree of freedom in the @xmath32-th measurement in a rectangular matrix @xmath33 . the degrees of freedom as well as the measurements may be correlated . this is expressed by the equation ( [ ca ] ) , which tells us that the covariance matrix for the correlations between degrees of freedom in the system is @xmath9 and for the ( auto)correlation between measurements is @xmath10 . note that in general the correlations between @xmath34 and @xmath35 may have a more complicated form : @xmath36 , where the matrix @xmath37 has double indices . such a situation takes place if the autocorrelations are different for various degrees of freedom . we shall not discuss this case here . moreover , we shall assume that only gaussian effects are important for the studied system . a perfect example of the situation described above is the problem of optimal portfolio assessment - one of the fundamental problems of quantitative finance . the portfolio assessment is based on the knowledge of the covariance matrix @xmath21 for stocks returns @xcite . in practice , the covariance matrix is estimated from the historical data which are stored in a rectangular matrix representing @xmath5 historical values of @xmath3 stocks . fluctuations of returns are well described by the gaussian ensemble ( [ preal ] ) . the estimator of the covariance matrix is given by ( [ ca ] ) . another problem of modern financial analysis which can be directly cast into the form ( [ preal ] ) is the problem of taste matching @xcite . this problem is encountered for instance in the large - scale internet trading . it is worth mentioning that the random matrix framework may also be used in a statistical description of data generated in monte carlo simulations for a system with many degrees of freedom , in particular of data concerning the correlation functions . one frequently encounters such a problem in monte - carlo simulations of lattice field theory , where the field is represented by correlated numbers distributed on a lattice . usually , one is forced to use a dynamical monte carlo algorithm to sample such a system . the basic idea standing behind a dynamical algorithm is to generate a markov chain a sort of a random walk in the space of configurations . the degrees of freedom on the lattice as well as the successive configurations are usually correlated . outside a critical region no long range correlations are observed and the fluctuations can be treated as gaussian . complex random matrices are useful for instance in telecommunication or information theory @xcite . let us come back to the ensemble of real matrices ( [ preal ] ) . as we mentioned the matrices ( [ ca ] ) can be treated as estimators of the correlation matrices @xmath21 and @xmath22 . indeed , from equation ( [ ca ] ) we see that : @xmath38 where @xmath39 and @xmath40 . this notation will be explained later . the last equation tells us that measuring the average of @xmath23 over the ensemble ( [ preal ] ) we obtain the matrix @xmath21 up to a constant . in other words having a realization of random matrices @xmath8 we can use ( [ ca ] ) to estimate @xmath21 . similarly , we can use @xmath24 to estimate @xmath22 . notice that the measure ( [ preal ] ) is invariant under the transformation @xmath41 and @xmath42 , where @xmath43 is an arbitrary positive real number . in particular @xmath44 and @xmath45 are independent of the rescaling factor @xmath43 . this independence is ensured by the presence of the factors @xmath46 and @xmath47 in equations ( [ cest],[aest ] ) . in practical calculations , if @xmath48 and @xmath49 are not specified , one can remove the redundancy with respect to the rescaling by @xmath43 , setting @xmath50 . in this case the constants @xmath51 can be determined from the data by evaluating the traces of @xmath23 or @xmath24 : @xmath52 while considering the covariance matrices for the wishart ensemble we can formulate two reciprocal problems , which we shall call * direct * and * inverse problem*. in the direct problem we want to learn as much as possible about the probability distribution of the estimators @xmath23 and @xmath24 ( [ ca ] ) assuming that the matrices @xmath21 and @xmath22 are given . in particular , we want to calculate the eigenvalue density functions : @xmath53 where @xmath54 and @xmath55 are eigenvalues of @xmath23 and @xmath24 , respectively . the determination of the eigenvalue density functions is equivalent to the determination of all their spectral moments : @xmath56 the moments @xmath57 are related to each other : @xmath58 where @xmath59 , as follows from the cyclicity of the trace : @xmath60 in the inverse problem we want to learn as much as possible about the genuine correlations in the system , which are given by @xmath21 and @xmath22 , using a measured sample of random matrices @xmath8 . we can do this by computing the estimators @xmath23 and @xmath24 ( [ ca ] ) and relating them to matrices @xmath61 . in particular we would like to estimate the eigenvalue distributions and the moments of @xmath61 : @xmath62 where @xmath63 and @xmath64 are eigenvalues of @xmath21 and @xmath22 , respectively . the inverse problem is very important for practical applications , since in practice it is very common to reconstruct the properties of the underlying system from the experimental data . in the analysis of the spectral properties of the matrices @xmath24 and @xmath23 it is convenient to apply the green s function technique . one can define green s functions for the correlation matrix @xmath21 and its statistically fluctuating counterpart @xmath23 : @xmath65 and correspondingly @xmath66 and @xmath67 for @xmath22 and @xmath24 . the symbol @xmath68 stands for the @xmath11 identity matrix . a corresponding symbol @xmath69 appears in the definition of @xmath66 and @xmath67 . the green s functions are related to the generating functions for the moments : @xmath70 or inversely : @xmath71 the analogous relations exist for @xmath66 and @xmath67 . the green s functions can be used for finding the densities of eigenvalues : @xmath72 and similarly for @xmath73 . the eigenvalue densities @xmath73 and @xmath74 are not independent . as follows from ( [ mak_mck ] ) the corresponding generating functions ( [ mcz ] ) fulfill the equation : @xmath75 combining the last equation with ( [ gm ] ) we obtain : @xmath76 applying now ( [ rhoc ] ) we have : @xmath77 the meaning of the last term on the right hand side of this equation is that there are @xmath78 zero modes in the matrix @xmath24 if @xmath79 . the zero modes disappear when @xmath80 . moving the term containing the delta function to the other side of equation , dividing both sides of the equation by @xmath81 and substituting the parameter @xmath82 by @xmath83 we obtain : @xmath84 therefore , for @xmath85 the zero modes appear in the spectrum @xmath74 . in this case it is more convenient to use the parameter @xmath86 instead of @xmath82 . the zero modes appear in the eigenvalue distribution of either @xmath24 or @xmath23 . the two equations ( [ rac ] ) and ( [ rca ] ) are dual to each other . for @xmath87 they are identical . because of the duality it is sufficient to solve the problem for @xmath88 . we will present a solution for the limit @xmath89 and @xmath90 neglecting effects of the order @xmath91 . using a diagrammatic method @xcite one can write down a closed set of equations for the green s function @xmath92 ( [ gc ] ) : @xmath93 the set contains four equation for four unknown matrices including @xmath92 which we want to calculate , and three auxiliary ones : @xmath94 , @xmath95 , @xmath96 ( see appendix 1 ) . each of them can be interpreted in terms of a generating function for appropriately weighted diagrams with two external lines : @xmath97 for all diagrams and @xmath98 for one - line - irreducible diagrams @xcite ( see appendix 1 ) . in the limit @xmath90 the weights of non - planar diagrams vanish at least as @xmath91 . thus in this limit only planar diagrams give a contribution to the green s function . therefore the large @xmath3 limit is alternatively called the planar limit . the diagrammatic equations ( [ 4gc ] ) hold only in this limit . an analogous set of equations can be written for the green s function @xmath67 . the equations are identical to those of ( [ 4gc ] ) if one exchanges @xmath99 , @xmath100 and @xmath101 . the two sets can be solved independently of each other . however , as follows from the duality ( [ gac ] ) it is sufficient to solve only one of them and deduce the solution of the other . the equations ( [ 4gc ] ) can be solved for @xmath92 by a successive elimination of @xmath94 , @xmath95 and @xmath96 . however , the resulting equation is very entangled @xcite : @xmath102 and can not be easily used in practical calculations of the moments @xmath103 or spectral density @xmath74 . another way of solving the equations ( [ 4gc ] ) was proposed in @xcite . it relies on introducing a new complex variable @xmath104 conjugate to @xmath105 which is defined by the equation : @xmath106 at the first glance this equation looks useless because it refers to an unknown function @xmath107 which we actually want to determine . quite contrary to this , as we shall see , the introduction of the conjugate variable @xmath104 allows us to write down a closed functional equation for @xmath107 . first , let us illustrate how the method works for @xmath108 @xcite . in this case , the elimination of the auxiliary functions ( [ 4gc ] ) leads to @xmath109 or equivalently to @xmath110 suppose we solve the direct problem . in this case we know the matrix @xmath21 and hence also the generating function @xmath111 . inserting ( [ zz ] ) to ( [ map ] ) we obtain a closed compact functional relation for @xmath107 : @xmath112 if @xmath113 has a simple form , one can solve the equation for @xmath107 analytically @xcite . in general , one can write a numerical program to calculate the eigenvalue density @xmath74 from the last equation . in case of solving the inverse problem , we assume that we can determine moments @xmath114 from the data and hence that we can approximate the generating function @xmath107 . then we can insert ( [ zz ] ) to ( [ map ] ) and obtain a functional equation for @xmath111 : @xmath115 the problem is solved in principle . however , in practical terms the inverse problem is much more difficult , because one can not compute all experimental moments @xmath114 with an arbitrary accuracy , unless one has an infinitely long series of measurements . but one never has . in practice one can estimate only a few lower moments @xmath114 with a good accuracy . because of this practical limitation one can not entirely solve the inverse problem . however , as we discussed in @xcite the inverse problem can be partially solved even in specific practical applications using a moments method . let us sketch this method below . we can gain some insight into the spectral properties of the correlation matrix @xmath21 by determining the relation between the moments @xmath116 and @xmath114 . expanding the functions @xmath113 and @xmath107 in ( [ mcmc ] ) in @xmath117 using ( [ mcz],[mcz ] ) and comparing the coefficients at @xmath118 we obtain : @xmath119 we can also invert the equations for @xmath116 . the result of inversion gives a set of equations which can be directly obtained from the @xmath120 expansion of the functions in the equation ( [ mcmc ] ) which is the inverse transform of ( [ mcmc ] ) . we can also determine the corresponding relations for negative moments @xmath114 and @xmath116 , that is for @xmath121 , or determine the spectral density @xmath74 @xcite . using a computer tool for symbolic calculations one can easily write a program which successively generates the relations between spectral moments ( [ mm ] ) from the equation ( [ mcmc ] ) . the calculations get more complicated in the general case when both @xmath122 and @xmath123 are arbitrary . the guiding principle is the same , though . we introduce the conjugate variable @xmath104 ( [ map ] ) and , using it , write down the solution of the equations ( [ 4gc ] ) . in the direct problem we assume that the generating functions @xmath111 and @xmath124 are known . we will show that in this case the solution of ( [ 4gc ] ) takes a form of an explicit equation for @xmath125 , where the function @xmath126 depends on the functions @xmath111 and @xmath124 . inserting this solution back to ( [ 4gc ] ) we eventually obtain a functional equation @xmath127 from which we can extract the function @xmath107 . the solution of ( [ 4gc ] ) takes the form : @xmath128 where @xmath64 are eigenvalues of @xmath123 . it can be rewritten as : @xmath129 and can be formally solved for @xmath105 : @xmath130 where @xmath131 is the inverse function of @xmath132 . thus we have obtained an explicit equation for @xmath125 in terms of the known functions @xmath132 and @xmath133 . one can easily check that for @xmath134 the last equation reduces to ( [ zz ] ) . in this case @xmath135 , @xmath136 . combining the equation for @xmath125 given by ( [ zz_ca ] ) with ( [ map ] ) we arrive at a closed equation for the generating function @xmath137 . it can be used for example to calculate the moments @xmath114 s ( see appendix 2 ) . the calculations yield a set of equations expressing @xmath114 s in terms of the bare moments @xmath138 and @xmath116 : @xmath139 the equations reduce to the form ( [ mm ] ) for @xmath134 . using the relations ( [ mak_mck ] ) we can also determine the moments of the matrix @xmath24 . it is more convenient to write them using the variable @xmath140 the dual counterpart of @xmath82 instead of @xmath82 itself : @xmath141 the equations are completely symmetric to ( [ mcmm ] ) with respect to the change @xmath142 ( which amounts to @xmath143 ) , and @xmath144 , @xmath145 . using this method one can obtain equations ( [ mcmm ] ) and ( [ mamm ] ) to an arbitrary order . the above relations are useful for computing the dressed moments @xmath146 for given matrices @xmath147 or inversely , the genuine moments @xmath148 from the experimental data . as mentioned , the spectral moments give us in principle full information about the eigenvalue distribution . in practice the reconstruction of the eigenvalue density may be difficult , because to do it we would need to know all moments with a very good precision . usually , in practical applications one can accurately evaluate only a few lower moments . in some special cases if we can make some extra assumptions about the form of the matrices @xmath21 or @xmath22 we can improve significantly the reconstruction of the eigenvalue density . in the previous work @xcite we have analysed the case of @xmath108 and of the matrix @xmath21 which had only a few distinct eigenvalues . in this case the green s function @xmath92 is given by an algebraic equation of the order which is equal to the number of distinct eigenvalues . it can be analytically solved when this number is less or equal four . if it is larger the problem can be handled numerically . the duality tells us that the solution also holds when we change the roles of @xmath22 and @xmath21 . below we will discuss the case of exponential autocorrelations . exponential correlations are encountered in many situations . the general solution , which we have discussed so far , simplifies in this case to a more compact relation for the green s function , which allows us to find analytically an approximate form of the eigenvalue density of the random matrices @xmath23 and @xmath24 . the approximation becomes exact in the large @xmath3 limit . we consider purely exponential autocorrelations given by the autocorrelation matrix : @xmath149 \ , \label{aexp}\ ] ] where @xmath150 controls the range of autocorrelations . the inverse of the matrix @xmath123 reads : @xmath151 . \label{binv}\ ] ] we have introduced here a shorthand notation @xmath152 , @xmath153 and @xmath154 . the spectrum of this matrix can be approximated by the spectrum of a matrix @xmath155 : @xmath156 , \label{m}\ ] ] whose eigenvalues can be found analytically : @xmath157 the corresponding eigenvectors are given by the fourier modes . the matrix @xmath158 can be viewed as of a sum : @xmath159 , of a unity matrix multiplied by a constant and a discretized one - dimensional laplacian @xmath160 for a cyclic chain of length @xmath5 . the matrix @xmath161 can be obtained from @xmath155 by adding to it a perturbation @xmath162 : @xmath163 , where @xmath162 has only four non - vanishing elements : @xmath164 and @xmath165 . the first order corrections to the eigenvalues of @xmath161 , which stem from the perturbation @xmath162 , behave as @xmath166 . the perturbation @xmath162 can be viewed as a change of a boundary condition of the laplacian . as usual , boundary conditions affect mostly the longest ( small momentum ) modes . indeed , a careful analysis shows that the two diagonal terms of the perturbation matrix , @xmath167 , introduce a constant correction independent of @xmath5 of the lowest eigenvalues which does not vanish when @xmath5 goes to infinity . however , since the differences between unperturbed eigenvalues of @xmath155 and the corresponding perturbed eigenvalues of @xmath161 disappear for all other eigenvalues , we expect that for @xmath168 the spectral properties of @xmath123 can be well approximated by the eigenvalues of @xmath169 : @xmath170 in this limit we can also approximate the sum ( [ zzsum ] ) by an integral : @xmath171 where @xmath172 and the symbol @xmath173 is introduced for brevity . note that in the definition of @xmath174 we have replaced @xmath111 , which would rather be dictated by ( [ zzsum ] ) , by @xmath107 . this change is legitimate due to ( [ map ] ) . the integral ( [ zzint ] ) can be done : @xmath175 setting back @xmath176 we eventually obtain : @xmath177 this is an explicit equation for @xmath178 which can be now inserted into @xmath179 giving us a compact relation for @xmath107 in the presence of the exponential autocorrelations ( [ aexp ] ) : @xmath180 in the limit @xmath181 , the parameters @xmath182 , @xmath183 and @xmath184 increase to infinity and @xmath185 . as a consequence , the form of equation ( [ z(z ) ] ) simplifies to ( [ zz ] ) , which corresponds to the case without autocorrelations , as expected . using the equation ( [ mmexp ] ) we can recursively generate equations for the consecuitive moments : @xmath186 where @xmath187 . the coefficients on the right hand side , which depend on @xmath188 , can be directly expressed in terms of the moments @xmath138 of the matrix @xmath123 . approximating again a sum by an integral in the large @xmath5 limit we can write : @xmath189 the integrals can be calculated yielding : @xmath190 we see that if we insert these coefficients into the equations ( [ mcmm ] ) we obtain ( [ mmsc ] ) . this is a consistency check for the approximation which we use here . the quality of this approximation can also be checked by comparing the moments @xmath138 of the matrix ( [ aexp ] ) for finite @xmath5 with the result ( [ approx ] ) which corresponds to @xmath191 . we expect that for @xmath168 the numerical values shall approach the result ( [ approx ] ) . the results of this comparison confirm our expectations ( see table 1 ) . @xmath192 thus we see that the formula ( [ mmsc ] ) for @xmath107 in the presence of the exponential autocorrelations becomes exact in the limit @xmath193 . this formula allows us to compute the eigenvalue distribution of the random matrices @xmath23 and @xmath24 ( [ ca ] ) . let us illustrate this on the simplest example of the system which has no correlations : @xmath194 and @xmath195 . in this case the equation ( [ mmexp ] ) for @xmath107 takes the form : @xmath196 where we have used the notation @xmath197 . for @xmath198 ( @xmath199 ) this equation reduces to : @xmath200 = 0 \ , \ ] ] which has a solution : @xmath201 where @xmath202 , which leads to the well - known result for the uncorrelated wishart ensemble : @xmath203 for @xmath204 it is still possible to find analytically a solution of ( [ eq : x ] ) . let us rewrite ( [ eq : x ] ) as a polynomial equation : @xmath205 it has two trivial solutions @xmath206 . dividing out the polynomial @xmath207 we get : @xmath208 this is a quartic equation which can be solved analytically by the ferrari method . we will not present the formal solution which is neither transparent nor informative . instead , we show in fig . [ fig1 ] the eigenvalue density functions @xmath74 , for different @xmath150 , resulting from this solution . the lower part of the distribution approaches zero when @xmath150 increases , but zero modes do not appear in the distribution as long as @xmath209 . for exponential matrix @xmath22 , @xmath210 and for three different autocorrelation times @xmath150 : @xmath211 ( solid line ) , @xmath212 ( dashed line ) and @xmath213 ( dotted line).,width=377 ] the formula ( [ mmexp ] ) applies to any correlation matrix @xmath21 but in the general case one has to use a numerical procedure to calculate from it the density function . let us stop here the presentation of results for the ensemble of real matrices . as we mentioned all results in the large @xmath3 limit hold also in the ensemble of complex matrices if the covariance matrices ( [ ca ] ) are replaced by ( [ cac ] ) . the reason why it is so is related to the fact that the moments of @xmath214 in the ensemble of complex matrices ( [ pcompl ] ) are equal to the moments of @xmath215 in the real ensemble ( [ preal ] ) up to a @xmath91 corrections which disappear in the large @xmath3 limit : @xmath216 let us illustrate this by explicit calculations of the second moment . using the wick s theorem for gaussian integrals and the equation ( [ ca ] ) for the two - point correlation function , we have : @xmath217 the corresponding calculations for the complex ensemble read : @xmath218 the difference between the two calculations appears in the third term which in the real ensemble gives a contribution of the order @xmath91 while in the complex ensemble disappears by virtue of ( [ cacc ] ) . we recognize that @xmath219 which are the leading terms in the @xmath91 expansion are identical as in the second equation in the set ( [ mcmm ] ) . generally one can show that the leading contributions which correspond to the planar diagrams in the expansion of @xmath92 are identical for both ensembles . non - planar diagrams are different but they contribute in the subleading orders : it turns out that in the diagrammatic expansion of the green s function @xmath220 for the complex matrix ensemble ( [ pcompl ] ) , which would be a counterpart of ( [ eq : fgraph ] ) in the appendix , all diagrams which contain a double arc with dashed and solid line crossed are identically equal zero since such an arc corresponds to the propagator @xmath221 or @xmath222 . a crossing of two arcs is however allowed and leads to a factor @xmath223 . to summarize : in the paper we have considered an wishart ensemble of correlated random matrices . we have obtained in the limit of large matrices a closed set of equations relating the green s function or equivalently the moments generating functions @xmath107 and @xmath224 for statistically dressed correlations to the generating functions for genuine correlation matrices @xmath113 and @xmath225 . the equations in the large @xmath3 limit are the same for the ensemble of real and complex matrices . using these equations we can write down exact relations between genuine and experimental spectral moments of correlation functions of an arbitrary order . the relations can be used in practical problems to learn about correlations in the studied system from the experimental samples . in the case of exponential correlations we have also found an explicit form the spectral density function of the covariance matrix . a natural generalization of the work presented here is to consider a more general type of time correlations than purely exponential ( [ aexp ] ) . if the correlations are of the form which depends on the time difference @xmath226 and if they are short - ranged then one can apply fourier transform to determine in the large @xmath5 limit an approximate spectrum of the matrix @xmath22 and approximate values of its spectral moments . another interesting issue which can be addressed in the future is the determination of the probability distribution for individual elements of the covariance matrices @xmath23 and @xmath24 similarly as it was done for the uncorrelated case @xcite . * acknowledgments * we thank r. janik , a. jarosz and m.a . nowak for discussions . this work was partially supported by the polish state committee for scientific research ( kbn ) grants 2p03b 09622 ( 2002 - 2004 ) and 2p03b-08225 ( 2003 - 2006 ) , and by eu ist center of excellence `` copira '' .

mapping the human proteome presents a significant scientific challenge , partly because of the complexity of the population and partly because of technological limitations . however , potential rewards in the diagnosis and treatment of diseases make proteomic characterization of human plasma a very worthwhile endeavor . the human proteome organization ( hupo ) represents an international consortium of academic and industrial partners whose common goal is to foster collaboration and facilitate a better understanding of the human proteome . recognizing the need for reproducibility , and following in the footsteps of the more mature field of gene expression analysis the human plasma proteome ( hpp ) project of hupo , which specifically targets plasma proteins , has made considerable progress while highlighting the complexity of plasma proteomics . for example , protein identification of the same specimen resulted in less than 50% agreement when repeated multiple times [ 5 , 6 ] , reflecting the challenges involved in biomarker discovery from human plasma [ 7 , 8 ] and underlining the need for improvements in plasma proteomic characterization . studies providing prefractionation and other sample preparation aspects are looking to improve this process [ 912 ] . a primary technological problem that needs to be addressed is the quantification of the experimental variation on a given proteomic platform . next , the baseline variation within individuals over time and the variation between multiple individuals also need to be quantitated . searching for disease - specific biomarkers makes sense only after these two steps are addressed . our recent study , referred to as the technical variation study ( tvs ) throughout the manuscript , addressed the first question for two - dimensional difference gel electrophoresis ( 2-d dige ) experiments by processing one human plasma sample eight times and analyzing each of the resulting eight technical replicates in triplicate on twelve gels [ 1316 ] . the present study is a follow - up to the tvs , whereby plasma samples from eleven healthy volunteer subjects , taken at three time points separated by two weeks , were analyzed in triplicate on 50 gels . the goal of this study was to assess longitudinal and individual variation in human plasma and to compare results to the experimental variation detected in the previously reported tvs . while differences were detected in the plasma proteome within individuals over time , our analyses indicate that individual variation contributes the largest observed proteomic variability . further , our results demonstrate that gender - related proteomic differences can be detected by 2-d dige and should also be considered in biomarker discovery . overall , this work represents a first step in quantitating the variability in human plasma by addressing the individual and longitudinal proteomic variation in human plasma . blood samples were collected from eleven healthy volunteers ( five males , six females ) at three time points separated by two weeks , with informed consent under institutional review board approval from lawrence livermore national laboratory . to minimize the effect of daily variations within an individual , the samples from a given subject were taken at approximately the same time , within a thirty - minute window , in the morning for each time point . other variables were not controlled for in order to better mimic the variability in typical human plasma samples ( age , fasting , illness , medication , etc . ) . to better examine the longitudinal variation and minimize the chance of an individual providing samples while experiencing an underlying condition such as a cold , two weeks between sample collection were chosen . each individual was assigned an identification number to blind the samples and ease the experimental design . to increase the resolution of the 2-d dige technique , the six most abundant plasma proteins were depleted using affinity chromatography , as previously reported . the sample cleanup and protein assay the 33 top-6-depleted plasma samples from the 11 individuals were analyzed in triplicate in a 50-gel 2-d dige experiment [ 1316 ] ( see table 1 in supplementary material available online at doi : 10.1155/2010/258494 ) . the internal pooled standard consists of an equal amount of each of the 33 samples and was labeled with the cy2 dye ( ge healthcare ) . each experimental sample was dye - swapped and labeled with both the cy3 and the cy5 dyes ( ge healthcare ) in the experimental design to mitigate the effect of potential dye - specific variations . samples from individuals obtained at different times were compared on some gels , while samples from two different individuals were compared on other gels . gels were run randomly in batches of twelve in order to minimize batch - to - batch variability . labeling first dimension ( pi ) separation , second dimension ( mw ) separation , and gel imaging was performed as described previously . the decyder differential analysis software v5.01 ( ge healthcare ) was used for quantitating differential abundance of proteins . the differential in - gel analysis ( dia ) module was used to determine the optimal spot detection settings . images were loaded into the batch processor module with the estimated number of spots set to 2,500 . each sample was grouped for analysis in the biological variation analysis ( bva ) module . during batch processing , the cy2 channel from each gel was used for normalization of the spot intensities and for automated matching between gels . for each spot on each gel , the software reported the standardized abundance ( sa ) as the ratio of the volume in the cy3 ( or cy5 ) sample to the volume of the pooled standard sample labeled with cy2 , where the volumes were normalized across the gels . standardized log abundance ( sla ) , defined as log 10 ( sa ) , was used in quantifying differential expression . fold change between groups was calculated as the ratio of the average sa in the two groups . if r denotes that ratio , the fold change f was defined as f = r if r 1 and f = 1/r otherwise . a k - fold expression increase / decrease corresponded to a + k/k value of f. using decyder , all possible pairwise comparisons were made between the 33 groups defined by the eleven subjects at the three times . within the bva module each comparison was filtered to find the spots having ( a ) p - value .05 and ( b ) greater than 1.5-fold change in expression between the groups . the analysis was converted into decyder 2d ( v6.5 ) , and the extended data analysis ( eda ) module ( ge healthcare ) was used to perform expression pattern clustering [ 2126 ] . data from the tvs were integrated into the analysis , pooled standards were normalized and principal component analysis was conducted [ 2730 ] on the spots that were successfully matched on > 75% of the gels from the tvs and the present study . spot characteristics calculated by decyder were exported for further statistical processing into the r statistical computing environment ( http://www.r-project.org/ ) . the high - quality spots , defined as the spots matched on at least 75% of the gels , were subjected to further analysis . spotwise standard deviations ( sds ) of the sla values and coefficients of variations ( cvs ) of the sa values were calculated , first by using all the data at a given spot to obtain one sd and one cv for that spot , then by performing the same calculations separately for the eleven subjects , thus obtaining eleven sd and cv values for each spot . the former method estimated the protein expression variation among all subjects and time points , while the latter addressed the variation within individuals through time . the results were compared to the spotwise sd and cv values obtained from the tvs . to quantitate the relative contribution of the components of variation , mixed - effects statistical modeling was performed . let yijk denote the sla at spot i on gel j measured with dye k , with i = 1 , , i , where i represents the number of spots matched on 75% of the gels , j = 1 , , 50 , and k = 1 , 2 . in addition , let l = 1 , , 11 and m = 1 , 2 , 3 indicate the subject and time indices , respectively . the assumed model was of the form ( 1)yijklm=+j+k+()jk+ig+ail+bil(m)+eijklm , where is the overall mean , j denote the coefficients for the fixed gel effects , k the coefficients for the fixed dye effects , ( )jk the coefficients for the gel - dye interactions , ig the coefficient for the fixed gender effect at spot i , and ail , bil(m ) , and eijklm the random effects components for subject ( individual ) , time ( longitudinal ) , and error at spot i , independent and normally distributed with mean zero and variance si , ti , and ei , respectively . the gender , subject , and time subscripts in ( 1 ) are redundant , as for any given j and k , the identity of the sample , including the subject , gender and time , was known . however , we included them for the clarity of the model description . since the gel and dye factors were balanced with respect to the spots ( the first four terms in the model were common to all spots ) , ( 1 ) was fit in two stages , with results equivalent to , and computationally more efficient than , the full one - stage solution in ( 1 ) repeated at each spot . , the data from all i spots were used to estimate the global dye and gel effects ; that is , only the first four terms in ( 1 ) plus error were included in the model . in the second stage , the last four terms in ( 1 ) were fit to the residuals from the first stage , one spot at a time . in essence , this first stage amounted to a normalization step , whereby the fixed dye and gel effects were estimated and removed by pooling the information across all the spots . in the second stage , a fixed gender effect and random variance components of subject , time , and error were estimated separately at each spot . thus , at spot i , the total variance yi was separated into its random components as yi = si + ti + ei . the effect of additional statistical normalizations of the sla on the variance component estimates and on the differentially expressed spots was investigated . the sla values obtained from decyder were further normalized by statistical methods that corrected for potential dye biases within gels and range differences among the gels as previously described . the spots that were determined to be of differential abundance ( > 1.5-fold difference with p - value < .05 ) were excised from the pick gel and identified by mass spectrometry as previously reported [ 12 , 18 , 20 ] . identified spots were selected in decyder for additional expression pattern clustering . the experimental design is shown in supplementary table 1 and supplementary figure 1 . rather than randomly pairing the samples on the gels , the design was selected to minimize the experimental variation among the samples whose comparison was of most interest . by placing the samples from a subject across different time points on the same gel , essentially , our design was based on the requirements that ( 1 ) each of the 33 samples has three replicates and ( 2 ) comparisons of the samples from the same subject were of more interest than comparisons of different subjects across time points . this led to an experimental design that contained 22 gels used for comparing the same individual at different time points and 28 gels to compare two individuals at different time points . in addition , the use of dye swapping and triplicates also contributed to overall quality of the data . our results suggest that gender variability may also be present . as individual and longitudinal variability was our main objective , we did not attempt to control for gender differences . we selected both males and females for our study to get a more appropriate human sample set . future work looking at human proteome variability should account for gender - specific variability in the design of the experiment . landmarks were placed manually on each gel to assist in the spot matching across the gels . spots of interest identified through the analyses were verified to have the three - dimensional profile characteristics of a protein spot . those spots with volumes close to background level and dust particles with very large slopes and small areas were eliminated . three hundred and ninety seven ( 15% ) spots were matched on at least 37 gels , and 1215 ( 46% ) spots were matched on at least 25 gels . the following statistical analyses were restricted to the 397 high - quality spots matched on 75% of the gels . these high - quality spots were chosen to focus on spots that did not require warping or imputing of any missing data . future data analysis may help determine if warping and data imputation can expand high - quality gel proteomic data . the latest version of decyder contains the ability to warp gels to potentially add missing data . these additions may provide additional spots that can be studied as high - quality , but this type of data manipulation may also create skewed expression values , as the results depend on the type of postrun imputation model that is utilized . our previous study with technical replicates of one human plasma sample had 42% of the spots matched on 8 of 12 gels . the addition of biological samples from different subjects at varying time points added to the complexity of the current dataset and reduced the matching accuracy . while most of the decrease in the matching accuracy is expected to stem from the biological complexity of the experiment , part of it may be attributed to the larger number of gels , which inevitably increases the expected experimental variation . a study of five commercial software programs showed that an average of only 3% of the total analysis time was automated as opposed to manual , and as the number of gels increased , the percentage of automatically generated correct matches was dramatically reduced . taken together , these studies suggest that improved spot detection and matching software and algorithms are needed to increase the quality of spot matching . one such study was accomplished that created algorithms to improve spot matching with an integrated approach using hierarchical - based and optimization - based methods . the pairwise comparisons among the 33 samples identified over 1400 spots with p - value < .05 and fold - change > 1.5 . down selection using manual inspection eliminated most of these spots ( due to three - dimensional profile characteristics not representative of protein or because of insufficient representation of the spot on enough gels ) resulting in 427 spots of further interest . the majority of the spots that did not pass manual verification were similar to background levels , lacking visual characteristics of protein spots . the sensitive detection parameters used in this study , while allowing for the detection of low abundance proteins , results in increased detection of artifacts that require manual verification . of the 427 spots with differential abundance , those exhibiting the greatest differences in abundance levels were further characterized , and 78 proteins spots were identified by mass spectrometry . the identified proteins are listed in table 2 , along with the theoretical pi and molecular weight calculated from the full - length amino acid sequence of each protein . figure 1 depicts the spatial distribution of the protein spots detected in human plasma by 2-d dige . sixteen proteins ( red dots ) were found to have differences between the theoretical and observed molecular weights . the discrepancies are potentially due to posttranslational modifications or experimental processing ; however , since all samples were treated identically , posttranslational modification is more likely . for example , spots 2189 and 2184 , both identified as complement component c4a , were found to be statistically significant with at least a 1.5-fold difference between individuals . complement component c4a has a theoretical molecular weight of 192.8 kda ; yet the protein spots identified indicate an approximate 32 kda fragment . since only c - terminal peptides were detected by mass spectrometry , the protein spot likely corresponds to the active complement c4c fragment ( mw = 33 kda ) , which is a known cleavage product of complement c4a [ 38 , 39 ] . variability in the amount of complement c4c fragment between individuals could be a reflection of immune status , which may be a considerable variable when comparing human clinical subjects . the spot - wise sd values of the sla for the 397 high - quality spots , when considering all samples , ranged from 0.04 to 0.53 , with a median of 0.10 . when broken down separately by subject , the range was 0.0002 to 0.50 , with 0.06 as the median , reflecting the lower variation of time - within - subjects than variation between the different subjects . both sets of values represented an increase from the spot - wise sds observed among technical replicates of the same human plasma sample , where the maximum was 0.20 and the median 0.04 . in the previous tvs work , the cv values of the sa had a median of 10% and a maximum of 42% . here , the range of the spot - wise cvs was 10% to 93% , with a median cv of 23% . the higher cvs of the present study reflect the additional complexity due to the heterogeneity of the samples from multiple human subjects . these results are comparable to the recently reported 6% ( min ) , 108% ( max ) , and 19% ( median ) cvs found in a 2-d dige study of normal liver samples from ten human subjects . here , about 90% of the spots had less than 40% cv , and only 21 spots ( 5% of the 397 high - quality spots ) had higher than 50% cv . the spots are likely not good biomarker candidates due to their high individual or longitudinal variability . these spots showing relatively high variation may correspond to a single isoform of individual proteins and do not represent all isoforms of any given protein . notably , several of the proteins identified ( albumin , transferrin , haptoglobin , igg , and iga ) are proteins removed by the top-6 depletion process , which was subsequently found to result in variability when processing multiple samples in series . in future studies , column equilibration steps are recommended between samples to reduce this variability and ensure more complete depletion of high - abundant proteins . in summary , the majority of the spots had small enough cv to indicate that the corresponding protein expressions were relatively constant across individuals , and thus could be potentially used as biomarkers . the minimum , maximum , and median cvs , when calculated separately for the subjects were 0.05% , 131% , and 14% , respectively . over 95% of the cvs were below 35% , indicating that for most subjects , the variation over the three timepoints was comparable to the experimental variation in the previously published tvs data . the effect of the normalization on the results is addressed as appropriate in the following sections . the f - tests for the analysis of variance calculations corresponding to ( 1 ) indicated significant gel ( p - value < 2.2e16 ) , dye ( p - value < 3.2e16 ) , and gel - dye interaction ( p - value < 2.2e16 ) effects . the residual diagnostic plots did not reveal major departures from the assumptions , thus indicating the validity of the model . similar analyses using the normalized sla resulted in slightly higher p - values ( gel effect p - value < 2.2e16 , dye effect p - value.003 , gel - dye interaction p - value < 3.0e09 ) but were consistent with the conclusions based on the calculations using the sla . the standard deviations corresponding to the random variance component estimates from the mixed - effects model ( figure 2 ) show the relative contribution of the three components at each of the spots matched on 75% of the gels . overall , the time - within - subject component was found to have the smallest contribution to the total variance , while subject - related variation had the highest . the corresponding frequency distributions of the three variance components ( table 1 ) confirm that for most spots ( 89% ) the contribution of the time component was less than 30% of the total variance . only 5% of the spots had 70% to 80% of their variation explained by the time component , and no spot had the time component greater than 80% of the total variance . for 21% of the spots , about 44% of the spots , the contribution of the subject component represented over 50% of the total variation . to further elucidate the contributing factors involved in spot variance , we performed a meta - analysis on these data . essentially , all the variances for the 397 high - quality spots were summed and the total variance that could be explained by the sum of the spot - wise subject , time within - subject , and error components was determined , respectively . a pooled estimate of the variance components was obtained by taking the average of the corresponding variance components over the spots . when aggregating the total variance over all the spots matched on at least 75% of the gels , the sum of the subject components explained 59% of the total variation and the sum of the time - within - subject components explained 12% of the total variation . the average subject variance component across the spots was 0.0097 ( corresponding to s = 0.098 on the sd scale ) , and the average time - within - subject variance component was 0.0019 ( t = 0.044 ) . the eda module of decyder 2d was used to visually display the results of the current study and the previous tvs study ( figure 3 ) . the multivariate expression profiles of the samples across 328 spots that were matched on > 75% of the spot maps from both studies were transformed into the principal component basis and the projection of the samples onto the first two principal components displayed ( figure 3 ) . the tight scatter of the samples from the tvs ( encircled in black ) indicates the small magnitude of the experimental variability when analyzing technical replicates of the same human sample . the magnitude of the longitudinal variation exceeded the technical variation , as evidenced by the larger scatter of the sample points of a given subject at the different time points . for example , the two red and green ellipses ( figure 3 ) highlight the longitudinal variation for subjects 1 and 11 , respectively . the differential scattering of the samples , from the subjects into varying regions of the principal components plot , indicates that the subject - to - subject variation exceeded the longitudinal variation within subjects . hierarchical clustering was used to group the 33 samples based on the similarity of their protein expression profiles along the 397 high - quality spots that were matched on > 75% of the gels ( figure 4 ) . clustering was performed in on the proteins and experimental samples , using euclidean distance and average linkage to define similarity . for all subjects , the first clustering step placed the three samples of the given subject into one cluster . samples of the same subject collected at the three time points were most similar to each other , as evidenced by the succession of self - similar bands of three rows ( highlighted by the yellow lines in figure 4 ) . the clustering also shows a general trend of clustering the samples based on gender appeared ( highlighted by the blue and red bars for males and females , resp . in addition to the results seen in the hierarchical clustering ( figure 4 ) , after fitting the mixed - effects model to the residuals from the sla at the spots matched on 75% of the gels , 17 spots showed gender - effect p - value < .01 . none of these spots were found to be significant ( p - value < .01 ) after the false discovery rate ( fdr ) method for multiple comparisons was applied suggesting that larger numbers of samples are needed to validate gender differences in the human plasma proteome . despite the lack of statistically significant data on gender differences , trends in this dataset suggest that future , larger datasets might enable the differentiation of protein expression levels due to gender . one spot , 1659 , had fdr - adjusted gender - effect p - value equal to.055 with a 1.49-fold - change between the male and female groups ( figure 5 ) . five additional spots ( 466 , 1626 alpha-2-hs - glycoprotein , 1650 alpha-2-hs - glycoprotein , 1652 alpha-2-hs - glycoprotein , 1678 ) had adjusted p - values of.11 . the results were similar when fitting the same model to the residuals from the statistically normalized sla , albeit with p - values that slightly exceeded their corresponding values based on the sla . three of the spots exhibiting gender effects were identified as alpha-2-hs - glycoprotein , which has been shown to vary between males and females . the concentration of alpha-2-hs - glycoprotein has been found to undergo a progressive age - related decrease in women , while men show no noticeable change . the removal of the dye and gel effects using the model in ( 1 ) proved to be a beneficial preprocessing step . without this step , when the mixed - effect model was fit to the original sla , the smallest fdr - adjusted gender - effect p - value was.19 ( spot 1659 ) . when the same model was fit to the statistically normalized sla , the smallest fdr - adjusted p - value was also.19 ( spot 1659 ) . the statistical normalization improved the quality of the data slightly , but it did not reduce dramatically the observed p - values . on the other hand , pooling the information across the gels to remove the common dye and gel effects strengthened the signal and reduced markedly the fdr - adjusted p - values . as explained in the previous paragraph , for spot 1659 , the new p - value was close to.05 . hierarchical clustering of the identified proteins ( figure 6 ) was conducted using the euclidean distance metric and average linkage methods . for all subjects , other than subject 10 , the first clustering step placed the three samples of that subject into one cluster . subject 10 had two time points grouped together ( x and z ) with the third point ( y ) separated by subject 3 . because the 78 identified proteins were the most differential between time and subjects , it is not unexpected to see clustering results that may not perfectly align all subjects or time points . for example , all protein spots identified as transferrin ( tf ) clustered together due to their similar expression patterns , while the vitamin d - binding protein ( gc ) spots were found in multiple clusters due to differences in expression patterns between the individuals . multiple proteins may cluster together due to coregulation and similar functions , and in the case of apoa4 and apoa1 ( figure 6 ) , coregulation has been reported [ 37 , 42 ] . statistical analysis of a 2-d dige experiment involving triplicate plasma samples from eleven human subjects taken at three time points separated by several weeks demonstrated that the subject - to - subject variation exceeded the time - within - subject variation . the variation in the human plasma proteome reported here was greater than a previous technical variation study wherein one plasma sample was processed multiple times . here , for 70% of the high - quality protein spots , the coefficient of variation of the sla was less than 30% across all subjects and time points , thus indicating that the baseline expression levels of those proteins are relatively stable in the population represented by the subjects in this study . only 21 spots had larger than 50% cv , suggesting that these protein isoforms should be avoided as biomarker candidates . many of these protein spots represent medium to high abundance plasma proteins . since they are higher abundance , they might bias lc / ms datasets , but since the total number of these spots relative to the total plasma proteome is small , their total influence on a sample is likely also small . in addition , protein spots with gender - related differences should be considered separately for males and females . however , more thorough studies , including the use of a larger population set with additional time points over longer periods of time , are recommended to more fully address individual , longitudinal , and gender variability as related to biomarker discovery . we noted that preprocessing the data by first removing the fixed effects of the gels and dyes was important in data analysis and improved the quality of the data . this step resulted in six protein spots showing a statistically significant gender effect at an fdr - adjusted 11% significance level . without the preprocessing step , the smallest gender effect p - value was.19 . while removing the gel and dye effects lead to stronger conclusions , the additional statistical normalization of the sla had only marginal effects and did not alter the conclusions . spot matching confounds gel- and software - related protein differences with real biological effects . in the present study , we only considered spots that were matched on at least 75% of the gels . spots with lower matching quality can be investigated separately , as they may correspond to proteins that are absent or have very low expression in certain individuals , but which may have biological significance . we envision that such studies will become more relevant as the field of personalized medicine matures , and as detection and matching algorithms continue to improve . this study represents a first step toward quantitating the longitudinal and individual variation in the human plasma proteome , as measured on the 2-d dige platform . interestingly , gender - related variations were also detected suggesting that gender variability should also be considered in biomarker discovery . future , larger - scale experiments that include more subjects representative of various population segments , encompassing differences in ethnicity , age , gender , disease status , and other relevant factors , have the potential to define baseline proteomic similarities and differences in the human population , which will in turn facilitate improved biomarker discovery .

quantifying the variation in the human plasma proteome is an essential prerequisite for disease - specific biomarker detection . we report here on the longitudinal and individual variation in human plasma characterized by two - dimensional difference gel electrophoresis ( 2-d dige ) using plasma samples from eleven healthy subjects collected three times over a two week period . fixed - effects modeling was used to remove dye and gel variability . mixed - effects modeling was then used to quantitate the sources of proteomic variation . the subject - to - subject variation represented the largest variance component , while the time - within - subject variation was comparable to the experimental variation found in a previous technical variability study where one human plasma sample was processed eight times in parallel and each was then analyzed by 2-d dige in triplicate . here , 21 protein spots had larger than 50% cv , suggesting that these proteins may not be appropriate as biomarkers and should be carefully scrutinized in future studies . seventy - eight protein spots showing differential protein levels between different individuals or individual collections were identified by mass spectrometry and further characterized using hierarchical clustering . the results present a first step toward understanding the complexity of longitudinal and individual variation in the human plasma proteome , and provide a baseline for improved biomarker discovery .

at the present time , there are some efforts to explain the observations for the accelerated expansion of the universe , based on the dynamics of a scalar ( quintessence ) or multiscalar field ( quintom ) as models for dark energy , ( see the review @xcite ) . the properties of the quintom models have been studied from different points of view . among them , the phase space studies , using the dynamical systems tools , are very useful in order to analyze the qualitative and asymptotic behavior of the model @xcite ) . in the present work we want to investigate the case of quintom cosmology constructed by using both quintessence ( @xmath0 ) and phantom ( @xmath1 ) fields , maintaining a nonspecific potential @xmath2 from the begining . in the literature one special class of potential used is the sum of the exponential potentials for each field @xcite . there are other works where other type of potentials are analyzed @xcite . we claim that the analysis of general potentials using dynamical systems was made considering particular structures of them , in other words , how can we introduce this mathematical structure within a physical context ? we can partially answer this question , when the amplitude - real - phase formalism is introduced , in the sense that , some potentials can be constructed @xcite . this work is arranged as follows . in section [ model ] we present the corresponding einstein - klein - gordon equation for the quintom model . also we introduced the hamiltonian apparatus which is applied to frw cosmological model in order to construct a master equation for barotropic perfect fluid and cosmological constant . furthermore , we present the classical equations for the flat frw , which are presented in section [ hamil ] for particular scalar potentials . in subsection [ qap ] we present the quantum scheme , where we will use the amplitude - real - phase ansatz in order to solve the wdw equation . this method was used by moncrief and ryan @xcite to obtain exact solutions for the bianchi type ix anisotropic cosmological model with a wavefunction of the form @xmath3 . this form of the wavefunction was motivated by the work of kodama @xcite . our treatment is applied to build the mathematical structure of quintom scalar potentials which allow us obtain exact solutions together with an arbitrary factorization of the wdw equation . in this work we have obtain the wave function of the universe in order to find the quantum potentials , which is a more important matter in order to find the classical trajectories , which is shown in section [ hamil ] , that is devoted to obtain the classical solutions for particular scalar potentials , also we show graphically the classical trajectory in the configuration space @xmath4 projected from its quantum counterpart . in this same section , we present the time dependence for the @xmath5 , and quintom scalar fields ( @xmath6 ) for the potentials treated in this section . in section [ remarks ] is devoted to final remarks of this work . we begin with the construction of the quintom cosmological theory , which requires the simultaneous consideration of two fields , namely , a canonical one @xmath0 , and phantom one @xmath1 ( see equation ( [ densidad ] ) below and reference @xcite ) . the lagrangian density of this theory with two fields , the cosmological term , and matter contribution , is @xmath7 the corresponding field equations for perfect fluid matter content are @xmath8 here @xmath9 is the energy density , p the pressure , and @xmath10 the velocity of the fluid , satisfying that @xmath11 . let us recall here the canonical formulation in the adm formalism for flat frw cosmological model . the metric has the form @xmath12,\label{metrici}\ ] ] where the scale factor is defined as @xmath13 , where @xmath14 . the lagrangian density ( [ lagra ] ) for frw cosmological model is written as @xmath15 , \label{lagra - i}\ ] ] where the overdot denotes time derivative , the fields were re - scaled as @xmath16 for simplicity in the calculations . the momenta are define in the usual way , @xmath17 , where @xmath18 are the fields coordinates of the model . @xmath19 writing ( [ lagra - i ] ) in the canonical form , @xmath20 and substituting the energy density of the barotropic fluid @xmath21 , which was found using the covariant derivative of the energy - momentum tensor ( [ energy - momentum ] ) , @xmath22 where @xmath23 is an integration constant . the corresponding hamiltonian density @xmath24 considering in this work the inflationary epoch , that corresponds to the value @xmath25 , becomes @xmath26 , \label{hami - i}\ ] ] where @xmath27 . the einstein field equations ( [ munu],[energy - momentum ] ) for the flat frw cosmological model with barotropic state equation , are @xmath28 which can be written as @xmath29 where the hubble parameter is define as @xmath30 and the deceleration parameter @xmath31 . we have done the time transformation @xmath32 . adding ( [ densidad ] ) and ( [ presion ] ) we obtain @xmath33,\ ] ] where @xmath34 which are useful when we study the behavior of dynamical systems . additionally we can introduce the total quintom energy density and pressure as : @xmath35 where @xmath36 for phenomenological analysis , ( [ baro ] ) will serve us as a test for the viable class of quintom potentials whose equation of state can cross the cosmological constant barrier which @xmath37 is mildly favored of observations @xcite . for instance , when @xmath38 and @xmath39 , then the kinetic terms satisfies @xmath40 , so , the barotropic parameter @xmath41 . in this case , the intensity of the phantom field @xmath42 always is larger than the intensity of the quintessence field @xmath43 . in other case , we have that @xmath44 . the particular value equivalent to cosmological constant is when the kinetic terms are null or equal in both fields . for constant potential , equations ( [ da - varsigma],[da - varphi ] ) can be solved in terms of the @xmath5 function , @xmath45 we obtain in implicit solution for @xmath5 in a quadrature @xmath46 where @xmath47 is given by @xmath48 with @xmath49 for particular values of the parameter @xmath50 , has analytical solution . for one scalar field , with constant potential , the formalism is like the one formulated by sez and ballester in 1986 , because both field are equivalent , see equations ( [ da - varsigma],[da - varphi ] ) @xcite . this formalism was studied by one of the author and collaborators , in the frw and bianchi type class a cosmological models , @xcite . the wheeler - dewitt equation for this model is obtained introducing the representation ( we choose @xmath51 ) @xmath52 into ( [ hami - i ] ) . the factor @xmath53 can be ordered with the momenta @xmath54 in many ways . hartle and hawking @xcite have suggested a semi - general factor ordering for @xmath55 as @xmath56 where q is any real constant that measure the ambiguity in the factor ordering in the variable @xmath5 . in the following we will assume this factor ordering for the wheeler - dewitt equation , which becomes @xmath57 where @xmath58 is the dalambertian in the field coordinates @xmath59 and @xmath60 . some time ago , moncrief and ryan tried successfully amplitude - real - phase ansatz in order to solve the wdw equation to obtain exact solutions for the bianchi type ix anisotropic cosmological model . this ansatz was motivated by the remarks of kodama @xcite on the relation between the adm wavefunction and the ashtekar wavefunction . this ansatz is as follows @xmath61 where @xmath62 is known as the superpotential function , w is like probability amplitude in the bohm formalism @xcite . then , the wdw equation ( [ wdwmod ] ) is written as @xmath63\right\ } = 0 , \label { mod}\ ] ] with @xmath64 , @xmath65 , @xmath66 , where @xmath67 , and @xmath68 is the potential term . the last equation is a difficult one to solve , in view of which we propose to factorize as below and set each factor to zero , obtaining simpler set of equations , [ wdwa ] @xmath69 we follow the approach presented in the references @xcite for solving these set of partial differential equations in order to obtain particular solutions to de wdw equation . we solve initially the einstein - hamilton - jacobi ( ehj ) equation ( [ hj ] ) , next we introduce the superpotential function s into equation ( [ wdwho ] ) in order to solve for the w function , and finally , these solutions must satisfy the quantum potential equation ( [ cons ] ) , that appears as a quantum constraint in our approach . to solve hamilton - jacobi equation ( [ hj ] ) @xmath70 we propose that the superpotential function has the following form @xmath71 and substituting into ( [ hj ] ) , @xmath72=0 , \label{ecuacion}\ ] ] in order to solve by separation of variables , this equation imply the foolowing structure for the potential @xmath73 , \label{potenti - u}\ ] ] where @xmath74 , @xmath75 , @xmath76 and @xmath77 are generic functions on their arguments , which will be determined under this process , and @xmath78 , @xmath79 are constants . then , by method of separation variables we find the following master equations for the quintom fields [ fields ] @xmath80 where @xmath81 is a constant of separation of variables . for particular choices of functions @xmath82 and @xmath83 we can solve for the @xmath74 and @xmath75 functions , and then use them to obtain the potential term u from ( [ potenti - u ] ) . some examples are shown in the tables [ t : solutions ] and [ potentials ] , thereby , the superpotential @xmath84 is known , and the possible quintom potentials are shown in table [ potentials ] . . [ t : solutions ] _ some exact solutions to eqs . ( [ varsigma],[varphi ] ) , where n is any real number , @xmath85 and @xmath86 are an arbitrary constants . _ [ cols="^,^,^,^",options="header " , ] to solve ( [ wdwho ] ) we assume the separation variables for the w function @xmath87 } , \label{ww}\ ] ] and introducing the corresponding superpotential function s ( [ sp ] ) into the equation ( [ wdwho ] ) , it follows the equation @xmath88 and using the method of separation of variables , we arrive to a set of ordinary differential equations for the functions @xmath89 , @xmath90 and @xmath91 ( however , this decomposition is not unique , because it depends on the way as we put the constants in the equations ) . @xmath92g,\\ \rm \frac{d^2h}{d\varsigma^2}+2\frac{dh}{d\varsigma } \frac{d\lambda}{d\varsigma}&= & \rm sh,\end{aligned}\ ] ] whose solutions in the generic fields g and h are ( given in table ( [ t : solutions ] ) ) @xmath93 then the solution for the function w is @xmath94 in a similar way , the constraint ( [ cons ] ) can be written as @xmath95 or in other words ( here @xmath96 ) @xmath97 when we use the different cases presented in the table ( [ t : solutions ] ) , the relations between all constants were found , which we presented in the same table [ potentials ] with the quintom potentials . so , the quantum solutions for each potential are presented in quadrature form , using the equations ( [ ans ] , [ sp ] ) and ( [ ww ] ) . for our study , we shall make use of a semi - classical approximation to extract the dynamics of the wdw equation . the semi - classical limit of the wdw equation is achieved by taking @xmath98 , and imposing the usual wkb conditions on the superpotential function s , namely @xmath99 hence , the wdw equation , under the particular factor ordering q = 0 , becomes exactly the afore - mentioned ehj equation ( [ hj ] ) ( this approximation is equivalent to a zero quantum potential in the bohmian interpretation of quantum cosmology @xcite ) . the ehj equation is also obtained if we introduce the following transformation on the canonical momenta @xmath100 in eq . ( [ hami - i ] ) and then eq . ( [ momenta ] ) provides the classical solutions of the einstein klein gordon ( ekg ) equations . moreover , for particular cases shown in table [ t : solutions ] , the classical solutions of the ekg , in terms of @xmath101 , arising from eqs . ( [ momenta ] ) and ( [ sp ] ) are given by @xmath102 the second equation appears in the w function ( [ ww2 ] ) , therefore w is simplified . we also have the corresponding relation with the time @xmath103 @xmath104 this particular case corresponds to an null potential function @xmath105 , ( see second line in table ( [ potentials ] ) ) . the particular exact solution for the wave function @xmath106 becomes @xmath107 , \label{xi}\ ] ] the classical trajectory implies that @xmath108 , then there is the simple relation between the fields @xmath109 and @xmath110 , @xmath111 so , the wavefunction can be written in terms of @xmath109 and @xmath5 , @xmath112 , \label{xii}\ ] ] using the equantion ( [ time ] ) , we find the _ classical trajectory _ on the @xmath113 plane as [ free ] @xmath114^{\pm \frac{p}{9 } } , \\ \delta \varsigma&=&\rm ln\left[\frac{3g_0 h_0}{4 } \delta \tau \right]^{\mp \frac{\ell}{9}},\\ \delta \omega&= & \rm ln\left[\frac{3g_0 h_0}{4 } \delta \tau \right]^ { \frac{1}{3}}+\nu_0,\end{aligned}\ ] ] where the first equation corresponds to constant phase of the second exponential in the w function ( [ ww2 ] ) . the last equation gives the scale factor which goes as a power law expansion , in a stiff matter epoch . for an exponential scalar potential , see the third line in table ( [ potentials ] ) , the exact solution of the wdw equation and the classical solutions are similar to the last case , only we redefine the constants , @xmath115 we present two solutions , depending of the value of the constant @xmath116 ; when @xmath117 , the scale factor which goes as a power law expansion , and @xmath118 , the scale factor have an exponential behavior . the corresponding classical solutions are 1 . case @xmath117 + [ free ] @xmath119^{\pm \frac{\sqrt{p^2+c_1g_0}}{9-c_0h_0-c_1g_0 } } , \\ \delta \varsigma&=&\rm ln\left[\frac{(9-c_0h_0-c_1g_0)g_0 h_0}{12 } \delta \tau \right]^{\mp \frac{\ell^2-c_0h_0}{9-c_0h_0-c_1g_0}},\\ \delta \omega&= & \rm ln\left[\frac{(9-c_0h_0-c_1g_0)g_0 h_0}{12 } \delta \tau \right]^ { \frac{3}{9-c_0h_0-c_1g_0}},\end{aligned}\ ] ] + if the scale factor must have an inflationary behavior as a power law expansion , the exponent @xmath120 , so , the constants @xmath117 . 2 . case @xmath121 + employing the equations ( [ const - final ] ) and ( [ time ] ) , we choose this value before to realize the integration , obtaining + [ free ] @xmath122 where the scale factor have an exponential behavior , which corresponding to inflationary epoch with exponential scalar fields . under canonical quantization we were able to determine a family of potentials that allows as to find exact solutions in classical and quantum cosmology in the inflation era . some of the potentials of this family satisfied the conditions that can cross the cosmological constant barrier @xmath37 , equation ( [ baro ] ) . one potential for which it to was not possible to solve analytically @xcite , by means of dynamical systems is possible to show that crosses this barrier . the exact quantum solutions to the wheeler - dewitt equation were found using the bohmian like scheme @xcite of quantum mechanics , using the amplitude - real - phase approach @xcite , where the ansatz to the wave function is @xmath123 includes the superpotential function s , which plays an important role in solving the hamilton - jacobi equation . we presented the corresponding einstein klein gordon equation for the quintom model , which is applied to the frw cosmological model with a barotropic perfect fluid and cosmological constant as the matter content ; the classical solutions are given in a quadrature form for constant scalar potentials , in an inflationary stage ( @xmath124 ) these solutions are related to the sez - ballester formalism , @xcite . for the inflationary stage with a potential that is a product of exponentials of the fields we found two exact solutions , one with a potential expansion law and the other with an exponential one . we emphasize that the quantum potential from the bohm like formalism will work as a constraint equation which restricts our family of potentials found , see table ( [ potentials ] ) , @xcite . in this work such a problem has been solved in order to find the quantum potentials , which was a more important matter for being able to find the classical trajectories , which were showed through graphics how the classical trajectory is projected from its quantum counterpart . we include some steps used to solve the imaginary like equation ( [ wdwho ] ) when we found the superpotential function s ( [ sp ] ) and particular ansatz for the function w , we found the equation ( [ solve ] ) , and using the separation variables method we find the set of equations that were necessary to solve . the recent astronomical data suggest the existence of the dark energy with negative pressure @xcite , with ratio @xmath125 between the pressure @xmath126 and the energy density @xmath127 seems to be near or less than -1 , @xmath128 @xcite . following the equation ( [ baro ] ) , in order to have agreement with these observational results , considering @xmath129 and @xmath130 , then the kinetic terms satisfies @xmath131 , so , the barotropic parameter @xmath132 . in this case , the intensity of the phantom field @xmath42 is always larger than the intensity of the quintessence field @xmath43 . in other case , we have that @xmath133 . the particular value corresponding to cosmological constant is when the kinetic terms are null or equal in both fields . however , the strange properties of the phantom field ( violation of energy conditions and related negative energy density , the theories are not quantum mechanically viable , either because they violate conservation of probability , or they have unboundedly negative energy density and lead to the absence of a stable vacuum state , @xcite ) . to avoid this kind of problem , one should consider theories where the interactions between phantom field and normal matter are as weak as possible , but we must allow the ghosts to interact gravitationally , since it is their gravitational interactions which are needed for them to have any cosmological consequences . for instance , in @xcite , the authors include some generalizations of phantom cosmology with quantum contribution . quantum effects may lead also to negative energy density or to negative pressure what may indicate that phantom corresponds to the effective description of some fundamental quantum field theory ( qft ) . those authors mention that qft can suggests some mechanism to introduce the phantom field at the early universe , and most of energy conditions are satisfied due to quantum effects . 99 copeland , e.j . , sami , m. , and tsujikawa s. : _ int . j. mod . d _ * 15 * 1753 , ( 2006 ) [ arxiv : hep - 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we construct the quintom potential of dark energy models in the framework of spatially flat friedmann - robertson walker universe in the inflationary epoch , using the bohm like approach , known as amplitude - real - phase . we find some potentials for which the wave function of the universe is found analytically and we have obtained the classical trajectories in the inflation era .

azoles remain the corner - stone of prevention and treatment of aspergillus diseases , including acute invasive aspergillosis ( ia ) . however , the clinical use of azoles is threatened by the emergence of azole resistance in aspergillus fumigatus , the primary cause of ia in many regions of the world . resistance that arises through the environmental use of azole fungicides this route of resistance development proves a clinical challenge with cases of azole - resistant ia occurring in patients without previous azole therapy , , and cases of azole - susceptible and azole - resistant a. fumigatus co - infection . resistance mutations commonly confer resistance to multiple azole drugs , including the recently clinically - licensed isavuconazole . however , based on in vitro and experimental models it was hypothesized that low - level azole - resistant a. fumigatus infection might be successfully treated with voriconazole or posaconazole provided that the treatment dose and exposure could be increased . we describe a case of azole - resistant ia in a bottlenose dolphin that was successfully managed by increasing posaconazole exposure . a 10 year old female captive bottlenose dolphin ( tursiops truncatus ) , weighing 175 kg , was treated with antibiotics for bacterial pneumonia caused by vibrio alginolyticus . treatment follow - up was conducted with blood samples , ct - scans , bronchoscopies , and protected brush samples from the tracheal and/or bronchial mucosa for histopathology and bacterial and fungal culture ( fig . the bacterial pneumonia required long - term antibiotic treatment and 6 months into therapy she developed multiple white , raised lesions in the trachea and bronchi , one of which was sampled with protected brush during bronchoscopy . no fungi were cultured but based on the bronchoscopic appearance of the lesions a candida infection was suspected . treatment with oral voriconazole with a loading dose of 5.5 mg / kg per day during 3 days and a maintenance dose of 5.5 mg / kg per week ( given in one single dose ) was started . follow - up bronchoscopies were performed one , two and three months after voriconazole treatment was started , showing no improvement . fungal culture of a protected brush sample , taken at one and two months of voriconazole therapy remained negative , but at three months a. fumigatus was cultured . retrospective analysis of a serum sample indicated the presence of circulating galactomannan ( gm ; gm - index 6.5 ) . the a. fumigatus isolate was sent to the mycology reference laboratory and was found to be resistant to voriconazole with a mic of > 16 mg / l and a posaconazole mic of 0.5 treatment was then changed to posaconazole at a dose of 600 mg / day ( day 0 ) . the oral solution formulation of posaconazole was used , which was incorporated in gelatin capsules and placed into the fish she was fed . the daily dose was divided into two doses and administered in the morning and late afternoon . posaconazole therapeutic drug monitoring was performed aiming at a target trough level of > 1 the clinical condition of the dolphin initially improved and follow - up bronchoscopy on days 29 , 101 , and 232 showed stable disease . however , the clinical condition of the dolphin deteriorated and a new bronchoscopy on day 279 showed increased lesion size . the posaconazole dose was increased on day 286 to achieve plasma levels above 2 mg / l . however , this did not result in clinical improvement nor reduction of the size of the trachea lesions . after 344 days of posaconazole therapy , a higher exposure target was advised based on preclinical studies , aiming at a plasma level of > 3 after initial clinical deterioration and stable size of the lesions , the dolphin started to improve clinically , which was supported by resolution of the lesions on the ct - scan ( fig . the improvement further was confirmed with bronchoscopy showing complete resolution of the lesions on day 459 . mg / l , with doses ranging from 800 to 1800 mg / day ( fig . 3 ) . after a total treatment duration of 593 days posaconazole therapy was discontinued . the a. fumigatus isolate recovered from the dolphin was identified using beta - tubulin sequencing . mic - testing using the eucast microdilution reference method showed a mic of 1 mg / l for amphotericin b , high level - resistance ( mic > 16 mg / l ) for itraconazole and voriconazole , and low - level resistance for posaconazole , 0.5 mg / l . a tr46/y121f / t289a resistance mutation was identified . we describe a case of pulmonary ia due to a. fumigatus in a bottlenose dolphin that was complicated by azole resistance . the fungus was cultured from plaques in the trachea and bronchi that were visualized through bronchoscopy , and computed tomography showed pulmonary lesions consistent with fungal disease . although gm detection is a well validated diagnostic tool in humans for the diagnosis of invasive aspergillosis and for treatment response evaluation , , the performance of the assay in dolphins remains unclear . as ia is the most commonly reported in fungal disease in captive and free - ranging bottlenose dolphins , , , further studies are needed to determine the performance of this biomarker in dolphins and other cetaceans . in addition to bronchoscopy , the presence of circulating gm would help to diagnose aspergillus infection and possibly be useful for monitoring of treatment response . gm however does not identify the species of aspergillus that is causing the fungal pneumonia , nor does it provide information regarding the presence of resistance . pcr - tests that identify the most prevalent aspergillus species as well as the presence of azole resistance mutations are commercially available . in humans such assays enabled the detection of azole - resistant a. fumigatus directly in bal - fluid , . the a. fumigatus strain recovered from our case harbored a resistance mutation that is associated with environmental resistance selection , indicating that the dolphin inhaled a. fumigatus conidia that were already azole - resistant . experts recommended to move away from azole monotherapy when resistance is documented , switching to liposomal amphotericin b or voriconazole and echinocandin combination therapy . in vitro and in vivo studies indicate that the activity of polyenes and echinocandins are not affected by the presence of azole resistance mutations , , . furthermore , voriconazole and anidulafungin combination therapy was shown to be effective in an animal model of disseminated ia due to a. fumigatus with low - level voriconazole resistance ( mic of 4 mg however , the efficacy of the combination against voriconazole high - level resistant a. fumigatus has not been studied . there is concern that voriconazole will not be effective in high - level resistant a. fumigatus infection and combination therapy will solely rely on anidulafungin efficacy , which is suboptimal . as intravenous therapy was no option in treating the dolphin , it was decided to increase the exposure of posaconazole . using results of pharmacokinetic and pharmacodynamic in vitro and in vivo models we have previously attempted to bridge these experimental results to human infection by calculating which posaconazole exposure would be required in relation to the a. fumigatus mic to treat successfully . for each mic the corresponding posaconazole exposure and plasma level were determined . based on our analysis a posaconazole plasma - level of 3.093.33 mg / l would be required to treat an infection with a posaconazole mic of 0.5 when a plasma level of > 3 mg / l was achieved in the dolphin , gradual clinical response was documented without significant toxicity ultimately leading to clinical cure . in the dolphin very high drug exposures were achieved using the oral solution formulation , but in humans posaconazole drug levels above 3 mg / l could not be achieved due to limited bioavailability associated with the oral suspension . however , phase i and phase ii pharmacokinetic studies indicate that a posaconazole plasma level above 3 mg / l can be achieved using the new intravenous and tablet formulations , without significant side - effects . as the majority of azole - resistant a. fumigatus isolates show low - level resistance to posaconazole , i.e. within the 0.5 mg / l to 1 mg / l mic range , intravenous posaconazole might be a treatment option in human cases of azole - resistant ia . our study shows proof - of - principle of high - dose posaconazole for the treatment of ia due to posaconazole low - level - resistant a. fumigatus . with the availability of new posaconazole formulations further studies need to explore this option for the management of azole - resistant ia in animals and humans . verweij has received research grants and served as consultant for gilead sciences , pfizer , msd , astellas , f2 g , and basilea . other authors :

invasive aspergillosis due to azole - resistant aspergillus fumigatus is difficult to manage . we describe a case of azole - resistant invasive aspergillosis in a female bottlenose dolphin , who failed to respond to voriconazole and posaconazole therapy . as intravenous therapy was precluded , high dose posaconazole was initiated aimed at achieving trough levels exceeding 3 mg / l . posaconazole serum levels of 39.5 mg / l were achieved without significant side - effects . follow - up bronchoscopy and computed tomography showed complete resolution of the lesions .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Integrity in Auditing Act of 2002''. SEC. 2. PROHIBITION ON CONTEMPORANEOUS PERFORMANCE OF AUDIT AND NON- AUDIT SERVICES. (a) In General.--Section 10A of the Securities Exchange Act of 1934 (15 U.S.C. 78j-1) is amended by adding at the end the following: ``(g) Auditor Independence.-- ``(1) Prohibited activities.--An independent public accountant, and any affiliated person thereof, may not provide to any covered issuer, during the same calendar year in which it provides any auditing or related service required by this title for that issuer-- ``(A) any management consulting service; ``(B) any other service that is not related to the audit, except as provided in paragraph (4); or ``(C) any other service that could result in a potential conflict of interest or otherwise impair the independence of the auditor, as determined by the Commission. ``(2) Auditor rotation.--No independent public accountant, or any affiliated person thereof, may provide auditing or related services required by this title for any one covered issuer in any year for more than 7 consecutive years. ``(3) Conflicts of interest.--No independent public accountant, or affiliated person thereof, may become employed in a management or other policymaking position, as determined by the Commission, by any covered issuer for which that accountant or affiliated person provided auditing services required by this title in any capacity during the one-year period preceding the date of employment. ``(4) Tax consulting exception.--Paragraph (1) does not prohibit the provision of tax consulting services to a covered issuer by an independent public accountant or affiliated person thereof contemporaneously with any auditing or related service, with the prior written approval of the audit committee of that issuer, or its equivalent. ``(5) Covered issuers.--In this subsection, the term `covered issuer' means an issuer, the securities of which are registered under section 12.''. (b) Commission Regulations.--Not later than 90 days after the date of enactment of this Act, the Securities and Exchange Commission shall issue final regulations to carry out subsection (g) of section 10A of the Securities Exchange Act of 1934, as added by this section, including, consistent with that subsection-- (1) a definition of the term ``management consulting service'' that includes consulting relating to-- (A) information technology infrastructure design and implementation; (B) organizational behavior; (C) marketing; and (D) business strategy; (2) the identification of other non-audit services prohibited by paragraph (1) of that subsection; and (3) a determination of management and other policymaking positions prohibited by paragraph (3) of that subsection. (c) Effective Date.--The amendments made by this section shall become effective on the date of final issuance of regulations under subsection (b). SEC. 3. DISCLOSURE OF AND LIMITS ON CORPORATE RELATIONSHIPS. (a) Regulations Required.--Not later than 90 days after the date of enactment of this Act, the Commission shall issue final regulations to require that-- (1) together with each financial statement or other report required to be filed with the Commission pursuant to the securities laws, each covered issuer shall disclose the nature, duration, and extent of each relationship described in subsection (b); and (2) the audit committee and compensation committee of each covered issuer shall consist solely of independent directors. (b) Relationships.--For purposes of subsection (a)(1), a relationship described in this subsection is-- (1) a relationship-- (A) by blood, marriage, or adoption, not more remote than first cousin; (B) of any professional nature; and (C) of any financial nature; and (2) a relationship between-- (A) any director, director nominee, an immediate family member of such director or director nominee, or any organization in which such director, director nominee, or immediate family member has an interest; and (B) the covered issuer, any other director or director nominee, any executive officer or executive officer nominee, an immediate family member of such other director, director nominee, executive officer, or executive officer nominee, or any organization in which such other director, director nominee, executive officer nominee, or immediate family member has an interest; (c) Definitions.--As used in this section-- (1) the term ``audit committee'' means a committee of the board of directors of a covered issuer responsible for reviewing-- (A) the financial reports and other financial information provided by that issuer to any governmental body or the public; (B) the systems of that issuer of internal controls regarding finance, accounting, legal compliance, and ethics that management and the board of directors have established; and (C) the auditing, accounting, and financial reporting processes of that issuer generally; (2) the term ``Commission'' means the Securities and Exchange Commission; (3) the term ``compensation committee'' means a committee of the board of directors of a covered issuer responsible for reviewing and setting the compensation of certain executive officers of the issuer; (4) the term ``covered issuer'' means an issuer, as defined in section 3 of the Securities Exchange Age of 1934 (15 U.S.C. 78c), the securities of which are registered pursuant to section 12 of that Act (15 U.S.C. 78l); (5) the terms ``director'' and ``affiliated person'' have the same meanings as in section 3 of the Securities Exchange Age of 1934 (15 U.S.C. 78c); and (6) the term ``independent director'' means an individual director of a covered issuer who is not, or in the 5 years preceding the date of commencement of service as a director, has not been-- (A) employed by that issuer or an affiliated person thereof in an executive capacity; (B) an employee or owner of a firm or other entity that is a paid adviser or consultant to that issuer or an affiliated person thereof; (C) employed by a significant customer or supplier of that issuer or an affiliated person thereof; (D) a party to a personal services contract with that issuer, its chairman, or other executive, officer, or affiliated person thereof; (E) an employee, officer, or director of a foundation, university, or other nonprofit organization that receives significant grants or endowments from that issuer or any affiliated person thereof; (F) a relative of an executive of that issuer or any affiliated person thereof; and (G) part of an interlocking directorate in which any executive officer of that issuer serves on the board of another corporation that employs the director. SEC. 4. SENSE OF THE SENATE REGARDING ENFORCEMENT. It is the sense of the Senate that-- (1) tough enforcement, including criminal prosecution whenever possible, is the most effective deterrent to fraudulent activity; and (2) the Commission should take a firm, swift approach to wrongdoers.

Integrity in Auditing Act of 2002 - Amends the Securities Exchange Act of 1934 to prohibit an independent public accountant from providing: (1) management consulting or any other non-audit-related services during the same calendar year in which it provides auditing services; (2) any service that could either result in a potential conflict of interest, or impair auditor independence; or (3) auditing or related services for an issuer for more than seven consecutive years.Bars an independent public accountant from employment in a management or other policymaking position for an issuer for whom that accountant (or affiliated person) has provided auditing services during the one-year period preceding the date of employment. Permits the performance, however, of tax consulting services contemporaneously with any auditing or related service.Directs the Securities and Exchange Commission to require: (1) issuer disclosure of the nature, extent, and duration of interrelationships between the issuer and the board of directors, senior officers of the corporation, and immediate family members; and (2) the audit committee and compensation committee of an issuer to consist solely of independent directors.Expresses the sense of the Senate that: (1) tough enforcement, including criminal prosecution whenever possible, is the most effective deterrent to fraudulent activity; and (2) the Commission should take a firm, swift approach to wrongdoers.

the term hydrophobicity @xcite refers to peculiar thermodynamic properties of the transfer process of an apolar solute into water . in such a process , one generally observes large positive transfer free energy , large negative transfer entropy ( at room temperature ) , and strong temperature dependence of the transfer enthalpy and entropy , i.e , large ( positive ) transfer heat capacity . such anomalous behavior seems to play a central role for relevant phenomena taking place in aqueous solutions , such as folding of macromolecules and proteins , and formation of micelles and membranes @xcite . for example , bio - polymers such as proteins contain a significant fraction of apolar chemical groups , and it is well established that the effective attraction between apolar groups , due to hydrophobicity , gives an important contribution both to the folding process and to stabilization of the folded protein . despite several decades of research , the theory of the hydrophobic effect is still incomplete . different theoretical models have been proposed to explain the anomalous behavior of water itself and hydrophobic interactions , which have been recognized to be closely related . a straightforward approach relies on the application of molecular dynamics or monte carlo simulation methods to models with more or less realistic three - dimensional water geometry @xcite . this approach is powerful , but has some limitations . first of all , large computational effort is needed , and properties involving multiple derivatives of the free energy ( such as transfer heat capacity , whose behavior is a fingerprint of hydrophobicity ) can not be determined easily . moreover , the amount of different interactions and geometric parameters included in the model makes it difficult to find out relevant physical mechanisms which determine observable properties . a complementary approach involves investigation of simplified models @xcite , with fewer parameters , geometric details , and degrees of freedom . such models should better allow to trace connections between microscopic structure and observed properties , while the latter can be usually analyzed in full detail , and in a large range of thermodynamic conditions , with relatively small computational effort . one of these attempts is based on the application of scaled - particle theory @xcite to hydrophobic hydration @xcite . these studies suggest that the hydrophobic effect results mostly from the small size of water molecules , and not from water structuring by the solute . a recent and interesting descendant of scaled - particle theory is the information theory approach by pratt and coworkers @xcite , based on previous knowledge of water properties , such as the pair correlation function , obtainable either by experiments or by simulations . the latter approach suggests that water structuring induced by the solute , though existing , may be scarcely relevant for a description of the hydrophobic effect . the simplified molecular thermodynamic theory of ref . is essentially in agreement with this conclusion . on the contrary , different theories stress that the large positive heat capacity variation , observed upon insertion of apolar solutes into water , can only arise from a cooperative phenomenon , that is from induced ordering of water molecules , so that a theory of the hydrophobic effect should be based on a description of this phenomenon . it can be observed that , at room temperature , hydration of apolar solutes is energetically favorable but sufficiently unfavorable entropically , with a resulting increased free energy . a simplified way to reproduce this effect is for instance the one - dimensional lattice model by kolomeisky and widom @xcite , extended also to two and three dimensions @xcite . in that case , entropy penalty is achieved by lowering the large number of possible orientations of a water molecule , if it has to accommodate a neighboring hydrophobic solute . another possibility is to give water molecules a geometric structure , as in the two - dimensional mercedes benz ( mb ) model , first introduced by ben - naim in 1971 @xcite . in the latter model , water molecules possess three equivalent bonding arms arranged as in the mercedes logo , and a geometric constraint ( arm alignment ) is required for bond formation . an mb model has been investigated quite recently by dill and coworkers by means of several different methods : constant pressure monte carlo simulations @xcite , entropy expansion @xcite , and integral equation theory @xcite . a coherent picture of the hydrophobic effect phenomenology has been worked out , allowing to obtain a microscopic view of several anomalous properties of water both as a pure substance and as a solvent . the latter studies follow the previously mentioned idea of simplified models , that nevertheless are based on well defined microscopic interactions , that is , on an energy function , without previous knowledge of water properties . one important reason to do so is the need of modelling water in a computationally convenient way , in order to investigations on complex systems such as biomolecules , for which water plays a key role . according to the same idea , we have recently investigated @xcite a lattice - fluid model of mb type on a ( two - dimensional ) triangular lattice , with the aim of reproducing qualitatively the thermodynamic anomalies of pure water . of course , the lattice allows important simplifications , so that a sufficiently accurate modelling of water on a lattice may be quite an interesting issue . our model hamiltonian includes van der waals interaction and hydrogen bonding , when two nearest neighbor mb water molecules point an arm to each other . bonds can be weakened by the presence of a third competing molecule , close to the formed bond , to mimic the fact that , if water molecules are too close to one another , hydrogen bonds may be perturbed or broken . as far as bonding properties are concerned , the model is equivalent to an early model proposed by bell and lavis @xcite , but the weakening criterion is different , that is , equivalent to the one employed in quite a recent investigation by patrykiejew and coworkers @xcite . nevertheless , in the latter analysis the possibility of nonbonding orientations for water molecules is neglected , and resemblance with real water behavior is poor . in ref . @xcite we observed that , introducing such additional orientations , which account for directionality of hydrogen bonds , the lattice model describes several anomalous properties of pure water in a qualitatively correct way . here we extend the model to the case of an aqueous solution , working out solvation thermodynamics for an inert ( apolar ) solute . the analysis is also extended to transfer properties of water in its own pure liquid . our purpose is to verify whether this simple model , which nevertheless accounts for the competition between van der waals interactions and hydrogen bonding in almost the same way as the off - lattice mb model , may be able to reproduce at least the main features of hydrophobicity . in particular , we also investigate how the model describes the solvation process at a microscopic level , by comparing the average number of hydrogen bonds formed by water molecules ( hydrogen bond coordination ) in the bulk or in the hydration shell . we shall carry out the analysis by means of a generalized first - order approximation on a triangle cluster , which has been verified to be quite accurate for the pure water model @xcite . the paper is organized as follows . in sec . ii we define the model and recall the first - order approximation . in sec iii we introduce the thermodynamic quantities used to characterize the solvation process , and compute them in the framework of the model . in particular , we analyze transfer quantities for an inert molecule , comparing them to the case in which hydrogen bonding interaction is `` turned off '' . model predictions about solvation of water in its own pure liquid are also reported . in sec . iv we investigate hydrogen bond coordination , drawing a comparison with the results of the off - lattice mb model . v contains some concluding remarks . the model is defined on a two dimensional triangular lattice . a lattice site can be empty or occupied by molecules of two different chemical species , water ( ) or solute ( ) . a water molecule has three equivalent bonding arms , separated by @xmath1 angles , whereas a solute molecule is assumed to have no internal structure . two nearest - neighbor ( nn ) molecules of species @xmath2 , @xmath3 ( with @xmath4 ) interact with an attractive energy @xmath5 , representing ordinary van der waals forces . moreover , if two arms of two nn water molecules point to each other , an energy term @xmath6 is added , to mimic the formation of a hydrogen ( h ) bond . due to the lattice structure , a water molecule can form @xmath7 bonds at most , and has only 2 bonding orientations , when its arms are aligned with the lattice . we also assume that @xmath8 nonbonding configurations exist , where @xmath8 is a model parameter , related to the h bond breaking entropy . the h bond is weakened by an energy term @xmath9 ( @xmath10 $ ] ) when a third molecule of @xmath2 species is on a site near a formed bond . in the triangular lattice there are @xmath11 such weakening sites per bond , so that , when both are occupied by @xmath2 molecules , the h bond contributes an energy @xmath12 . the resulting water - solute interaction has two components : the nonorientational van der waals term @xmath13 and the weakening term @xmath14 . the latter , which is an effective 3 body interaction , can be viewed as a perturbation effect of the solute on a h bond between two water molecules . let us write the model hamiltonian . in order to introduce the first order approximation , it is convenient to express it as a sum over elementary triangles : @xmath15 where @xmath16 is a contribution which will be referred to as triangle hamiltonian , and @xmath17 label site configurations for the 3 vertices @xmath18 , respectively . possible site configurations are ( see tab . [ tab - site - conf ] ) : `` empty '' ( @xmath19 ) , `` bonding water '' ( site occupied by a water molecule in one of the @xmath11 orientations which can form bonds : @xmath20 ) , `` nonbonding water '' ( site occupied by a water molecule in one of the @xmath8 orientations which can not form bonds : @xmath21 ) , `` solute '' ( site occupied by a solute molecule : @xmath22 ) . l|ccccc config . & empty & & & & @xmath23 & 0 & 1 & 2 & 3 & 4 @xmath24 & 1 & 1 & 1 & @xmath8 & 1 @xmath25{i}$ ] & 0 & 1 & 1 & 1 & 0 @xmath26{i}$ ] & 0 & 0 & 0 & 0 & 1 [ tab - site - conf ] even if all configurations have unit multiplicity , except @xmath21 , it is convenient to introduce a generic multiplicity parameter @xmath24 , defined as in tab . [ tab - site - conf ] . the triangle hamiltonian can be written as @xmath27 where @xmath28{i } \nocc[y]{j } - \eta h_{ij } \left ( 1 - c_{\textsf{x } } \nocc[x]{k } \right ) , \label{eq : triham2}\ ] ] @xmath29{i}$ ] is an occupation variable for the @xmath2 species , defined as in tab . [ tab - site - conf ] , while @xmath30 if the pair configuration @xmath31 forms a h bond , and @xmath32 otherwise . conventionally , repeated @xmath2 and @xmath3 indices are summed over their possible values @xmath33 . let us notice that triangle vertices are set on three triangular sublattices , say @xmath34 , and @xmath35 are assumed to denote configurations of sites placed on @xmath34 sublattices respectively . assuming also that @xmath34 are ordered counterclockwise on up - pointing triangles ( whence clockwise on down - pointing triangles ) , we can define @xmath30 if @xmath36 and @xmath37 and @xmath32 otherwise . let us also notice that both van der waals ( @xmath38{i } \nocc[y]{j}$ ] ) and h bond energies ( @xmath39 ) , that are 2-body terms , are split between two triangles , whence the @xmath40 prefactor in eq . . on the contrary the 3-body weakening terms ( @xmath41{k}/2 $ ] ) are associated each one to a given triangle , and the @xmath40 factor is absorbed in the prefactor . let us denote the triangle configuration probability by @xmath42 , and assume that the probability distribution is equal for every triangle ( no distinction between up- or down - pointing triangles ) . taking into account that there are 2 triangles per site , we can write the following expression for the internal energy per site of an infinite lattice @xmath43 the multiplicity for the triangle configuration @xmath44 is given by @xmath45 , where @xmath24 is the previously mentioned multiplicity parameter . the details of the finite temperature analysis of the model , by a generalized first order approximation on a triangle cluster , follow the previous paper @xcite . not being interested in symmetry broken phases ( ice ) , we introduce a homogeneity condition since the beginning , after which generalization is trivial . the grand - canonical free energy per site @xmath46 ( @xmath47 and @xmath48 being respectively the chemical potential and the density , or site occupation probability , for the @xmath2 species , @xmath49 and @xmath50 being respectively the temperature and the entropy per site ) , can be written as a functional in the triangle probability distribution as @xmath51 where @xmath49 is expressed in energy units ( whence entropy in natural units ) . it is noteworthy that the only variational parameter in @xmath52 is the triangle probability distribution , that is the 125 variables @xmath53 , because @xmath54 ( the site probability ) can be expressed as a marginal . according to the homogeneity hypothesis , we can use the symmetrized expression @xmath55 the latter turns out to be convenient , in that it gives rise to iterative ( fixed point ) equations which preserve homogeneity . the energy part in eq . is given by the modified hamiltonian @xmath56 , defined as @xmath57{i } + \nocc[x]{j } + \nocc[x]{k}}{3 } \label{eq : trihamtilde } .\ ] ] the minimization of @xmath52 with respect to @xmath53 , with the normalization constraint , yields the equations @xmath58 where @xmath59 is a normalization constant . such equations can be solved numerically by simple iteration ( natural iteration method @xcite ) . as a result , we obtain the triangle probability values at equilibrium , from which one can compute the thermal average of every observable . the substitution into eqs . and gives respectively the equilibrium internal energy and free energy , and , by the way , it is possible to show that @xmath60 let us first introduce the thermodynamic quantities , generally used to describe solvation from a macroscopic point of view , which we shall evaluate for our model in the following . the physical process we are interested in is the transfer of a component ( @xmath61 ) into a water - solute mixture , with solute density tending to zero . according to the ben - naim standard @xcite , this process is well characterized by variation of the pseudo - chemical potential @xmath62 , related to the ordinary chemical potential @xmath47 of the given component by @xmath63 let us notice that , in the latter term on the right hand side , the momentum partition function is missing , due to the fact that we are dealing with a lattice model @xcite . the solvation free energy per molecule @xmath64 is defined as the difference between pseudo - chemical potential values of a molecule @xmath2 in the ideal gas phase ( @xmath65 ) and in the liquid phase ( @xmath66 ) . for practical purposes , the differences between ideal and real gas can be generally neglected @xcite . for a molecule of species @xmath2 we then have @xmath67 where @xmath68 and @xmath69 are pseudo - chemical potentials of @xmath2 in the liquid and gas phases , respectively . now , if liquid and gas phase coexist in equilibrium , as usual in experiments , the ordinary chemical potentials of @xmath2 in both phases must be equal , and by simple algebra we obtain @xmath70 where @xmath71 and @xmath72 are respectively the @xmath2 species densities in the liquid and in the gas . derived quantities , of interest in experiments , are the solvation entropy @xmath73 the solvation enthalpy @xmath74 and the solvation heat - capacity @xmath75 let us notice that , in principle , we should distinguish between a constant pressure derivative ( as stated by definition ) and a temperature derivative taken along the liquid - vapor equilibrium curve . in particular , we could not even use eq . , because we would move out of the equilibrium curve , at which the ordinary chemical potentials are equal . nevertheless , numerical results @xcite show that the difference is negligible , definitely from a qualitative point of view . therefore , we shall always use the latter temperature derivative definition in our calculations . let us start studying solvation of an inert molecule in water . we set water parameters as follows : @xmath76 , @xmath77 , and @xmath78 . as shown in our previous analysis @xcite , this choice corresponds to a waterlike behavior , with a liquid - vapor critical point at @xmath79 , and with a temperature of maximum density for the liquid around @xmath80 at low pressure . solvation thermodynamics concepts introduced above are independent of density of components in the mixture . we choose to let solute density assume very low values with respect to water density ( dilute solution limit ) , in order to compare with experiments . the `` inert '' nature of the solute is described , in the model framework , by setting to zero the solute - solute ( @xmath81 ) and water - solute ( @xmath82 ) van der waals interaction energies . at the moment , we also set the weakening parameter @xmath83 to zero , assuming that the ideally inert solute does not weaken h bonds in its neighborhood . the effect of nonzero values for this parameter , which may describe for instance a volume interaction , resulting in a perturbation of the geometry ( and hence of the energy ) of h bonds , will be taken into account later . the temperature trends of the free energy , entropy , and enthalpy of transfer are given in fig . [ fig : solute - water](a ) ; the transfer heat capacity in fig . [ fig : solute - water](c ) . in order to compare with experimental data @xcite , all quantities are evaluated at liquid - vapor coexistence . for the perfectly inert solute , we have verified that concentration does not affect the results at all . to represent roughly the experimental temperature range ( between @xmath84 and @xmath85 ) we report model results between @xmath86 ( just below the temperature of maximum density for pure liquid water ) and @xmath87 ( about half way between the previous temperature and the critical temperature ) . remarkably , it turns out that the model , despite its simplicity , displays the defining feature of the hydrophobic effect : the solvation free energy is positive and large , while the solvation entropy is negative at low temperatures and becomes positive upon increasing temperature ; the heat capacity is positive and large , and also the decreasing trend with temperature is essentially reproduced . the increasing trend at high temperature is related to the the fact that we are approaching the liquid - vapor critical point . negative solvation entropy at low ( room ) temperature is a clear indication that solute insertion into the mixture orders the system . the corresponding positive ( unfavorable ) contribution to free energy compensates a negative ( favorable ) enthalpic contribution , giving rise to a positive solvation free energy . at higher temperature , enthalpic and entropic contributions change sign , but they still have the same trend of compensating each other . as observed in experiments , the model predicts two different temperatures @xmath88 and @xmath89 at which the transfer enthalpy and entropy vanish , respectively [ see fig . [ fig : solute - water](b ) ] . this behavior is to be ascribed to the thermodynamics of h bonding and , in order to rationalize this fact in the model framework , let us also analyze transfer quantities for the case @xmath90 , i.e. , turning off h bond interactions [ see fig . [ fig : solute - water](a),(c ) ] . as expected , the results are similar in the high temperature regime , where there is a high probability that hydrogen bonds are broken by thermal fluctuations , whereas they change more and more dramatically upon decreasing temperature , and in particular the regions of negative transfer entropy and enthalpy completely disappear . this facts confirm that h bonding is the key element for system ordering , upon insertion of an inert molecule . accordingly , also the divergentlike trend of the heat capacity upon decreasing temperature ( related to the fact that the liquid phase is approaching a stability limit @xcite ) is suppressed . the process is now completely dominated by the transfer enthalpy , with a large and positive transfer free energy , and a positive transfer entropy . the transfer quantities behave qualitatively as those observed in solvation experiments of noble gas molecules in ordinary liquids @xcite , and are relatively independent of temperature . in fact , with @xmath90 , a water molecule can be viewed as a nonpolar molecule with van der waals interaction energy @xmath91 . let us now consider also the solvation of water in its own pure liquid . the corresponding transfer energies obtained by the model are displayed in fig . [ fig : water - water](a ) , where we have reduced the temperature interval , in order to compare with available experimental results @xcite , reported in fig . [ fig : water - water](b ) . in contrast to the inert molecule case , here the absolute values of solvation free energy and entropy are considerably lower and the enthalpy , rather than the entropy , dominates the solvation process , and all quantities are relatively independent of temperature . these features characterize a regular transfer process , like the solvation of an ordinary fluid molecule from a gas phase into its pure liquid phase . in this case , upon removing h bond interactions [ thin lines in fig . [ fig : water - water](a ) ] , very little changes are observed in the solvation energies , except at very low temperature , where we are approaching the stability limit for liquid water @xcite . let us discuss two issues about these results . first , the fact that so little changes are caused by turning on or off h bonds can be rationalized on the basis of the microscopic model interactions . the insertion of a water molecule into pure liquid water should imply in principle the formation of new h bonds , but the model is such that insertion of a new water molecule also weakens other h bonds in its neighborhood , and the two effects nearly compensate each other . second , let us notice that solvation enthalpy decreases upon increasing temperature , that is , the solvation heat capacity is negative , in contrast with experiments . we do not have an explanation for this fact , but we can observe that an analogous effect is observed when the model is reduced to describe a regular solvation process , that is when h bonds are turned off . this suggest that there is probably a limitation of the lattice description , that anyway has nothing to do with the peculiarities of water . the effect is quantitatively small , so that it is hidden by other large enthalpic and entropic effects observed in the case of hydrophobic solvation . so far , we have always considered an ideal , perfectly inert solute , setting to zero all interactions with water ( @xmath92 , @xmath83 ) and with itself ( @xmath93 ) . now we investigate the role of the @xmath83 parameter , which represents a weakening of h bonds , induced by the presence of a solute molecule . let us recall that , in our model , the presence of too many water molecules close to one another weakens the h bond strength , through the @xmath94 parameter , to mimic the fact that too low average distance is unfavorable for h bonds . on the contrary , a different ( lower ) weakening parameter @xmath83 for a solute molecule , can represent a perturbation of h bonds , due to an excluded volume effect . anyway , the solute weakening parameter @xmath83 is a way of tuning the degree of water ordering induced by the solute . in order to characterize this effect , together with the role of the @xmath83 parameter , let us investigate the h bond coordination , that is , the average number of hydrogen bonds per molecule . in quite recent papers , dill and coworkers @xcite suggested , on the basis of their off - lattice mb model , that this parameter is the appropriate one to rationalize the temperature @xmath89 at which the transfer entropy vanishes . in particular they distinguished between h bond coordination for molecules in bulk water and in a hydration shell . we can evaluate analogous parameters also for our model , in the framework of the first order approximation . each water molecule can form bonds with nn molecules only , therefore it is necessary to compute the joint probability distributions of a given site with its 6 nns ( hexagon probability ) . according to the husimi lattice formulation of the first order approximation , it is easy to see that only certain triangle correlations are taken into account , as shown schematically in fig [ fig : hexagon ] . therefore , @xmath95 being the central site configurations and @xmath96 the nns configurations , the hexagon probability distribution reads @xmath97 ( 0,0 ) # 1#2#3#4#5 @font ( 2170,1789)(-179,-839 ) ( 316,794)(0,0)[lb ] ( 316,-781)(0,0)[lb ] ( 1576 , 74)(0,0)[lb ] ( 856,119)(0,0)[lb ] ( -179 , 74)(0,0)[lb ] ( 1126,-781)(0,0)[lb ] ( 1126,794)(0,0)[lb ] we shall evaluate bond coordinations according to this factorization , which , let us notice , is perfectly consistent with our approximation scheme @xcite . let us consider a water molecule in a bonding configuration , for example @xmath36 . it is not necessary to consider also the other ( @xmath98 ) bonding configuration , due to the fact that the liquid phase is isotropic , whereas we do not take into account nonbonding configurations ( @xmath21 ) , because in that case the probability of forming a bond is zero . the bulk and shell coordinations can be written respectively as @xmath99 where @xmath100 , or @xmath101 respectively , is the probability that the given molecule forms @xmath102 bonds , given that its nn sites host no solute molecules ( bulk water ) or at least one solute molecule ( hydration shell ) . working in the infinite dilution limit , the probability of configurations with more than one nn solute is actually a small corrections over the probability of having just one solute molecule . making use of the bayes theorem , the bulk conditional probability can be rewritten as @xmath103 where @xmath104 is the probability that the central molecule forms @xmath102 bonds , _ and _ that its nn sites host no solute molecules , while @xmath105 is simply the probability that nns host no solute molecules . moreover , making use also of the total probability theorem , the shell conditional probability can be rewritten as @xmath106 where @xmath107 is the total probability that the central molecule forms @xmath102 bonds . we can now evaluate the required probabilities , making use of the factorization . first of all , it is easy to see that @xmath108 where @xmath109 in fact , the central molecule , in the given @xmath36 configuration , can form bonds along its @xmath7 arms . therefore , @xmath110 is the probability that a bond is formed along @xmath102 given arms , while @xmath111 is the probability that bond is not formed along the remaining @xmath112 arms . the probability factorizes , because arms lie on different triangles , which are uncorrelated , according to eq . . the binomial coefficient accounts for different choices of @xmath102 bonds along @xmath7 arms , while the denominator is due to the fact that @xmath113 , though not specified by the notation , is a conditional probability , with respect to the presence of a central water molecule in the @xmath36 configuration . the joint probability @xmath104 can be evaluated in similar way @xmath114 where we have to assume that no solute molecule is present in the neighborhood , that is @xmath115 finally , the probability that no solute molecule is in the neighborhood ( bulk condition ) can be written as @xmath116 in the work of dill and coworkers @xcite , at low temperatures h bond coordination for shell water @xmath117 is greater than h bond coordination for bulk water @xmath118 . this behavior is reversed in the high temperature region , where h bonds are preferably formed by bulk water . in this model , the crossing temperature @xmath119 ( where @xmath120 ) is approximately equal to @xmath89 ( where @xmath121 ) . as a consequence , average h bond coordination seems to be strictly related to the transfer entropy . let us analyze what happens in our model . first of all , we observe that the range of values of h bond coordination is generally much lower than the maximum value of 3 h bonds , which can be formed by a single water molecule ( see fig . [ fig : hbcoord ] ) . this fact may be related to a peculiarity of the lattice model , in which h bonds can be formed just along given directions . moreover , as far as the temperature behavior is concerned , upon varying the weakening parameter @xmath83 , we can have in principle four different scenarios . as shown in fig . [ fig : hbcoord](a ) , at low values of @xmath83 ( low h bond weakening near a solute molecule ) , shell coordination @xmath117 is greater than bulk coordination @xmath122 for all temperatures . increasing the parameter , it is possible to observe a scenario similar to the one found by dill and coworkers : a crossing temperature @xmath119 between a low temperature region dominated by @xmath117 and a high temperature one dominated by @xmath122 [ fig [ fig : hbcoord](b ) ] . increasing @xmath83 further , a more complicated scenario , involving two crossing temperatures , can be observed . the region where @xmath117 is greater than @xmath122 is upper - bounded by @xmath119 , as in the previous scenario , and lower - bounded by a different crossing temperature [ fig . [ fig : hbcoord](c ) ] . this means that the high temperature behavior is restored at low temperature , though in a region very close to the stability limit for the liquid phase , which would be very difficult to reach in a real system . finally , for very high values of @xmath83 ( high weakening of h bonds near a solute molecule ) a fourth scenario is observed , reversing the behavior of the first scenario , that is , @xmath123 for all temperatures . all possible behaviors are summarized in fig . [ fig : ts_cs ] , where the crossing temperatures @xmath89 and @xmath119 are displayed as functions of the weakening parameter @xmath83 . as a comparison , in the same figure , we have reported the zero entropy temperature @xmath89 , as a function of the same weakening parameter @xmath83 . it can be easily observed that , while h bond coordination is strongly dependent on the weakening parameter , the transfer entropy turns out to be a much more `` robust '' effect , and the @xmath89 temperature has only a relatively slight dependence on the weakening parameter . in this paper we have considered a two - dimensional waterlike lattice model , defined on the triangular lattice , which we had previously shown to reproduce qualitatively typical thermodynamic anomalies of pure water , and extended the model to the case of an aqueous solution . water molecules are of the mercedes benz type , with three equivalent bonding arms , while solute molecules have no internal degrees of freedom . we have performed our calculations by means of a generalized first order approximation on a triangle cluster , which requires quite a small computational effort , and had been shown to behave quite accurately for the pure water model . in particular , in this paper we have addressed the issue of dilute solutions of inert ( apolar ) solutes , that is , the hydrophobic effect , and we have investigated thermodynamic equilibrium between liquid and vapor , working out solvation quantities in this case . it turns out that the model qualitatively reproduces the peculiar features that are usually believed to be the fingerprints of hydrophobicity . the solvation free energy is positive , meaning that solvation is unfavorable , while the entropy and enthalpy display an increasing trend and cross zero at two different temperatures . the solvation heat capacity is large and decreases upon increasing temperature . the model results compare qualitatively well with experimental results about solvation of noble gases into water . we have investigated the effect of h bonding , by comparing the previously mentioned results with those obtained by setting to zero the h bond energy parameter . in this case , we have obtained transfer quantities that approach the ones computed _ with _ h bonds at high temperatures , but that largely deviates from them upon decreasing temperatures , in the region were h bonding begins to dominate . in particular , we have observed that , while the disaffinity of the solute for the solvent remains , and is signaled by the positive large value of the solvation free energy , such a disaffinity is mainly of enthalpic nature , and both the enthalpy and entropy of solvation remain positive at all observed temperatures , so that the strong temperature dependence , which is typical of the hydrophobic effect , disappears . in order to a check of the model , we have also investigated solvation of water into water at liquid - vapor equilibrium , for which experimental data are available . we have found qualitative agreement in the values of solvation free energy , entropy and enthalpy , though there is some discrepancy in the temperature dependence of enthalphy , which indicates a negative solvation heat capacity , in contrast with experiments . though not reporting details in the paper , we have verified that this fact is neither to be related to the approximation of the ideal / real gas phase , nor with the temperature derivative approximation , mentioned in sec . iii . on the contrary , we have observed that the same kind of discrepancy may be observed in the case of zero h bond energy , that is , for a regular solution . therefore , we suspect that the discrepancy is to be related to an intrinsic limitation of lattice modelling . the effect is relatively small , so that it is completely invisible , when the dominant effect of h bonding is turned on . finally , we have performed a calculation of the average number of h bonds formed by a single water molecule ( h bond coordination , in short ) , in two different cases , namely when the molecule is placed in the first hydration shell of a solute molecule ( shell coordination ) , and when it is not ( bulk coordination ) . according to dill s mercedes benz model , these two parameters are clearly related to the solvation entropy behavior , namely , negative solvation entropies ( low temperature ) correspond to higher shell coordination , while positive solvation entropies correspond to higher bulk coordination . due to the fact that our purpose was to obtain a kind of lattice version of the mb model , describing essentially the same physics underlying the observed phenomenology , we have tried to verify whether the same effect could be observed in our model or not . the answer is essentially no , but some interesting observations can be done . we have performed the investigation , upon varying the solute weakening parameter , which , in our model , is a way of tuning the degree of water ordering induced by the solute . we have observed that such parameter strongly affects the behavior of h bond coordination , and in particular the temperature at which shell and bulk coordinations become equal . on the contrary the temperature of zero entropy @xmath89 , which is actually one of the striking features of the hydrophobic effect , is quite `` robust '' and relatively independent of variations of the weakening parameter . two questions arise from the discussed behavior . on the one hand , we may suspect that the lattice model is definitely too simple to capture the microscopic physics of the hydrophobic effect in a correct way , or that the approximation level is insufficient . but the robustness of the zero entropy temperature may also suggest that the simple relationship between the balance of bulk and shell h bonds and the zero of transfer entropy , proposed by dill and coworkers , may be model - dependent , and ought to be verified more carefully . we plan to investigate on such issues in future works .

in a previous work , we investigated a two - dimensional lattice - fluid model , displaying some waterlike thermodynamic anomalies . the model , defined on a triangular lattice , is now extended to aqueous solutions with apolar species . water molecules are of the `` mercedes benz '' type , i.e. , they possess a @xmath0 ( equilateral triangle ) symmetry , with three equivalent bonding arms . bond formation depends both on orientation and local density . the insertion of inert molecules displays typical signatures of hydrophobic hydration : large positive transfer free energy , large negative transfer entropy ( at low temperature ) , strong temperature dependence of the transfer enthalpy and entropy , i.e. , large ( positive ) transfer heat capacity . model properties are derived by a generalized first order approximation on a triangle cluster .

in the nearby universe , galaxies have a bimodal color distribution , with a blue peak of star forming galaxies separated from a red sequence of quiescent galaxies by a sparsely populated gap @xcite . the number of red galaxies has roughly doubled since @xmath2 @xcite . red galaxies , on average , are more luminous than blue galaxies . therefore , a simple cessation of star formation in a fraction of the blue galaxies followed by fading and reddening can not explain this build - up of the red sequence . starbursts are often suggested as a way of increasing a blue galaxy s stellar mass before letting it fade onto the red sequence @xcite , with mergers and interactions as possible starburst triggers @xcite . mergers and starbursts have the additional appeal that they offer an explanation for the cessation of star formation : gas is being consumed by the starburst @xcite and is being expelled by agn or supernova feedback @xcite . thus , previously blue galaxies turn red and , through further dry mergers , can lead to the formation of the most massive elliptical galaxies observed in the nearby universe @xcite . this prompted us to investigate the crucial but transient poststarburst phase , during which a galaxy crosses the color gap , of this particular evolutionary pathway . poststarburst galaxies ( psgs , or e+a galaxies ) have optical spectra with strong balmer absorption lines , revealing young stars , but faint if any emission lines , ruling out major star formation @xcite . psgs offer us a unique window on how starbursts affect galaxy evolution . the starburst population is fading but still quite prominent and we can study both the burst and the underlying intermediate - age and/or old stellar populations . due to their high surface brightness , we can study their stellar kinematics out to several half - light radii ( @xmath3 ) . clearly , the poststarburst phase is of crucial importance to furthering our understanding of the photometric evolution of the galaxy population . in this _ letter _ , we present for the first time two - dimensional spatially - resolved kinematics and stellar population parameters for a gas - rich psg , selected from the @xcite catalog , . with a redshift @xmath4 , luminosity distance @xmath5 mpc ( adopting a spatially flat cosmology with @xmath6 km s@xmath1 mpc@xmath1 , @xmath7 , @xmath8 ) , distance modulus @xmath9 mag , and a spatial scale 1.27 kpc arcsec@xmath1 , this is a relatively nearby psg . the few galaxies with known systemic velocities in a 200 kpc wide search column centered on do not coincide in redshift and are spread over a very large redshift range ( @xmath10 ) , making it unlikely that they are physically connected with . we confirm the classification of by @xcite as a field psg . this is the first paper in a series based on our vlt / vimos observations of 3 psgs . the data have been obtained with the integral field unit ( ifu ) mode of the vimos spectrograph at eso / vlt - melipal by eso staff in mid-2006 . with the high - resolution `` hr - blue '' spectral setup , the 0.67@xmath11 per lens spatial scale provides a field of view ( fov ) of @xmath12 ( 40@xmath1340 lenses ) . this setup offers a spectral resolving power @xmath14 between 4200 and 6300 . in total , we use eleven out of twelve obtained exposures , spatially dithered in order to work around broken ifu fibers , and each with an on - source time of 2,000 sec . the seeing fwhm varies between 0.7 and 1.2@xmath11 . arc line and flat field calibration frames have been taken for every observing block ( ob ) . for the data recuction , we use the generic ifu data reduction pipeline implemented in itt idl . a brief description of the data reduction steps can be found in @xcite . detailed information including all vimos - specific aspects concerning these data will be provided in a forthcoming paper . each of the four vimos quadrants , labeled q1 through q4 , of every ob was reduced independent from the others until the flux calibration step . the relative flux calibration of the quadrants is performed using twilight sky frames and requires extra care since we use spatial dithering . the absolute flux calibration was done using observations of spectrophotometric standards included in the standard vimos calibration plan . night sky spectra are reconstructed from the lenses outside 5 r@xmath15 of the galaxy to minimize contamination by the galactic stellar continuum and are subtracted from the science frames . then , individual exposures are co - added , applying iterative sigma - clipping to remove cosmic ray hits , spatial and spectral shifts to account for spatial dithering , different heliocentric corrections and atmosphere differential refraction . noise frames are computed using photon statistics and are processed through the same reduction steps as the science frames , up to the sky subtraction . we use twilight and science frames contaminated by moon ( 4 out of 12 ) to assess the data reduction quality and obtain quantitative estimates of the vimos spectral line spread function variations across the fov , along the wavelength axis , and between different obs . we fit the solar spectrum , taken from the elodie.3.1 stellar library @xcite , against the observed spectra in every lens at six wavelength intervals between 4000 and 6300 using the ppxf procedure @xcite . from this test , we conclude that ( 1 ) wavelength calibration quality is better than 5 km s@xmath1 between 4000 and 5900 ; ( 2 ) spectral resolution ( @xmath16 ) exhibits no significant variations across the fov for individual quadrants , neither between observing blocks , although ( 3 ) it does change along wavelength ( 60 to 40 km s@xmath1 from blue to red ) and between quadrants ; ( 4 ) high - order moments of the gauss - hermite parametrisation ( @xmath17 and @xmath18 , @xcite ) are close to zero except q3 at @xmath19 , where @xmath17 is modestly negative due to imperfect focusing ; ( 5 ) systematic errors of the wavelength calibration become very important at @xmath20 , changing significantly between individual obs so we restrict our analysis to shorter wavelengths . we use the nbursts full spectral fitting technique @xcite with high - resolution ( @xmath21 ) pegase.hr @xcite simple stellar population ( ssp ) models to extract kinematics and stellar population from the absorption - line spectra . first , we rebin the data to a target signal - to - noise ratio of 15 per bin using the voronoi adaptive tessellation technique @xcite . we use only that part of the vimos ifu fov where the sky - subtraction uncertainty is sufficiently small , with a size of 18@xmath1318 lenses ( @xmath22 ) . the subsequent fitting procedure comprises the following steps : ( 1 ) a grid of ssp spectra with a fixed set of ages ( spaced nearly logarithmically from 20 myr to 18 gyr ) and metallicities ( from @xmath232.0 to @xmath240.5 dex ) is convolved with the wavelength - dependent instrumental response of vimos in every voronoi tessella as explained in @xcite ; ( 2 ) a non - linear least square fitting against an observed spectrum is done for a template picked from the pre - convolved ssp grid using 2d - spline interpolation on age ( @xmath25 ) , and metallicity ( @xmath26 ) , broadened with the line - of - sight velocity distribution ( losvd ) parametrized by @xmath27 , @xmath28 , @xmath17 , and @xmath18 and multiplied pixel - by - pixel by an @xmath29 order legendre polynomial ( multiplicative continuum ) , resulting in @xmath30 parameters to be determined ( we use @xmath31 ) . we exclude narrow 12 - wide regions around the h@xmath32 , h@xmath33 , [ oiii ] ( @xmath34 ) , and [ ni ] ( @xmath35 ) lines from the fit in order to be able to detect faint emission lines . as shown in @xcite , reliable ssp - equivalent age and metallicity estimates are obtained even if the balmer absorption lines are excluded . using the approach described in @xcite we estimate the excluded regions to contain only @xmath36% of age - sensitive information . we present the maps derived from the full - spectrum fitting in fig [ figmaps ] . those regions where the parameters have large uncertainties ( e.g. @xmath37 km s@xmath1 for @xmath27 and @xmath28 ) or are not fit ( @xmath17 and @xmath18 in the outer regions ) are masked . the isophotes from the reconstructed continuum image ( datacube collapsed along the spectral dimension ) are shown as black solid contours . line - of - sight velocities can be determined with adequate precision out to larger radii from the galaxy centre than the velocity dispersion and the stellar population parameters , because they are insensitive to the sky subtraction . exhibits very regular , symmetric pure disc rotation with a semi - amplitude of 90 km s@xmath1 without any evidence for significant isovelae twist . however , there is a significant misalignment of the kinematical and photometrical axes . we mention the evident large - scale bar oriented exactly along the galaxy s minor axis ( roughly north - south ) , which is visible on sdss images and also noticeable here in the reconstructed image . the rotation curve flattens out at @xmath38 from the centre , corresponding to @xmath39 kpc or @xmath40 @xcite ( see fig . [ figrvpr ] ) . the velocity dispersion declines from a central maximum of @xmath41110 km s@xmath1 to @xmath42 km s@xmath1 at 6@xmath11 . the rather high @xmath43 in the outskirts of the galaxy also argue for the presence of a disc . one has to be careful with interpreting the high very central values , because a rapidly rotating circumnuclear component smeared by atmospheric seeing may produce very similar effects . weighing all the evidence , is best classified morphologically as a barred lenticular or sb0 galaxy . this is not surprising since , although the diversity is quite large , many e+as have s0-like morphologies @xcite . we use a technique similar to that proposed by @xcite to determine the galaxy s inclination , @xmath44 , and the position angle of the major axis , pa , from the stellar radial velocity field ( the main difference being the non - parametric representation of the rotation curve ) . fitting the velocity field in elliptical annuli in the radial range @xmath45 gives pa@xmath46 deg and @xmath47 deg . these values agree well with the shape and axial ratio of the outer isophote displayed in fig [ figmaps ] . the peak projected velocity @xmath48 km s@xmath49 , after correcting for inclination effects , yields @xmath50 km s@xmath1 for the mean tangential velocity . we adopt the value @xmath51 , provided by sdss , for the exponential scale - length of the stellar density profile . using these numbers , we estimate the circular velocity @xmath52 at a radius of 4@xmath11 , corrected for asymmetric drift using the method outlined in paragraph 4.8.2(a ) of @xcite . for the outskirts of the galaxy , we assume the rotation curve to be flat ( @xmath53 ) and the velocity dispersions to be independent of radius . we then arrive at the following expression for the circular velocity : @xmath54 here , @xmath55 is the tangential velocity dispersion . unfortunately , along the major axis , @xmath28 is a function of both @xmath55 and @xmath56 , the vertical component of the velocity dispersion tensor . if we assume we are dealing with a thin disc then @xmath57 and @xmath58 km s@xmath1 . in the case of an isotropic velocity dispersion tensor , @xmath59 km s@xmath1 . the first case yields @xmath60 ; the latter leads to @xmath61 . the velocity width ( w20 ) of the hi 21 cm emission of this galaxy is @xmath62 km s@xmath1 . this corresponds to a circular velocity @xmath63 km s@xmath64 km s@xmath1 ( buyle et al . , in prep . ) , sitting comfortably between the two extreme values derived from stellar kinematics . we will adopt it here as our best - guess value . using these numbers , we estimate the total dynamical mass within a 5 kpc radius at @xmath65 m@xmath66 . with a total b - band absolute magnitude m@xmath67 mag ( buyle et al . , in prep . ) , logarithm of the peak circular velocity @xmath68 , logarithm of the central velocity dispersion @xmath69 , sits exactly on the tully - fisher ( @xcite ) relation for elliptical and s0 galaxies @xcite . it is slightly offset from the e / s0 faber - jackson relation @xcite , being almost @xmath70 mag too bright in the b - band for its velocity dispersion . in fig . [ figfp ] , we present the fundamental plane ( fp , @xcite ) in @xmath71-space @xcite . on the @xmath72 vs. @xmath73 plot ( the plane s `` face - on view '' ) , the distinct regions are occupied by dwarf @xcite and intermediate luminosity and giant early - type galaxies @xcite . the latter region is extended towards the upper - left corner of the plot by low - luminosity bulges and compact elliptical galaxies with m59co @xcite being the most extreme case . , indicated by the red filled circle , falls in the region occupied by high - surface brightness low - luminosity bulges and ellipticals . since the fp is defined for early - type galaxies ( e / s0 ) assumed to be virialised systems , we should include the rotational energy into the total balance at a first approximation as @xmath74 . this moves to the position indicated by the end of the green vector in fig [ figfp ] , toward the locus of bright e / s0 galaxies . in the stellar population maps , we clearly see a barely resolved core with a shape and size similar to that of the central @xmath28-bump . the galaxy center reaches a significantly super - solar metallicity , up to @xmath75 dex . the central ssp - equivalent age is 650 myr , increasing to approximately 3 gyr at 3@xmath11 from the galaxy nucleus . the starburst region , where the very young population resides , is about 2 arcsec ( 2.5 kpc ) across . @xcite observed using long - slit spectroscopy and found large h@xmath76 equivalent widths out to 2.5 arcsec . the vimos data confirm the existence of an extended region showing a young stellar population , although the positive age gradient is significant . for a comparison with the sdss dr6 spectrum @xcite of this galaxy , we integrate the light in the data - cube inside a 3@xmath11 circular aperture and apply the full - spectrum fitting technique to both spectra . we find excellent agreement : all the kinematical and stellar population parameters , including @xmath18 , are consistent within the uncertainties . we fit the brightest emission line ( [ oiii ] @xmath77 ) with a gaussian to determine its amplitude ( see fig [ figspec]a ) . unfortunately , no precise measurements of radial velocities can be made due to the very low emission - line flux . the [ oiii ] emission is very centrally concentrated , arguing for the presence of a spatially unresolved emitting region . careful inspection of the fitting residuals in the central region ( fig [ figspec]b ) reveals barely - detectable emission in the forbidden [ ni ] line ( @xmath78 ) , which is a typical signature of a liner or agn . we therefore connect the central peak of the [ oiii ] distribution to possible nuclear activity . fitting the sdss dr6 spectrum in the full wavelength range of pegase.hr ( @xmath79 ) and subtracting the best - fitting template from the data reveals strong emission lines in h@xmath80 and [ nii ] ( @xmath81 ) . the high @xmath82n ii@xmath83/h@xmath84 and @xmath82o iii@xmath85/h@xmath86 ratios support the liner interpretation @xcite . this would make the second well - studied psg to date in which low - power nuclear activity has been detected @xcite . as proposed by @xcite , agn feedback may play a crucial role in quenching star formation in massive psgs by expelling the gas . @xcite find that most of the hi gas in the binary psg system ea01a / b resides _ outside _ the stellar bodies of the galaxies , suggesting a feedback process powerful enough to physically displace large quantities of gas , such as agn feedback @xcite . at the same time , the faint h@xmath32 and [ oiii ] ( @xmath87 ) emission lines are detected almost everywhere out to @xmath88 from the galaxy centre , suggesting weak ongoing star formation over a large part of the galaxy . the distance to corresponds to a light travel time of @xmath89 myr . we estimate its @xmath90-band luminosity evolution using the pegase.2 @xcite evolutionary synthesis code . if we imagine evolving passively during this period , it will fade by , at maximum , 1 mag if all its stars formed 700 myr ago . in the more plausible case of a composite stellar population , the effect on the total @xmath90 magnitude will be even smaller , because the old population evolves slower than the young one , which has a lower mass fraction . this will make resemble present - day intermediate - luminosity early - type galaxies ( e / s0 ) in its position on the faber - jackson relation , the kormendy relation @xcite , and the fundamental plane ( see red vector in fig [ figfp ] ) . 4@xmath11 , or @xmath91 , encloses about 75 % of the light , resulting in a mass - to - light ratio of @xmath92 in solar units . after 700 myr of passive evolution , this will have increased to @xmath93 , at maximum . this is compatible with present - day early - type galaxies @xcite . turns to be a fast rotator if one applies the recently proposed classification @xcite . however , despite its regular morphology , given the presence of a dominating large - scale dynamically cold disc , we should not classify this object as a typical early - type galaxy . major mergers and interactions may lead to strong , abruptly truncated star formation episodes , as shown statistically using numerical simulations by @xcite , resulting in the e+a phenomenon . such violent events heat and often even completely destroy the discs , leaving little opportunity to explain the observed velocity field of . on the other hand , a minor merger of a large disc - dominated lenticular or early - type spiral with an intermediate - mass gas - rich satellite may be an acceptable explanation : young stars will actively form in the disc from the accreted intermediate - metallicity ism while the central star formation peak will consume the metal - rich gas often present in the circumnuclear regions of early - type galaxies . given the presence of neutral gas @xcite , the quenching of star formation in could very well be a transient phase . for instance , the gaseous component could have been dispersed by supernova or agn feedback and may re - accrete after several hundred myrs , possible restarting the star formation . if this object had been observed during a star - forming episode , it would have been classified as a barred late - type spiral ( sbcd ) . deep hi radio observations have led to the detection of 21 cm emission in about 60 per cent of the targeted psgs @xcite . some of the detected psgs are as gas - rich as local lirgs and mergers , possible progenitors of psgs in the local universe @xcite . the presence of large quantities of gas indicates that many psgs might actually be observed during an inactive phase of the star - formation duty cycle . this suggests that the evolution from blue to red galaxy may encompass several cycles back and forth in the colour magnitude diagram before the galaxy finally settles on the red sequence . our study makes use of sdss dr6 . funding for the sloan digital sky survey ( sdss ) and sdss - ii has been provided by the alfred p. sloan foundation , the participating institutions , the national science foundation , the u.s . department of energy , the national aeronautics and space administration , the japanese monbukagakusho , and the max planck society , and the higher education funding council for england . the sdss web site is http://www.sdss.org/. the sdss is managed by the astrophysical research consortium ( arc ) for the participating institutions . the participating institutions are the american museum of natural history , astrophysical institute potsdam , university of basel , university of cambridge , case western reserve university , the university of chicago , drexel university , fermilab , the institute for advanced study , the japan participation group , the johns hopkins university , the joint institute for nuclear astrophysics , the kavli institute for particle astrophysics and cosmology , the korean scientist group , the chinese academy of sciences ( lamost ) , los alamos national laboratory , the max - planck - institute for astronomy ( mpia ) , the max - planck - institute for astrophysics ( mpa ) , new mexico state university , ohio state university , university of pittsburgh , university of portsmouth , princeton university , the united states naval observatory , and the university of washington . , i. , prugniel , p. , silchenko , o. , & koleva , m. 2007 , in iau symposium , vol . 241 , stellar populations as building blocks of galaxies , ed . a. vazdekis & r. r. peletier ( cambridge , uk : cambridge university press ) , 175176

we present the first 3d spectroscopic observations of a nearby h i detected poststarburst , or e+a , galaxy , , obtained with the vimos ifu spectrograph at eso vlt . using the nbursts full spectral fitting technique , we derive maps of stellar kinematics , age , and metallicity out to 23 half - light radii . our analysis reveals a large - scale rapidly rotating disc ( @xmath0 km s@xmath1 ) with a positive age gradient ( 0.6 to 1.5 gyr ) , and a very metal - rich central region ( [ fe / h]=+0.25 dex ) . if a merger or interaction is responsible for triggering the starburst , the presence of this undisturbed disc suggests a minor merger with a gas - rich satellite as the most plausible option , rather than a disruptive major merger . we find spectroscopic evidence for the presence of a liner or agn . this is an important clue to the feedback mechanism that truncated the starburst . the presently observed quiescent phase may well be a temporary episode in the galaxy s life . is gas - rich and may restart forming stars , again becoming blue before finally settling at the red sequence .

the classification of `` active '' galaxies based on their optical spectra alone provides an incomplete or even deceiving description of the true nature ot this class of objects . in some `` classical '' starburst galaxies , x - ray and vlbi observations have found indications for the presence of an active galactic nucleus ( agn ) @xcite . mid - infrared ( mir ) spectroscopy with iso has shown that some galaxies , which were optically classified as agns , are in fact dominated by starbursts . conversely , the presence of a heavily obscured agn was revealed in some systems previously classified as starburst @xcite . mid - ir observations are particularly useful for detecting dust - enshrouded agns for a number of reasons . most importantly , the mir is much less affected by dust extinction than , e.g. , the optical regime ( @xmath2 , * ? ? ? while the extinction is even lower at far - ir wavelengths , warm dust emission in the @xmath3 regime can be powered both by agns and starbursts and is therefore not distinctive of the nature of activity . in contrast , significant emission from hot dust at wavelengths between 2 and @xmath4 is generally characteristic of heating by an active nucleus @xcite . finally , the mir allows diffraction - limited , arcsecond - scale imaging from large ground - based telescopes , in contrast to observations at far - ir wavelengths which have to rely on space observatories with limited aperture sizes and hence limited resolution . as a case in point , mir spectroscopy with iso is often unable to detect the nuclear hot dust emission , since the host galaxy and circumnuclear starburst emission dilute the nuclear agn emission in the large beam of the iso observations . a classical example is ngc4945 . this galaxy hosts one of the brightest agns at @xmath5 , although the x - ray source is heavily absorbed ( @xmath6 , * ? ? ? however , both optical and near - ir data do not show any indication for the presence of the active nucleus and appear , instead , dominated by a powerful nuclear starburst along with its superwind cavity @xcite . even the mir iso spectra appear dominated by the starburst @xcite . because of the reasons outlined above , sensitive mir observations with high spatial resolution hold the promise to identify heavily obscured agns within starburst galaxies , even if they are missed in optical and near - ir imaging and/or in iso spectroscopy , both because of heavy obscuration or dilution by the nuclear starbursting activity . if such mir observations were to find that the fraction of galaxies with agns is significantly higher than estimated from optical , near - ir , or iso mir surveys , it would provide support to the idea of a connection between starbursts and agns , which has been suggested by various studies @xcite . the observations described here were carried out with maniac , the mid- and nearinfrared array camera @xcite . the data were taken during a four week period in february / march 1998 at the eso / mpi @xmath7 telescope in lasilla , chile . most galaxies were observed during multiple nights with varying integration times . table [ tbl - obs ] summarizes the target list and observational parameters . all galaxies were observed through the maniac n - band filter which comprises the spectral region between 8 and @xmath8 . we employed standard chopping and beam switching techniques to account for the high and rapidly variable sky emission in the mid - infrared regime . in brief , a large number of frames with typical integration times of a few milliseconds are co - added in a hardware buffer for both the on - source and off - source chopper position . both buffer sums are saved to the maniac control pc after typically 30 s , corrected for bad pixels , and subtracted from each other . we offset the telescope by exactly one chop throw about every minute to correct for the slightly different illumination patterns in the two chop beams . because most of our objects are fairly compact , we decided to keep the chop throw small enough that the `` off '' beams still fell on the chip . subtraction of the two difference images images obtained at both beam positions then yields a triple image of the source in which the thermal background from sky and telescope is reduced to about @xmath9 . this procedure , which has been described in more detail in @xcite , improves the signal to noise ratio for a given integration time , since the `` off '' beam images can be combined with the center image . however , in the case of an extended source , overlap of the negative beams with the center image can cause confusion . while there are algorithms that can recover the information in the overlap regions @xcite we did not attempt to employ such reconstruction methods because we are mainly interested in the nuclear , often unresolved , source for which this problem is not important . since the data for many of our targets were taken over several nights with varying seeing conditions , we smoothed the maps of the individual nights to the worst nights seeing profile by convolving with appropriate gaussians . the maps then were shifted to a common center position , and median combined . images taken under the best seeing conditions were used to determine the upper limits on the size of the point - like nuclear source for each object ( see table [ tbl - obs ] ) . in order to discriminate between the flux of the unresolved nuclear source and the underlying extended emission , we constructed a mean point spread function ( psf ) from standard star images close in time to the respective galaxy observations during each night . more specifically , we weighted the standard star images by each night s effective integration time on the galaxy before averaging . we then scaled the resulting `` galaxy specific '' psf appropriately to subtract the nuclear source , and derived the integrated flux . the scale factor was determined such that no residual unresolved emission remained after subtraction while assuring a smooth interpolation of the underlying extended emission ( if present ) . the quality of the subtraction of the point source and remaining uncertainties were assessed by inspecting the images . table [ tbl - photometry ] lists the calibrated fluxes of both emission components of all target galaxies together with their @xmath10 uncertainties . the uncertainties include contibutions from the absolute calibration , background level , and psf fitting . flux calibration of the data was performed via observations of the stars @xmath11 vel and @xmath12 cru , with assumed n - band magnitudes of -1.78 and -3.36 , respectively . we have adopted the vega - based photometric system , with the n - band zeropoint corresponding to @xmath13 . the objects observed with maniac were selected to have at least some indications of nuclear ( seyfert ) activity and non - negligible mid - ir emission . more specifically , we selected observable `` active '' nuclei whose central 10@xmath14 m emission is brighter than @xmath150.3 jy based on previous ground - based observations ( @xmath16 aperture , e.g. * ? ? ? * ) . we present the resulting n - band maps of our sample of galaxies in figure [ fig - maps ] . table [ tbl - photometry ] summarizes the n - band photometry of the unresolved nuclear component and of the extended emission ( if present ) as derived from these images . we also list in table [ tbl - photometry ] literature values for the visual extinction towards the central region as inferred by various indicators such as narrow emission lines , pah features and near - ir colors of the stellar population which typically trace the extinction on scales of a few hundred pc . more details on our extinction estimates are given below in the discussion of individual objects . the adopted extinction values were used to derive the unobscured n - band flux of the nuclear point source by assuming that it is affected by the same reddening as the circumnuclear region . we caution , however , that in the context of the unified model for seyfert nuclei , the @xmath4 emission is believed to originate from an obscuring torus on scales much smaller than the circum - nuclear starburst , typically a few pc ( e.g. * ? ? ? therefore , the extinction values table [ tbl - photometry ] more likely represent lower limits for the true extinction towards to mir emission . this issue is discussed further in [ subsec : correlation ] . in addition , table [ tbl - photometry ] contains x - ray fluxes in the @xmath17 energy band . these were taken from the literature , and typically have been corrected for the photoelectric absorption as measured in the same band . details are again given in the discussion of the individual objects below . the extinction inferred from the optical and ir indicators is generally much lower than that derived from gas column densities as measured in the x - rays by assuming a galactic dust - to - gas ratio and extinction curve . this effect is at least partly due to the larger size of the region sampled by optical and ir indicators as discussed above ( few @xmath18 ) compared to the nuclear x - ray source and the putative obscuring torus . also , various pieces of evidence suggest that the dust in the circumnuclear region of agns is characterized by properties significantly different from the galactic diffuse interstellar medium which is most likely the reason for the reduced @xmath19 ratio commonly observed in this class of objects @xcite . in what follows , we briefly discuss the n - band morphology as derived from the maps in figure [ fig - maps ] , the x - ray data , and extinction estimate of all sample targets on an individual basis . ngc1808 is a morphologically peculiar starburst galaxy @xcite , which has being suspected of harbouring a hidden seyfert nucleus @xcite . in particular , the decline of the hard x - ray flux suggests that the nuclear activity has been gradually fading during the past few years @xcite . our n - band image shows a pronounced nucleus sourrounded by strong extended emission . the extended emission can safely be attributed to the extended starburst @xcite . the total n - band flux within @xmath20 is in excellent agreement with the @xmath21 iras flux of @xmath22 . the nuclear point source only accounts for less than 8% of the total flux . ngc4945 is a bright infrared galaxy revealing a powerful starburst in its nuclear region @xcite . evidence for a heavily obscured agn comes from hard x - ray observations @xcite . however , ngc4945 is peculiar in that the the agn has not yet been succesfully traced , neither in the nir @xcite nor in the mir @xcite . so far , the role of the agn for the bolometric luminosity has remained unclear . our n - band image reveals for the first time an unresolved point source at the nucleus of ngc4945 together with strong extended emission along the major axis of the galaxy . the extracted observed n - band flux of the central source is only 8% of the total n - band flux of ngc4945 , which has been determined within an ellipse @xmath23 tilted to match the major axis of the galaxy ( table [ tbl - photometry ] ) . our total n - band flux within this area is consistent with iso observations @xcite . the low value for the nuclear emission in conjunction with the dilution of the much larger iso beam explains why iso has not detected the agn . the extinction towards the central region can be assessed from mir data . @xcite and @xcite determined the spatially averaged ( @xmath24 ) extinction towards the circumnuclear starburst and find @xmath25 within a 50% error . this value is probably a lower limit since usually the foreground extinction rised towards the nucleus . indeed , the nuclear ( @xmath26 ) isocam spectrum of ngc4945 indicates a much higher extinction , based on the ratio of the 6.2@xmath14 m and 7.7@xmath14 m pah features @xcite . here , we adopt @xmath27 with an uncertainty of 40% . circinus is the closest _ bona fide _ seyfert 2 galaxy . it is characterized by a prominent ionization cone , extending to the north - west , and by a circimnuclear starburst ring with a radius of about @xmath28 , i.e. @xmath29 @xcite . the active nucleus of circinus is heavily obscured by a large column density of gas ( @xmath30 , * ? ? ? the n - band map of circinus is dominated by the central nuclear point souce . its flux is so high that limits in the bandwidths of the electronic detector readout circuitry result in a notable elongated shadow of the nucleus towards south . since the emission morphology can not be reliably determined over the affected area , it has been masked out in the image . the eastern and western boundaries of the image are defined by residual signals from the negative beams due to chopping and nodding , which have also been masked out . our image also shows circumnuclear n - band emission , which has not been detected previously . this continuum emission is rather smothly distributed but shows a shallow peak with a flux level of @xmath31 offset by @xmath32 from the nucleus . this position coincides with the intersection of the major axis and the circumnuclear ring where a region of intense star formation is found @xcite . perpendicular to the major axis of circinus , in particular towards the north - west the region of the cone of the nlr @xcite , we find significantly less extended emission . subtracting a stellar psf from the radial profile of the nuclear source reveals a small deviation from the psf profile , peaking at about @xmath33 at a radius of @xmath34 ( figure [ fig - profile ] ) . given the limited spatial resolution of our images this possible extended emission needs to be confirmed at higher spatial resolution . however , it can not be explained by seeing - induced broadening of the psf . at a distance of @xmath35 , centaurus a is one of the closest agns in our sample , along with ngc4945 and circinus . the presence of a hidden active nucleus is revealed both through its hard x - ray emission and the presence of a radio jet @xcite . the notion of an agn in centaurus a is also supported by our n - band image which only reveals a prominent unresolved central source ( not shown in figure [ fig - maps ] ) . while @xcite found extended mir emission from iso observations , our high resolution image is not sensitive to such diffuse emission on scales much larger than the maniac field of view . nevertheless , the photometry of the nuclear source is unaffected from this uncertainty because it is measured differentially against the background . our n - band image of ngc6240 was obtained during an earlier observing run in 1997 . it is dominated by the two nuclei of the well known merger system ( e.g. * ? ? ? * ) which are just resolved in our map . the southern nucleus is about twice as bright as the northern one ( table [ tbl - photometry ] ) . the low - level structure in our map does indicate the presence of faint extended emission in the vicinity of the nuclei , consistent with @xcite . however , its contribution to the overall flux is only minor . for flux calibration , we used the photometry of @xcite , since the maniac calibration was not yet well established for these earlier observations hard x - ray observations provide evidence for the presence of a powerful agn which is heavily absorbed by a column density of @xmath36 @xcite . their absorption - corrected @xmath17 luminosity is @xmath37 ( @xmath38 ) which places this object in the qso luminosity range @xcite . the n - band map of ngc3081 reveals a point source which is most likely due to dust emission associated with the seyfert 2 nucleus . any extended emission is below our detection limit , even if integrated over an aperture of 25@xmath39 in diameter ( table [ tbl - photometry ] ) . assuming that the foreground extinction is comparable to values determined by @xcite from nir lines towards the narrow line region , we adopt @xmath40 . the image of ngc3281 is also dominated by a point source . in addition , there is marginal evidence for an extended emission component in our map . while its detailed morphology is probably not reliable , the residual flux within a 25@xmath39 aperture after subtraction of the unresolved component is about 13% of the point source flux . despite the uncertainties in the zero level of the map , this is significant . if true , the integrated extended emission puts an upper limit to the extended flux per beam to about @xmath41 , which is more than 1000 times fainter than the nucleus . our n - band flux density is consistent with j through m photometry by @xcite . ngc1566 , the brightest member of the doradus group , is an almost face on spiral galaxy with a seyfert nucleus . the exact classification , however , varies in the literature between seyfert 1 ( e.g. * ? ? ? * ) and seyfert 2 ( e.g. * ? ? ? our n - band map ( not shown in figure [ fig - maps ] ) reveals a point source with no significant circumnuclear emission above our sensitivity limit . for ngc1566 , no @xmath17 data are available . from einstein data , @xcite determine a @xmath42 flux of @xmath43 ( converted to our h@xmath44 ) . @xcite do not find evidence for foreground absorption in excess to the galactic value , based on rosat data . by extrapolating the @xmath42 flux to the @xmath17 band with a typical photon index of 1.7 , we obtain @xmath45 , where the large errors account for the uncertainty in the spectral slope . in order to compare the mir and x - ray properties of seyfert galaxies with those of prototypical starburst galaxies , we searched the literature for additional objects with both high resolution mir images and hard x - ray fluxes . table [ tbl - comp ] lists the results of our search including the references that contain the relevant data . some of the objects ( ngc7552 and ngc253 ) have also been observed with the maniac camera , and have been reduced in an identical fashion . in general , there is a scarcity of high - resolution mir maps of starburst galaxies , a fact that is likely to change in the near future due to the comissioning of a number of large ir telescopes such as gemini or the large binocular telescope . specific aspects of the objects in table [ tbl - comp ] are discussed in the appendix . generally , the mid - ir continuum emission from the central region of agns is ascribed to thermal emission from dust which is irradiated by the nuclear uv - optical radiation , and possibly associated to the obscuring torus postulated by the unified model @xcite . typical dust temperatures are about 300 k. for the luminosities of most of the seyfert nuclei considered here ( @xmath47 of a few times @xmath48 ) an equilibrium temperature of about @xmath49 is reached at a distance of a few pc from the nuclear source @xcite . with our high signal - to - noise mid - ir images we can set an upper limit of about @xmath50 on the size of the nuclear unresolved source , which corresponds to a projected size of @xmath51 ( for circinus , cena , ngc4945 ) , @xmath52 ( for ngc1808 , ngc1566 ) , and between @xmath53 and @xmath54 for the more distant targets , i.e. consistent with the size of the warm dust emitting region discussed above . compared to normal and sb galaxies , agns are generally very effective in heating dust to temperatures high enough to emit at mid - ir wavelengths @xcite . as a consequence , the detection of an unresolved mid - ir source in the galactic nucleus is generally a good indication for the presence of an agn . in this regard , the identification of nuclear unresolved mir emission in our n - band maps of ngc4945 , ngc3081 , ngc3281 , and ngc1566 is a case in point . in particular , all previous attempts to detect the nucleus of ngc4945 have remained unsuccessful , even at nir wavelengths @xcite . on the other hand , the presence of an unresolved mir nucleus alone is not necessarily a proof for the presence of an agn . starburst galaxies may also harbor unresolved nuclear emission . for example , both ngc7552 and ngc1808 have nuclear point sources in the mir , yet they show no signs for an agn ( see discussion below ) . in summary , detecting and isolating the nuclear @xmath4 flux provides a necessary prerequisite to further constrain the nuclear activity of galaxies , but it alone is not sufficient to distinguish between various kinds of nuclear activity . the x - ray emission from agns is generally assigned to the nuclear engine itself . the strong uv / optical continuum radiation is believed to be responsible for heating the circumnuclear dust , which in turn is the source of the nuclear mir emission via thermal radiation . therefore , a correlation between x - ray and mir nuclear radiation in agns would be a natural result . in most type 2 seyferts , large column densities of cold gas along the line of sight absorb the soft x - ray flux . in particular , the superposition of the absorption edges of various metals introduces a photoelectric cutoff towards the lower energies . the energy of the cutoff increases with the gaseous column density along the line of sight . however , as mentioned above , at energies above the photoelectric cutoff ( generally in the range @xmath1 ) , it is possible to observe the transmitted radiation and to infer the intrinsic ( absorption - corrected ) luminosity of the nuclear source @xcite . if the absorbing column is thick to compton scattering ( @xmath55 ) , the radiation is completely absorbed up to at least @xmath56 . therefore , the traditional `` hard '' x - ray band between 2 and @xmath56 is dominated by scattered and reflected radiation . if the column density is not higher than about @xmath57 , x - rays in the @xmath58 band are at least partly transmitted , and can indeed be observed with x - ray satellites sensitive in this band ( e.g. bepposax ) . in such cases , the intrinsic x - ray luminosity of the nuclear source can be inferred . examples for this method include ngc4945 , circinus , or ngc6240 @xcite . in contrast , the @xmath17 emission of starburst galaxies without an agn is mainly produced by young supernova remnants , x - ray binaries and/or hot diffuse gas , the latter possibly produced in supernova induced superwinds @xcite . however , the cumulative hard x - ray emission of these components is significantly weaker than the emission produced by agns ( e.g. * ? ? ? * ) . on the other hand , the young stellar population in starburst galaxies is quite effective in heating the dust which radiates mir thermal emission and in exciting the pah features which also contributes significantly to the mir observed flux . therefore , a comparison of the nuclear @xmath4 emission with the intrinsic ( i.e. absorption - corrected ) nuclear @xmath17 x - ray flux should allow to discriminate between star formation and active nuclei . in practice , however , one has to account for an additional complication . the nuclear component of the @xmath17 radiation can not be determined with the same spatial resolution as the nuclear @xmath4 emission , because the angular resolution of satellites with hard x - ray sensitivity such as asca or bepposax is limited to @xmath59 , so that in cases where both starburst and agn activity is present , the x - ray measurements may contain contributions from both sources . for his reason one has to be cautious when determining the nature of these nuclei based on @xmath17 data alone . only the combination of nuclear mir and hard x - ray emission seems to provide a reliable tool for constraining the nature of the nuclear activity of theses sources , as demonstrated in the next section . in figure [ fig - plot ] , we compare the @xmath4 flux density of the unresolved nuclear component to the observed x - ray fluxes in the @xmath17 band after correction for their respective absorptions . the error bars account for uncertainties in the photometry itself and in the estimates for foreground extinction ( see table [ tbl - photometry ] ) . figure [ fig - plot ] shows that , within the statistical limits of our sample , the nuclear mir flux density of type 2 seyferts is proportional to the intrinsic hard x - ray flux . four other seyfert 1 galaxies , for which we found comparable data ( ngc7469 , ngc4051 , ngc4151 and ngc3227 ) , follow the same correlation , which is robust against modifying single values by factors of the order of 2 . a similar correlation holds for the starburst galaxies , however , their hard x - ray flux is about a factor of 15 less than for seyferts . the straight lines in figure [ fig - plot ] are linear fits to the data which have been forced to cross the origin . ngc6240 lies significantly above the correlation and will be discussed further down . the proportionality between the n - band and x - ray flux densities in figure [ fig - plot ] is encouraging . the correction on the x - ray emission is quite accurate : even in the most extremely obscured cases ( ngc4945 , ngc6240 ) the uncertainty is below a factor of 2 , which is small when reported on a logarithmic scale . in previous attempts to find similar correlations between x - ray and mir / fir fluxes ( e.g. * ? ? ? * ; * ? ? ? * ) , no correlation had been found or the scatter was much larger , mostly due to lack of spatial resolution and sensitivity . having established the existence of a correlation in flux , we can now convert to luminosities in order to investigate correlations between intrinsic properties of the galaxies . by doing so , i.e. multiplying the mir and x - ray fluxes of each object in both axis by the square of the distance and some factors , the data points in figure [ fig - plot ] will be rearranged parallel to the solid line , thus conserving the scatter of the correlation . the result is displayed in figure [ fig - lum ] . within the uncertainties and excluding ngc6240 for the moment , the distribution is still compatible with a slope of 1 ( solid line in figure [ fig - plot ] ) , covering more that 3 orders of magnitude in luminosity . the location of ngc6240 in figure [ fig - lum ] is above the correlation for the other seyfert galaxies . more specifically , is is overluminous in hard x - rays by about an order of magnitude . possibly , the dust extinction towards the nucleus of ngc6240 is much higher than assumed based on nir colors @xcite . indeed , ngc6240 is the most distant object of our sample and the observations sample larger spatial scales ( @xmath15kpc ) . it is therefore likely that extinction estimates are diluted by regions farther from the nucleus with lower optical depths and that the intrinsic mid - ir emission of ngc6240 is higher than derived from our data . thus , a much larger fraction of the radiation of the very hot dust may already have been reprocessed and shifted to longer wavelengths before it left the nuclear environment . a foreground extinction in the range a@xmath60 mag is required to increase the dereddened nuclear n - band emission such that ngc6240 complies with the correlation of the other agns . the nuclear @xmath4 fluxes were corrected for the extinction observed in the circumnuclear region as inferred from either nir color maps , recombination line ratios or from the ratio between pah features . the fact that the tight correlation between @xmath4 and x - ray fluxes appears to be the same for both seyfert types indicates that the @xmath4 emission from the nuclear source is not affected by an extinction much higher than inferred for the circumnuclear region . this indicates that either the @xmath4 emitting region is more extended than the putative obscuring torus predicted by the unified model for agns , or that the optical depth of the torus is not much higher than that of the circumnuclear region for these objects . this result appears to be in contradiction with previous studies which claimed significant differences in the nuclear @xmath4 emission between obscured and unobscured seyferts @xcite . this discrepancy can probably be explained by limited angular resolution and sensitivity of those earlier studies . an alternative explanation which is likely to important at least to some extent stems from the selection criteria of our sample . because the maniac targets were selected to have strong nuclear mir emission , the sample is potentially biased towrads agns which are little absorbed at this wavelength . therefore , possible differences between different classes of seyferts in terms of their mid - ir absorption might have been missed . additional high resolution mir observations of seyfert nuclei are required to solve this issue . the x - ray emission from the comparison sample of pure ( to present knowledge ) starburst nuclei in figure [ fig - lum ] is significantly lower and appears to follow a line with a slope different from proportionality . we caution that the apparently different slope might be caused by the small number statistics of our sample . on the other hand , it can plausibly be explained by the very different aperture sizes that were used for the measurements : about @xmath61 for the n - band and between @xmath62 and about @xmath63 for the x - rays . thus , for starburst galaxies , one would measure hard x - rays from almost the entire extended starburst region , but only a distance - dependent fraction of the n - band emission . in support of this argument , we note that using a larger aperture for the mir measurement , e.g. the @xmath64 iras luminosity from table [ tbl - comp ] , the proportionality slope appears to be restored ( although at increased scatter ) , as shown in figure [ fig - lum ] on the lower right . the vertical distance between the two proportionality lines is a factor of 190 , which indicates the different physical processes that prevail in these two classes of objects . more specifically , classical starburst galaxies appear to have x - ray fluxes that are a large factor of almost 200 below those of agns with similar @xmath4 emission . yet , we can not completely rule out that the nuclear unresolved @xmath4 source in some of the starburst nuclei ( e.g. ngc 7552 ) is the counterpart of a heavily obscured agn . indeed , if the nuclear obscuring medium is completely compton thick ( @xmath65 ) , the @xmath17 emission from the agn would be completely suppressed and instead be dominated by the starburst radiation . an important result of our study is that in figure [ fig - plot ] , ngc4945 definitely falls into the region occupied by agns , despite the rather large uncertainty of its intrinsic @xmath4 flux . this result suggests that the unresolved nuclear mir source is indeed powered by the obscured active nucleus detected in hard x - rays . the position of ngc1808 in the regime of starburst galaxies suggests that the active nucleus in this galaxy - if present at all - has faded @xcite . currently , the x - ray and mir emission are instead dominated by an ( unresolved ) circum - nuclear starburst . it is also interesting that the archetypical starburst galaxy m82 falls into the regime of the seyfert nuclei . this statement is robust against any uncertainty in the x - ray flux due to the observed variability . in order for m82 to fall into the regime occupied by starburst nuclei , its x - ray flux should have to be a factor of 30 lower in figure [ fig - plot ] , certainly incompatible with observations . we therefore concluded that m82 is likely to harbor an agn , in agreement with @xcite and @xcite . meanwhile , subsequent observations with chandra at about @xmath66 spatial resolution suggest that a highly variable source about @xmath67 off the nucleus , which is dominating the hard x - ray flux , is compatible with a mid - mass black hole candidate @xcite . if this can be proven it would explain the location of m82 in figure [ fig - plot ] , since the same kind of physics is applied . in figure [ fig - lum ] , the n - band luminosity of the m82 black hole candidate has been corrected for the @xmath67 offset and slightly shifted its position . it is important to note that the position of m82 in the diagram largely depends on the mir aperture . this provides additional support for the argument already discussed with ngc4945 : a weak agn can easily be diluted and `` drowned '' in a large beam due to circumnuclear starburst activity . this demonstrates the need for observations with the highest possible spatial resolution if the correlation is to be extended towards more distant targets . otherwise , less luminous agns will be easily missed at higher distances . previous studies found evidence for extended mid - ir emission in seyfert 2 galaxies based on the comparison between ground - based observations and iras data @xcite . such extended emission is ascribed to enhanced star forming activity in the host galaxies of these obscured active nuclei . our images show such extended emission in most of the objects of our sample , thus supporting and reinforcing those early results , although with limited statistics . furthermore , our images indicate that generally the starforming activity occurs in the vicinity of the active nucleus ( within a few 100 pc ) . this supports the idea of a tight connection between starburst and agn activity as claimed in the past by various authors based both on observational and theoretical grounds @xcite . we have presented new n - band maps of a sample of 8 nearby seyfert galaxies . in all of our targets , we have identified an unresolved nuclear emission source , some of which were previously undetected . in those cases where additional extended emission is present , we have separated the unresolved component by means of psf fitting . this demonstrates the importance of high resolution mir imaging for detecting agn and isolating them from the extended emission component . after complementing our sample by literature data for a number of starburst galaxies and some additional seyferts , we have compared the mir luminosity of the nuclear sources to their hard x - ray emission . we find that both `` pure '' starbursts and agn follow a tight mir x - ray correlation , but the two populations are separated by about a factor of 15 without and 190 with aperture correction in their hard x - ray fluxes . we propose to use this correlation as a powerful diagnostic tool to distinguish between these two classes of objects in cases where evidence for nuclear activity is ambiguous . we are grateful to a number of people who have contributed significantly to the success of the maniac observing campaigns . in particular , we are indebted to john storey , craig smith , thomas lehmann , and gerd jakob . we also wish to thank the eso staff at lasilla for their support , and especially ueli weilenmann and hans gemperlein for help with the chopper control electronics . we thank the referee , bob joseph , for helpful comments to improve this paper . the nuclear emission of the starburst galaxy * ngc253 * was derived from the @xmath68 continuum image of @xcite which is in good agreement with that published by @xcite . we estimate the background level at the location of the nucleus of ngc253 to be of the order of 20% of the peak flux in figure 2 of @xcite , whereas the nucleus is at 40% of the peak flux in the figure . accounting for the fact that the spectral band of the data of @xcite is not identical with the n - band , we estimate the n - band flux to be @xmath69 . the nuclear emission of the prototypical starburst galaxy * m82 * was derived using the data of @xcite . from their figure 5 , we estimate that the upper limit to the contribution of the nucleus is @xmath70 , which corresponds to one contour spacing in their figure . the foreground extinction was estimated using @xcite and @xcite . m82 shows variable hard x - ray flux @xcite , which led these authors to speculate about wether m82 might be harboring an agn . we used the amplitude of the variability @xcite as a realistic value for the uncertainty of the x - ray flux level . the seyfert 1 galaxy * ngc7469 * was included in this list to compare with the seyfert 2 targets . taking into accout the differences in bandwidth and wavelength between @xcite and @xcite we obtain an n - band flux of the nucleus alone of @xmath71 . * ngc7552 * is a starburst galaxy with a prototypical circum - nuclear starburst ring seen in the near- and mid - infrared . the n - band map of @xcite also shows a faint nuclear source . we obtained the n - band flux of the nucleus from table 2a in @xcite , estimating that about 1/3 of the flux within @xmath61 are due to the background emission . @xcite determined an absorption corrected @xmath72 x - ray flux of @xmath73 , consistent with @xcite , who find variable fluxes in the range @xmath74 . they assumed a low absorbing column density consistent with the derived low @xmath75 number above . assuming a shape of the x - ray spectrum of ngc7552 similar to other starburst galaxies in @xcite , one can assess the @xmath1 flux to be about 1/3 of the @xmath72 flux or @xmath76 . * ngc3690 * is a merging system with an eastern and western component . the sum of their nuclear n - band fluxes can be obtained from @xcite . the @xmath17 hard x - ray flux is integrated over both nuclei , with only low foreground absorbing column density @xcite . individual hard x - ray fluxes for the two dominant components of ngc3690 are not yet available . however , the combined mid - infrared and hard x - ray fluxes of both nuclei can safely be used in this investigation since both nuclei show only starburst activity , without any evidence for an agn . the nuclear n - band flux of the starburst galaxy * ngc3256 * was determined to be 1.7 jy within @xmath77 @xcite and 1.9 jy within 14@xmath78 @xcite . however , according to the map in @xcite the nucleus is dominated by a point source sourrounded by notable extended emission within this aperture . we therefore adopt for the flux density of the nucleus alone 0.9 jy , which is about half of the value above . * ngc6946*:the background subtracted nuclear n - band flux density derived from the @xmath79 resolution map of @xcite is 250@xmath80 , assuming that the lowest contour reflects the background . n - band aperture photometry of different sizes by @xcite sums to @xmath81 within @xmath82 . therefore we average the n - band flux density to @xmath83 . the absorption corrected @xmath17 x - ray flux can be read off figure 2 and table 12 ( source s3 ) of @xcite . however , comparison of their data with rosat @xmath84 data of @xcite , in particular his figure 4 , clearly shows that the x - 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fienberg , r. , fazio , g.g . , gezari , d.y . , hoffmann , w.f . , lamb , g.m . , shu , p.k . , & mccreight c.r . 1987 , apj , 312 , 542 van bever , j. & vanbeveren , d. 2000 , a&a , 358 , 462 weaver , k. a. , yaqoob , t. , holt , s. s. , mushotzky , r. f. , matsuoka , m. , & yamauchi , m. 1994 , apj , 436 , l27 veron - cetty , m. p. & veron , p. 1985 , a&a , 145 , 425 vignati et al . 1999 a&a , 349 , l57 wilson , a.s , shopbell , p.l . , simpson , c. , storchi - bergmann , t. , barbosa , f.k.b . , ward , m.j . , 2000 , aj , in press yaqoob , t. & warwick , r. s. 1991 , mnras , 248 , 773 zezas , a. l. , georgantopoulos , i. , & ward , m. j. lcccccccc ngc1566 & 04 20 00.6 & -54 56 17 & 17.6 & 85 & sy1 & 02 - 98 & 24 & 1.1 + ngc1808 & 05 07 42.3 & -37 30 46 & 11.1 & 54 & sy2 & 02 - 98 & 56 & 1.1 + ngc3081 & 09 59 29.5 & -22 49 35 & 28.9 & 140 & sy2 & 02 - 98 & 125 & 1.3 + ngc3281 & 10 31 52.0 & -34 51 13 & 43.0 & 209 & sy2 & 02 - 98 & 48 & 1.0 + ngc4945 & 13 05 27.5 & -49 28 06 & @xmath87 & 18.9 & sy2 & 02 - 98 & 83 & 1.2 + cena & 13 25 27.6 & -43 01 09 & @xmath88 & 17.0 & sy2 & 07 - 97 & 10 & 1.1 + circinus & 14 13 09.3 & -65 20 21 & @xmath89 & 19.4 & sy2 & 02 - 98 & 54 & 1.1 + ngc6240 & 16 52 58.9 & + 02 24 03 & @xmath90 & 471 & sy2 & 07 - 97 & ? ? & 1.1 lccccc ngc1566 & @xmath91 & - & @xmath92 & @xmath93 & @xmath94 + ngc1808 & @xmath95 & @xmath96 & @xmath97 & @xmath98 & @xmath99 + ngc3081 & @xmath100 & - & @xmath101 & @xmath102 & @xmath103 + ngc3281 & @xmath104 & @xmath105 & @xmath106 & @xmath107 & @xmath108 + ngc4945 & @xmath109 & @xmath110 & @xmath111 & @xmath112 & @xmath113 + ngc5128 ( cen a ) & @xmath114 & - & @xmath115 & @xmath116 & @xmath117 + ngc6240 ( north ) & @xmath118 & - & @xmath119 & @xmath120 & @xmath121 + ngc6240 ( south ) & @xmath122 & - & @xmath123 & @xmath124 & @xmath121 + circinus & @xmath125 & @xmath126 & @xmath127 & @xmath128 & @xmath129 lccccc ngc253 & @xmath130 & @xmath131 & @xmath132 & @xmath133 & @xmath134 + ngc6946 & @xmath135 & @xmath136 & @xmath137 & @xmath138 & @xmath139 + ngc7469 & @xmath140 & @xmath141 & @xmath142 & @xmath143 + ngc7552 & @xmath144 & @xmath145 & @xmath146 & @xmath147 & @xmath148 + m82 & @xmath149 & @xmath150 & @xmath151 & @xmath152 & @xmath153 + ngc3690 & @xmath154 & @xmath155 & @xmath156 & @xmath157 & @xmath158 + ngc3256 & @xmath159 & @xmath160 & @xmath161 & @xmath162 & @xmath163 + ngc4051 & @xmath164 & @xmath165 & @xmath166 & @xmath167 + ngc3227 & @xmath168 & @xmath165 & @xmath169 & @xmath170 + ngc4151 & @xmath171 & @xmath172 & @xmath173 & @xmath174 +

we present new mid - infrared ( n - band ) images of a sample of eight nearby seyfert galaxies . in all of our targets , we detect a central unresolved source , which in some cases has been identified for the first time . in particular , we have detected the mid - infrared emission from the active nucleus of ngc4945 , which previously remained undetected at any wavelength but hard x - rays . we also detect circumnuclear extended emission in the circinus galaxy along its major axis , and find marginal evidence for extended circumnuclear emission in ngc3281 . the high spatial resolution ( @xmath0 ) of our data allows us to separate the flux of the nuclear point sources from the extended circumnuclear starburst ( if present ) . we complement our sample with literature data for a number of non - active starburst galaxies , and relate the nuclear n - band flux to published hard ( @xmath1 ) x - ray fluxes . we find tight and well - separated correlations between nuclear n - band flux and x - ray flux for both seyfert and starburst nuclei which span over 3 orders of magnitude in luminosity . we demonstrate that these correlations can be used as a powerful classification tool for galactic nuclei . for example , we find strong evidence against ngc1808 currently harbouring an active seyfert nucleus based on its position in the mid - infrared - x - ray diagram . on the other hand , we confirm that ngc4945 is in fact a seyfert 2 galaxy . # 1 ' '' '' # 1 ' '' '' # 1 ' '' '' _ # 1 _ ' '' ''

type ia supernovae are now used as fundamental probes of the cosmological parameters , based on a tight empirical relation between their peak luminosity and the width of their light - curve ( riess et al . 1996 , perlmutter et al . it has been recognized early than sn ia were not `` standard '' candles , since important variations of their peak luminosities are observed , as a function of metallicity , age , environment , morphological type of the supernovae hosts . but most of these variations can be calibrated , and corrected away , if the correlation between the peak luminosity and the rate of decline is taken into account ( phillips 1993 ) : the scatter in distances is then much reduced . the problem arises with evolution , since these effects are not known a priori , and could mimick a cosmological constant . + in particular the presence and nature of dust could vary with redshift , or the rate of supernovae explosions and their nature could vary systematically . a striking example of evolution of supernovae with redshift is the observation that high - z sn ia have bluer colours than local ones ( cf fig . 1 , leibundgut 2001 ) . this result is surprising , since it goes against extinction and reddening . to better understand the origin of these evolutions , we must know more on the progenitors of these sne , to predict age or metallicity effects . type ia supernovae are likely to be thermonuclear explosion ( by fusion of carbon and oxygen ) of white dwarfs having approached the chandrasekhar mass of 1.39 m@xmath1 ( cf the review by hillebrandt & niemeyer 2000 ) . their principal characteristic constraining models is their absence of hydrogen in their spectrum . they correspond to the total explosion of a carbon - oxygen white dwarf ( c+o wd ) . they must accrete mass through binary evolution ( since these wd are not massive enough at the beginning ) , and there are two possibilities : either two c+o white dwarfs merge ( double - degenerate model ) , in a time - scale of a few 100 myr , or only one c+o wd is accreting ( single degenerate ) , with a longer time - scale , a few gyrs , the most likely scenario . the merger scenario is not supported by the homogeneity of observed quantities , since the obtention of the critical mass by fusion introduces more freedom in initial parameters . the range of luminosities is assumed to be connected to the amount of radioactive @xmath2ni produced in the explosion , decaying to @xmath2co and @xmath2fe . the amount of nickel available can not vary by much more than a factor 2 . the merger scenario is supposed to lead to a collapse supernova instead . + recently , hydrogen ( broad h@xmath3 line ) has been discovered in a type ia supernova ( hamuy et al 2003 ) , which has been considered to support the single - degenerate progenitor . however , it could be interpreted as a double - degenerate case also ( livio & riess 2003 ) , and in any case is too rare to clarify definitively the issue . some of the observed variations could be due to the various time - scales and ages of the progenitors : the most luminous sn ia are found in spirals , the dimmest in ellipticals . the rate of sn ia has been estimated ( pain et al . 1996 , 2002 ) , and could bring insight into the problem : 6% of the stars between 3 - 9 m@xmath1 experience such an explosion . smaller carbon abundance of progenitors leads to dimmer type ia supernovae ( umeda et al 1999 ) . the c fraction varies between 0.36 - 0.5 just before the explosion . the mass of the progenitors are smaller at lower metallicity , and the model predicts dimmer sn at high z , with lower scatter . timmes et al . ( 2003 ) confirm that the peak luminosity should vary linearly with metallicity z , and this could already explain a scatter of 25% for a region like the solar neighborhood , where z varies between 0.3 and 3 solar . however , observations do not confirm this strong predicted influence of metallicity : in elliptical and s0 galaxies , where metallicity varies with radius , no significant radial gradients of sne ia peak absolute magnitudes or decay rates have been detected ( ivanov et al . the variations in brightness and light curve width of supernovae reveal high values , that are attributed more to age . once the light - curve shape method is applied , there does not remain any radial gradient of colours . this supports the validity of the empirical calibrations . + the effect of age could be partly due to metallicity ( stars being less metallic in the past ) , but also due to different explosions scenarios . at high redshift the progenitors were obviously younger , which favors the short - time scale double - degenerate scenario . however this explosion model leads to brighter sne , which is not observed . brightest objects have a slowly declining light curve . at high z no slow decline are observed , as if the brightest sn are not seen , ( contrary to the malmquist bias ) . the relation between the peak luminosity of sne ia and their initial rate of decline , is different in the various bands : the decline is faster in the b - band , than in v and i , and the colours at maximum depends on the decline rate ( phillips 1993 ) ; the fastest declining light curves ( the less bright objects ) correspond to the reddest events . all these characteristics are used to reduce the range of peak luminosities , and to approach the standard candle regime . various methods have been used by the two main teams , the supernova cosmology project ( scp , perlmutter et al 1997 ) , and the high - redshift supernova search team ( hzt , riess et al 1998 ) . the methods are ( see fig . 2 ) : + mlcs : multicolor light - curve shape ( hzt ) , calibrated on nearby sne ia in the local universe ( z @xmath4 0.15 ) , uses the color characteristics to estimate corrections for extinction and reddening due to material in the host galaxies ; + tf : template fit ( hzt ) uses several template curves , from peak to 15 days afterwards , to fit a particular high - z sn ia ; + sf : stretch factor ( scp ) : the shift in the peak magnitude is proportional to how much the light - curve width must be stretched to fit a standard curve . + what is striking in the comparison of the various methods in fig . 2 ( made by drell et al . 2000 ) is that the amount of corrections are quite different , and in particular the sf method corrections are very small , meaning that these sne ia are almost standard candles . the samples are different , although 14 objects are in common for the 3 methods . the study by drell et al . ( 2000 ) did not reveal any systematic differences in distances between the two methods mlcs and tf as a function of redshift ( only a scatter of about 0.4 mag ) , but a little dependence on absolute magnitude , for the high - z sample . + drell et al . ( 2000 ) made interesting simulation of cosmic evolution of sne , as for instance their peak luminosity varying slightly with ( 1+z ) linearly , and showed clearly how the determination of cosmological parameters and cosmic evolution is degenerate . with the number of high - z sne ia observed up to now , observing a larger number will not raise the degeneracy , but a better understanding of the explosion process is more needed . the possibility that intergalactic dust , distributed uniformly between galaxies , produce the extinction able to account for the dimming of high - z sne ia , has been investigated by aguirre ( 1999 ) and aguirre & haiman ( 2000 ) . the exctinction must not be accompanied by reddenning , which is not observed ( this must be gray dust ) . this hypothesis is compatible with the data , given that a large amount of gas is observed in the intergalactic space ( ly@xmath3 absorbants ) , and that the metallicity of the gas appears high ( 0.1 to 0.3 solar ) , a significant fraction of metals can be intergalactic . the grains have to be of large size ( @xmath5 0.1@xmath6 ) for the `` gray '' requirement . very small grains provide most of the reddening but less than half of the opacity for optical extinction . this gray dust would however absorb the cosmic uv - optical background and by re - emission , contribute significantly ( 75% ) to the cosmic infrared background ( cib ) . there are no measurable distortions of the cmb predicted , but the dust fir background is only marginally compatible with the data . also , this component is not detected by x - ray scattering ( paerels et al 2002 ) . the extinction could as well be provided by intervening galaxies , but this hypothesis appears unlikely also ( goobar et al 2002 ) . + extinction from host galaxies appears more likely , although high - z sne ia are not reddened , and apparently not obscured , according to their correction factors , which is difficult to explain , except through selection effects and malmquist bias ( farrah et al . the proportion of morphological types for the hosts do not show evolution : 70% are found in spiral galaxies and 30% in ellipticals , as for local events . the radial distribution of sne in their host galaxies is observed to be similar at low and high z , at least for the samples observed with ccd , but not with the samples discovered photographically ( shaw effect ( cf shaw 1979 ) , where the center of galaxies is undersampled in sne , howell et al . sne in the outer regions of galaxies are dimmer than those in the central regions by 0.3 mag ( riess et al . this could explain the anti - malmquist bias observed for high - z sne . another concording feature is that sne in early - type galaxies tend to be dimmer , and large - distance sne are in general in early - types ( hamuy et al . 1996 ) . physical explanations for the dependence of peak luminosity with radius might be searched in the metallicity gradient of the galaxy host , or in the possible different progenitors between disk and bulge ( age effect ) . sullivan et al ( scp , 2003 ) have recently studied in details coherent samples of sne ia , and their host morphologies . they built a hubble diagram ( fig . 3 ) according to the host types , omitting outliers ( too large stretch factors , highly reddened objects ) . the classification of the hosts is made from colours , hst images and spectral types when available , the evolution of colours with redshifts being compared to stellar population models ( poggianti 1997 ) . when stretch factors ( sf ) are compared for all types , early - types sf are more scattered . a striking feature is that sf are less scattered for high - redshift objects . this might be due to the age effect : at low redshift , stellar populations have a larger range of ages than at high z. + the hubble diagram shows more scatter for late - type hosts , which might be attributed to dust extinction , since there is more gas in late - type galaxies . there is also more scatter with sne discovered in the central parts of the galaxies , which confirms that the scatter might be due to dust . there is no or little evolution of the amount of dust extinction with redshift . the estimated average extinction suffered by sne ia is small ( a@xmath7 @xmath0 0.3 , but may be @xmath51 when all sne are considered , including outliers ) . this is consistent with what is expected from galaxies , where the mean exctinction is weighted by a small number of objects highly obscured . selection effects eliminate the more obscured sne . since the peak luminosity of sne varies with galaxy hosts , it is interesting to study the sne rates as a function of galaxy types , and evolution of types with redshift . as for core - collapse supernovae ( ccsn ) and in a less measure for sne ia , it is legitimate to expect a larger sne rate for starbursting galaxies . starburst galaxies are dusty , and this rate has been studied in the infrared ( mattila & meikle 2001 ; mannucci et al . the rate of supernovae in starburst galaxies is found to be about 10 times more than in quiescent galaxies . but it is still 3 - 10 times less than expected from the star formation rate ( sfr ) estimated with fir emission , which means that many sne are still obscured ( av @xmath5 30 ) . alternatively , the fir tracer of star formation might not follow closely the sn rate , as the latter is found also relatively too large in low - mass galaxies ( melchior et al other possibilities is that starburst and quiescent galaxies have different imf , leading to a different sn - rate / sfr ratio . + the type ia sn rate shows also a sharp increase toward galaxies with higher activity of star formation , suggesting that a significant fraction of type ia sne are associated with young stellar populations ( della valle & livio 1994 ; mannucci et al . this is important , in view of the large increase of star formation activity with redshift . + it is well known also that the supernova rates is strongly correlated with hubble types ( branch & van den bergh 1993 ; hamuy et al . late - type systems are more prolific in sne ia , but selection effects are severe , and it is difficult to disentangle effects of age and metallicity . large statistics are needed to better understand the evolution of star formation as a function of galaxy types , and in consequence the sn rate as a function of host type . large surveys of galaxies are currently carried out , and the first results on 10@xmath8 galaxies in the sloan digital sky survey ( sdss ) give already such statistics ( kauffmann et al 2003a , b ) . two stellar absorption line indices ( the strength of the 4000i break d@xmath9(4000 ) , and the balmer absorption line index h@xmath10 ) with the help of models , yield the amount of dust extinction , the stellar masses and the fraction of mass involved in bursts in the last 1 - 2 gyr . the distribution of dust attenuation ( cf fig . 4 ) reveals a median value of a@xmath11 = 0.3 , which corresponds in the b - band to a@xmath12 0.6 . there is as expected a broad wing at high extinction . 4 shows also that the extinction is higher for young and low - mass galaxies ( the index d@xmath9(4000 ) being an age index ) . + one of the most striking result of the survey is the bimodality in the distribution of galaxies , with a separation in mass of 3 10@xmath13 m@xmath1 . the surface density is a function of mass , as shown in fig . high - mass galaxies have also a high surface density , which is about constant ( hsb ) . the low mass galaxies are characterized by low surface brightness ( lsb ) , which is a power - law function of mass ( with a slope near 0.54 ) . the dependence of surface density with mass might well be interpreted as a lower efficiency of star formation at the low - mass end , due to supernovae feedback ( dekel & woo 2003 ) . lsb galaxies have younger stellar populations , low concentrations , and appear less evolved . the star formation history is more related to the stellar surface density than to the stellar mass . in the low - mass range , 50% of galaxies are likely to have recent bursts ( 10% with large certainty ) , while it is only 4% for high - mass galaxies . today , starbursts ( and sne ? ) mostly occur in dwarfs and lsb galaxies . it might not have been the case in the past , at high z ( kauffmann et al . sne ia are not exactly `` standard candles '' , but the shape of their light curve allows their calibration towards this goal . age and metallicity effects can then be corrected , and their evolution with redshift is being tested . there is a surprisingly low average obscuration for high - z sn ia , a@xmath7= 0.3 mag , twice lower than the average for galaxies , but this could be due to selection effects . + sne ia occur more frequently in spiral galaxies , and in outer parts of e / so galaxies . the scatter in their peak luminosities and in the correction factors is larger for late - types , which are likely to be more frequent at high redshift . this trend is however compensated by the smaller range in progenitor age , leading to less scatter at high z. the physics of sne ia explosions is not yet well known , but statistics as a function of metallicity and age of the host stellar populations should help to understand better the evolution of their properties . aguirre a. : 1999 , apj 525 , 583 aguirre a. , haiman z. : 2000 , apj 532 , 28 branch , d. , van den bergh , s. : 1993 , aj 105 , 2231 dekel a. , woo j. : 2003 , in press ( astro - 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it is of prime importance to recognize evolution and extinction effects in supernovae results as a function of redshift , for sn ia to be considered as distance indicators . this review surveys all observational data searching for an evolution and/or extinction , according to host morphology . for instance , it has been observed that high - z sne ia have bluer colours than the local ones : although this goes against extinction to explain why sn are dimmer with redshift until z @xmath0 1 , supporting a decelerating universe , it also demonstrates intrinsic evolution effects . + sne ia could evolve because the age and metallicity of their progenitors evolve . the main parameter is carbon abundance . smaller c leads to a dimmer sn ia and also less scatter on peak brightness , as it is the case in elliptical galaxy today . age of the progenitor is an important factor : young populations lead to brighter sne ia , as in spiral galaxies , and a spread in ages lead to a larger scatter , explaining the observed lower scatter at high z. + selection biases also play a role , like the malmquist bias ; high - z sne ia are found at larger distance from their host center : there is more obscuration in the center , and also detection is easier with no contamination from the center . this might be one of the reason why less obscuration has been found for sne ia at high z. + there is clearly a sample evolution with z : currently only the less bright sne ia are detected at high z , with less scatter . the brightest objects have a slowly declining light - curve , and at high z , no slow decline has been observed . this may be interpreted as an age effect , high - z sn having younger progenitors . supernovae , galaxies , star formation , morphological type

SECTION 1. SHORT TITLE. This Act may be cited as the ``Fusion Energy Sciences Act of 2001''. SEC. 2. FINDINGS. The Congress finds that-- (1) economic prosperity is closely linked to an affordable and ample energy supply; (2) environmental quality is closely linked to energy production and use; (3) population, worldwide economic development, energy consumption, and stress on the environment are all expected to increase substantially in the coming decades; (4) the few energy options with the potential to meet economic and environmental needs for the long-term future must be pursued aggressively now, as part of a balanced national energy plan; (5) fusion energy is a long-term energy solution that is expected to be environmentally benign, safe, and economical, and to use a fuel source that is practically unlimited; (6) the National Academy of Sciences, the President's Committee of Advisers on Science and Technology, and the Secretary of Energy Advisory Board have each recently reviewed the Fusion Energy Sciences Program and each strongly supports the fundamental science and creative innovation of the program, and has confirmed that progress toward the goal of producing practical fusion energy has been excellent; (7) each of these reviews stressed the need for the Fusion Energy Sciences Program to move forward to a magnetic fusion burning plasma experiment, capable of producing substantial fusion power output and providing key information for the advancement of fusion science; (8) the National Academy of Sciences has also called for a broadening of the Fusion Energy Sciences Program research base as a means to more fully integrate the fusion science community into the broader scientific community; and (9) the Fusion Energy Sciences Program budget is inadequate to support the necessary science and innovation for the present generation of experiments, and cannot accommodate the cost of a burning plasma experiment constructed by the United States, or even the cost of key participation by the United States in an international effort. SEC. 3. PLAN FOR FUSION EXPERIMENT. (a) Plan for United States Fusion Experiment.--The Secretary of Energy (in this Act referred to as ``the Secretary''), on the basis of full consultation with, and the recommendation of, the Fusion Energy Sciences Advisory Committee (in this Act referred to as ``FESAC''), shall develop a plan for United States construction of a magnetic fusion burning plasma experiment for the purpose of accelerating scientific understanding of fusion plasmas. The Secretary shall request a review of the plan by the National Academy of Sciences, and shall transmit the plan and the review to the Congress by July 1, 2004. (b) Requirements of Plan.--The plan described in subsection (a) shall-- (1) address key burning plasma physics issues; and (2) include specific information on the scientific capabilities of the proposed experiment, the relevance of these capabilities to the goal of practical fusion energy, and the overall design of the experiment including its estimated cost and potential construction sites. (c) United States Participation in an International Experiment.--In addition to the plan described in subsection (a), the Secretary, on the basis of full consultation with, and the recommendation of, FESAC, may also develop a plan for United States participation in an international burning plasma experiment for the same purpose, whose construction is found by the Secretary to be highly likely and where United States participation is cost effective relative to the cost and scientific benefits of a domestic experiment described in subsection (a). If the Secretary elects to develop a plan under this subsection, he shall include the information described in subsection (b), and an estimate of the cost of United States participation in such an international experiment. The Secretary shall request a review by the National Academies of Sciences and Engineering of a plan developed under this subsection, and shall transmit the plan and the review to the Congress no later than July 1, 2004. (d) Authorization of Research and Development.--The Secretary, through the Fusion Energy Sciences Program, may conduct any research and development necessary to fully develop the plans described in this section. SEC. 4. PLAN FOR FUSION ENERGY SCIENCES PROGRAM. Not later than 6 months after the date of enactment of this Act, the Secretary, in full consultation with FESAC, shall develop and transmit to the Congress a plan for the purpose of ensuring a strong scientific base for the Fusion Energy Sciences Program and to enable the experiment described in section 3. Such plan shall include as its objectives-- (1) to ensure that existing fusion research facilities and equipment are more fully utilized with appropriate measurements and control tools; (2) to ensure a strengthened fusion science theory and computational base; (3) to encourage and ensure that the selection of and funding for new magnetic and inertial fusion research facilities is based on scientific innovation and cost effectiveness; (4) to improve the communication of scientific results and methods between the fusion science community and the wider scientific community; (5) to ensure that adequate support is provided to optimize the design of the magnetic fusion burning plasma experiments referred to in section 3; and (6) to ensure that inertial confinement fusion facilities are utilized to the extent practicable for the purpose of inertial fusion energy research and development. SEC. 5. AUTHORIZATION OF APPROPRIATIONS. There are authorized to be appropriated to the Secretary for the development and review of the plans described in this Act and for activities of the Fusion Energy Sciences Program $320,000,000 for fiscal year 2002 and $335,000,000 for fiscal year 2003.

Fusion Energy Sciences Act of 2001 - Instructs the Secretary of Energy to: (1) develop a plan for U.S. construction of a magnetic fusion burning plasma experiment; (2) request a plan review for Congress by the National Academy of Sciences; and (3) develop and transmit to Congress a plan for the Fusion Energy Sciences Program and for the magnetic fusion burning plasma experiment.Authorizes the Secretary to develop a plan for U.S. participation in an international burning plasma experiment: (1) whose construction is highly likely; and (2) where Federal participation is cost effective relative to the cost and scientific benefits of a domestic experiment.

materials with strong spin - orbit coupling ( soc ) open up exciting possibilities in the rapidly developing area of solid state physics spintronics . such perspective materials are , for example , topological insulators ( ti ) which simultaneously combine the properties of a semiconductor in the bulk and a metal on the surface.@xcite the metallic behavior of the surface is caused by the presence of special spin - polarized surface states with dirac - type dispersions which are topologically protected from backscattering . other promising candidates for spintronics are bismuth tellurohalides ( bite@xmath0 , @xmath0=i , br , cl ) . these non - centrosymmetric compounds are topologically trivial but characterized by a giant bychkov - rashba - type spin splitting @xcite of bulk and surface electronic bands.@xcite . both topological insulators and bismuth tellurohalides can be used for designing new spintronic and magnetoelectric devices such as spin transistors @xcite as well as for the creation of quantum computers . recently it was predicted that bitei transforms from a trivial phase into a topological insulator by applying an external pressure of 1.74.1 gpa.@xcite the topological phase transition ( tpt ) was also observed experimentally at 22.9 gpa and 3.5 gpa using infrared spectroscopy @xcite and shubnikov - de haas oscillations measurements,@xcite respectively . in ref . , within optical measurements the tpt does nt observed . in the theoretical study within density functional theory ( dft ) the tpt was found at 4.5 gpa.@xcite using _ ab initio _ based tight - binding ( tb ) calculations it was shown @xcite that the tpt is accompanied by the formation of an intermediate phase , a weyl semimetal , which is characterized by one or more pairs of band - touching points ( weyl nodes ) between valence and conduction bands . the possibility of topological phase transition in the related tellurohalides , bitebr and bitecl , has not been studied yet . to draw a conclusion about the existence of pressure - induced topological phases in these compounds , one should first find out whether any pressure - induced crystal phase transitions ( cpt ) would occur under pressure . in the case of bitei , the experimental observation of x - ray diffraction @xcite and raman @xcite spectra reveals the cpt at pressure of @xmath189 gpa which is by factor of 2 - 3 higher then the pressure of tpt . in ref . , the orthorhombic pnma structure was proposed as a high - pressure phase by comparing the dft - obtained enthalpy for the low - pressure phase and pnma . it was also shown that this hexagonal orthorhombic cpt occurs at a pressure of @xmath16 gpa.@xcite for the bitebr compound , the cpt has been experimentally observed at similar pressures ( 67 gpa).@xcite a thorough investigation of the topological transition in bitei requires a careful consideration of surface electronic properties . the fact is that in the bismuth tellurohalides , the band - bending is of special significance because this effect induces additional spin - polarized surface states which have been observed both in angle resolved photoemission spectroscopy ( arpes ) measurements and in dft calculations @xcite . the band - bending arises from the polar nature of the compounds and is caused by a charge redistribution at the surface vacuum boundary . the redistribution changes the effective potential level in the surface region relatively to the bulk and , thereby , shifts the chemical potential near the surface . till now the surface electronic structure of bitei under pressure has been investigated without taking into account the band - bending . , @xmath2 ) for bitei under pressure of 3.84 gpa in the ( @xmath3 ) plane at @xmath4 @xmath5 . the insert shows schematically the positions of all weyl points . the bz region demonstrated in the main figure is marked by a green square . ] here we present a theoretical study both of the topological and crystal phase transitions in the bismuth tellurohalides . in the case of bitei , we demonstrate the features of bulk and surface electronic spectra in the topologically trivial phase , in the case of weyl semimetal and in the topological insulator . it is found that the intermediate phase in bitei , a weyl semimetal , appears in the pressure range of 3.73.9 gpa which can be experimentally detected . it is also shown that the effect of band - bending plays a crucial role in the surface electronic structure formation . by tracing the modification of surface electronic spectra with pressure the mechanism of changing the dispersion of surface states is revealed . an analysis of bitebr and bitecl shows the absence of tpt in these compounds . in bitebr , a crystal phase transition occurs before the tpt that precludes the latter . in bitecl , the topological phase does not appear due to a relatively large band gap at zero pressure . the bulk electronic structure calculations were carried out within dft using the projector augmented - wave ( paw ) method realized in the vasp code and the pbe exchange - correlation functional @xcite . the spin - orbit coupling was accounted by a second - variation method . crystal lattice parameters and atomic positions were optimized for pressures up to 8 , 10 , 18 gpa for bitei , bitebr and bitecl , respectively , using pbe exchange - correlation functional . under the structural relaxation the crystal symmetry kept the same . the optimization was performed for all structures of bitex ( x = i , cl , br ) considered in the paper . at zero pressure , for bitei and bitecl compounds overstimation of @xmath6 and @xmath7 parameters is 2% and 7% , respectively . for bitebr compound 2% and 6% , respectively . for simulation surface under pressure , the large slab has been constructed on the basis relaxed parameters of bulk structure under the pressure . the large slab hamiltonian derived from the bulk one is then used to calculate surface green functions . @xcite so , tight - binding models were constructed using wannier90 code.@xcite . the chosen basis consists of six spinor @xmath8-type orbitals for each atom : @xmath9 , @xmath10 , @xmath11 , @xmath12 , @xmath13 , @xmath14 . the low - lying @xmath15 orbitals are not taken into consideration . to study the bulk electronic spectra near the point of tpt two tight - binding hamiltonians are constructed : one for the topologically trivial phase of bitei and the other for the ti phase , @xmath16 and @xmath17 , respectively . for each intermediate pressure the hamiltonian is taken as a linear combination : @xmath18 . here @xmath19 and @xmath20 correspond to a pressure of 3.6 gpa and 4 gpa , respectively . the band - bending effect was accounted by shifting the on - site matrix elements of surface atoms . the value of shifting is determined by the potential gradient obtained in the first - principles calculations for slabs of bitex ( x = i , cl , br ) at zero pressure.@xcite these values of band bending shift were applied for all surfaces of bitex ( x = i , cl , br ) under pressure . dynamical properties of the bulk bismuth tellurohalides were calculated within the density - functional perturbation theory@xcite in a mixed - basis pseudopotential approach.@xcite . the details of the calculation as well as the spin - orbit coupling implementation within the mixed - basis pseudopotential method can be found in ref . . bitei crystalizes in a hexagonal structure , p3m1 ( fig . [ fig : structure](a ) ) . at zero pressure , the compound is a semiconductor . using fully optimized crystal structure parameters ( @xmath6 , @xmath7 and atomic coordinates ) , we obtained the band gap width of 408 mev which is in good agreement both with experimental measurements ( 380 mev @xcite ) and @xmath21-calculations ( 400 mev in the lda+@xmath21 scheme @xcite ) . such an agreement which is unusual for dft is explained by some overestimation of structural parameters in the relaxation process . the valence and conduction gap edge bands are composed of tellurium and bismuth @xmath8 states ( fig . [ fig : structure](c ) ) , respectively . a strong spin - orbit interaction leads to a large bychkov - rashba type spin splitting of the bulk states and thus two pairs of extrema along the h - a - l line are formed : ( @xmath22 ) and ( @xmath23 ) . under pressure the value of @xmath22 diminishes and at a certain pressure,@xmath24 , shrinks to zero that indicates normal semiconductor - weyl semimetal transition . these does nt happen with gap along the a - l direction , @xmath23 . upon further increase of pressure a band gap appears with inverted edges in the vicinity of the a point : now the lowest conduction band is formed by tellurium @xmath8 states while the top valence band consists of bismuth @xmath8 orbitals ( fig . [ fig : structure](c ) ) . the calculated value of @xmath25 equal to @xmath13.73 gpa ( fig . [ fig : structure](d ) ) agrees well with the experimental one , @xmath25 = 3.5 gpa.@xcite due to a small overestimation of the band gap compared to the experimental value ( @xmath17% ) , the @xmath24 parameter is also slightly overestimated . the calculated value of @xmath24=3.5 gpa contradicts @xmath24=10 gpa obtained in the @xmath21 calculation.@xcite as a result according to the ref . the @xmath24=10 gpa indicates the impossibility of tpt in bitei due to the crystal phase transition at 9 gpa . the discrepancy is explained by a strong overestimation of the band gap width at zero pressure in the @xmath21 calculations . switching on the corrections on van der waals forces lead to a strong underestimation of the band gap at zero pressure ( 230 mev ) . for this reason , we do not present the results obtained after the relaxation of crystal structure with van der waals corrections . the behaviour of band gap @xmath22 and the trajectory of crossing ( weyl ) points near the topological phase transition are plotted in figs . [ fig : structure](e ) and ( f ) . @xmath26 is the smallest value of @xmath22 in the entire bz . the position of weyl points in the reciprocal space depends on the value of pressure . the weyl points are formed at the bz boundary , @xmath27 , along each ah direction . at the phase transition pressure , @xmath25 , each weyl point splits up into pair of nodes with a clockwise and counterclockwise propagation on the ( @xmath3 ) plane ( fig . [ fig : structure](f ) ) . also , these two nodes shift in opposite directions along @xmath28 . the weyl points are observed up to @xmath13.93 gpa and then the band degeneracy is lifted and bitei converts into a topological insulator . thus , the weyl semimetal phase exists within the pressure interval from 3.73 to 3.93 gpa . the range is not small , so the phase can be experimentally observed . the pairs of weyl points appeared along the ah directions have opposite topological charges ( chirality ) which are defined by chern numbers as the flux of berry phase gauge field over a sphere around each weyl point : @xmath29 , where @xmath30 surface normal vector and @xmath31 is the berry curvature . here @xmath32 is the berry connection defined as @xmath33 for n - th bloch state , @xmath34 , ( in our case the highest occupied band ) with quantum number @xmath35 . the calculation reveals that the weyl points which move clockwise ( counterclockwise ) have a positive ( negative ) chern number , @xmath36=1 ( -1 ) , that corresponds to drain ( source ) points of the berry gauge field . the in - plane components of the berry curvature at @xmath4 @xmath5 are demonstrated in fig . [ fig : berry ] . to illustrate surface electronic properties of the systems with bychkov - rashba - type spin splitting of bands in the topological and weyl semimetal phases we considered within tight - binding method a hypothetical model of the bismuth tellurohalides surface under pressure . as was mentioned above to construct the surface under pressure we used large slab with fully relaxed parameters of the bulk structure under the pressure . to do the model more realistic , we included the effect of band bending because of lack of inversion symmetry in the bismuth tellurohalides . the topological phase transition is accompanied by qualitative changes in the surface electronic structure . the bitei has two possible surface terminations : iodine or tellurium with positive and negative band bending , respectively . @xcite let us first trace the evolution of surface electronic states with pressure without considering the effect of band bending ( see fig . [ fig : surf](a f ) ) . in the absence of external pressure ( figs . [ fig : surf](a ) and ( d ) ) , the surface states on the te(i)-terminated surface appear along the outer ( inner ) brunch of unoccupied spin - orbit split bulk bands and are mainly localized in the topmost trilayer . in the pressure - induced weyl semimetal phase ( figs . [ fig : surf](b ) and ( e ) ) , the surface states on the te - terminated surface remain along the outer edge of the bulk bands while in the case of iodine termination they shift into the band gap and exhibit a cone - like dispersion with crossing at the bz center . the surface states touch the crossing ( weyl ) points of the conduction and valence bulk bands . in the topological phase ( figs . [ fig : surf](c ) and ( f ) ) , the surface states become gapless linking the valence and conduction bands . in the case of i - terminated surface , the crossing of two surface states occurs in the band gap slightly above the bulk conduction band minima while on the te - terminated surface the crossing ( dirac ) point is inside off the valence bands due to the mixing of surface and bulk electronic bands . the surface electronic structure obtained with taking into account the effect of band bending as well as its evolution under pressure is different . the overall band structure is strongly modified because a set of well - defined bychkov - rashba type spin split surface bands appearing due to the band - bending effect.@xcite in the topologically trivial phase ( figs . [ fig : surf](g ) and ( j ) ) , the lowest surface band on the te - terminated surface lies within the energy gap and is strongly localized in the topmost trilayer . the states with higher energies are confined within three upper trilayers . on the i - terminated surface , a set of surface bands splits off from the valence bulk band . the occupied surface electronic states appear mainly inside or at the edge of the bulk bands except the topmost state which is shifted upwards into the energy gap . such a hierarchy of surface states was also observed in arpes experiments.@xcite in the weyl semimetal phase ( figs . [ fig : surf](h ) and ( k ) ) , when passing through the bulk weyl nodes the surface states localized in the upper trilayer become discontinuous . in the topological phase ( fig . [ fig : surf](i ) and ( l ) ) , the surface states are breaking up into two parts near the bulk edge extrema , and gapless surface states with a linear dispersion in the band gap are formed . on both surface terminations , the crossing point of the gapless surface states is inside the bulk bands where they turn into surface resonances . the surface electronic structure of weyl semimetals is characterized by the presence of fermi arcs connecting the weyl points with opposite chirality . figure [ fig : fermi_arcs ] shows the electronic spectra at the fermi level of the ( 001 ) surface for both terminations . the isoenergetic surface spectra were calculated with and without the account of the band - bending at a pressure of 3.84 gpa which corresponds to a weyl semimetal phase ( see fig . [ fig : structure](e ) ) . also shown are the positions of weyl points on the ( @xmath3 ) plane . the pairs of weyl points lie on the trajectory connecting the positions of weyl points at the @xmath24 pressure ( 3.73 gpa ) and at the annihilation point ( 3.93 gpa ) ( see fig . [ fig : structure](f ) ) . without taking band bending into account the fermi arcs link up the pair of weyl points induced originally along the a - h ( @xmath37@xmath38 ) direction of the bulk ( surface ) bz . the form of fermi arcs depends on the surface termination . on the te - terminated surface , they form arc - like curves coinciding with the trajectory of a pair of nodes which move clockwise and counterclockwise over the bz . in the case of i - termination , the fermi arcs connect the pairs of weyl points by a straight line . on further increase in pressure , the length of fermi arcs increases and when the weyl semimetal ti phase transition occurs the arcs connect with each other forming a gapless topological surface state . with the account of band bending , in addition to the fermi arcs a circular surface state appears which originates from the outer branches of bychkov - rashba type spin split surface states ( figs . [ fig : surf](h ) and ( k ) ) . in the case of i - termination , the outer circular state is found farther from the surface bz center as compared to the te - terminated surface . however the isoenergetic curves for both terminations are qualitatively similar , unlike the previous case . in addition , with the account of band bending the fermi arcs link up the weyl points from neighbouring pairs . upon increasing pressure , the length of fermi arcs decreases up to zero at @xmath13.9 gpa when the transition to topological phase occurs . after the transition the isoenergetic electronic structure is presented by a single closed curve of the topological surface state . the formation of fermi arcs is closely related to the spin texture of the surface states . without account of band bending , the single closed contour in the topological phase has a clockwise spin helicity.@xcite in the weyl semimetal phase , fermi arcs inherit this behaviour the helicity also has a clockwise character . the spin texture `` connects '' the source and drain weyl points in the clockwise order , so the fermi arcs link up the pair of points emerged along the a - h direction . subject to the band bending , the situation is opposite . the fermi arcs get the spin texture from the inner closed contour of bychkov - rashba type spin split surface states in the trivial phase which have a counterclockwise helicity.@xcite the spin texture `` connects '' the source and drain weyl points in counterclockwise order , so the weyl points from neighbouring pairs are connected . thus , in the calculations the modification of the surface state under pressure depends on whether the band - bending effect is taken into account or not . the modifications are closely related to the alteration of the fermi arcs which characterize the isoenergetic spectra of weyl semimetals . our additional calculations revealed that this picture does not change qualitatively with a strong modification of band bending potential . also , all prognosticated peculiarities of the bitei surface electronic structure in topological phase can be revealed in other noncentrosymmetric alloys where the appearance of the topological or trivial phases can depends , for instance , on the concentrations . note , such systems were proposed in ref . and shown that in cases labi@xmath39sb@xmath40te@xmath41 , lubi@xmath39sb@xmath40te@xmath41 the topological phase can be induced by variation of the sb concentration , @xmath42 . mc phase ( central image ) which is the structure of bitecl at ambient pressure . ] ) . ( b ) raman mode frequencies of bitei as a function of pressure . stars denote experimental data,@xcite triangles ( inverted triangles ) and circles show the values obtained for bitei in the hexagonal p3m1 ( p6@xmath43mc ) and orthorhombic ( pnma ) structures , respectively , in the calculation . in the case of pnma , blue ( green ) circles indicate the modes which involve mostly vibrations of i ( te ) atoms . the pressure range where the p3m1 crystal phase exists is marked by orange color . ] since bitei undergoes crystal phase transitions ( cpt ) under hydrostatic compression @xcite it is necessary to compare the pressures corresponding to the tpt and cpt . the x - ray diffraction data@xcite showed that bitei remained in the p3m1 ( ambient pressure ) structure up to 89 gpa . the stability of the hexagonal phase up to @xmath19 gpa was also confirmed by high - pressure raman spectra measurements.@xcite for the higher pressure phase the orthorhombic pnma structure with 12 atoms per unit cell were suggested ( see fig . [ fig : structures]).@xcite as our calculation show , this structure is normal non - direct gap semiconductor . we calculated the difference in enthalpy between the hexagonal p3m1 and orthorhombic pnma phases depending on pressure ( fig . [ fig : raman](a ) ) . as follows from the calculation the cpt should occur at @xmath16.5 gpa . this value is somewhat smaller than the experimental cpt pressure . despite this discrepancy , the cpt takes place after the topological phase transition and at pressures which are beyond the pressure range ( 3.733.93 gpa ) where the weyl semimetal phase exists . thus the cpt is accompanied by a tpt from a topological insulator to a normal semiconducting phase . to additionally verify the proposed structure we have also calculated raman mode frequencies for the p3m1 phase up to 8 gpa and for the pnma structure at pressures 10 , 12 , and 14 gpa ( fig . [ fig : raman](b ) ) . in the hexagonal p3m1 phase with 3 atoms per unit cell , there are two a@xmath44 and two e ( twofold degenerate ) zone center optical modes , which are both raman and infrared active because of the lack of inversion symmetry . at pressures below the cpt , the theoretical data are in excellent agreement with experimental results with the exception of mode e@xmath45 between 48 gpa where experimental data are absent apparently due to decreasing of the mode intensity . in the experimental raman spectra@xcite three modes are visible up to 8 gpa with an expected increase upwards with pressure . a sudden change in the number and frequency of raman active modes which points out to a structural transition is observed at @xmath19 gpa . the raman spectrum for the orthorhombic phase has a rather complicated character . all the modes are non degenerate . some of them coincide with the experimental data . in general , variation of raman mode frequencies with pressure ( 101214 gpa ) resembles the behaviour of the experimental raman modes . however , the number of the calculated raman modes in the pnma structure ( 13 are shown in the figure while the total number of raman modes is equal to 18 ) is almost twice as large as the experimental data . although the experimental raman spectrum at high pressures bears some similarity to the calculated pnma spectrum the measured modes apparently correspond to a more symmetric structure . the character of the measured spectrum indicates some orthorhombic phase with similar enthalpy . another candidate@xcite can be the hexagonal p6@xmath46c structure with 6 atoms per unit cell which is the structure of another compound , bitecl , at ambient pressure.@xcite the raman active modes calculated for bitei in the hexagonal p6@xmath46c structure at 10 and 12 gpa are continuations of the corresponding modes in the low - pressure phase . the number of e modes is doubled and the two lower e modes are shifted down in energy compared to the e@xmath45 . so the raman spectrum does not reproduce the high - pressure experimental data and the p6@xmath46c structure can not be considered as a high - pressure phase of bitei . for bitebr and bitecl there is no experimental information about the possibility of topological phase transition under pressure . it was thought that bitebr crystallizes in the hexagonal structure , p@xmath47m1 , with te and br atoms statistically distributed within two layers adjacent to the bi layer.@xcite later an ordered stacking of te and br sublattices , like in bitei , was confirmed by x - ray diffraction measurements and , moreover , arpes images revealed a well - defined bychkov - rashba type spin split states.@xcite the structure of bitecl at ambient pressure is hexagonal , p6@xmath46c , with 6 atoms per unit cell.@xcite we also considered bitecl in the p3m1 crystal phase which was found in the calculation to be energy preferable up to the cpt . to evaluate the probability of cpt we also examine both compounds in the orthorhombic pnma structure which was originally proposed as a high - pressure structure for bitei.@xcite this phase is considered for bitebr and bitecl compounds because most v - vi - vii semiconductors crystallize in this structure.@xcite as follows from fig . [ fig : btb_btc](a ) the cpt in bitebr takes place at a pressure of @xmath16.3 gpa . although the band gap ( fig . [ fig : btb_btc](b ) ) decreases with pressure its lowest value is of @xmath180 mev at the point of cpt and therefore the system possesses a trivial topology . the cpt pressure is in good agreement with experimental results of ref . the data exclude the possibility of tpt in the low - pressure phase of bitebr . note , if another high - pressure structure which is energy preferable compared to the p3m1 and pnma structures is realized then the pressure of cpt would be lower than 6.3 gpa and in any case the cpt occurs before a tpt . due to relatively closer the pressures of tpt and cpt and lacking of experimental investigations of both transitions , additional calculations have been provided by inclusion van der waals correction within dft - d3 @xcite scheme . so , the correction lead to shifting cpt and tpt in the area of smallest pressures : @xmath14 gpa and @xmath18 gpa , respectively . however , the conclusion is preserved : in bitebr tpt is absent . the case of bitecl is more complicated from the crystallographic point of view . first of all , our results indicate the possibility of cpt from p6@xmath43mc to the p3m1 structure at very small pressures because the calculated difference in enthalpy ( fig . [ fig : btb_btc](c ) ) , red line ) turns out to be @xmath10.8 mev even at zero pressure . with increasing pressure , the p3m1 phase remains energy preferable up to 4.3 gpa when the cpt to the pnma structure takes place . however , these results do not affect the general conclusion about a possibility of tpt in this compound . a tpt does not occur either in the p3m1 or in the p6@xmath43mc crystal phases because although the band gap width decreases with pressure ( fig . [ fig : btb_btc](d ) ) this decreasing practically ceases at a value of @xmath1100 mev ( @xmath180 mev ) for the p3m1 ( p6@xmath43mc ) structure . a relatively large band gap width makes impossible the tpt both in the p3m1 and in the p6@xmath43mc hexagonal phase . this conclusion contradicts the data reported in ref . where by apres measurements a topological insulator phase in bitecl with dirac - type surface states was found at zero pressure . the observation of the ti phase might be explained by a possible crystallization of the material in another hexagonal structure what is confirmed by a very small bulk band gap width ( @xmath1220 mev ) obtained in the experiment . the latter contradicts the electronic structure calculations within the gw - approximation that reveal the band gap width of 800 - 900 mev.@xcite . for additional verification of the trivial character of bitecl in the hexagonal phases , we have calculated the surface electronic structure at a pressure of 18 gpa with taking into account the band bending effect . figures [ fig : btb_btc](e ) and ( f ) show the electronic spectra of the te - terminated surface for the p3m1 and p6@xmath43mc crystal phases , respectively . it is obvious that there are no topological surface states in the bulk band gap and therefore the system is a trivial semiconductor . both crystal phases are only characterized by the presence of well known bychkov - rashba type split surface states . it should be noted , that additional extrema of the conduction band appear , one at the @xmath48 point and the other in the @xmath37-@xmath49 direction which results in an indirect band gap in the case of the p6@xmath43mc structure . we have investigated a possibility of topological phase transitions in bismuth tellurohalides . for bitei , our results support the pressure - induced tpt in agreement with experimental data.@xcite . the study of bulk and surface electronic structures of bitei under pressure revealed that an intermediate phase , a weyl semimetal , is formed during the transition from a trivial semimetal to a topological insulator in the pressure interval of @xmath13.73.9 gpa . the range is not too small , so the intermediate phase can be experimentally observed . the inclusion of the band bending effect in the calculation allowed us to consider surface modifications caused by the polarity of bitei . as a result , we revealed the mechanism of changing of the surface states from a bychkov - rashba type spin split state to a gapless surface state that occurs during the tpt . in the ti phase , the surface states feature a linear dispersion which depends on the surface termination . this result is relevant for all asymmetric materials where tpt can be induced not only by applying hydrostatic pressure but also by a doping . we have also compared the raman mode frequencies obtained experimentally for bitei under pressure with those calculated for bitei . at low pressures the theoretical data for the p3m1 crystal phase reproduce well the experimental measurements . as for the high - pressure phases , the experimental raman spectrum bears some similarity to the calculated spectrum in the pnma phase but the measured modes apparently correspond to a more symmetric structure . we also showed the absence of tpt in bitebr and bitecl . in bitebr , the cpt occurs before a tpt becomes possible . in bitecl , a relatively large value of band gap width prevents the possibility of tpt up to 18 gpa . this study ( research grant no . 8.1.05.2015 ) was supported by the tomsk state university academic d.i . mendeleev fund program in 2015 , by grant of saint - petersburg state university for scientific investigations no . 15.61.202.2015 ; 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we study the possibility of pressure - induced transitions from a normal semiconductor to a topological insulator ( ti ) in bismuth tellurohalides using density functional theory and tight - binding method . in bitei this transition is realized through the formation of an intermediate phase , a weyl semimetal , that leads to modification of surface state dispersions . in the topologically trivial phase , the surface states exhibit a bychkov - rashba type dispersion . the weyl semimetal phase exists in a narrow pressure interval of 0.2 gpa . after the weyl semimetal ti transition occurs , the surface electronic structure is characterized by gapless states with linear dispersion . the peculiarities of the surface states modification under pressure depend on the band - bending effect . we have also calculated the frequencies of raman active modes for bitei in the proposed high - pressure crystal phases in order to compare them with available experimental data . unlike bitei , in bitebr and bitecl the topological phase transition does not occur . in bitebr , the crystal structure changes with pressure but the phase remains a trivial one . however , the transition appears to be possible if the low - pressure crystal structure is retained . in bitecl under pressure , the topological phase does not appear up to 18 gpa due to a relatively large band gap width in this compound .

chronic obstructive pulmonary disease ( copd ) is present in approximately one - third of all congestive heart failure ( chf ) patients , and is a key cause of underprescription and underdosing of -blockers , owing largely to concerns about precipitating respiratory deterioration in these patients.14 despite increasing evidence that -blockers are safe and could be beneficial in patients with copd , most large - scale chf trials exclude patients with copd.5 the national institute for health and care excellence and european society of cardiology guidelines state that copd is not a contraindication to the use of -blockers , and mild deterioration in pulmonary function and symptoms should not result in prompt discontinuation . low - dose initiation and gradual uptitration is recommended.6,7 in addition , some studies have suggested differences in the pulmonary effects between cardioselective and non - cardioselective -blockers , but the results of these studies are not fully conclusive.813 of the -blocker class of drugs , carvedilol is a non - selective -adrenergic receptor ( ar ) blocker that also blocks 1-ar signaling and that has been shown to improve the state of hf patients in many studies.1418 however , some patients are not able to continue or uptitrate the drug because of various adverse symptoms and signs , which seem to be mainly related to the 2-ar blocking effect . on the other hand , bisoprolol , a highly selective 1-ar blocker , has also been shown to be effective for hf patients in several studies.1921 although it has been reported that cardioprotective -blockers do not worsen the pulmonary function in chf patients with copd , the impact of -blocker selectivity on the long - term outcomes has not yet been well evaluated in these patients . in a sub - analysis of the optimize - hf study , patients receiving non - cardioselective -blockers were found to have a lower event rate compared to patients receiving cardioselective -blockers.22 thus , taking this into consideration , the aim of the present study was to evaluate the impact of -blockers on the long - term outcomes in hf patients with copd . in addition , we also compared the effects of carvedilol and bisoprolol in this patient population . this study was a retrospective , non - randomized , single center trial based on data collected over a 48-month period ( january 1 , 2009 to december 31 , 2012 ) from 212 consecutive acute decompensated hf patients with copd who were admitted to our hospital with hf categorized as new york heart association class 3 or 4 . patients with acute coronary syndromes ( n=34 ) , including acute myocardial infarction , or with end - stage renal disease that required dialysis therapy ( n=14 ) as well as patients who did not finish the treatment course after discharge ( n=32 ) were excluded from the study . the diagnosis of hf was made on the basis of the criteria recommended in the framingham heart study.23 the diagnosis of copd was made on the basis of the global initiative for chronic obstructive lung disease criteria.24 at the time of registration , the copd of all patients was in the stable phase . finally , of the identified 212 patients , 132 met all inclusion criteria and were enrolled in this study . the patients were divided into two groups according to the agents administered after admission and followed - up for a mean period of 33.9 months . the first group was treated without any -blockers ( non--blocker group , n=46 ) , whereas the second group was administered -blockers before discharge ( -blocker group , n=86 ; carvedilol [ n=52 ] or bisoprolol [ n=34 ] ) . after discharge , the patients continued treatment with either carvedilol or bisoprolol , with the dose being carefully increased to tolerance . the subjects were followed - up at intervals of 12 months in the outpatient department of our hospital from january 2009 through december 2013 . the patients health status was checked during each follow - up , and was recorded using electronic clinical records ; furthermore , all - cause death and hospitalization due to chf and/or copd exacerbation were also verified using these electronic clinical records . the protocol used complies with the declaration of helsinki and was approved by our institutional ethics committee , which waived the need for patient consent because of the retrospective nature of the study . the heart rate ( hr ) and systolic blood pressure ( sbp ) were measured at rest , simultaneously with the electrocardiogram measurements . height and weight were measured at the time of discharge , and the body mass index ( kg / m ) was calculated as an index of obesity . hypertension was defined as an sbp of 140 mmhg or greater , a diastolic blood pressure of 90 mmhg or greater , or the current use of antihypertensive agents . chronic kidney disease was defined as a glomerular filtration rate ( gfr ) 60 ml / min/1.73 m. the gfr was estimated using the simplified prediction equation derived from the modification of diet in a renal disease study.25 during each echocardiographic study , the left ventricular ejection fraction ( lvef ) was calculated using the modified simpson s method . the tricuspid regurgitation velocity was obtained by continuous wave doppler from the right ventricular inflow or the apical four - chamber view position . the tricuspid regurgitation pressure gradient ( trpg ) was calculated as follows : trpg = 4 tricuspid regurgitation velocity.2 clinical data were obtained just prior to discharge when the hemodynamic conditions of the patients had stabilized . twelve months after the treatment initiation , all parameters were re - measured and compared with the initial data . the primary endpoint was the differences in all - cause mortality between the -blocker use and non - use groups during the mean clinical follow - up of 33.9 months . the secondary endpoints were the differences in composite events , including the all - cause mortality and hospitalization rates for chf and/or copd exacerbation , between patients receiving carvedilol and bisoprolol . the spss software package version 20.0 ( ibm corporation , armonk , ny , usa ) was used for the statistical analyses . all continuous values are expressed as means standard deviations , and data of categorical variables are expressed as the number and percentage of patients . survival and cardiac event - free curves were created using the kaplan meier method , and differences in the survival and cardiac event - free rates among the groups were analyzed using the log - rank test . the relative risks in each group were calculated using cox regression analyses , and p - values of less than 0.05 were considered statistically significant . this study was a retrospective , non - randomized , single center trial based on data collected over a 48-month period ( january 1 , 2009 to december 31 , 2012 ) from 212 consecutive acute decompensated hf patients with copd who were admitted to our hospital with hf categorized as new york heart association class 3 or 4 . patients with acute coronary syndromes ( n=34 ) , including acute myocardial infarction , or with end - stage renal disease that required dialysis therapy ( n=14 ) as well as patients who did not finish the treatment course after discharge ( n=32 ) were excluded from the study . the diagnosis of hf was made on the basis of the criteria recommended in the framingham heart study.23 the diagnosis of copd was made on the basis of the global initiative for chronic obstructive lung disease criteria.24 at the time of registration , the copd of all patients was in the stable phase . finally , of the identified 212 patients , 132 met all inclusion criteria and were enrolled in this study . the patients were divided into two groups according to the agents administered after admission and followed - up for a mean period of 33.9 months . the first group was treated without any -blockers ( non--blocker group , n=46 ) , whereas the second group was administered -blockers before discharge ( -blocker group , n=86 ; carvedilol [ n=52 ] or bisoprolol [ n=34 ] ) . after discharge , the patients continued treatment with either carvedilol or bisoprolol , with the dose being carefully increased to tolerance . the subjects were followed - up at intervals of 12 months in the outpatient department of our hospital from january 2009 through december 2013 . the patients health status was checked during each follow - up , and was recorded using electronic clinical records ; furthermore , all - cause death and hospitalization due to chf and/or copd exacerbation were also verified using these electronic clinical records . the protocol used complies with the declaration of helsinki and was approved by our institutional ethics committee , which waived the need for patient consent because of the retrospective nature of the study . the heart rate ( hr ) and systolic blood pressure ( sbp ) were measured at rest , simultaneously with the electrocardiogram measurements . height and weight were measured at the time of discharge , and the body mass index ( kg / m ) was calculated as an index of obesity . hypertension was defined as an sbp of 140 mmhg or greater , a diastolic blood pressure of 90 mmhg or greater , or the current use of antihypertensive agents . chronic kidney disease was defined as a glomerular filtration rate ( gfr ) 60 ml / min/1.73 m. the gfr was estimated using the simplified prediction equation derived from the modification of diet in a renal disease study.25 during each echocardiographic study , the left ventricular ejection fraction ( lvef ) was calculated using the modified simpson s method . the tricuspid regurgitation velocity was obtained by continuous wave doppler from the right ventricular inflow or the apical four - chamber view position . the tricuspid regurgitation pressure gradient ( trpg ) was calculated as follows : trpg = 4 tricuspid regurgitation velocity.2 clinical data were obtained just prior to discharge when the hemodynamic conditions of the patients had stabilized . twelve months after the treatment initiation , all parameters were re - measured and compared with the initial data . the primary endpoint was the differences in all - cause mortality between the -blocker use and non - use groups during the mean clinical follow - up of 33.9 months . the secondary endpoints were the differences in composite events , including the all - cause mortality and hospitalization rates for chf and/or copd exacerbation , between patients receiving carvedilol and bisoprolol . the spss software package version 20.0 ( ibm corporation , armonk , ny , usa ) was used for the statistical analyses . all continuous values are expressed as means standard deviations , and data of categorical variables are expressed as the number and percentage of patients . survival and cardiac event - free curves were created using the kaplan meier method , and differences in the survival and cardiac event - free rates among the groups were analyzed using the log - rank test . the relative risks in each group were calculated using cox regression analyses , and p - values of less than 0.05 were considered statistically significant . we divided the patients into two groups according to whether a -blocker was prescribed at discharge or not ( -blocker group , n=86 ; non--blocker group , n=46 ) . there were no significant differences between the two groups in terms of age , sex , prevalence of hypertension , atrial fibrillation , chronic kidney disease or ischemic heart disease , brain natriuretic peptide ( bnp ) levels , forced expiratory volume in 1 second ( fev1 ) , or medical treatment at the time of discharge . however , patients not receiving -blockers had a significantly higher hr at the 1-year follow - up compared with patients receiving -blockers . in the -blocker group , 52 patients ( 60.5% ; mean dose : 6.69 mg / day ) received carvedilol at discharge , whereas 34 patients ( 39.5% ; mean dose : 2.96 mg / day ) received bisoprolol . regarding the different -blockers , the clinical characteristics , excluding the hr and lvef , did not significantly differ between the carvedilol and bisoprolol groups ( table 1 ) higher hr and ejection fraction ( ef ) were observed in the patients receiving bisoprolol . the mean baseline fev1 values were 1.70 l and 1.52 l in patients receiving carvedilol and bisoprolol , respectively ( p=0.344 ) . during the mean follow - up period of 33.9 months , the primary endpoint event ( all - cause mortality ) occurred in 9 patients ( 10.5% ) in the -blocker group and 12 patients ( 26.1% ) in the non--blocker group ( log - rank p=0.039 ) ( figure 1 ) . -blocker therapy significantly reduced the risk of all - cause death in the univariate analysis ( unadjusted hazard ratio [ hr ] : 0.41 ; 95% confidence interval [ ci ] : 0.170.99 ; p=0.047 ) ( table 2 ) . however , no significant association was observed between -blocker use and all - cause mortality in the multivariate analysis ( table 2 ) . evaluation of the causes of death revealed that in the non--blocker group , six , three , two , and one patients died of infection - unrelated copd exacerbation , copd exacerbation , sudden cardiac death , and acute hf , respectively . in the -blocker group , three , two , two , and two patients died of infection - unrelated copd exacerbation , copd exacerbation , sudden cardiac death , and acute hf , respectively . the percentages of each cause of death did not significantly differ between the two treatment groups . the secondary endpoint events occurred in 35 patients ( 67.3% ) in the carvedilol group and 9 patients ( 26.5% ) in the bisoprolol group ( log - rank p=0.112 ) ( figure 2 ) . chf and/or copd exacerbation occurred in 29 patients ( 55.8% ) in the carvedilol group and 6 patients ( 17.6% ) in the bisoprolol group ( log - rank p=0.033 ) ( figure 3 ) . the rate of all - cause death did not significantly differ between the two groups ( 11.5% vs 8.8% in the carvedilol vs bisoprolol groups , data not shown ) . univariate cox regression analysis revealed that bisoprolol significantly reduced the risk of re - hospitalization due to chf and/or copd exacerbation ( unadjusted hr : 0.38 ; 95% ci : 0.150.98 ; p=0.046 ) but carvedilol did not ( table 3 ) . in the multivariate analysis , only a past history of copd exacerbation significantly increased the risk of re - hospitalization due to chf and/or copd exacerbation ( adjusted hr : 3.11 ; 95% ci : 1.476.61 ; p=0.003 ) ( table 3 ) . table 4 presents the values of sbp , hr , lvef , trpg , bnp levels , and estimated gfr at baseline and at the 1-year follow - up . the 1-year changes in sbp , lvef , trpg , bnp levels , and estimated gfr were not significantly different between the two groups . however , the decrease in hr was greater in the bisoprolol group than in the carvedilol group . during the mean follow - up period of 33.9 months , the primary endpoint event ( all - cause mortality ) occurred in 9 patients ( 10.5% ) in the -blocker group and 12 patients ( 26.1% ) in the non--blocker group ( log - rank p=0.039 ) ( figure 1 ) . -blocker therapy significantly reduced the risk of all - cause death in the univariate analysis ( unadjusted hazard ratio [ hr ] : 0.41 ; 95% confidence interval [ ci ] : 0.170.99 ; p=0.047 ) ( table 2 ) . however , no significant association was observed between -blocker use and all - cause mortality in the multivariate analysis ( table 2 ) . evaluation of the causes of death revealed that in the non--blocker group , six , three , two , and one patients died of infection - unrelated copd exacerbation , copd exacerbation , sudden cardiac death , and acute hf , respectively . in the -blocker group , three , two , two , and two patients died of infection - unrelated copd exacerbation , copd exacerbation , sudden cardiac death , and acute hf , respectively . the percentages of each cause of death did not significantly differ between the two treatment groups . the secondary endpoint events occurred in 35 patients ( 67.3% ) in the carvedilol group and 9 patients ( 26.5% ) in the bisoprolol group ( log - rank p=0.112 ) ( figure 2 ) . chf and/or copd exacerbation occurred in 29 patients ( 55.8% ) in the carvedilol group and 6 patients ( 17.6% ) in the bisoprolol group ( log - rank p=0.033 ) ( figure 3 ) . the rate of all - cause death did not significantly differ between the two groups ( 11.5% vs 8.8% in the carvedilol vs bisoprolol groups , data not shown ) . univariate cox regression analysis revealed that bisoprolol significantly reduced the risk of re - hospitalization due to chf and/or copd exacerbation ( unadjusted hr : 0.38 ; 95% ci : 0.150.98 ; p=0.046 ) but carvedilol did not ( table 3 ) . in the multivariate analysis , only a past history of copd exacerbation significantly increased the risk of re - hospitalization due to chf and/or copd exacerbation ( adjusted hr : 3.11 ; 95% ci : 1.476.61 ; p=0.003 ) ( table 3 ) . table 4 presents the values of sbp , hr , lvef , trpg , bnp levels , and estimated gfr at baseline and at the 1-year follow - up . the 1-year changes in sbp , lvef , trpg , bnp levels , and estimated gfr were not significantly different between the two groups . however , the decrease in hr was greater in the bisoprolol group than in the carvedilol group . in the present study , we examined the effects of -blockers in patients with hf and copd . approximately , 70% of the hf patients with copd had received -blockers , and these were found to significantly reduce the all - cause mortality . moreover , the baseline hr and ef before -blocker administration were found to be higher in patients receiving bisoprolol compared with patients receiving carvedilol , whereas re - hospitalization due to chf and/or copd exacerbation occurred less frequently in patients receiving bisoprolol compared to patients receiving carvedilol . up to one - third of all deaths in patients with copd can be attributable to cardiovascular disease , and , for every 10%-decrease in the fev1 , the risk of cardiovascular mortality reportedly increases by 28%.2628 the mechanistic links between copd and cardiovascular disease are complex , multifactorial , and not entirely understood . hyperinflation and increased falls in the intrathoracic pressure might compromise the ventricular preload and afterload , consequently leading to left ventricular dysfunction and acute heart failure . as most of these factors occur concurrently at the moment of acute exacerbation , these episodes are often associated with major cardiovascular events and high mortality.29 despite increasing evidence that -blockers are safe30,31 and can be beneficial in patients with copd , their use continues to be limited in this group . this is a worldwide phenomenon32 and might be related to historical concerns that -blockers could be harmful in patients with copd , for example , by inducing bronchospasm . such concerns , however , have been challenged by recent evidence,33 with several recent studies having advanced arguments in support of the use of -blockers for copd patients.3438 one of these studies showed that -blockers might reduce the risk of mortality and exacerbations in patients with copd.34 similarly , a systematic review and meta - analysis of nine retrospective cohort studies reported a reduction in copd - related mortality of 31% after -blocker use,39 and yet another study clearly showed the safety of -blockers during copd exacerbations.32 moreover , the use of -blockers when started either at the time of hospital admission for myocardial infarction or before a myocardial infarction has been demonstrated to be associated with improved survival after myocardial infarction in patients with copd.40 in our study , similar to in these previous reports , -blocker use was found to be associated with lower mortality compared to non--blocker use in chf patients with copd . receiving -blockers decreases the mortality rate through lowering the hr and through their sympatholytic effects,41 and -blockers might benefit patients with hf and copd , not only because of their effect on the chf but also because they can affect the course of the copd itself . regarding the different types of -blockers , we here compared carvedilol , a typical non - selective -adrenergic , and 1-ar blocker with bisoprolol , a typical highly selective 1-ar blocker , in order to determine which -blocker is more appropriate for hf and copd patients , a question that remains controversial . bisoprolol is highly 1-selective , providing a wide split between the 1- and 2-adrenocepter blockades.42,43 further , bisoprolol has recently been shown to be safe in patients with copd . in a cochrane database analysis , cardioselective -blockers were demonstrated to not adversely affect the fev1 , respiratory symptoms , or the response of fev1 to 2 agonists.44 conversely , it has been reported that carvedilol may aggravate pulmonary complications through blocking of the 2 receptors , and its effects markedly differ between individuals due to different genetic polymorphisms , as compared with bisoprolol.4547 accordingly , switching from carvedilol to bisoprolol may provide beneficial effects with regard to the prognosis and/or reverse remodeling in patients who experience difficulty with the continuation or uptitration of carvedilol due to adverse effects such as dizziness or hypotension.48,49 several studies have shown that the mortality benefits of carvedilol and other -blockers are dose dependent,14,18,50 and the dose of carvedilol is moreover considered important for the management of cardiac sympathetic nerve activity.51 cardioselective -blockers are also dose dependent,5 and it is also recommended to use -blockers that are more selective for the 1-ar but without intrinsic sympathomimetic activity at the lowest dose and to titrate them slowly , while paying close attention to lung function and symptoms.52 the doses of the two -blockers used in our study were lower than the doses commonly used in many large - scale trials . however , trials on japanese patients with hf have indicated that the bp and hr can be adequately decreased with the use of low doses of carvedilol and bisoprolol.18,53 these differences in the doses administered to japanese patients and patients of other nationalities may be related to the pharmacological heterogeneity of -blockers . furthermore , bisoprolol is less likely to cause bronchospasm compared to non - selective -blockers,9 and the risk of bronchospasm can be further reduced by starting the -blockers at a lower dose and slowly titrating up . in our study , the reduction in hr was more prominent in the bisoprolol group than in the carvedilol group at the 1-year follow - up . this result suggests that bisoprolol has a greater ability to suppress the hr of patients with hf and copd than carvedilol , as the former is a highly selective 1-ar blocker . in addition , treatment with bisoprolol was also associated with a significantly reduced risk of re - hospitalization due to chf and/or copd exacerbation . on the other hand , in the sub - analysis of the optimize - hf study , patients receiving non - cardioselective -blockers had a lower event rate compared to patients receiving cardioselective -blockers.22 however , it should be noted that , compared to the optimize - hf study , the sample size and number of events of this study were relatively small , and re - hospitalization due to copd exacerbation was also included in the analyzed events , owning to difficulty in distinguishing chf from copd exacerbation . furthermore , only bisoprolol was used as the cardioselective -blocker in this study , whereas several different selective -blockers were used in the optimize - hf study . further , our results suggested that low doses of bisoprolol could also reduce the all - cause mortality in patients with hf and copd , and it was moreover found to be associated with a significantly reduced risk of re - hospitalization due to chf and/or copd exacerbation compared with carvedilol . however , further prospective randomized controlled studies are needed to confirm our results and before initiation of -blocker therapy to achieve a mortality benefit in copd patients can be widely recommended . the main limitations of the present study were the relatively small number of enrolled patients and the retrospective study design . moreover , the -blockers were prescribed at discharge for the -blocker group ; at this time , the use of -blockers was left at the discretion of the treating physicians . therefore , the beneficial effects of the -blockers in the present study can only be attributable to the time period of discharge , and we could not exclude the possibility that the addition and selection of the two -blockers were made on the basis of the clinical status of the patients . the baseline ef was higher in patients receiving bisoprolol compared with patients receiving carvedilol ; however , the ef did not significantly correlate with the incidence of chf or copd exacerbation in our study . lastly , regarding the two -blockers used in this study , different doses were prescribed , given that the equivalent dose of bisoprolol is only one - fifth that of carvedilol.54,55 although most confounders were included in the multivariate regression analysis , it is nonetheless possible that some potential bias exists , and large - scale , prospective randomized controlled trials are needed in the future to clarify the effects of -blockers in patients with hf and copd . the use of a selective -blocker reduced the incidence of chf and/or copd exacerbation compared with non - selective -blocker use in the univariate analyses in the present study ; however , after controlling for other variables , the effect of -blockers ceased to be significant . further studies with longer duration and larger numbers of hf and copd patients are needed to confirm whether there are any differences between the effects of the two types of -blockers on hf and copd improvement .

backgroundchronic obstructive pulmonary disease ( copd ) is present in approximately one - third of all congestive heart failure ( chf ) patients , and is a key cause of underprescription and underdosing of -blockers , largely owing to concerns about precipitating respiratory deterioration . for these reasons , the aim of this study was to evaluate the impact of -blockers on the long - term outcomes in chf patients with copd . in addition , we compared the effects of two different -blockers , carvedilol and bisoprolol.methodsthe study was a retrospective , non - randomized , single center trial . acute decompensated hf patients with copd were classified according to the oral drug used at discharge into -blocker ( n=86 ; carvedilol [ n=52 ] or bisoprolol [ n=34 ] ) and non--blocker groups ( n=46 ) . the primary endpoint was all - cause mortality between the -blocker and non--blocker groups during a mean clinical follow - up of 33.9 months . the secondary endpoints were the differences in all - cause mortality and the hospitalization rates for chf and/or copd exacerbation between patients receiving carvedilol and bisoprolol.resultsthe mortality rate was higher in patients without -blockers compared with those taking -blockers ( log - rank p=0.039 ) , and univariate analyses revealed that the use of -blockers was the only factor significantly correlated with the mortality rate ( hazard ratio : 0.41 ; 95% confidence interval : 0.170.99 ; p=0.047 ) . moreover , the rate of chf and/or copd exacerbation was higher in patients treated with carvedilol compared with bisoprolol ( log - rank p=0.033 ) . in the multivariate analysis , only a past history of copd exacerbation significantly increased the risk of re - hospitalization due to chf and/or copd exacerbation ( adjusted hazard ratio : 3.11 ; 95% confidence interval : 1.476.61 ; p=0.003).conclusionthese findings support the recommendations to use -blockers in hf patients with copd . importantly , bisoprolol reduced the incidence of chf and/or copd exacerbation compared with carvedilol .

S.A.-area father found safe after strange disappearance Super Bowl Sunday Photo: Courtesy Image 1 of / 8 Caption Close Image 1 of 8 Lee Arms, 44, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. He was found alive the week of Valentine's Day 2017. less Lee Arms, 44, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. He was found alive the ... more Photo: Courtesy Image 2 of 8 Lee Arms, 44, center back, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. Lee Arms, 44, center back, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. Photo: Courtesy Image 3 of 8 Lee Arms, 44, is believed to be the man in these surveillance photos from a gas station near San Antonio. He went missing on Sunday, Feb. 5, 2017. Lee Arms, 44, is believed to be the man in these surveillance photos from a gas station near San Antonio. He went missing on Sunday, Feb. 5, 2017. Photo: Facebook Image 4 of 8 Lee Arms, 44, is believed to be the man in these surveillance photos from a gas station near San Antonio. He went missing on Sunday, Feb. 5, 2017. Lee Arms, 44, is believed to be the man in these surveillance photos from a gas station near San Antonio. He went missing on Sunday, Feb. 5, 2017. Photo: Facebook Image 5 of 8 Lee Arms, 44, is believed to be the man in these surveillance photos from a gas station near San Antonio. He went missing on Sunday, Feb. 5, 2017. Lee Arms, 44, is believed to be the man in these surveillance photos from a gas station near San Antonio. He went missing on Sunday, Feb. 5, 2017. Photo: Facebook Image 6 of 8 Lee Arms, 44, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. Lee Arms, 44, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. Photo: Courtesy Image 7 of 8 Lee Arms, 44, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. Lee Arms, 44, went missing on Feb. 5, 2017, and was last seen in his vehicle. Anyone with information is asked to contact the Heidi Search Center or the Bexar County Sheriff's Office. Photo: Courtesy Image 8 of 8 S.A.-area father found safe after strange disappearance Super Bowl Sunday 1 / 8 Back to Gallery SAN ANTONIO — Lee Arms, the 44-year-old father of three who went missing Super Bowl Sunday in the San Antonio area, was found alive and unharmed Thursday, according to the Bexar County Sheriff's Office. His disappearance was not the result of an accident, but the result of his own decision to leave, according to BCSO. Heidi Search center, US Marshals Office and other agencies located Arms Thursday morning, after following a lead obtained earlier in the week. RELATED: Surveillance photos show what S.A.-area father was wearing day of strange disappearance According to previous reports, Arms was last seen at about 5:30 p.m. on Feb. 5 in his silver Ford Fusion, which was abandoned near Loop 1604 and Interstate 10. The Falls City resident was also seen on video surveillance at a gas station in the San Antonio or Falls City area, with people online commenting he may have been getting gas from that station. The circumstances surrounding his disappearance were "very unusual," according to his nephew, Derek Moy. RELATED: Search underway for S.A.-area father who mysteriously went missing Sunday Moy said his uncle's vehicle was found running with the emergency flashers on, with a box of some kind embedded into the front of it. They found Arms' wallet at the scene as well as other belongings. Boots were also found near the scene, according to Moy, with one shoe away from the other. Arms works the night shift at an area UPS. Text "Breaking" to 48421 for breaking news alerts from mySA.com [email protected] Twitter: @tylerlwhite ||||| Starting in 1996, Alexa Internet has been donating their crawl data to the Internet Archive. 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– Super Bowl Sunday was the last time anyone saw Texas man Lee Arms in the San Antonio area, and he hadn't been seen since—until late last week, when the 44-year-old was found safe in Ohio, the San Antonio Express-News reports. And it looks like he was there of his own volition, per the Akron Beacon Journal. "He wanted to escape his life … and his situation," says Bath Township Police Chief Michael McNeely. That situation back in the Lone Star State includes having a wife and three kids (ages 19, 16, and 8, per the Karnes Countywide newspaper), and while McNeely didn't elaborate much on the case, he did offer something of a motive for why Arms chose Ohio as his new home, explaining to the Journal, "He met somebody online." Arms' Ford Fusion was found Feb. 5 near a local interstate with its hazards blinking, his wallet and other personal items left behind. He was tracked down by the Heidi Search Center, US Marshals, and other agencies after a tip came in. The center's executive director tells the Journal it's "very rare" for a missing person to turn up this way, and despite the uncomfortable circumstances, McNeely said his department was at least glad they could tell Arms' wife and kids he was alive. While some back in San Antonio are breathing sighs of relief that Arms, a UPS worker, was never in harm's way, others are confused and angry. "As a community we deserve answers," one commenter wrote on the Heidi Search Center's Facebook post about Arms, adding, "You can't blame us for being upset." (A Colorado man disappeared from the stadium during a Broncos game.)

a relatively symmetric poly(acrylic acid)-polybutadiene copolymer denoted ab1 ( mn = 10,050 g / mol , with hydrophilic fraction , f 0.50 ) yields polymersomes and micelles as a function of ph and salt , whereas the non - ionic poly(ethylene oxide)-polybutadiene denoted ob18 ( mn = 10,400 g / mol , f ~ 0.35 ) yields coexisting cylinders and vesicles independent of ph and salt . when ob18 is labeled with a rhodamine fluorophore ( ob18 * ) and mixed with unlabeled ab1 in various proportions , calcium - induced domains or rafts can be clearly seen in almost all giant vesicles ( fig . polymersomes were immobilized by aspiration into a micropipette , which not only facilitated z - stack imaging by laser scanning confocal microscopy ( lscm ) but also established that the membranes are stable under applied tension . analysis of the area fraction of ab1 domains corresponds closely to the copolymer blend ratio ( supporting information table s1 ) ; for example , 25% ab1 gave a total area fraction of 0.22 0.10 ( n = 5 vesicles ) . the low diffusivity of ob18 1 minimizes drift effects that have frustrated similar high resolution studies of lipid vesicles . moreover , domains here could be visualized for years after vesicle formation , and yet domains also dissipate within minutes upon addition of a calcium chelator ( fig . strong lateral segregation ( sls ) of the two copolymers was confirmed by simultaneous two - color imaging of vesicles made with both ob18 * and a fluorescently - labeled ab1 ( denoted ab1 * ) ( fig . analysis of the fluorescence intensity of each color in both phases reveals a > 3-fold enrichment of ob18 * in ob18-rich domains and a similar enrichment of ab1 * in ab1-rich domains although this is probably a minimum estimate that is limited by optics . the importance of calcium suggests that this divalent cation acts as a crossbridge between polyanionic ab1 chains , and while the electrostatic basis for domain formation might seem intuitive we show below that domain formation occurs only in a highly restricted regime of ph and ion concentration . to assess the possible generality of the effect , a highly anionic and fluorescently - labeled lipid phosphatidylinositol-4,5-bisphosphate ( pip2 ) , was added to the polymer film ; this , too was found enriched in the ab1-rich domains of vesicles ( fig . 1e ) . in a second test of the electrostatic interactions , another divalent cation , copper(ii ) transition metal , was added and indeed found to cause domain formation , although the domains appear more fractured ( fig . s3 ) , probably as a result of the stronger interactions between transition metals and paa21 , 22 . the weaker crossbridging of ab1 by calcium apparently led to phase separation but not strong gelation , so that ab1 molecules can diffuse to form circular domains that coarsen with time in minimizing boundary energy . indeed , a hint of coarsening was seen in our initial studies with a few fully segregated the results above were obtained by making polymersomes with overnight hydration of polymer films heated to 60 c ; longer hydration times indeed give larger domains which coarsen until there is only ~ 1 domain per ( 15 m vesicle ) after roughly 40 hours ( fig . the total area fraction of domains per vesicle remains constant at the initial mixing ratio , independent of hydration time , indicating that phase separation is always complete . calcium - responsive janus vesicles thus controllably form on time scales of days and prove stable for far longer . in using micropipette aspiration to immobilize vesicles , we observed that the extent of aspirated membrane within the pipette depended on the phase being aspirated . 1a , b ) were seen at pressures of 70 pa , whereas no significant projection could be obtained in the continuous ab1 phase ( fig . the difference in domain deformability seemed consistent with an increase in membrane stiffness caused by calcium - mediated bridging between polyanionic chains , but to study this in more detail , we aspirated pure ab1 polymer vesicles and determined an effective rigidity eapp for the membranes as a function of ph and calcium concentration23 . for gel networks21 or polymer brushes composed of weak polyelectrolytes like paa22 , increased ionization results in a greater calcium bridging effect evident in gel or brush volume changes . indeed 3a ) , membrane rigidity increases 20-fold with ionization from eapp(ph0 4 ) 0.6 mn / m to eapp(ph0 6 ) 12.7 mn / m , consistent with a 100-fold decrease in [ h ] across paa s pka ~ 5 . the low - ph polymersomes also exhibit a spherical contour outside of the pipette , typical of liquid - phase vesicles , whereas the stiffer , high - ph vesicles flatten near the pipette mouth as they buckle and distort , similar to covalently crosslinked solid polymersomes23 . whether fluid or gel - like , these vesicles sustain membrane tensions and strains far above those achievable with lipid membranes . the stability is due to polymer membranes being several - fold thicker than lipid bilayers ( d ~ 4 nm ) rather than being intrinsically stiffer . with increasing ph , ab1 membranes become negatively charged , which promotes calcium bridging and membrane rigidification ( fig . 3b ) . however , eapp is more sensitive to calcium concentration than to ph ( fig . the effective rigidity in either case is fit to a power law form : eq . 1eapp = a([ion]/k)a where [ ion ] is either [ h ] or [ ca ] , k is the relevant dissociation constant , a is a pre - factor , and a is a power law exponent . best - fit parameters indicate stronger scaling for calcium than for protons ( aca = 2.5 versus |ah+| = 0.34 ) . calcium also gives much stronger scaling than the linear scaling of polymer network rigidity that is expected with simple covalent crosslinkers ; the enhancment implicates cooperative calcium interactions , perhaps via calcium - induced increases in brush ionization22 . based on these results , domains in the spotted polymersomes at low ph and only moderate [ ca ] are likely to be liquid - like or weak gels consistent with both circular domain shapes and also the noted resistance to aspiration . fluorescence recovery after photobleaching ( frap ) confirmed gelation in the 100% ab1 system . a cationic fluorescent dye ( dio : c18 ) mixed into the ab1 membranes allowed photobleaching of a small circular area ( radius ~ 0.5 m ) on top of individual vesicles , and the time - dependent fluorescence recovery ( fig . 3d ) gave characteristic diffusion times , d , that proved small at very low ph but immeasurably long at ph0 = 5 . 3e ) is nearly linear with proton concentration in the transition regime ( ph0 ~ 4 ) even when fitted to a form similar to that for rigidity ( eq.1 ) , i.e. d = b ( [ h ] / k ) ( b 0.9 and b = 910 m / s ) . frap studies with a neutral hydrophobic dye showed no diffusivity dependence on ph or calcium , confirming that the gelation effects were confined to the paa brush ( fig . s4 ) . based on the measured ph - dependence of membrane rigidity ( fig.3b : | ah+ | = 0.34 ) , the ratio of mobility / rigidity exponents , |b / a| 2.5 , is much larger than that seen with dynamically crosslinked entanglements in bulk polymers for which |b / a| 0.55 24 . electrostatic interactions are apparently more effective in slowing diffusion of ab1 chains than at rigidifying the brush , whereas polymer entanglements have the opposite effect . poly(acrylic acid ) at high ph becomes so highly charged that electrostatic repulsion in ab1 curves the core - brush interface and generates cylindrical micelles20 . mixtures with ob18 * behave no differently except for the narrow range of ph and calcium in which cylinders appear striped ( fig . 4a ) . image overlays clearly show that phase - separated cylinders are both continuous and flexible , with a persistence length of 510 m that is similar to pure systems20 . alternating dark and fluorescent segments are 0.31 m in length , and their area fractions are in approximate proportion to the blend ratios of ab1:ob18 * ( fig . 4b ; table s1 ) . striped nano - scale demixing with strongly segregating block copolymers has been predicted for small diameter cylinders25 and has been observed by electron microscopy both for fluoropolymer - based triblock copolymers10 and for semicrystalline diblocks in epitaxial growth of single nano - stripes13 . here , calcium - mediated interactions yield periodic meso - scale domains that alternate in a periodic fashion that is correlated at length scales up to 17 m ( fig . 4c , fig . distributions of fluorescent domain length l for all compositions fit well ( r _ 0.95 ) to a linear growth model with termination by combination or coarsening , p(l ) ~ l exp(2l / ln ) ( fig . 4d ) , giving a characteristic length ln that proves linear in copolymer ratio ( fig . 4d , inset r = 0.96 ) ) and that predicts tunable , ligand - dependent domain sizes from nm to m . the uniformity in the width of the stripes could be due to the kinetics of domain formation . for example , if the ab1-rich domains have a lower spontaneous curvature than the ob18 domains , then phase separation might proceed via a periodic peristaltic mode26 . coarsening of domains is unlikely in the quasi-1d geometry of a cylinder micelle , since there is little decrease in interfacial area with coarsening . systematic mapping of the ph- and calcium - dependent phase diagram for the 25:75 copolymer mixture ( fig . 5a , fig . s6a ) expands otherwise similar morphological studies with pure ab120 , ( shaded gray with ab1 morphology designated as spherical micelles ( s ) , worm - like micelles ( w ) , and vesicles ( v ) ) , and pinpoints a relatively narrow regime of strong lateral segregation ( sls ) . from ph 3.5 to 5.5 and at [ ca ] = 0.025 to 0.4 mm this stable window of sls corresponds to chemical potential widths of just ~ 25 kbt (= kbt logn{[ion]max/[ion]min } ) . spotted polymersomes dominate at intermediate ph and calcium , but increases in ph and calcium destabilize the membranes and generate higher ph plus high calcium leads , as predicted27 , to re - entrant micelles that are likely over - charged , so that their net charge is positive ( fig . , the blend also exhibits a morphological vesicle - cylinder transition striped cylinders rather than spotted polymersomes form by film rehydration with a slight decrease in calcium and an increase in ph . the fluid - to - gel transition of pure ab1 polymersomes ( filled circles ) and worm - like micelles ( filled squares ) is indicated by the blue ( fluid ) and orange ( gel ) points in the phase diagram . the dashed line provides an estimate of this transition , and clearly indicates that aqueous conditions must be permissive for ab1 gels to achieve phase separation in these assemblies . the generality of the phase diagram was tested with initial studies of giant unilamellar vesicles ( guvs ) containing fluorescent - pip2 , which is amongst the most anionic of natural lipids ( 4 charge near ph 7 ) and which is also a major signaling lipid in the cytoplasmic leaflet of cell membranes28 . guvs composed of 95% dopc , 4.9% pip2 , and 0.1% bodipytr - pip2 and formed by electroformation at 37 c appeared homogeneous at ph 7.5 ( fig . the addition of lipid guvs to calcium - containing buffer ( [ ca ] = 500 m ) induced domains enriched in pip2 within minutes ( fig . guvs incubated in ph = 3 buffer ( where pip2 has a net charge near -1 ) appeared homogeneous ( fig . s7d ) , and no domains were visible in guvs incubated at ph = 3 , [ ca ] = 500 m ( fig . these lipid results show that calcium induces phase separation in mixed lipid vesicles as well as mixed polymer vesicles , and also emphasize that sls occurs only in a narrow region in ph . a simple equilibrium model for sls was derived based on calcium - mediated attraction between polyanionic chains . while attractions , or crossbridges , lead to gelation ( above the blue dashed line in fig . 5a ) , a medley of competing effects restricts calcium - mediated lateral segregation to an even narrower window of calcium concentration and ph . a high net charge favors mixing , since electrostatic repulsion is high in domains rich in polyanion . as a result , sls does not occur at low [ ca ] , where there is little counterion condensation and the net charge of the aggregates is highly negative . the same effect prevents segregation at high [ ca ] , where the charge apparently inverts to a high net positive charge on the aggregates . at high [ h ] ( ph < pka for paa ) few charged groups on the ab1 chains condense the ca required to form crossbridges , therefore mixing is observed between the nearly neutral ab1 and neutral ob18 . as [ h ] decreases , the system segregates with increasing crossbridging , but at lower [ h ] , the entropic penalty associated with confining condensed ca in paa - rich domains increases , favoring mixing once again . the free energy of the polymer - counterion system is calculated as a function of [ h ] , [ ca ] , and , the local fraction of ab1 chains . the role of proton concentration is approximated as setting the bare charge of the ab1 , using standard acid dissociation with a pka ~ 5 . assuming either cylindrical or bilayer geometry , the ion concentrations in the hydrophilic brush of the assembly , [ h]b and [ ca]b are calculated using oosawa s two - state approach to counterion condensation29 including electrostatic screening . in a full electrostatic treatment , ca crossbridges would arise naturally from counterion correlations beyond counterion condensation . here , we treat them phenomenologically , so that the effective attraction energy per crossbridge , ec , is a fitting parameter and the number of crossbridges is estimated by interpolating between two expected limiting behaviors . we assume that every ca ion in the brush is close to a charged acrylic acid group . a crossbridge then forms when a ca ion is also close to a second charged acrylic acid group in a second ab1 molecule . in regions of low ( and hence low [ ca ] ) , this process is limited by the lateral fluctuations of the paa chains , and the crossbridge density is nc , small = [ aa][ca ] . the prefactor depends on the chain lengths and brush density . if all densities are expressed in per polymer chain units then = 0.83 , but our result is robust against variations of this parameter . at moderately large , the crossbridge density is limited by the available ca ions and is therefore nc , large = [ ca ] . the free energy includes a term for electrostatic self - energy and a flory - huggins - like term for the polymer chains . we determine the phase behavior using a double - tangent construction in ; the region in which phase separation occurs is enclosed by a solid black line in fig . the darkness within this region corresponds to the magnitude of a contrast function ( 0 when mixed , 1 when separated into domains of = 0 and = 1 ) , and the dashed - dotted line corresponds to the contour with a contrast of 0.5 . such contours are plotted for worms ( dotted ) and vesicles ( dashed - dotted ) at ab1 fractions of 25% , 50% , 75% ( fig . note that this simple model can not capture the charge inversion of the aggregates , which is a counterion correlation effect , and therefore can not reproduce the high [ ca]-end of the phase diagram correctly . the model also predicts phase separation at [ ca ] significantly lower than observed experimentally . this result is not unexpected as phenomenological treatment of the electrostatics does not yet account for the cooperative interaction between calcium and paa that was demonstrated here by rigidity measurements in which aca / ah+ 7 ( fig . 3b ) exceeds the simple doubling expected from charge differences between ca and h. however , close to the line of zero net charge , the present model reproduces the finite region of phase separation as observed in experiment . responsive janus structures that are highly tunable and stable even at near - physiological conditions ( fig . sls is only observed within a narrow window of solution conditions but in structures as diverse as polymer vesicles , lipid vesicles , and polymer cylinder micelles . the results indicate that the phenomenon is electrostatic in origin and can therefore occur in a wide range of systems : domain shape should be influenced by the addition of different metal cations ( thus far copper and calcium but not sodium ) or chelating agents ( eg . edta ) and domain formation should also occur with polybasic amphiphiles although the limited biological application of positively charged assemblies ( because they bind non - specifically to all negatively charged cell membranes and extracellular matrix ) motivates further study of additional polyanionic assemblies with physiological cations such as calcium . the results here thus open up new routes to dynamic control over structural organization and functionalization within self - assembled synthetic materials . block copolymers of poly(ethylene oxide)-poly(butadiene ) ( peo80-pbd125 , mn = 10,400 g / mol , polydispersity pd = 1.1 , designated ob18 ) or poly(acrylic acid)-poly(butadiene ) ( paa75-pbd103 , mn = 10,050 g / mol , pd = 1.1 , designated ab1 ) were synthesized by standard polymerization or used as described20 . lipids were purchased from either avanti polar lipids ( sopc , pip2 , nbd - pip2 ) or echelon biosciences ( bodipyfl - pip2 , bodipytr - pip2 ) . domain formation in polymersomes and worm - like micelles was visualized by dissolving fluorescently - labeled ob18 ( ob18 * ) and ab1 polymers in chloroform and methanol and then drying to form a blended polymer film . the films were then hydrated in aqueous solution with known ph and calcium concentrations tuned by the addition of hcl and cacl2 . ob18 * was made by attaching tetramethyl rhodamine-5 carbonyl azide ( tmrca ) to the hydroxyl end group of the peo block . the modification involves tmrca conversion to an isocyanate , which then modified the hydroxyl end group of peo to a urethane . this end - group modification was carried out in toluene at 80c for 12 hours . excess , unreacted tmrca dye was removed by a recrystallization and washing process with methanol as verified by gel permeation chromatography . ab1 * was made by attaching the amine - containing cascade blue to acrylic acid monomers along the backbone of the paa chain using standard carbodiimide chemistry . cascade blue was added in 3 times excess of ab1 polymer , and unreacted dye was removed by dialysis and washes with water and methanol . fluorescence microscopy and micropipette aspiration were performed as previously described15 , 25 ( see methods in si for additional details ) .

selective binding of multivalent ligands within a mixture of polyvalent amphiphiles provides , in principle , a mechanism to drive domain formation in self - assemblies . divalent cations are shown here to crossbridge polyanionic amphiphiles that thereby demix from neutral amphiphiles and form spots or rafts within vesicles as well as stripes within cylindrical micelles . calcium and copper crossbridged domains of synthetic block copolymers or natural lipid ( pip2 , phosphatidylinositol-4,5-bisphosphate ) possess tunable sizes , shapes , and/or spacings that can last for years . lateral segregation in these responsive janus assemblies couples weakly to curvature and proves restricted within phase diagrams to narrow regimes of ph and cation concentration that are centered near the characteristic binding constants for polyacid interactions . remixing at high ph is surprising , but a theory for strong lateral segregation ( sls ) shows that counterion entropy dominates electrostatic crossbridges , thus illustrating the insights gained into ligand induced pattern formation within self - assemblies .

the world health organization has estimated that vector - borne diseases account for nearly 17% of the global burden of all infectious diseases.1 mosquitoes are one of the most important disease vectors and can transmit many pathogens including those that cause malaria , dengue , west nile fever and encephalitis , st . louis encephalitis , yellow fever , japanese encephalitis , zika , and chikungunya.2 the risk of exposure to mosquito - borne pathogens is often estimated using indices that include estimates of vector abundance . vectorial capacity , for example , takes into account the vector , host , and vector host interaction , and is a commonly used risk index for assessing the prevalence of malaria and dengue.35 similarly , dengue transmission risk is often measured using the house index , which is the percentage of houses infested with the larvae or pupae of aedes mosquitoes.6 estimates of interactions between vectors and hosts are also commonly used to estimate the risk of west nile virus ( wnv ) transmission.7 due to the multi - host transmission cycle of wnv , kilpatrick et al developed an index combining vector abundance , the fraction of blood meals taken from mammals , wnv infection prevalence , and a vector competence index for alternative vector species to assess wnv transmission risk.8 a simpler vector index , measured as the product of mosquito abundance and the wnv infection rate in mosquitoes , has also been used for wnv transmission risk estimation.911 the advantage of the later method is that it is simple to calculate , and data are more readily collected ; however , it does not consider vector competence . because mosquitoes of different species transmit different pathogens , vector - pathogen - host interactions differ across systems , so system - specific abundance and infection risk estimates must be tailored for particular mosquito - borne diseases and particular areas.12 in the united states , mosquitoes of the genus culex are the vectors for wnv transmission , with nearly 96% of the wnv positive pools obtained from just a few culex species.13 the proportional distribution of these species varied by region , with culex tarsalis , culex quinquefasciatus , and culex pipiens pipiens and culex restuans being dominant in the western , southern , and north central regions , respectively.13 in the chicago , illinois , region , which is the focus of this study , culex pipiens complex and c. restuans have played the most important role in the enzootic as well as the epidemic cycle of wnv transmission.14 the c. pipiens form molestus has been detected in this region as well , but data are limited.15 the life history of culex mosquitoes includes aquatic stages ( eggs , larvae , and pupae ) and the adult terrestrial stage . females lay rafts of eggs on the surface of standing water , with a preference for water rich in organic content . depending upon weather and food availability , adults emerge in about 1014 days.16 adult gravid female c. pipiens enter diapause in the fall to overwinter.16,17 temperature and precipitation play an important role in the life history and population dynamics of mosquitoes . in temperate climates , warmer weather in the spring accelerates mosquito activity , and higher temperatures generally shorten the time between blood meal acquisition and oviposition.12,18 the lifespan of adult culex spp . varies considerably depending on the temperature.19,20 adult female mosquitoes raised over a range of constant temperatures had an average longevity ranging from 11 days to over 92 days.20 the shortest observed life span for both sexes was less than two weeks at 30 c , while they survived more than 90 days at 15 c.20 this suggests that mosquito survival is higher when the temperature is between 15 c and 30 c , and lower when it exceeds 30 c . in natural systems , weather conditions in the weeks prior to mosquito capture ( lagged weather ) can predict the number of mosquitoes captured.2123 even off - season meteorological conditions can affect mosquito abundance due to diapause conditions24 and because prior year drought conditions may reduce the number of predators , resulting in increased mosquito populations.25 many other factors can affect the local abundance of mosquitoes . for example , the availability and distribution of larval habitats depend on both weather and local landscape features . suitable larval habitats , such as natural water bodies , catch basins , and containers , are required to maintain the mosquito population in an area26 and rainfall plays a key role in maintaining these habitats . culex mosquitoes need wet conditions to reproduce , but heavy rainfall can reduce the survival rate of culex vectors both at the adult stage and during larval development.27,28 local vegetation influences mosquito abundance by providing resting sites and sugars to mosquitoes , and different species of vegetation can promote or reduce the emergence rates of adult culex mosquitoes.29,30 in urban areas of connecticut , significantly higher numbers of c. pipiens and c. restuans were found in areas with moderate vegetation as measured from imagery using a vegetation index.31 in other studies , orchard habitat,32 forested areas33 and medium height trees were associated with higher culex abundance.34 in a study conducted in amherst , erie county , ny , culex abundance increased with more mixed urban land use , grass and agriculture land cover , and industrial and recreational areas.35 the abundance of culex spp . mosquitoes collected per trap and then adjusting that for the number of nights in which traps were actually set . the most commonly used traps to collect culex mosquitoes are co2-baited cdc light traps and infusion - baited gravid traps . light traps baited with co2 attract nocturnal phototactic mosquitoes and rely on chemotaxis by host - seeking females , whereas gravid traps attract ovipositing mosquitoes by providing breeding habitat.36 light traps attract host - seeking female mosquitoes that may be parous , but are more often unfed and nulliparous36 and are useful to capture a diversity of mosquito species37 , whereas gravid traps primarily collect ovipositing female culex mosquitoes.38 mosquitoes collected in gravid traps are especially suitable for wnv surveillance if detection of infection status is included in the surveillance plan because gravid mosquitoes have had at least one gonotropic cycle and are thus more likely to be infected.39,40 underlying weather conditions and trap locations might affect the number of culex being captured in light and gravid traps ; however , the differences in these relationships are not well documented . the main objective of this study was to compare abundance measures and factors associated with differences between two common methods for trapping culex vectors in illinois : cdc light traps baited with dry ice and gravid traps containing a liquid oviposition attractant . we evaluated the effects of the trapping method on estimates of culex abundance , taking into account weekly weather conditions and landscape features . we conducted the study between 2009 and 2012 in a suburban chicago , illinois , a region with significant wnv activity . secondarily , we evaluated the relationship between culex abundance and wnv mosquito infection rate during the same period . the study area was in south cook county , illinois , located in the near suburbs of the city of chicago ( fig . the study area is approximately 17 km with a population of around 20,000 people in several municipalities . this study was part of a broader investigation of wnv transmission ecology.41,42 mosquitoes were collected for 18 weeks from late may to early october each year ( weeks 2239 ) from 2009 to 2011 and for 17 weeks ( weeks 2339 ) in 2012 , using both cdc miniature light traps and infusion - baited gravid traps . light traps were hung from a tree or any other structure at a height of about 1.5 m above the ground with a cooler containing dry ice attached each night . gravid trap oviposition attractant was made by placing a half cup of alfalfa pellets in five gallons of water in a carboy that was placed in the sun for about seven days prior to use ( to allow fermentation of organic matter ) and changed every two to four weeks . a portion of both types of traps was set up in the evening and collected the following morning each collection day during each week of collection . traps were distributed throughout the study area in different representative landscapes , including semi - natural sites ( cemeteries , parks , and rights of way ) , and residential areas . the basis for the specific site selections has been described elsewhere.14,4143 over the four - year study period , the number of light trap locations ranged from 29 to 76 per year , with 119 unique locations ; and the number of gravid trap locations ranged from 11 to 31 per year , with 48 unique locations . any trap locations with coordinates recorded less than 20 m apart were treated as a single location . within a single year nearly 99% of the traps were located 50 m away from each other in the same year , with a few exceptions when separated by physical barriers such as a road or thick vegetation . some , but not all , of the trap locations were used in all four years . among the light traps , 55 , 42 , 16 , and 6 trap locations were used for one , two , three , or four years , respectively . among the gravid traps , 24 , 11 , 10 , and 3 trap locations were used for one , two , three , or four years , respectively . after collection , trained personnel determined the mosquito species and sex , and then pools of up to 50 female culex spp . ( c. pipiens complex and c. restuans ) were tested for wnv using quantitative rt - pcr.44 given the difficulties in morphologically differentiating c. pipiens complex and c. restuans , these two species were pooled together and hereafter are referred to as culex spp.45 culex spp . are considered the primary enzootic and bridge vectors of wnv in this area.13,45 the average number of culex spp . per trap night the minimum infection rate ( mir ) of wnv in mosquitoes was estimated using the maximum likelihood method implemented in the program pooledinfrate version 4.0.46 in addition to calculating the mir for the local study - related mosquito collections , we obtained and calculated the mir of culex spp . from wnv testing reported to the illinois department of public health for the broader region ( cook county ) during the same time period . daily weather records from january 2009 to december 2012 were obtained from the nearest noaa weather station at the midway international airport , chicago , illinois , nine miles north of the study area . weather records included daily minimum and maximum temperature , precipitation , average humidity , and average and maximum wind speed . average weekly temperature ( c ) was calculated as the mean of the daily minimum and the maximum temperatures for each week . weekly averages of daily humidity , average wind speed , and maximum wind speed were calculated as the mean of their respective seven readings from that week , and weekly precipitation was calculated as the sum of the precipitation during that week . the study area was in south cook county , illinois , located in the near suburbs of the city of chicago ( fig . the study area is approximately 17 km with a population of around 20,000 people in several municipalities . this study was part of a broader investigation of wnv transmission ecology.41,42 mosquitoes were collected for 18 weeks from late may to early october each year ( weeks 2239 ) from 2009 to 2011 and for 17 weeks ( weeks 2339 ) in 2012 , using both cdc miniature light traps and infusion - baited gravid traps . light traps were hung from a tree or any other structure at a height of about 1.5 m above the ground with a cooler containing dry ice attached each night . gravid trap oviposition attractant was made by placing a half cup of alfalfa pellets in five gallons of water in a carboy that was placed in the sun for about seven days prior to use ( to allow fermentation of organic matter ) and changed every two to four weeks . a portion of both types of traps was set up in the evening and collected the following morning each collection day during each week of collection . traps were distributed throughout the study area in different representative landscapes , including semi - natural sites ( cemeteries , parks , and rights of way ) , and residential areas . the basis for the specific site selections has been described elsewhere.14,4143 over the four - year study period , the number of light trap locations ranged from 29 to 76 per year , with 119 unique locations ; and the number of gravid trap locations ranged from 11 to 31 per year , with 48 unique locations . any trap locations with coordinates recorded less than 20 m apart were treated as a single location . within a single year nearly 99% of the traps were located 50 m away from each other in the same year , with a few exceptions when separated by physical barriers such as a road or thick vegetation . some , but not all , of the trap locations were used in all four years . among the light traps , 55 , 42 , 16 , and 6 trap locations were used for one , two , three , or four years , respectively . among the gravid traps , 24 , 11 , 10 , and 3 trap locations were used for one , two , three , or four years , respectively . after collection , trained personnel determined the mosquito species and sex , and then pools of up to 50 female culex spp . ( c. pipiens complex and c. restuans ) were tested for wnv using quantitative rt - pcr.44 given the difficulties in morphologically differentiating c. pipiens complex and c. restuans , these two species were pooled together and hereafter are referred to as culex spp.45 culex spp . are considered the primary enzootic and bridge vectors of wnv in this area.13,45 the average number of culex spp . per trap night the minimum infection rate ( mir ) of wnv in mosquitoes was estimated using the maximum likelihood method implemented in the program pooledinfrate version 4.0.46 in addition to calculating the mir for the local study - related mosquito collections , we obtained and calculated the mir of culex spp . from wnv testing reported to the illinois department of public health for the broader region ( cook county ) during the same time period . daily weather records from january 2009 to december 2012 were obtained from the nearest noaa weather station at the midway international airport , chicago , illinois , nine miles north of the study area . weather records included daily minimum and maximum temperature , precipitation , average humidity , and average and maximum wind speed . average weekly temperature ( c ) was calculated as the mean of the daily minimum and the maximum temperatures for each week . weekly averages of daily humidity , average wind speed , and maximum wind speed were calculated as the mean of their respective seven readings from that week , and weekly precipitation was calculated as the sum of the precipitation during that week . the weekly abundance estimates from light trap collections were compared with the abundance measured from gravid traps . the response variable for all analyses was the average number of culex per trap night . data from traps , where a trap failed on a given night , were removed from analyses to avoid the artifact of pseudo - negative catches . predictor variables for temporal analyses included weekly average temperature , total precipitation , average humidity , average wind speed , and average maximum wind speed of the same week . in addition , we assessed each of these predictor variables at one to four week lags . in total , there were 25 weather variables : five each for temperature , precipitation , average humidity , average wind speed , and average maximum wind speed ( table 1 ) . descriptive statistics were calculated using the command proc univariate in sas 9.4 ( sas institute inc . ) . wilk w statistic ( > 0.9 ) was used to test the normality of outcome variables . in the original dataset , the culex spp . per trap night in both light and gravid traps per trap night data above the 95th percentile , and captures higher than that value were assigned the value of the 95th percentile , after which data were normally distributed ( w > 0.9 ) . pearson s product - moment correlation coefficient was used to measure the association between weekly average culex spp . per trap night by trap type . bivariate correlation analyses of individual predictor variables were conducted , and variables with p < 0.2 were selected for inclusion in a multivariable regression model . multiple linear regression analysis was performed to explore the relationship between the response variable and the selected predictor variables using the command proc glm in sas . the variance inflation criterion ( vif < 10 ) was used to evaluate multicollinearity among explanatory variables . the akaike information criterion ( aic ) the model with the lowest aic value was selected as the model that best fit the data.47 the variable selection criterion for the final multivariate regression was p < 0.05 . for spatial analysis , light and gravid trap locations from 2009 to 2012 were classified as being either in residential areas or in semi - natural areas . the independent variable was the landscape type ( whether the traps were located in residential or semi - natural areas ) . mosquitoes from 3,444 trap nights with 1476 light traps set per week during 71 weeks from 2009 to 2012 . across all light trap collections , per trap night , with an overall mean of 5.5 ( 12.9 sd ) . over the 71 weeks , the weekly light trap collections with all locations combined averaged between 0.4 and 24.3 culex spp . per trap the next highest average abundance estimate per trap night was 4.5 ( 3.1 sd ) in 2009 , followed by 4.4 ( 3.4 sd ) in 2012 , and 4.1 ( 2.8 sd ) in 2011 . gravid traps captured a total of 22,345 culex spp . from 1,561 trap nights with 631 gravid traps set per week during 71 weeks from 2009 to 2012 . across all gravid trap collections , per trap night with a mean of 14.3 ( 33.2 sd ) . over the 71 weeks , the weekly gravid trap collections with all locations combined averaged from 0.1 to 192.6 culex spp . per trap the highest overall average culex per trap night was in 2009 , with a value of 26.2 ( 44.5 sd ) . the next highest average abundance estimate per trap night was 18.6 ( 13.1 sd ) in 2010 , followed by 10.1 ( 9.1 sd ) in 2012 , and 8.4 ( 7.0 sd ) in 2011 . the highest annual mir for the small study area alone was 15.7 in 2009 , followed by 11.8 in 2010 , 9.2 in 2012 , and 0.6 in 2011 . county - level mir was 1.0 in 2009 , 5.3 in 2010 , 9.8 in 2012 , and 3.5 in 2011 . the exception was during the weeks 3539 in 2011 and weeks 3638 in 2012 , when the light traps had higher capture rates . this happened when weather conditions during those weeks were within the average range for those weeks . 3 ) averaged across the four years demonstrated that there was greater variance in culex spp . abundance collected in gravid traps compared to light traps , and there was a slight peak in gravid trap collections around weeks 2629 and again at weeks 3234 . in light traps , a bimodal distribution was observed with a first peak at week 26 and a second peak at weeks 3234 ( fig . ( about mid - august ) , abundance was generally low and decreasing in both trap types , and most of the anomalous culex spp . of the more than 5,000 collections , 95 data points ( individual collections ) were removed from the analysis in four years from light traps and gravid traps due to trap failures . with 71 weeks of data without truncating for outliers , there was no measurable correlation between average abundance in light traps and the average abundance in gravid traps ( r = 0.03 ) . however , after truncating the outliers , the correlation was stronger , although still marginal ( r = 0.219 ; p = 0.06 ; n = 71 ) ( fig . using aic , light trap data were best fit with a model that included five weather variables ( aic = 319.6 ) , which explained 28% of the variation in culex spp . abundance ( adjusted r = 0.276 ) ( table 2 ) . for gravid traps , data were best fit with an analogous model including five weather variables ( aic = 484.2 ) , which explained about 30% of the variability of abundance ( adjusted r = 0.303 ) ( table 3 ) . in light traps , the culex spp . abundance was higher with higher temperature in the same week , higher precipitation one , two , and four weeks before , and a lower maximum average wind speed in the same week ( table 4 ) . abundance was higher with higher temperature in the same week and one week before , higher precipitation two and four weeks before , and lower temperature four weeks before ( table 5 ) . of the 119 light trap locations , 53 were in semi - natural areas and 66 were in residential areas . from the light traps , the average number of culex spp . captured in natural areas was 5.3 ( 5.0 sd ) and was 2.7 ( 3.1 sd ) in residential areas . of the 48 gravid trap locations , 29 were in semi - natural areas and 19 were in residential areas . from gravid traps , the average number of culex spp . captured in natural areas was 12.4 ( 8.5 sd ) , whereas for residential areas it was 11.8 ( 7.5 sd ) . while both light and gravid trap collections resulted in higher numbers of culex spp . when traps were located in the semi - natural areas ( fig . 5 ) , the difference was statistically significant only for light traps ( p = 0.0002 ) . our results demonstrated that culex abundance estimates across urban landscapes vary with the trapping method , and that spatial , temporal , and weather - related factors influence these estimates . in particular , strong winds reduced abundance in light traps but did not noticeably affect gravid trap collections . abundance estimates were generally higher in semi - natural areas from both trap types , but this difference was stronger for light traps . both gravid and light traps had higher abundance when set during weeks with warmer temperatures and when conditions were wetter during the previous several weeks . higher abundance in gravid traps also followed warmer temperatures during the prior week , but this effect was not seen in light traps . the differences observed in the collections from light and gravid traps may be related to their tendency to collect mosquitoes from different life stages . temperature is an important factor in mosquito abundance because it affects the life history traits of mosquitoes . the positive association between prior temperature and culex abundance has been observed in several other studies.21,4852 mechanistically , high temperatures may support faster growth of mosquito larvae53 and adult emergence and increase the number captured . however , following emergence , the ambient temperature may either increase or decrease adult mosquito longevity . lebl et al found that higher temperatures two weeks prior to capture increased culex abundance in light traps21 , while accumulated temperature one to four weeks before capture was negatively correlated with c. pipiens abundance.54 these equivocal findings suggest that there may be a temperature threshold , above or below which mosquito survival and activity markedly decrease . higher abundance of mosquitoes in gravid traps after cooler temperatures four weeks before suggests that mosquito longevity may increase in cooler temperatures , making a larger pool of adults ready to oviposit with higher temperatures.55 precipitation also appears to drive culex abundance . the positive relationship between precipitation at one to four weeks prior and culex abundance has also been observed in other studies.21,42,45,47 however , the relationship between precipitation and culex abundance is not necessarily linear . pecoraro et al found no association between weekly precipitation and culex abundance,51 but at more protracted temporal scales , correlations were positive in some years and negative in others.48 lebl et al found that precipitation had a weaker association with abundance than other weather variables , with higher precipitation over 10 weeks associated with higher abundance . in the same chicago study system , gardner et al documented that culex larval abundance was associated with low rainfall , and suggested that precipitation greater than 3.5 cm during a single week may flush immature culex out of larval habitats.28 our data with adult mosquitoes demonstrate a similar pattern , where precipitation in the weeks prior to sampling increases adult abundance by providing habitat for adult females to lay egg rafts . alternatively , this relationship between high culex abundance following rain events might have more to do with favorable ambient conditions for adults ( eg , higher humidity reducing desiccation risk ) , which could promote activity and increase trapping success . though the gravid traps can themselves act as a larval habitat because of the water availability in those traps , we found positive relationships between prior rainfall and culex spp . abundance estimates in both light and gravid traps , without an indication that gravid traps collected more mosquitoes during dry periods . wind speed affects mosquito host - seeking activities and flight direction . in this study , the maximum average wind speed of the same week of capture was negatively associated with culex abundance in light traps but not gravid traps . cdc light traps were set approximately 1.5 m above the ground , whereas gravid traps were placed directly on the ground : it is possible that this subtle difference in trap height may have exposed host - seeking and adult females to different wind conditions.56 indeed , hamer et al found that culex spp . may move as far as 2.48 km , but that this dispersal was likely mediated by wind.42 similarly , lebl et al found that average wind speed three weeks prior to capture was negatively associated with culex abundance.21 landscape features may also affect mosquito production through variation in breeding habitat and resting places for adult mosquitoes . mosquitoes were captured in natural areas than in residential areas , whereas in the gravid traps , this variability was negligible . availability of hosts and competition with natural container habitats , respectively , may modify these relationships . for example , more birds in natural areas could result in more host - seeking mosquitoes being present and thus available for light trap capture . lower numbers of culex mosquitoes in light traps in residential areas may also be related to mosquito abatement practices that target those areas , such as pesticide treatments for adult mosquitoes and the placement of larvicides in urban catch basins.57 in a study conducted in suffolk county , new york , the highest abundance of c. pipiens was in areas where wnv was mostly prevalent in birds , not in humans , and this may be the case in the current study region as well.58 further , comparison of our findings to other studies is somewhat confounded by how landscapes are defined . our study occurred within an urban area , and our semi - natural areas were relatively small patches within a highly urbanized landscape . if we had used the same index of urbanization that was used to assess culex spp . abundance in new york , for example , all our sites would have been classified as urban.59 the estimated abundance of mosquitoes was not clearly correlated with mosquito infection rates or negative public health outcomes . the illinois department of public health reported only one human wnv case in cook county illinois in 2009 when abundance estimates from gravid traps were higher than any of the four years . there were 30 cases of wnv reported in 2010 , 22 cases in 2011 , and 174 cases in 2012 , clearly indicating that 2012 was a locally notable wnv outbreak year.60 during 2012 , temperatures were above average ( hot ) and rainfall was below average ( dry ) , supporting prior patterns of higher mir observed by ruiz et al.61 the mir was also higher in 2012 in cook county at large , but the local mir in 2012 in our smaller study area was higher in 2009 and 2010 than in 2012 , highlighting the variability of the wnv transmission potential and surveillance outcomes at different scales . messina et al found that mir in the chicago area was not associated spatially with human illness after controlling for other factors in a multivariate regression , and differences in mosquito abundance or a failure to capture temporal and spatial dynamics may have accounted for this.62 it was not possible to compare the relationship between mosquito abundance , mir , and the reported wnv human illness at a broader level due to the lack of comprehensive mosquito abundance data at that scale . future work should include the collection of additional abundance estimates and consider alternative spatio - temporal approaches . mosquito vector abundance is an important theoretical predictor of human infection , especially for multi - host pathogens . the weak correlation between the fine - scale mosquito abundance estimates and regional measures of human wnv illnesses observed in our study area may be related to the differences in the geographic scale of analysis . our data demonstrate that in the cook county , illinois , gravid and light traps set at the same time in similar conditions do not produce identical abundance estimates . these findings highlight both the importance of local weather and landscape features in combination with the trapping methods for the development of mosquito abundance measures that are relevant to public health . our findings indicate that abundance estimates obtained from only one type of trap , for a short period of time , and from a limited sampling of landscape types , may not truly represent mosquito abundance . consequently , investment into long - term surveillance that accounts for different habitats within a control district , and that implements different trapping methods , will give better estimates of mosquito abundance for use in the assessment of arboviral transmission risk in human populations .

the local abundance of culex mosquitoes is a central factor adding to the risk of west nile virus transmission , and vector abundance data influence public health decisions . this study evaluated differences in abundance estimates from mosquitoes trapped using two common methods : co2-baited cdc light traps and infusion - baited gravid traps in suburban , chicago , illinois . on a weekly basis , the two methods were modestly correlated ( r = 0.219 ) across 71 weeks over 4 years . lagged weather conditions of up to four weeks were associated with the number of mosquitoes collected in light and gravid traps . collections in light traps were higher with higher temperature in the same week , higher precipitation one , two , and four weeks before the week of trapping , and lower maximum average wind speed . collections in gravid traps were higher with higher temperature in the same week and one week earlier , lower temperature four weeks earlier , and with higher precipitation two and four weeks earlier . culex abundance estimates from light traps were significantly higher in semi - natural areas compared to residential areas , but abundance estimates from gravid traps did not vary by the landscape type . these results highlight the importance of the surveillance methods used in the assessment of local culex abundance estimates . measures of risk of exposure to west nile virus should assess carefully how mosquito abundance has been estimated and integrated into assessments of transmission risk .

WASHINGTON — Michelle Obama had a rare face-off with a heckler at a Democratic fund-raiser on Tuesday evening before the protesting woman, shouting for gay rights, was escorted out by party supporters. When Mrs. Obama was roughly 12 minutes into her 20-minute remarks at a home in Northwest Washington, a woman at the front of a crowd of about 200 people began shouting for President Obama to issue an executive order barring federal contractors from discriminating against employees based on sexual orientation or gender identity. But where Mr. Obama, more accustomed to such interruptions, typically waits in place for the protester to stop and perhaps acknowledges the complaint, his wife chose direct confrontation. She left the lectern and moved toward the heckler. “One of the things I don’t do well is this,” she said, to loud applause. She said the protester could “listen to me, or you can take the mike, but I’m leaving. You all decide. You have one choice.” The crowd yelled for Mrs. Obama to stay, with one woman nearby telling the protester, “You need to go!” Attendees escorted the protester out as she yelled further, at one point identifying herself as a “lesbian looking for federal equality before I die.” ||||| WASHINGTON -- First lady Michelle Obama's speech Tuesday evening at a private Democratic National Committee fundraiser was interrupted by a protester, who demanded equality for gays and lesbians. About 12 minutes into Obama's 20-minute speech, a woman standing at the front of the crowd began yelling for an executive order on lesbian, gay, bisexual and transgender rights. "One of the things that I don't do well is this," replied Obama to loud applause. She left the lectern and approached the protester, inviting the woman to "listen to me, or you can take the mic, but I'm leaving. You all decide. You have one choice." The crowd shouted that they wanted Obama to stay, and one woman near the protester said, "You need to go!" The protester was then escorted out, saying she wanted "federal equality before I die." Heather Cronk, co-director of the pro-LGBT rights group GetEQUAL, said the protester was Ellen Sturtz, 56, one of the organization's activists. Sturtz was calling for an executive order to bar discrimination by federal contractors based on sexual orientation or gender identity. LGBT groups have been disappointed that President Barack Obama has refused to issue such an order, while the Employment Non-Discrimination Act -- which would prohibit such discrimination in hiring more broadly -- remains stuck in Congress. In an interview later with The Huffington Post, Sturtz, a divorced lesbian, said she didn't go to the event intending to interrupt Obama. She said she instead planned to reach out to someone from the DNC about her concerns. But as the first lady urged the audience to make the country a better place for the next generation, Sturtz said she decided to speak up. "I want to talk about the children," she said. "I want to talk about the LGBT young people who are ... being told, directly and indirectly, that they're second-class citizens. I'm tired of it. They're suffering. ... We've been asking president to sign that ENDA executive order for five years. How much longer do we need to wait?" Sturtz donated to the DNC in 2008, she said, in large part because she believed the president would fight to end workplace discrimination. She said she was disappointed in the first lady's response at the fundraiser. "Basically, I was asked by the first lady to be quiet, and I can't be quiet any longer. ... I was surprised by how negative the crowd seemed to be. It was actually a little unsettling and disturbing," said Sturtz. "She obviously thought she was going to make an example of me or something. I wasn't scared at all," she added. Cronk said there were three other GetEQUAL activists at the event. One was Autumn Leaf, 22, who interrupted DNC Chair Rep. Debbie Wasserman Schultz's (D-Fla.) speech beforehand, also calling for the executive order. Leaf said Wasserman Schultz replied that the way to get ENDA passed was to help Democrats retake the House. He said he was "disappointed" in Obama's reaction to Sturtz and surprised she "approached Ellen as aggressively as she did." The DNC fundraiser on Tuesday took place in the backyard of the home of donors Karen Dixon and Nan Schaffer in Washington. Tickets for the event ranged from $500 to $10,000, according to a DNC official, although Cronk said there was also a $100 student/young professional rate that several of the GetEQUAL activists qualified for. Obama's main thrust in her speech was to urge donors to stay engaged and back the president's agenda, even though there's no presidential election coming up. "That is why it is simply not enough to just elect a president every four years," she said. "We need you to be engaged in every election -- every election -- because special elections matter. Mid-term elections really matter. It matters who we send to Congress. It matters. And if you don't believe me, just look at the record. Look at the difference just a few votes in Congress can make when it comes to the issues that we say we care about." This article has been updated with additional information.

– Michelle Obama—taking a harder line on heckling than her husband tends to do—confronted a woman who interrupted her speech at a Democratic fundraiser last night, the New York Times reports. After the woman shouted about gay rights, Obama said, "One of the things I don’t do well is this," and moved toward the heckler. As the crowd cheered, she said the woman could "listen to me, or you can take the mike, but I’m leaving. You all decide. You have one choice." The crowd shouted that they wanted Obama to stay and the heckler was escorted out of the room. The woman, who demanded that the president sign an executive order banning federal contractors from discriminating against gays and lesbians, says she was "taken aback" by the first lady's response—and the reaction from the audience. "I was surprised by how negative the crowd seemed to be," she tells the Huffington Post. "It was actually a little unsettling and disturbing."

a historical description of developments in endocarditis closely reflects concurrent developments in laboratory medicine , particularly microbiology . much of the innovations and developments relating to infective endocarditis were made by physicians in europe , particularly in france ( table a1 ) . important contributions were , however , made by several german physicians , particularly in association with the birth of bacteriology ( table a1 ) . more recently , the united states has played a strong role in helping define guidelines and diagnostic criteria that facilitate diagnosing infective endocarditis , including the beth israel ( 5 ) , duke ( 6 ) ( table 1 ) , and modified duke criteria ( 7,8 ) ( table 2 ) . in addition , the american heart association has published several seminal articles on the antibiotic treatment and prevention of infective endocarditis ( 9 ) . source ( 6 ) ; hacek , haemophilus aphrophilus , actinobacillus actinomycetemcomitans , cardiobacterium hominis , eikenella corrodens , and kingella kingae group ; toe , transesophageal echocardiogram . sources ( 7,8 ) ; crp , c - reactive protein ; esr , erythrocyte sedimentation rate . for approximately the first 200 years after the disease was initially described , the anatomy of the heart and heart valves in the diseased state of infective endocarditis was comprehensively elucidated in medical anatomical sketches made after postmortem examination . ( for a comprehensive account of the early description of endocarditis , see contrepois . ) not until the early to mid-1800s were descriptions recorded of the medical signs and symptoms of the disease in live patients . detection of such murmurs was aided by the development of the stethoscope in 1816 . from 1830 to 1840 , elevated body temperature was recorded as an important symptom of the disease . however , not until the late 1800s and early 1900s was a comprehensive synthesis of information formed by various scholars in europe and north america , including sir william osler in canada ( 2 ) and thomas horder in england ( 11 ) ( table a1 ) . osler and horder were instrumental in establishing fundamental mechanisms regarding the pathophysiology of infective endocarditis and are , to a large degree , responsible for how we view endocarditis today . the figure and table a1 chronologically map the history of infective endocarditis , including diagnostic developments , treatment , and prevention , and emerging causal agents . historial timeline describing concurrent developments regarding the history of emerging causal agents of infective endocarditis ( ie ) , diagnostic developments , treatment options , and diversity of causal agents . the birth of bacteriology as a separate discipline of pathology gave rise to the introduction of the important description of microbiology in the etiology of infective endocarditis . with the early technical innovations of pasteur in france in the 1880s , routine blood cultures were introduced in the late 19th century as an important part of laboratory investigation into the microbiologic causes of infective endocarditis . although causal agents of infective endocarditis could now be detected and clearly described , little could be achieved in terms of their eradication because the existence of antibiotics was as yet unknown . however , in germany , gerard domagk , bacteriologist and pathologist , was appointed as director of the i.g . domagk was innovative in that he began to experiment with dyes , looking for their possible effects against various infections . he described the effect of prontosil red against streptococcal infections in mice ; the active component of prontosil was later described as sulfanilamide . at approximately the same time , sir alexander fleming discovered the antibacterial effects of a secondary metabolite ( penicillin ) , produced from a filamentous fungus . such discoveries were revolutionary because medicine now had an effective means of treating bacterial infections , including infective endocarditis , caused by a wide variety of bacterial pathogens , most notably streptococcus species . since wild - type pathogens had not had sufficient time to develop resistance to these newly described antimicrobial agents , treatment failures due to resistance were infrequent . fleming did observe , however , that some organisms were resistant to penicillin and suggested that the phenomenon be followed up . approximately 60 years later , the marked increase in resistance to antimicrobial agents is cause for concern on all continents . the tangible consequence is that clinicians may have fewer antimicrobial agents to treat both benign and serious infections , including infective endocarditis . to combat the threat of such a " postantibiotic era , " the global pharmaceutical industry has responded by producing novel antimicrobial agents , including the carbapenems ( imipenem and ertapenem ) , the oxozolidones ( linezolid ) , and improved antifungal agents ( caspofungin and voriconazole ) , which prolong antimicrobial effectiveness before the problem of resistance evolves with such new agents . over the past century , streptococci and staphylococci have remained the main causative organisms associated with infective endocarditis , with an increase in cases due to staphylococci associated with injection drug users and hiv patients . with substantial advances made in the isolation and identification of microorganisms , although rare , infective endocarditis is caused by gram - negative organisms such as the hacek ( haemophilus aphrophilus , actinobacillus actinomycetemcomitans , cardiobacterium hominis , eikenella corrodens , kingella kingae ) group , bartonella spp . , and coxiella burnetii . more recently , cases of fungal endocarditis have increased , particularly in postoperative patients , injection drug users , and immunocompromised patients ( 4 ) . a history of rheumatic fever can serve as a risk factor for acquiring infective endocarditis . the incidence of rheumatic fever , which was common as recently as a century ago , is relatively rare today ( 12 ) . this decline in the incidence of rheumatic fever has not been mirrored by a pro rata decrease in the incidence of infective endocarditis , which suggests that additional etiologic factors are becoming more important in acquiring endocarditis . although endocarditis has been documented for approximately 450 years , the diagnostic challenges and treatment dilemmas are as real today as they were in the time of fernel ( 3 ) . major advances have been made in the diagnosis of endocarditis , in both laboratory and clinical ( imaging ) parameters , but we are witnessing the emergence of several newly described causal bacterial species , such as tropheryma whipplei and bartonella spp . , as well as sporadic case reports of unusual and uncommon causal organisms , including finegoldia sp . , gemella spp . , and abiotrophia defectiva . in addition , since diagnostic methods , mainly 16s rdna polymerase chain reaction ( pcr ) and sequencing , are now beginning to identify such infections , no evidence base exists to help determine effective antimicrobial drug regimens to successfully treat endocarditis caused by such organisms . furthermore , as specimens from many of these infections are culture - negative , conventional antibiotic susceptibility testing does not help the cardiologist decide on the most suitable antimicrobial drug regimens . another current concern is that we may be returning to a time in which we are largely unable to successfully treat simple infections from panresistant organisms , a scenario that some have described as the postantibiotic era . indeed , in northern ireland , we have now witnessed our first cases of penicillin - resistant pneumococcal meningitis and endocarditis . the increasing incidence of congenital heart disease in children and changing social trends accentuate risk factors for endocarditis . endothelial cell dysfunction , resulting from a combination of atypical mechanical forces due to altered cardiac architecture and microbial infection , may lead to an episode of infective endocarditis . because the endothelium helps regulate vascular tone , inflammation , thrombosis , and vascular remodeling , any insult to the host endothelium may result in infective endocarditis , in which the valves may show changes in the synthetic , morphologic , and metabolic functions of the valvular endothelial cells ( 13 ) . although a relatively uncommon infection , infective endocarditis has been the primary cause of death of several well - known persons , particularly those involved with the arts . one of the late 19th and early 20th century 's most influential composers , gustav mahler ( 18601911 ) , died from streptococcal endocarditis ( 10,14 ) . the first sign of valvular problems was observed in 1907 , where a compensated mitral contraction was noted . for the next 3 years , he showed little evidence of symptoms of valvular disease until late 1910 , when he spent christmas and the new year 's holiday nursing a sore throat . he was in new york city where he conducted a philharmonic orchestra concert on january 17 , including the first performance of a revised version of his fourth symphony . on february 24 , he became ill with endocarditis , initially diagnosed as influenza . he was attended by one of the most prominent physicians in the city , emanuel libman , an important exponent of the value of bacterial blood cultures . libman demonstrated the presence of viridans streptococci in a large volume ( 200 ml ) of blood drawn from mahler . mahler 's initial treatment consisted of a " serum treatment " of the times , as well as metchnikoff 's bulgarian milk . the latter treatment appeared to work , until early may when blood cultures returned positive with viridans streptococci . the endocarditis was now very marked , with septic abscesses beginning to appear in other parts of his body . on may 18 his untimely death prevented society from hearing him conduct a completed version of his tenth symphony as well as his own opportunity to hear the first public performance of his ninth symphony , which took place on june 26 , 1912 , by the vienna philharmonic orchestra . ottorino respighi ( 18791936 ) was an italian composer who died at the age of 57 from endocarditis . the first signs of respighi 's endocarditis were noted in late 1935 , when he was working on his opera lucrezia ; at that time , he was observed to be extremely fatigued , but the cause was unknown ( 14 ) . in january 1936 , s. viridans endocarditis was noted when this organism was isolated from his blood . although sulfonamide drugs were dispatched from berlin for his treatment , the treatment was unsuccessful , possibly due to the advanced stages of sepsis . one of scotland 's most famous poets , roberts burns ( 17591796 ) , perhaps best known for writing auld lang syne , also had infective endocarditis . some historians claim that burns 's work in his teenage years on his father 's tenant farm in southwest scotland did the primary damage to his health . burns was attended medically by william maxwell ( 17601834 ) , who described burns 's symptoms as " flying gout " and prescribed sea - bathing in country quarters and horse riding , so - called cures that probably hastened burns 's death . however , burns 's affinity for alcohol may have contributed to the suppression of his immune system , thus hastening the illness and ultimately his death . one of the most famous physicians to die of endocarditis was alois alzheimer ( 18641915 ) . alzheimer is most widely known for his description of an " unusual disease of the cerebral cortex , " which affected a woman in her fifties , causing memory loss , disorientation , hallucinations , and ultimately her death at age 55 . the disease was named after him by his senior mentor at the munich medical school , emil kraepelin . alzheimer was also cofounder and copublisher of the journal zeitschrift fr die gesamte neurologie und psychiatrie . alzheimer 's last position was professor of psychiatry at the university of breslau ( now wroclaw , poland ) , which he held for the last 3 years of his life . historians report that a severe cold was the beginning of alzheimer 's final illness , but endocarditis was responsible for his death at the age of 51 years ( 16 ) . orville gibson , guitar manufacturer ( 18561918 ) , was another musician who died from endocarditis ( 17 ) . gibson 's patent contained his ideas for the construction of a mandolin with a carved top and back and with sides , which were constructed from a solid section of wood rather than from thin strips . in 1902 , gibson 's physical and mental health began to fail , and he had a history of poor health until 1911 . lawrence state hospital , ogdensburg , new york , in august 1916 , a psychiatric center . on august 21 , 1918 , gibson died of endocarditis while a patient in the institution . rudolph valentino ( 18951926 ) , a famous actor of the silent screen , also had endocarditis , which also led to his death ( 18 ) . valentino had a perforated gastric ulcer closed on august 15 , 1926 ; however , he died from endocarditis on august 23 , 1926 , at the age of 31 years . more recently , endocarditis has been described as the cause of death for john glascock ( 19511997 ) , the recording bass player with the rock band jethro tull . glascock had a tooth abscess , which was believed to be the site of entry for an infectious agent that caused endocarditis . endocarditis developed in brian littrell ( 1975 ) , singer with the backstreet boys , at the age of 5 years ( he was born with a ventricular septal defect , although surgery was not recommended at the time ) ( 19 ) . endocarditis also developed in a young american actor , sebastian hitzig , after he accidentally stepped on a toothpick contaminated with staphylococcus aureus . in conclusion , considering infective endocarditis to be an " emerging " problem in the 21st century may seem unusual , given that the illness has been well documented over the last 450 years . however , such emergence can be attributed to several factors : 1 ) the emergence of antimicrobial resistance in classic infective endocarditis microflora , namely , the gram - positive cocci ; 2 ) the existence of antimicrobial resistance in complex ecologic biofilms ; 3 ) the changing pattern of causal agents now regarded as important pathogens of infective endocarditis , e.g. , bartonella spp . , t. whipplei , and fungi ; and 4 ) changing epidemiologic trends of persons who acquire infective endocarditis , including injection drug users , persons with hiv / aids , children with congenital heart defects , and persons undergoing body piercing . furthermore , the way we provide inpatient medical care has also been associated with the emergence of nosocomial infective endocarditis , which can result from invasive procedures such as catheterization , although no cardiac surgery has been performed . the next 100 years will likely witness the emergence of even more changing trends of infective endocarditis , which as yet have not been well recognized . although this " old " disease has evolved over the last 450 years , diagnostic and treatment options have developed in tandem , and the prognosis of this disease has markedly improved . however , the emergence of novel etiologic agents , changing social trends , and increased antimicrobial resistance have allowed this disease to remain evasive , which will require new approaches , particularly relating to treatment options in the future . historial timeline describing concurrent developments regarding the history of emerging causal agents of infective endocarditis ( ie ) , diagnostic developments , treatment options , and diversity of causal agents .

infective endocarditis , a serious infection of the endocardium of the heart , particularly the heart valves , is associated with a high degree of illness and death . it generally occurs in patients with altered and abnormal heart architecture , in combination with exposure to bacteria through trauma and other potentially high - risk activities involving transient bacteremia . knowledge about the origins of endocarditis stems from the work of fernel in the early 1500s , and yet this infection still presents physicians with major diagnostic and management dilemmas . endocarditis is caused by a variety of bacteria and fungi , as well as emerging infectious agents , including tropheryma whiplei , bartonella spp . , and rickettsia spp . we review the evolution of endocarditis and compare its progression with discoveries in microbiology , science , and medicine .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Nurse Loan Forgiveness Act of 2002''. SEC. 2. ESTABLISHMENT OF PROGRAM. (a) Stafford Loans.--Part B of title IV of the Higher Education Act of 1965 is amended by inserting after section 428K (20 U.S.C. 1078-11) the following new section: ``SEC. 428L. LOAN FORGIVENESS FOR NURSES. ``(a) Statement of Purpose.--It is the purpose of this section to encourage individuals to enter and continue in the nursing profession. ``(b) Program Authorized.--From the amount appropriated under subsection (g) for any fiscal year, the Secretary shall, in accordance with subsection (c), carry out a program, through the holder of the loan, of assuming the obligation to repay a qualified loan amount for a loan made under section 428 or 428H for any borrower who-- ``(1) has been employed for 3 consecutive calendar years as a full-time registered nurse in a health care facility or a health care setting approved by the Secretary of Health and Human Services for purposes of this section; and ``(2) is not in default on a loan for which the borrower seeks forgiveness. ``(c) Qualified Loans Amount.-- ``(1) In general.--Except as provided in paragraph (2), the Secretary may, from funds appropriated under subsection (g)(1), repay not more than $5,000 in the aggregate of the loan obligation on a loan made under section 428 or 428H that is outstanding after the completion of the third complete year of nursing described in subsection (b)(1). ``(2) Additional amounts.--Notwithstanding the amount specified in paragraph (1), the aggregate amount that the Secretary may, from funds appropriated under subsection (g)(2), repay is a total amount equal to not more than $12,000 for any registered nurse who, in addition to meeting the requirements of subsection (b), has been employed as required by such subsection for 5 consecutive calendar years. ``(3) Award basis.--The Secretary shall make payments under this subsection on a first-come first-served basis, subject to the availability of appropriations. ``(4) Treatment of consolidation loans.--A loan amount for a loan made under section 428C may be a qualified loan amount for the purposes of this subsection only to the extent that such loan amount was used to repay a Federal Direct Stafford Loan, a Federal Direct Unsubsidized Stafford Loan, or a loan made under section 428 or 428H for a borrower who meets the requirements of subsection (b), as determined in accordance with regulations prescribed by the Secretary. ``(d) Regulations.--The Secretary is authorized to issue such regulations as may be necessary to carry out the provisions of this section. ``(e) Construction.--Nothing in this section shall be construed to authorize any refunding of any repayment of a loan. ``(f) Prevention of Double Benefits.-- ``(1) National and community service.--No borrower may, for the same service, receive a benefit under both this subsection and subtitle D of title I of the National and Community Service Act of 1990 (42 U.S.C. 12571 et seq.). ``(2) Direct loan forgiveness.--No borrower may receive a reduction of loan obligations under both this section and section 460A. ``(g) Authorization of Appropriations.--For fiscal year 2003 and for each of the 4 succeeding fiscal years, there are authorized to be appropriated such sums as may be necessary-- ``(1) to repay loans in the amount specified in subsection (c)(1); and ``(2) to repay loans in the additional amount specified in subsection (c)(2).''. (b) Direct Loans.--Part D of title IV of the Higher Education Act of 1965 is amended by inserting after section 460 (20 U.S.C. 1087j) the following new section: ``SEC. 460A. LOAN FORGIVENESS FOR NURSES. ``(a) Statement of Purpose.--It is the purpose of this section to encourage individuals to enter and continue in the nursing profession. ``(b) Program Authorized.--From the amount appropriated under subsection (g) for any fiscal year, the Secretary shall carry out a program of canceling the obligation to repay a qualified loan amount in accordance with subsection (c) for Federal Direct Stafford Loans and Federal Direct Unsubsidized Stafford Loans made under this part for any borrower who-- ``(1) has been employed for 3 consecutive calendar years as a full-time registered nurse in a health care facility or a health care setting approved by the Secretary of Health and Human Services for purposes of this section; and ``(2) is not in default on a loan for which the borrower seeks forgiveness. ``(c) Qualified Loans Amount.-- ``(1) In general.--Except as provided in paragraph (2), the Secretary may, from funds appropriated under subsection (g)(1), cancel not more than $5,000 in the aggregate of the loan obligation on a loan made under section 428 or 428H that is outstanding after the completion of the third complete year of nursing described in subsection (b)(1). ``(2) Additional amounts.--Notwithstanding the amount specified in paragraph (1), the aggregate amount that the Secretary may, from funds appropriated under subsection (g)(2), cancel is a total amount equal to not more than $12,000 for any registered nurse who, in addition to meeting the requirements of subsection (b), has been employed as required by such subsection for 5 consecutive calendar years. ``(3) Award basis.--The Secretary shall cancel loan amounts under this subsection on a first-come first-served basis, subject to the availability of appropriations. ``(4) Treatment of consolidation loans.--A loan amount for a loan made under section 428C may be a qualified loan amount for the purposes of this subsection only to the extent that such loan amount was used to repay a Federal Direct Stafford Loan, a Federal Direct Unsubsidized Stafford Loan, or a loan made under section 428 or 428H for a borrower who meets the requirements of subsection (b), as determined in accordance with regulations prescribed by the Secretary. ``(d) Regulations.--The Secretary is authorized to issue such regulations as may be necessary to carry out the provisions of this section. ``(e) Construction.--Nothing in this section shall be construed to authorize any refunding of any repayment of a loan. ``(f) Prevention of Double Benefits.-- ``(1) National and community service.--No borrower may, for the same service, receive a benefit under both this subsection and subtitle D of title I of the National and Community Service Act of 1990 (42 U.S.C. 12571 et seq.). ``(2) Stafford loan forgiveness.--No borrower may receive a reduction of loan obligations under both this section and section 428L. ``(g) Authorization of Appropriations.--For fiscal year 2003 and for each of the 4 succeeding fiscal years, there are authorized to be appropriated such sums as may be necessary-- ``(1) to repay loans in the amount specified in subsection (c)(1); and ``(2) to repay loans in the additional amount specified in subsection (c)(2).''.

Nurse Loan Forgiveness Act of 2002 - Amends the Higher Education Act of 1965 (HEA) to include, under HEA student loan forgiveness and cancellation programs, nurses who serve three consecutive complete years in an approved health care facility or setting.

the study of neutron stars is attractive in part because of the fundamental issues of physics that can be addressed . these include the behavior of spacetime in strong gravity , the equation of state of matter at supranuclear densities , and the propagation of thermonuclear burning in degenerate matter , an issue which has relevance to many astrophysical events including classical novae and type ia supernovae . the discovery with the _ rossi x - ray timing explorer _ ( _ rxte _ ) of highly coherent brightness oscillations during type i ( thermonuclear ) x - ray bursts from six low mass x - ray binaries ( lmxb ) ( for reviews see , e.g. , strohmayer , zhang & swank 1997b ; smith , morgan & bradt 1997 ; zhang et al.1996 ; and strohmayer et al . 1997c ) has provided a potentially sensitive new tool to understand these fundamental issues . the burst oscillations are thought to be produced by spin modulation of one or two localized thermonuclear hot spots that are brighter than the surrounding surface . the existence of the oscillations , as well as some of the reported behavior of their amplitudes ( see , e.g. , strohmayer et al . 1997b ) seems to confirm the pre - existing theoretical expectation that x - ray bursts on neutron stars are caused by ignition at a point followed by thermonuclear propagation around the surface ( e.g. , fryxell & woosley 1982 ; nozakura et al . 1984 ; bildsten 1995 ) . the observed waveforms of these oscillations , and their dependence on time and photon energy , can in principle be used to constrain the mass and radius of the star and the velocity and type of thermonuclear propagation . such information can only be extracted by detailed comparison of theoretical waveforms with the data . here we conduct the most complete existing survey of the properties of the light curves and resultant oscillation amplitudes for one or two expanding hot spots . we calculate light curves and oscillation amplitudes as a function of stellar compactness , rotational velocity at the stellar surface , spot size and location , orientation of the line of sight , angular dependence of the specific intensity , and spot asymmetries . our calculations follow a procedure similar to that of pechenick , ftaclas , & cohen ( 1983 ) , strohmayer ( 1992 ) , and miller & lamb ( 1998 ) , but our survey is more comprehensive than these previous treatments in that we fully investigate the effects of an expanding spot size on the light curves and oscillation amplitudes , while also exploring the effects of gravity , stellar rotation , viewing geometries , and anisotropic emission . in addition , we present the first calculations of the effects of having two non - antipodal spots as well as the effects of asymmetries in spot brightness . in 2 we describe our assumptions and the calculational method . in 3 we present our results . we show that for small spot sizes the oscillation amplitude has only a weak dependence on spot size , but that as the spot grows the dependence becomes very strong . we also show that stellar rotation , beaming functions and spot asymmetries all tend to increase the observed oscillation amplitudes whereas greater compactness and larger spot sizes tend to decrease the amplitudes . in 4 we exhibit applications of these results to data on the amplitudes of two harmonics in 4u 1636536 and on the phase lags versus energy for sax j18083658 . we discuss our results and present our conclusions in 5 . we make the following assumptions in our calculations : 1 . _ the observed radiation comes from one or two emitting spots on the surface . _ the sources with strong bursts tend to have persistent accretion rates a factor of @xmath110100 less than the eddington critical luminosity @xmath2 at which the radial radiation force balances gravity , whereas the peak luminosity of the bursts is typically close to @xmath2 . the flux from the burning regions therefore greatly exceeds the flux from the quiescent regions , so for much of the burst this is a plausible approximation . the radiation is homogeneous and emitted isotropically unless noted otherwise . _ this assumption is made for simplicity , as presently there is no physical evidence that suggests whether or not the photon emission from the hot spots is isotropic and homogeneous . _ if there are two spots , they are identical and both grow at the same velocity unless noted otherwise . _ this assumption is also made for simplicity . although the geometry of the two magnetic poles is unlikely to be identical , not enough is known about their structure to realistically model non - identical spots . the exterior spacetime of the neutron star is the schwarzschild spacetime . _ we neglect the effect of frame dragging due to stellar rotation because it only generates small second order effects for the rotation rates of interest ( see lamb & miller 1995 and miller & lamb 1996 ) . we compute the waveform of the oscillation as seen at infinity using the procedure of pechenick et al . figure [ coords ] shows our coordinate system and angle definitions . the photons emitted from the star travel along null geodesics which , for a schwarzschild geometry , satisfy the equation ( misner , thorne , and wheeler 1973 , p. 673 ) @xmath3 where @xmath4 and @xmath5 are spherical coordinates , @xmath6 is the gravitational mass of the star , and @xmath7 is the impact parameter of the photon orbit . in both the above equation and throughout , we use geometrized units in which @xmath8 . if the photon is initially at a global azimuthal angle @xmath9 , then the global azimuthal angle at infinity follows from equation ( 1 ) and is ( pechenick et al . 1983 , eq . [ 2.12 ] ) @xmath10^{-1/2 } \,du\ ] ] where @xmath11 . note that not all of this angle is due to light deflection : for example , a photon emitted tangent to the radial vector in flat spacetime will have an angle @xmath12 at infinity . the maximum angle occurs when @xmath13 and is given by ( pechenick et al . 1983 , eq . [ 2.13 ] ) @xmath14^{-1/2 } \,du\ ] ] the observer at infinity can not see the spot if the observer s azimuthal angle exceeds @xmath15 . for each phase of rotation we compute the projected area of many small elements of a given finite size spot . we then build up the light curve of the entire spot by superposing the light curve of all the small elements . we chose a grid resolution such that the effect of having a finite number of small elements produces a fractional error @xmath16 in the computed oscillation amplitudes . for isotropic emission the intensity of radiation at a given rotational phase as seen by an observer at infinity is directly proportional to the projected area of the spot . to investigate the effect of anisotropic emission we include a flux distribution function in the intensity , @xmath17 , where @xmath18 is the angle between the surface normal and the photon propagation direction . the intensity is then proportional to the product of the projected area of the spot ( which is proportional to @xmath19 ) and @xmath17 . we consider two types of anisotropic emission : cosine ( pencil " ) beaming , in which @xmath20 , and sine ( fan " ) beaming , in which @xmath21 . the intensity distribution of an emitting spot is aberrated by the rotation of the star , and the photon frequency is doppler shifted by the factor @xmath22 $ ] . here @xmath23 is the velocity at the stellar equator , @xmath24 , and @xmath25 is the angle between the direction of photon propagation and the local direction of rotation . the inferred spin frequencies of these neutron stars are @xmath1300 hz , implying surface velocities @xmath26c for stellar radii @xmath27 km . after computing the oscillation waveform using the above approach , we fourier - analyze the resulting light curve to determine the oscillation amplitudes and phases as a function of photon energy at different harmonics . as discussed in the introduction , the basic quantities of interest include the mass and radius of the neutron stars in bursting sources and the nature and speed of thermonuclear propagation on the stellar surface . we therefore need to relate these fundamental quantities to the observables , such as the oscillation waveform as a function of time and photon energy . we do this by computing theoretical waveforms using different assumptions about the compactness of the star , the angular size of the burning region , the angular location of the observer and magnetic pole relative to the stellar rotation axis , the surface rotation velocity of the star , and the angular distribution of the specific intensity at the surface . in this section we consider each of these effects separately , to isolate the effect they have on the waveform and facilitate interpretation of the data . here we always quote the fractional rms amplitude of brightness oscillations . we also quote only bolometric amplitudes in this section ; as shown by miller & lamb ( 1998 ) , oscillations in the energy spectrum of the source may yield substantially higher amplitudes in the countrate spectrum measured by bandpass - limited instruments such as _ rxte_. the decrease in oscillation amplitude as the bursts in some sources progress ( strohmayer et al . 1997b ) may suggest an initially localized emission spot that expands via relatively slow ( @xmath28 cm s@xmath29 ) thermonuclear propagation . if so , we would expect that the waveforms from burst oscillations would reflect a variety of spot sizes . we therefore consider spots that range from pointlike to those with an angular radius of 180@xmath30 . also , physical conditions existing in the region of emitting spots may alter photon emission as in the case of some radio pulsars . accordingly , we consider the effects of including cosine and sine beaming functions in the calculations of the waveforms . figure [ waveforms ] shows the waveforms from a single emitting spot ( left - hand column ) and two emitting spots ( right - hand column ) for various spot sizes . as expected , the amplitude of the intensity oscillations decreases as the spot size increases . furthermore , in the case of a single emitting spot there is a critical spot size ( @xmath31 for the case of @xmath32 ) at which the spot is never completely out of view and hence the intensity remains greater than zero for the entire rotational phase . as the waveforms illustrate , the cosine beaming function , which enhances emission along the magnetic field axis , tends to narrow the width of the waveform peaks . the sine beaming function enhances emission near the tangential plane and will produce a four peaked waveform for the case of a small single emitting spot ( see pechenick et al . 1983 ) . we are also interested in the effect of the compactness of the star on the observed amplitudes . figure [ ampvssize]a shows the fractional rms amplitudes at the first two harmonics as a function of spot size and stellar compactness for one emitting spot centered at @xmath33 ( i.e. , for an observer and spot both in the rotational equator ) . the curves for the first harmonic illustrates the general shape of most of the first harmonic curves . initially , the amplitude depends only weakly on spot size . however , once the spot grows to @xmath34 there is a steep decline in the oscillation amplitude which flattens out only near the tail of the expansion . figure [ ampvssize]b shows the fractional rms amplitude at the second harmonic under the same assumptions but for two identical , antipodal emitting spots . the range in spot size here is @xmath35 since two antipodal spots of @xmath36 radii cover the entire stellar surface . note that in this situation , there is no first harmonic . these curves illustrate two interesting features of the two spot configuration . first , the strength of the strongest oscillation amplitude in the two spot case is @xmath37 weaker than the strength of the strongest oscillation amplitude in the one spot case considered above . furthermore , the curve of the second harmonic does not exhibit the same sharp falloff seen in the first harmonic curve . thus , the detection of a particularly large fractional rms amplitude with a steep amplitude decline can verify that what is being observed is a first harmonic ( i.e. , power generated at the stellar spin frequency ) rather than any higher harmonics ( see miller & lamb 1998 ) . the second interesting feature is that the curve of the second harmonic in figure [ ampvssize]b is nearly identical in both magnitude and shape to the first @xmath36 of the curve of the second harmonic for the case of one spot shown in figure [ ampvssize]a . thus , for this geometry , the introduction of a second emitting spot antipodal to the first tends to destroy the first harmonic while leaving the second harmonic unaffected . this result obtains whenever : ( 1 ) the physical assumptions ( e.g. , compactness , rotational velocity , flux distribution function ) made for both the one and two spot configurations are the same , and ( 2 ) the viewing geometry for both configurations is @xmath38 . in this figure we also display the effect gravity has on the oscillation amplitudes . from equation ( 3 ) we know that more compact stars have a larger @xmath39 , and hence a larger fraction of their surface is visible to observers . as a result , oscillation amplitudes for more compact neutron stars are smaller . an exception occurs at the second harmonic of very compact stars ( @xmath40 ) , in which case gravitational light deflection focuses the emitted radiation enough to raise the oscillation amplitude ( see pechenick et al . 1983 and miller & lamb 1998 ) . note that the stellar compactness affects the amplitude at the second harmonic far more than the amplitude at the first harmonic . figure [ ampvsang]a shows the oscillation amplitude as a function of @xmath41 ( i.e. , for the observer and the center of the spot at the same rotational latitude ) for a single emitting spot with @xmath42 and @xmath43 . as @xmath44 increases , the width of the peaks in the light curve decrease ( see pechenick et al . 1983 ) and hence the oscillation amplitudes increase . the interesting feature here is that the second harmonic has a significant amplitude only for @xmath45 . since 50% of the time @xmath44 will be between @xmath46 and @xmath36 ( assuming randomly distributed observers ) , only half of all observers will detect a second harmonic during a typical burst involving one spot . in figure [ ampvsang]b we make the same assumptions as in figure [ ampvsang]a but for two emitting spots rather than one . if we had assumed flat space - time and an infinitesimal spot size then the second emitting spot would become visible only for @xmath47 . therefore , for @xmath48 only one spot would be observable . for @xmath43 , @xmath49 , and therefore a second , infinitesimal , spot would begin to be visible at @xmath50 . since in figure [ ampvsang ] , the calculation was done with @xmath42 , the spot begins to become visible at @xmath51 , explaining the appearance of the second harmonic at this @xmath44 value . note that in the two spot case the first harmonic generates significant power for a wide range of @xmath44 . this occurs because for @xmath52 one spot is more directly aligned with the observer s line of sight , and as a result the intensity maxima of the two spots are unequal . in general , whenever an asymmetry exists between the two emitting spots such that the intensity maxima of the two spots are unequal , power is generated at the first harmonic . in figure [ ampvsvel ] we include the effects of doppler shifts and aberrations on the oscillation amplitudes . we assume a surface rotation velocity of @xmath53c , which corresponds to a neutron star with radius @xmath54 km and spin frequency @xmath55 hz . as can be seen , the amplitude of the second harmonic is increased significantly more than the amplitude of the first harmonic as a result of rotation . the tendency to generate more power at the higher harmonics than at the spin frequency is a general property of the rotation ( see miller & lamb 1998 for a discussion of this effect ) . physical conditions in the region of emitting spots might cause anisotropic emission of radiation . the results of including a cosine beaming function and a sine beaming function for the case of one spot are shown in figure [ ampvsbeam]a and for two antipodal spots in figure [ ampvsbeam]b . as is apparent from figure [ waveforms ] , the enhanced emission along the magnetic axis for the cosine beaming tends to narrow peaks in the light curves ( see pechenick et al . 1983 for a discussion of the light curves for beamed emission ) and hence raise the oscillation amplitudes . for the sine beaming the peaks in the light curve are broadened , tending to lower the amplitude at the first harmonic . both beaming functions do , however , generate substantial additional power at the higher harmonics . recent work by miller ( 1999 ) gives evidence for the presence of power at the stellar spin frequency for a source ( 4u 1636536 ) consisting of two emitting spots . earlier we saw that one possible mechanism for generating significant power at the stellar spin frequency for the case of two emitting spots is to vary the viewing geometry . another possible mechanism is to have the spots be non - antipodal . this can occur , for instance , if the star s dipolar magnetic field has its axis slightly displaced from its center . in the left panel of figure [ asymmetric ] we show the oscillation amplitude as a function of spot separation for the case of two emitting spots with @xmath56 , @xmath33 , and @xmath43 . the spots are perfectly antipodal at a spot separation of @xmath57 . as the figure shows , the oscillation amplitude at the second harmonic is relatively constant while the oscillation amplitude at the first harmonic is a linear function of spot separation . at a spot separation of @xmath58 the fractional rms amplitudes of the first and second harmonic are equal . another way to produce power at the spin frequency is to have differences in brightness between the two spots . such an asymmetry can occur , for example , if the strength of the magnetic field at the location of the two spots is different , thereby pooling different amounts of nuclear fuel onto the hot spot regions . in the right panel of figure [ asymmetric ] we show the oscillation amplitude as a function of the percent difference between the brightness of the two spots . as in the case of the non - antipodal spots , the amplitude at the second harmonic is essentially constant while the amplitude at the first harmonic increases linearly with increasing percent difference in spot brightness . these figures reinforce the conclusion , also evident from figure [ ampvssize ] , that only with two spots can the oscillation at the first overtone be stronger than the oscillation at the fundamental . therefore , within the general theoretical model explored in this paper , 4u 1636536 has two nearly antipodal hot spots . _ doppler model of phase lags._the hard x - ray spectrum of low - mass x - ray binaries is well - fit by a comptonization model , in which the central neutron star is surrounded by a hot corona of electrons and the photons injected into this corona are relatively soft . it was therefore expected that the observed hard photons , having scattered more often than the soft photons and thus having a longer path length before escape , would lag the soft photons . instead , in several sources a hard _ lead _ was discovered . one explanation for this lead was suggested by ford ( 1999 ) . he proposed that doppler shifting of photons emitted from rotating hot spots , as in thermonuclear burst oscillations , would tend to produce a hard lead because the approaching edge of the spot would precede the trailing edge . he compared a simplified calculation of this effect with burst data for aql x-1 and showed that an adequate fit could be obtained ( ford 1999 ) . the millisecond x - ray pulsar sax j18083658 provides a stronger test of this hypothesis . this source has strong oscillations ( @xmath15% rms ) at @xmath1401 hz , which as usual are attributed to rotational modulation of a hot spot on the surface . cui , morgan , & titarchuk ( 1998 ) obtained precise measurements of the oscillation phase as a function of energy , and found that in this source as well there is a hard lead . figure [ lagfigs ] shows sample calculations of the time lag as a function of energy . in the left panel we focus on the dependence of the lag on mass , and in the right panel we concentrate on the effect of changing the surface temperature . in both cases the surface emission pattern is the pattern for a gray atmosphere , and we assume @xmath59 and a stellar spin frequency of 401 hz , which is the spin frequency of sax j18083658 . in panel ( a ) we assume a surface effective temperature of @xmath60 kev as measured at infinity . in panel ( b ) we assume a stellar gravitational mass of 1.6 @xmath61 , which gives a surface equatorial rotation velocity of 0.1 c as measured at infinity . from this figure it is clear that the effect of increasing the mass is to increase the phase lead , whereas the effect of increasing the temperature is to increase the energy at which the curve starts to flatten . _ comparison with data._comparing these models with the data for sax j18083658 introduces additional complications . in order to improve statistics , cui et al . ( 1998 ) averaged the phase lags over the period from 11 april 1998 to 29 april 1998 . the calculation of the phase leads by cui et al . ( 1998 ) also involves averaging the phase over energy bins several kev in width . examination of figure [ 1808data ] shows that the phase changes rapidly over such an energy range , implying that the measured phase lead depends sensitively on the input spectrum . the effective area of rxte also decreases rapidly below 4 kev , which strongly affects the observed average phase in the 23 kev reference bin . finally , given that the observed spectrum is not a blackbody , but is instead approximately a power law of index 1.86 from @xmath13 kev to @xmath130 kev ( heindl & smith 1998 ) , compton reprocessing has taken place and the observed phase lags are the result of a convolution between the unscattered phase lags and the compton redistribution function . figure [ 1808data ] plots the data along with a simplified model of the phase lags taking some of these complications into account . we ignore the changing effective area of rxte and assume a constant response with energy . based on the power - law nature of the spectrum , we approximate the process of comptonization by assuming that the energy of the injected photons is much less than the observed photon energies or the temperature of the electrons . we also assume an isothermal atmosphere , in contrast to the gray atmosphere we used for figure [ lagfigs ] , which gives too low a hard lead . the best fit has @xmath62 kev as observed at infinity , @xmath63 km , and @xmath64 . the total @xmath65 of the fit is 38.6 for 6 degrees of freedom . the dominant contribution to this @xmath65 comes from the underprediction of the hard lead at low energies . this is as expected , because we assumed an instrumental effective area that is constant with energy , whereas in reality the effective area rises rapidly with increasing photon energy at low energies . this changing effective area gives greater weight to the larger leads at higher energies , which is in better agreement with the data . therefore , given the simplifications of the model , our fit to the data is encouragingly good and supports the doppler interpretation of the observed hard lead . _ relative amplitudes of harmonics._we have presented calculations of the waveforms and amplitudes at different harmonics of the spin frequency for one or two hot spots and many realistic combinations of stellar compactness , spot size and emission pattern , observation angle , and magnetic inclination . these calculations show that typically either the fundamental or the first overtone has an amplitude much larger than the amplitude of any other harmonic . this corresponds well to the observations of the six sources with burst brightness oscillations , in which there is a strong oscillation at only one frequency . we also find that if the first overtone is the dominant harmonic , there must be two similar and nearly antipodal bright spots , because a single spot always produces a much stronger oscillation at the fundamental than at any overtone . in contrast , if the fundamental is much stronger than the overtone , this is consistent with but does not require a single spot : if there are two bright spots that are sufficiently dissimilar or far away from antipodal , or if our line of sight is such that one of the spots is hidden , then the oscillation at the fundamental will dominate . this implies that the three sources with detectable oscillations near @xmath1300 hz ( 4u 172834 [ strohmayer et al . 1996 ] , 4u 170243 [ markwardt , strohmayer , & swank 1999 ] , and 4u 1636536 [ miller 1999 ; this source has a strong oscillation at @xmath1580 hz but a detectable oscillation at @xmath1290 hz ] ) have spin frequencies of @xmath1300 hz , whereas the three sources with detectable oscillations only at @xmath1500600 hz ( aql x-1 [ zhang et al . 1998 ] , mxb 174329 [ strohmayer et al . 1997a ] , and ks 1731260 [ smith et al . 1997 ] ) could have spin frequencies at either this frequency or half of it . therefore , all six burst oscillation sources are consistent with having spin frequencies @xmath1300 hz . _ information content of waveforms._our results also show clearly that power density spectra , which contain information only on the relative amplitudes of different harmonics , are much less informative than the waveforms themselves . figure [ fixedratio ] shows three different waveforms that all have an amplitude at the first overtone that is 2.3 times the amplitude at the fundamental , which is the ratio found by miller ( 1999 ) for 4u 1636536 . in all three cases there are two bright spots . the solid line shows the waveform for two identical pointlike spots that are 175@xmath66 apart , the dotted line shows the waveform for two antipodal spots with brightnesses differing by 10% , and the dashed line shows the waveform for two identical and antipodal spots that are 75@xmath66 from the rotational pole and observed from a line of sight that is also 75@xmath66 from the rotational pole . although the amplitude ratio is the same in each case , the waveforms are quite different from each other , and the physical implications are also different . this underscores the importance of calculating waveforms and not just power density spectra , both observationally and theoretically . _ searches for weak higher harmonics._the amplitudes and phases of higher harmonics potentially contain important clues about the propagation of nuclear burning and about the compactness of the star , but as yet there are no sources in which a higher harmonic of a strong oscillation has been observed . our plots of amplitude versus spot size suggest that it is best to look for weaker higher harmonics when the dominant oscillation is strong . the reason is that , in general , the ratio of the second to first harmonic drops with increasing spot size , and therefore with decreasing amplitude at the fundamental . hence , a search only of data showing strong oscillations may more sensitively reveal the presence of higher harmonics . _ shape of amplitude decrease as a function of spot size._in our calculations , as the spot size increases the amplitude decreases slowly until the angular radius of the spot is @xmath67 but quickly thereafter . this apparently conflicts with the observations of 4u 172834 reported in strohmayer et al . ( 1997 ) , in which the error bars are large but it appears that the decrease in amplitude is fast from the start and then slows down . further quantification of this result is important , but if confirmed it could be caused by a number of effects . for example , the spot size might never be small : if ignition were nearly simultaneous over a large area , further spreading would already be in the large - spot regime , and hence the amplitude would decrease quickly . if the spreading velocity were initially high but then decreased , this would have a similar effect on the amplitudes . alternately , if there is a corona with a non - negligible scattering optical depth around the star and the optical depth increases as the burst approaches its peak flux , this would also decrease the amplitude faster than expected when the optical depth is zero . _ phase lags as a probe of surface rotation velocity._we find that the hard lead observed in sax j18083658 is fit reasonably well by a model ( see ford 1999 ) in which rotational doppler shifts cause higher - energy x - rays to lead lower - energy x - rays . this fit lends support to the model , and suggests that with better fitting and more data ( especially from a future high - area timing mission ) it may be possible to use phase lag versus energy data to help constraint the mass @xmath6 or the compactness @xmath68 of the star .

the discovery of high - amplitude brightness oscillations during type i x - ray bursts from six low - mass x - ray binaries has provided a powerful new tool to study the properties of matter at supranuclear densities , the effects of strong gravity , and the propagation of thermonuclear burning . there is substantial evidence that these brightness oscillations are produced by spin modulation of one or two localized hot spots confined to the stellar surface . it is therefore important to calculate the expected light curves produced by such hot spots under various physical assumptions , so that comparison with the observed light curves may most sensitively yield information about the underlying physical quantities . in this paper we make general relativistic calculations of the light curves and oscillation amplitudes produced by a rotating neutron star with one or two hot spots as a function of spot size , stellar compactness , rotational velocity at the stellar surface , spot location , orientation of the line of sight of the observer , and the angular dependence of the surface specific intensity . for the case of two emitting spots we also investigate the effects of having spot separations less than @xmath0 and the effects of having asymmetries in the brightness of the two spots . we find that stellar rotation and beaming of the emission tend to increase the observed oscillation amplitudes whereas greater compactness and larger spot size tend to decrease them . we also show that when two emitting spots are either non - antipodal or asymmetric in brightness , significant power at the first harmonic is generated . by applying these results to 4u 1636536 , whose two emitting spots produce power at the first harmonic , we place strong constraints on the neutron star s magnetic field geometry . we also show that the data on the phase lags between photons of different energies in the persistent pulsations in sax j180858 can be fit well with a model in which the observed hard leads are due to doppler beaming .

post treatment apical periodontitis or endodontic failure is associated with persistence of microbial infection in the root canal system and/or the periradicular area . microorganisms present in untouched areas such as missed canals , isthmuses , and irregularities may remain unaffected by endodontic disinfection procedures . these microorganisms continue to multiply to significant number and gain access to the periradicular region , causing inflammation in the periradicular tissues . therefore , the successful root canal treatment depends on adequate cleaning , shaping , and filling of the root canal system . there have been numerous studies that describe the complex morphology of teeth , including mandibular first molars . in 1974 , vertucci and williams , as well as barker et al . , described the presence of an independent middle mesial ( mm ) canal . the presence of mm root canal of mandibular molars has been reported to have an incidence rate of 1 - 15% in various in vitro studies and case reports . the incidence of four canals in mesial root of mandibular molar have been reported by two authors ininvitro studies and by three authors as case reports . the aim of this case report is to present and describe the management of a mandibular first molar with four canals in the mesial root and single canal in the distal root . a 37-year - old male patient with a noncontributory medical history reported to our department with discomfort and pain in the right mandibular region . history of present illness showed that there were few episodes of recurrent pain in that region for the past 1 year . there was a large carious lesion and a draining sinus in relation to left mandibular first molar with pain on palpation in the periapical region . intraoral periapical ( iopa ) radiograph revealed a large radiolucency around the periapex of left mandibular first molar [ figure 1a ] . gutta - percha tracing of sinus showed that the sinus originated from the periapical radiolucency around the tooth . treatment plan was explained to the patient and endodontic treatment was initiated under rubber dam isolation . three canals were located , two in the mesial and one in the distal . under magnification , it was evident that the mesiobuccal ( mb ) and mesiolingual ( ml ) were placed well apart with an isthmus joining the two canals . with the above mentioned pulpal floor anatomy over the mesial root , a possibility of mmcanalwas anticipated in the isthmus between mb and ml . on exploration with dg-16 , there was a catch or a stick feeling where a mm canal was located close to mb canal . the distance between the mm canal and ml canal with a prominent isthmus between the two , prompted us to look for a second mm canal . stick feeling which on penetration with profinder revealed to be a second mm located closer to the ml canal [ figure 1b ] . iopa radiograph revealed one mm joining the mb canal and another joining the ml canal in the middle third [ figure 1c ] . the orifices were enlarged using # 2 gatesglidden drill ( mani , japan ) to enhance access and visualization . after confirming the working length with an apex locator ( root zx , j morita , tokyo , japan ) , the mesial canals were enlarged up to size 25 - 6% ( m two , dentsplymaillefer ) and the distal canal was instrumented with hand k - files ( dentsplymaillefer ) by crown down method with apex enlarged to size40 . since the anatomy was unusual , a cone beam computed tomography ( cbct ) image was taken to confirm the anatomy [ figure 1d ] . cbct image confirmed the presence of two mm canals of which one joined the mb and another joined the ml canal at the middle third and exited as a single canal at the apex . this was followed by an intracanal medication with caoh ( dentocal , anabond stedman ) with chlorhexidine ( asep - rc , anabond stedman ) after a week for 3 weeks . caoh was not placed in the first sitting as the radiopaque caoh may obscure the cbct image . obturation was performed at the third appointment using cold lateral compaction of gutta - percha and ah-26 ( dentsply maillefer ) as a root canal sealer . figure 2a and b shows the iopa images immediately after obturation in buccal and distal view . figure 2c is 6 month follow - up image showing a good healing of the periapical lesion . ( d ) cone beam computerised tomography image showing the presence offour canals in the mesial root ( a ) iopa radiograph after obturation , buccal view . pomeranz et al . , in a report of 100 cases found that 12 molars had mm canals and classified them into three morphologic categories as follows : fin , confluent , and independent . fin , where there is free communication between all three canals and confluent , where mm canal joins one of the main canals . according to fabra - campos , this mm canal more commonly joins the mb canal . in a systematic review by de pablo et al . , the mm canal was present in 2.6% mandibular first molars . they reported that intracanal communications existed in about 55% of mesial roots of the first molar . the pulpal floor of first molar may or may not show a clear isthmus between the two canals . the isthmus is generally obscured by a dentinal projection which can be removed with specialized ultrasonic tip or one - fourth round bur . if the isthmus isevident clinically , presence of a mm canal should always be anticipated . hsu and kim classified isthmus configurations , where type v ( single , broad , and elongated canal ) was the most frequent among mesial roots of mandibular molars . according to a study by yesilsoy et al . , the groove between the mb and ml can be as deep as 3.5 mm from the orifice and between 4 and 6 mm from the apical foramen . this groove is a potential area to be addressed and there is a need to modify the access to disinfect the root canal system effectively . catch or a stick feeling if there is a canal in the isthmus . a fin type mm canal may be seen in younger age patients as canal differentiation in isthmus region with complete division of the root canal system starts only after 16 years of age and is seen in all roots only after the age of 30 years . and if numerous partitions form , extensive differentiation of the root canal system results in a reticular form in which three or more vertical canals are present with lateral interconnections . thus , a possibility of additional canals should be expected in patients above the age of 30 years . most of the reported cases of third mesial canal have been in patients of 40 years of age or more . though the presence of a third mesial canal has been reported by many authors , presence of fourth mesial canal has been reported only thrice . in an in vitro study on indian population reported an incidence of 3.3% of four canals in the mesial root of mandibular first molar . , in pakistan , which is of a similar ethnic population as this patient ( indian ) , one out of 30 teeth showed a vertucci typeviii configuration . in a study on 2,800 teeth by sert and bayirli , 36 teeth showed morphology which does not come under vertucci 's classification and it occurred twice as often inmandibular teeth . they described four canals in mesial root exiting as one canal , but does not mention a 4 - 2 - 1pattern as seen in this case . , described a four canal pattern , but exiting as two canals , in burmese population as type xi . thus , an absence of report of such a pattern and with only three previous case reports of four canals in the mesial root makes this report unique and worth mentioning to understand the complexity of root canal system of mandibular first molar . despite report of such extra canals , mortman and ahn describes these extra mesial canals are a sequelae of instrumenting the isthmus between the mb and ml canals . but according to navarro et al . canal in an isthmus can assist in cleaning and reshaping it , as many canals as necessary ( without damaging the root structure ) may be prepared so as to divide the isthmus and make it easier for the disinfectants to penetrate the spaces that can not be reached with a file . care should be taken while instrumenting such confluent canals with nickel - titanium rotary instruments , as they have a tendency to break where two canals join at a sharp angle into one small canal . failure to locate and clean extra canals decreases the long - term prognosis of endodontic treatment . endodontic management of aberrant root canal is often challenging . adequate knowledge of aberrancies , the will to search for them , combined with usage of magnification , and modern imaging techniques will beget us greater success . this case report describes a successful management of an aberrant morphology in a mandibular molar with four canals in the mesial root and one canal in the distal root .

successful root canal treatment depends on adequate cleaning , shaping , and filling of the root canal system . the presence of middle mesial ( mm ) root canal of mandibular molars has been reported by various authors . but incidence of four canals in mesial root of mandibular molar is very rare . the aim of this case report is to present and describe the identification and management of a mandibular first molar with four canals in the mesial root and single canal in the distal root .

extremely low birth weight infants ( elbw ) pose a heavy resource burden in perinatal healthcare . while it is inevitable that elbw infants would have relatively long neonatal intensive care unit ( nicu ) length of stay ( los ) , there may be opportunities for improving and standardizing care , as unexplained variation in los has been described for premature infants . depending on the patient , hospital , and payer , there may be financial considerations that could influence practice in such a manner to discharge such infants sooner or later . for these reasons , after baseline characteristics that contribute meaningful increments in explanatory power are accounted for , los may be considered a quality of care measurement . in order to use elbw los as a quality measurement amongst hospitals , we need to reveal the impact of practice variation among providers via a model employing inclusion / exclusion criteria and baseline patient characteristics that are broadlyaccepted by relevant stakeholders . previous studies on modeling length of stay for premature infants have been limited due to being confined to one or a few centers or concerned only certain level nicus . a population - based study in sweden evaluated moderately preterm infants 3034 weeks . a study of 30 nicus in the uk included a broad group of premature infants including those 23 to 32 weeks gestation and with birth weight up to 3000 grams . our aim was to characterize los for the smallest , most vulnerable infants who draw especially heavily on nicu resources , across wide levels of hospital care . the purpose of this study was to modellos for elbw infants in order to examine provider variation and thus to inform quality assessmentwithin a population - based dataset . because both widely heterogeneous patient care needs and patient care in more than one discrete system of care can obscure the true contribution of various independent risk factors to los , we studied elbws who survived and were cared for from birth or shortly after birth at a single institution until discharge to home . in particular , we considered : 1 ) type of risk adjustment model , 2 ) the potential for bias from excluding patients who died before discharge , and 3 ) the potential for bias from excluding patients who were transferred to a lower level hospital for convalescent care . we used data from the california perinatal quality care collaborative ( cpqcc ) , a voluntary collective of 129 nicus that report demographic and clinical data into a central repository . more than 90% of nicus in california participated in this collaborative between january 1 , 2008 , and december 31 , 2010 . member nicus collect data on their patients in a prospective manner , and each record undergoes a variety of range , logic , and missing data checks . the period of analysis included infants cared for in cpqcc nicus for the three years , 2008 to 2010 . inclusion criteria were infants with birth weight 4011,000 grams who were cared for at a cpqcc hospital from birth or within the first day after delivery , until discharge to home . exclusion criteria were patients who died , those with congenital anomalies , and infants who had any surgery except circumcision . the primary outcome ofinterest was length of stay ( los ) , defined as the number of days from admission to discharge . for infants those infants not cared for at a cpqcc hospital on the first day , the first day of hospital stay at a cpqcc hospital counted as day one . the following baseline characteristics were considered in risk adjustment : infant characteristics ( sex , birth weight , gestational age , small for gestational age ( sga ) ) , maternal and intrapartum variables ( maternal age , race / ethnicity , prenatal care , location of birth ( inborn / outborn ) , antenatal steroid use , multiple birth , mode of delivery , antenatal conditions ) , and delivery room variables ( 5 minute apgar scores ) . in considering sga ( defined as birth weight < 10th percentile for gestational age ) , it was noted that sga infants had shorter los , particularly those with gestational age > = 30 weeks . as birth weight < 1,000 grams was an inclusion criterion , we used an approach that accounted for the birth weight restriction of the eligible cohort . the sga variable was categorized into 2 different groups : 1 ) sga infants < 30 weeks of gestational age , and 2 ) sga infants > = 30 weeks ) . we chose 30 weeks as the cut point because the 3rd percentile of 1,000 gram infants is approximately 30 weeks . the rationale was to distinguish small size by infants developmental stage in terms of gestational age . previous research has shown a survival advantage for sga neonates of < 31 weeks associated with cesarean delivery . we examined collinearity among the model variables under consideration , as collinearity may influence estimation and inference for the primary parameters and lead to a loss of power , considering variance inflation factors and tolerance ( see appendix and table e1 for details on this selection process ) . from this analysis , we included birth weight and sga , but not gestational age as explanatory variables in models . skewness in the empirical distribution with a long positive side tail suggested that the use of the non - parametric test ( kruskal - wallis ) would be preferable when comparing los between different levels in each risk factor . as the los of each infant cared for within a hospital may not be independentfrom that of another infant in the same hospital , even after adjusting for the fixed risk factors under study , we accounted for this hospital - level clustering by using generalized linear mixed models with hospital of care accounted for as a random effect . we used a randomly selected 50% of the elbw cohort ( n=1,006 ) for model building , with the remaining 50% serving as a validation set . further details of model selection are noted in the appendix and online table e2 . in our review of the literature as described in the appendix , these seven models were tested for goodness of fit and other characteristics . model 6 , a generalized linear model with negative binomial distribution and model 2 , a linear mixed model using the log scale were considered the two optimal los models . the results of primary analyses and tests for biases ( described below ) were similar for both models , and model 2 formed the basis for the remainder of the study ( see appendix ) . in model 2 we use a mixed model to account for clustering within nicus and we use the log transformation of los to reconcile the non - normal distribution that results from the very long los of some elbws with modeling assumptions . having selected the linear mixed model using log transformation as the preferred solution to estimating risk adjustedlos , the model was applied to the whole study cohort . we started from an unconditional means model , then added infant - level risk factors . final risk factor selection for the model was determined by backward selection ( alpha < 0.05 significance level ) . the model diagnostics and validation of model assumptions were checked again in the final model . when residuals for the final model fitting were examined , there were two extreme outlier observations ( with significantly higher dffits and cook s distance statistics ) . these two extreme data points were excluded from analysis in order to optimize model fit . as a linear mixed model does not generate an r statistic , we estimated r by using the same covariates in a model without random effects . based on infant - level estimates , hospital level results risk adjusted los at each hospital was computed in the following fashion : ( a ) for each infant , estimate an expected los(b ) obtaina calibration factor and apply to infant expected los . the calibration factor was obtained by the overall ratio of ( sum of actual los / sum of expected los ) across the whole study cohort , as described in previous studies in order to center the estimate around 1.0.(c ) sum infants actual los and their expected los obtained in the previous step by hospital(d ) divide hospitals actual los sum by expected los sum to obtain o / e ratio(e ) multiply hospitals o / e ratio by overall average los ( a ) for each infant , estimate an expected los ( b ) obtaina calibration factor and apply to infant expected los . the calibration factor was obtained by the overall ratio of ( sum of actual los / sum of expected los ) across the whole study cohort , as described in previous studies in order to center the estimate around 1.0 . ( c ) sum infants actual los and their expected los obtained in the previous step by hospital ( d ) divide hospitals actual los sum by expected los sum to obtain o / e ratio ( e ) multiply hospitals o / e ratio by overall average los in order to examine variation by hospital , we estimated risk - adjusted observed to expected los ratios for each hospital . in order to facilitate root cause analysis of a nicu s infants with excessive los , outliers for los at the individual patient level these infants were considered individual outliers . as infants who died were excluded from the analysis , we wanted to examine the possibility that hospitals that may have shorter mean los could have higher rates of mortality , thereby having a less acutely ill surviving population of infants that would be biased toward shorter los . to examine this potential bias on average los the mortality rate was computed from an established cpqcc algorithm , a modification of a vermont oxford network model , using all elbw infants excluding delivery room death in the cpqcc dataset between 20082010 ( n=7,270 ) . observed to expected mortality ratios were computedand their relationship to hospital los was evaluated using weighted correlation . in this regression model , each hospital was assigned a weight of the number of eligible patients cared for at that hospital . another potential source of bias could be the exclusion of infants who are transferred out to lower levels of care . when elbw infants cared for at level iii centers are transferred out for feeding and growing at lower levels of care , it is possible that the infants remaining in that nicu may present more complex cases who could be biased toward longer los . similar to the analysis of mortality , we considered the relationship of transfer - out rates for feeding and growing with average los by hospital for nicus with weighted correlation . all statistical analyses were conducted using sas version 9.3 ( sas , cary , nc ) . we used data from the california perinatal quality care collaborative ( cpqcc ) , a voluntary collective of 129 nicus that report demographic and clinical data into a central repository . more than 90% of nicus in california participated in this collaborative between january 1 , 2008 , and december 31 , 2010 . member nicus collect data on their patients in a prospective manner , and each record undergoes a variety of range , logic , and missing data checks . the period of analysis included infants cared for in cpqcc nicus for the three years , 2008 to 2010 . inclusion criteria were infants with birth weight 4011,000 grams who were cared for at a cpqcc hospital from birth or within the first day after delivery , until discharge to home . exclusion criteria were patients who died , those with congenital anomalies , and infants who had any surgery except circumcision . the primary outcome ofinterest was length of stay ( los ) , defined as the number of days from admission to discharge . for infants those infants not cared for at a cpqcc hospital on the first day , the first day of hospital stay at a cpqcc hospital counted as day one . the following baseline characteristics were considered in risk adjustment : infant characteristics ( sex , birth weight , gestational age , small for gestational age ( sga ) ) , maternal and intrapartum variables ( maternal age , race / ethnicity , prenatal care , location of birth ( inborn / outborn ) , antenatal steroid use , multiple birth , mode of delivery , antenatal conditions ) , and delivery room variables ( 5 minute apgar scores ) . in considering sga ( defined as birth weight < 10th percentile for gestational age ) , it was noted that sga infants had shorter los , particularly those with gestational age > = 30 weeks . as birth weight < 1,000 grams was an inclusion criterion , we used an approach that accounted for the birth weight restriction of the eligible cohort . the sga variable was categorized into 2 different groups : 1 ) sga infants < 30 weeks of gestational age , and 2 ) sga infants > = 30 weeks ) . we chose 30 weeks as the cut point because the 3rd percentile of 1,000 gram infants is approximately 30 weeks . the rationale was to distinguish small size by infants developmental stage in terms of gestational age . previous research has shown a survival advantage for sga neonates of < 31 weeks associated with cesarean delivery . we examined collinearity among the model variables under consideration , as collinearity may influence estimation and inference for the primary parameters and lead to a loss of power , considering variance inflation factors and tolerance ( see appendix and table e1 for details on this selection process ) . from this analysis , we included birth weight and sga , but not gestational age as explanatory variables in models . skewness in the empirical distribution with a long positive side tail suggested that the use of the non - parametric test ( kruskal - wallis ) would be preferable when comparing los between different levels in each risk factor . as the los of each infant cared for within a hospital may not be independentfrom that of another infant in the same hospital , even after adjusting for the fixed risk factors under study , we accounted for this hospital - level clustering by using generalized linear mixed models with hospital of care accounted for as a random effect . we used a randomly selected 50% of the elbw cohort ( n=1,006 ) for model building , with the remaining 50% serving as a validation set . further details of model selection are noted in the appendix and online table e2 . in our review of the literature as described in the appendix , these seven models were tested for goodness of fit and other characteristics . model 6 , a generalized linear model with negative binomial distribution and model 2 , a linear mixed model using the log scale were considered the two optimal los models . the results of primary analyses and tests for biases ( described below ) were similar for both models , and model 2 formed the basis for the remainder of the study ( see appendix ) . in model 2 we use a mixed model to account for clustering within nicus and we use the log transformation of los to reconcile the non - normal distribution that results from the very long los of some elbws with modeling assumptions . having selected the linear mixed model using log transformation as the preferred solution to estimating risk adjustedlos , the model was applied to the whole study cohort . we started from an unconditional means model , then added infant - level risk factors . final risk factor selection for the model was determined by backward selection ( alpha < 0.05 significance level ) . the model diagnostics and validation of model assumptions were checked again in the final model . when residuals for the final model fitting were examined , there were two extreme outlier observations ( with significantly higher dffits and cook s distance statistics ) . these two extreme data points were excluded from analysis in order to optimize model fit . as a linear mixed model does not generate an r statistic , we estimated r by using the same covariates in a model without random effects . based on infant - level estimates , risk adjusted los at each hospital was computed in the following fashion : ( a ) for each infant , estimate an expected los(b ) obtaina calibration factor and apply to infant expected los . the calibration factor was obtained by the overall ratio of ( sum of actual los / sum of expected los ) across the whole study cohort , as described in previous studies in order to center the estimate around 1.0.(c ) sum infants actual los and their expected los obtained in the previous step by hospital(d ) divide hospitals actual los sum by expected los sum to obtain o / e ratio(e ) multiply hospitals o / e ratio by overall average los ( a ) for each infant , estimate an expected los ( b ) obtaina calibration factor and apply to infant expected los . the calibration factor was obtained by the overall ratio of ( sum of actual los / sum of expected los ) across the whole study cohort , as described in previous studies in order to center the estimate around 1.0 . ( c ) sum infants actual los and their expected los obtained in the previous step by hospital ( d ) divide hospitals actual los sum by expected los sum to obtain o / e ratio ( e ) multiply hospitals o / e ratio by overall average los in order to examine variation by hospital , we estimated risk - adjusted observed to expected los ratios for each hospital . in order to facilitate root cause analysis of a nicu s infants with excessive los , outliers for los at the individual patient level were identified based on studentized residuals outside of the 2 to + 2 range . as infants who died were excluded from the analysis , we wanted to examine the possibility that hospitals that may have shorter mean los could have higher rates of mortality , thereby having a less acutely ill surviving population of infants that would be biased toward shorter los . to examine this potential bias on average los the mortality rate was computed from an established cpqcc algorithm , a modification of a vermont oxford network model , using all elbw infants excluding delivery room death in the cpqcc dataset between 20082010 ( n=7,270 ) . observed to expected mortality ratios were computedand their relationship to hospital los was evaluated using weighted correlation . in this regression model , each hospital was assigned a weight of the number of eligible patients cared for at that hospital . another potential source of bias could be the exclusion of infants who are transferred out to lower levels of care . when elbw infants cared for at level iii centers are transferred out for feeding and growing at lower levels of care , it is possible that the infants remaining in that nicu may present more complex cases who could be biased toward longer los . similar to the analysis of mortality , we considered the relationship of transfer - out rates for feeding and growing with average los by hospital for nicus with weighted correlation . all statistical analyses were conducted using sas version 9.3 ( sas , cary , nc ) . there were 2,012 elbw infants in the eligible cohort cared for in 111 hospitals ( figure e1 in online supplementary materials ) , with an average birth weight of 830 grams ( sd 126 ) and gestational age 27.2 weeks ( sd 2.0 ) . the majority of patients were cared for in community level nicus ( 64% ) , with 32% of infants cared for in regional nicus , 1% in intermediate nicus , and 4% in non - classified nicus . the median los was 79 days , with a range of 23 to 219 days ( table e3 in online supplementary materials ) . infants who had antenatal steroid exposure and were born by cesarean delivery had shorter mean los . over the 3-year study period , los variation between years was not statistically significant ( p=0.11 ) . the results of the risk adjusted los model are shown in table 1 , and the distribution of observed and predicted los is shown in figure 1 . birth weight , gender , sga , ethnicity , antenatal steroid use , fetal distress , maternal hypertension , and 5 minute apgar score were significant risk factors for longer los . the random hospital intercept was strongly significant , indicating significant variation in los between hospitals . the model without hospital included as a random effect had r of 0.45 . in order to assess the possibility of bias for nicus that had higher mortality rates leading to shorter los , we investigated the relationship between risk - adjusted mortality to the mean risk - adjusted los in hospitals ( figure 2 ) . the mean mortality rate at the nicu level was 15.3% with interquartile range : 8.7% to 22.4% ( risk adjusted mortality rate mean 16.0% , interquartile range 9.9% to 23.5% ) . the regression fit between los and risk adjusted mortality rate was poor with a slope of 0.00351and r = 0.0207 , indicating no relationship between mortality rate and length of stay by nicu . as our study included only infants who were discharged home , another potential bias that we considered was that hospitals that transferred more infants to lower levels of care for feeding and growing may have higher los . the average transfer - out rate for growth and discharge planning was 7.5% overall for elbw infants , with range between 0 to 31% . the mean adjusted los for nicus with transfer out rate < 10% ( n=96 nicus ) was 80.7 days ( interquartile range 79.1 83.0 ) while the mean adjusted los for nicus with transfer out rate greater than or equal to 10% ( n=15 nicus ) was 82.5 days ( interquartile range 80.4 83.5 ) . figure 3 displays the relationship between transfer - out rate and risk - adjusted los . overall , the impact of transfer - out rate on our risk - adjusted los appeared limited . after risk adjustment , the mean nicu los among 27 nicus with more than 20 eligible patientswas 81.3 days with an interquartile range of 80.781.8 days and a total range of 78.283.7 days . for the 84 centers with 20 eligible infants , the mean adjusted los was 81.8 days with a hospital interquartile range of 78.783.7 days and a total range of 54.0104.5 days . if these smaller nicus were considered a single unit , the observed to expected ratio would be 1.003 . at the patient level , there were 91individual outliers identified of which 56 had observed los exceeding predicted . using a large population dataset , we developed a risk adjustment model for nicu los for elbw infants , for estimating individual patient los , and for comparing nicu variation . the methodology employed in this study also forms a basis for further development of los models for other nicu sub - populations . there was wide variance in los by birth weight , by gestational age , and other factors ( table e3 ) . these differences should be noted as various stakeholders may consider los to be a benchmark of quality of care , highlighting the need for the development of optimal risk adjustment models . because of the non - normality of los , we tried several forms of transformation as well as different conditional distribution models to fit the data . the log - scale model was chosen as the primary model due to favorable model characteristics . we made certain exclusions in order to get a group of elbw infants that would best represent the typical los of a patient in this nicu subgroup . as deaths can occur soon after birth and all the way up to several weeks or months of age , the noise in this group of patients would make assessment of nicu los difficult . however , by excluding deaths , there was the possibility that nicus that perform poorly in survival could be perceived as having lower los , as their sickest patients would not be counted in the analysis . in a study by cotten examining infants born at or before 28 weeks gestational age , there was noted to be an inverse relationship of los and mortality , with centers having less infants with prolonged los more likely to have higher mortality . in contrast , across 111 nicus that included regional , community , and intermediate nicus , and caring for a few to many elbw patients , we found less concern for this potential bias , as there was no correlation between los and risk - adjusted mortality . in the study by cotten , the cohort included births during 1998 to 2001 , and mortality rate was higher overall at 28.5% vs. 15.3% in our cohort . although we have addressed one aspect of the question of how deaths are incorporated into analyses on los , this is a complex issue that will require ongoingstudy to develop optimal strategies for assessment , as well as study in other settings where the death to los relationship may differ . on the other hand , nicus that transfer many of their less acute patients to nicus with lower level of care could falsely have an increased los , as their sickest patients would be over - represented in the analysis . some centers may have a networkof several lower level nicus at outlying hospitals for transferring convalescing infants , whereas other nicus may not have that capacity . within our heterogeneous group of nicus , we did not find a significant relationship between risk - adjusted los and transfer - out rates for feeding and growing , alleviating this concern . however , as our analysis only concerned elbw infants , these potential biases would need to be further tested for other nicu populations . further work in evaluating models that include transferred patients , both transferred in to a higher level of care , as well as those transferred out to lower level of care may increase the potential to assess larger systems of care . there may be several limitations to our analysis in regard to the data available for modeling . there may be some socio - demographic factors that were not accounted for in the dataset , such as family income . although we accounted in part for severity of illness by including variables such as birth weight and apgar score in the model , other measures obtained at time points such as admission to the nicu or in the early hospital course could potentially strengthen the model fit . on the other hand , as antenatal and delivery room management could impact both severity of illness and length of stay , the ultimate purpose of the los assessment may guide inclusion of such variables in modeling . in our random effects model , the hospital intercept was highly significant , indicating that there are opportunities for reducing the variation of elbw los across nicus . when the hospital effect was removed from the model , the explanatory power of the model ( r = 0.45 ) was comparable to that reported in a previous study of nicu all patient diagnosis - related groups , a classification system for inpatient hospital care . as our model incorporated both clinically and statistically significant maternal and neonatal factors for risk adjustment , it may be useful as a basis for assessing and comparing nicu los for an individual center across time , as well as between centers . we have developed a patient - level risk - adjusted model for assessing los for elbw infants , which additionally accounts for clustering of outcomes by nicu ( hospital ) . our study also allows hospitals to assess their risk adjusted los and will give the ability for each nicu to identify infants whose los are extreme and could serve as a starting point for root cause analysis of excessive los . this work forms the basis for developing models for los for other nicu sub - populations . further research will focus on optimal methods to compare hospitals in los for the purpose of quality improvement , public reporting , and optimizing payment structures . this work also forms the foundation for studying the relationship of los to short- and long - term clinical outcomes , and future research on how family resources and competency , nicu processes , and hospital factors such as level of care may influence risk - adjusted los . * discharged home with eligibility criteria ( inborn or outborn admitted within 24 hours from birth ) * * transfer or discharge home cases where eligibility criteria were not met

objectiveto develop a length of stay ( los ) model for extremely low birth weight ( elbw ) infants.study designwe included infants from the california perinatal quality care collaborative with birth weight 4011,000 grams who were discharged to home . exclusion criteria were congenital anomalies , surgery , and death . los was defined as days from admission to discharge . as patients who died or were transferred to lower level of care were excluded , we assessed correlation of hospital mortality rates and transfers torisk adjusted los.resultsthere were 2,012 infants with median los 79 days ( range 23219 ) . lower birth weight , lack of antenatal steroids , and lower apgar score were associated with longer los . there was negligiblecorrelation between risk - adjusted los and hospital mortality rates ( r = 0.0207 ) and transfer - out rates ( r = 0.121).conclusionparticularly because elbw infants have extended hospital stays , identification of unbiased and informative risk - adjusted los for these infants is an important step in benchmarking best practice and improving efficiency in care .

recent observations of the disk properties of intermediate mass herbig ae and late herbig be stars suggest a close parallel to ttauri stars , revealing the same size range of disks , similar optical surface brightness and similar structure consisting of inner dark disk and a bright ring . models of magnetically driven accretion and outflows successfully reproduce many observational properties of low - mass pre - main sequence stars , the classical ttauri stars . however , due to the very poor knowledge of the magnetic field strength and magnetic field topology in herbig stars , current theories are not able to present a consistent scenario of how the magnetic fields in herbig ae / be stars are generated and how these fields interact with the circumstellar environment , consisting of a combination of accretion disk , magnetosphere , and disk - wind region or jets . as of today , only about 20 late herbig be and herbig ae stars have been reported to possess large - scale organized magnetic fields ( e.g. , @xcite ; @xcite ) , using low- and/or high - resolution spectropolarimetric observations . moreover , only for the two herbig ae stars hd101412 and v380ori @xcite , the magnetic field geometry has been constrained in previous studies . it is very likely that the rather low detection rate of magnetic fields in herbig ae stars can be explained by the weakness of these fields and/or by rather large measurement uncertainties . indeed , in the currently largest high - resolution spectropolarimetric survey of the magnetic field in these stars by @xcite with 132 measurements for 70 herbig stars , the measurement uncertainty is worse than 200 g for 35% of the measurements , and for 32% of the measurements it is between 100 and 200 g , i.e. only 33% of the measurements showed a measurement accuracy below 100 g . therefore , any new detection / confirmation of the presence of a magnetic field in a herbig ae / be star is important to increase the sample of magnetic herbig stars . clearly , only after we gain knowledge of the magnetic field strength and its topology , can we start to understand how it interacts with the circumstellar environment . polarimetric observations of the herbig ae star pds2 ( cd@xmath153@xmath2251 ) were obtained on two different epochs using the harps polarimeter . this star has been identified as a herbig ae candidate star in the pico dos dias survey by @xcite . pds2 displays h@xmath3 in emission , and the pre - main sequence nature is indicated by its _ iras _ colours . the mass accretion rate was determined by @xcite on eight epochs using different spectral accretion indicators from the near - uv to the near - ir . this work revealed short - term night - to - night variability , as well as long - term variability on a time scale of tens of days . using the 0.6 m r.e.m . telescope on la silla , a preliminary analysis of pds2 by @xcite showed the presence of @xmath4 scuti - like pulsations with three frequencies on a time scale of 1.01.7h . the refined analysis of the same data by @xcite revealed pulsations at four frequencies with pulsation periods between 0.9 and 2h . the relatively low projected rotation velocity , @xmath5kms@xmath6 , and the fundamental parameters , @xmath7k and @xmath8 , were recently determined by @xcite using high - resolution harps spectra . according to their results , pds2 belongs to the class of herbig ae stars resembling the chemical composition of @xmath9 boo stars . due to the relative faintness of pds2 ( @xmath10 ) , the presence of a magnetic field was not previously studied using high - resolution polarimetric spectra . in the past , this star was included in two magnetic studies based on low - resolution spectropolarimetric observations obtained with fors1 ( focal reducer low dispersion spectrograph ) mounted at the 8-m kueyen telescope of the vlt . while in the first study by @xcite no convincing evidence for the presence of a magnetic field in pds2 was found , @xcite reported on the detection of a mean longitudinal magnetic field @xmath11 g . @xcite disputed this detection after re - examining the fors1 data using their semi - automatic measurement procedure . in sect . [ sect : obs ] , we describe the observations and data reduction , and in sect . [ sect : mf_meas ] we discuss the methods and results of our magnetic field measurements . the density distribution of longitudinal magnetic fields in magnetic late herbig be and herbig ae stars is presented in sect . [ sect : mf_compilation ] . finally , in sect . [ sect : disc ] we discuss the significance of the obtained results for the improvement of our knowledge of the role of magnetic fields in intermediate - mass pre - main sequence stars . two spectropolarimetric observations of pds2 were obtained with the harps polarimeter ( harpspol ; @xcite ) attached to eso s 3.6 m telescope ( la silla , chile ) on the nights of 2012 july 15 and 18 . these spectra were originally recorded as part of eso programme 187.d-0917(c ) ( pi : alecian ) and were downloaded from the eso archive under request mschoeller 77411 . each observation was split into eight subexposures with an exposure time of 15min , obtained with different orientations of the quarter - wave retarder plate relative to the beam splitter of the circular polarimeter . the time to complete the cycle of eight subexposures for each observation accounted for 2h and 4min . the achieved signal - to - noise ratio ( @xmath12 ) in the final stokes @xmath13 spectra summed over eight subexposures is rather low , accounting for a @xmath14 during the night of 2012 july 15 , and a @xmath15 for the second night on 2012 july 18 . the spectra have a resolving power of about @xmath16 and cover the spectral range 37806910 , with a small gap between 5259 and 5337 . the reduction and calibration of these spectra was performed using the harps data reduction software available at the eso headquarter in germany . the normalisation of the spectra to the continuum level consisted of several steps described in detail by @xcite . the stokes @xmath13 and @xmath17 parameters were derived following the ratio method @xcite , and null polarisation spectra were calculated by combining the subexposures in such a way that polarisation cancels out . these steps ensure that no spurious signals are present in the obtained data ( e.g. @xcite ) . cc|cr@@xmath18l|r@@xmath18lr@@xmath18l + & & & + & & & & & + & & & & & + + 2456123.906 & 74 & 2420 & 5 & 5 & 23 & 25 & 22 & 26 + 2456126.904 & 65 & 2350 & 33 & 5 & 85 & 26 & 18 & 28 + + the software packages used by our group to study stellar magnetic fields are the moment technique developed by @xcite ( e.g. @xcite ) and the so - called multi - line singular value decomposition ( svd ) method for stokes profile reconstruction recently introduced by @xcite . usually , before we apply the svd method , we examine the presence of wavelength shifts between right- and left - hand side circularly polarized spectra ( interpreted in terms of a longitudinal magnetic field @xmath19 ) in a sample of clean unblended spectral lines using the moment technique . this technique allows us not only the estimation of the mean longitudinal magnetic field , but also to prove the presence of crossover effect and of the quadratic magnetic field . this information is highly important as , depending on the magnetic field geometry , even stars with rather weak longitudinal magnetic fields can exhibit strong crossover effects and kg quadratic fields ( see e.g. @xcite ; @xcite ; @xcite ) . in the study of pds2 , for each line in the selected sample of 44 unblended fe ii lines , the measured shifts between the line profiles in the left- and right - hand circularly polarized harps spectra are used in a linear regression analysis in the @xmath20 versus @xmath21 diagram , following the formalism discussed by @xcite . our measurements @xmath22 g and @xmath23 g achieved on the first and second epochs , respectively , indicated the probable presence of a weak magnetic field on the second epoch . no crossover or mean quadratic magnetic field at a significance level of 3@xmath24 has been detected on either observing night , probably due to the rather low s / n of the observed spectra . the measured values for the mean longitudinal magnetic field @xmath25 are presented in the fifth column of table [ tab : log_meas ] . in the last column , we also present the results of the magnetic field measurements using the null polarisation spectra , labeled with @xmath26 . since no significant fields could be determined from the null spectra , we conclude that no noticeable spurious polarisation is present . the basic idea of the svd method is similar to the principal component analysis ( pca ) approach @xcite , where the similarity of the individual stokes @xmath17 profiles allows one to describe the most coherent and systematic features present in all spectral line profiles as a projection onto a small number of eigenprofiles . profiles in the subexposures recorded on the nights of 2012 july 15 ( top ) and 18 ( bottom ) . _ left panels _ : overplotted stokes @xmath13 profiles computed for the individual subexposures obtained with a time lapse of 15min . _ right panels _ : differences between the stokes @xmath13 profiles computed for the individual subexposures and the average stokes @xmath13 profile . , title="fig:",scaledwidth=22.0% ] profiles in the subexposures recorded on the nights of 2012 july 15 ( top ) and 18 ( bottom ) . _ left panels _ : overplotted stokes @xmath13 profiles computed for the individual subexposures obtained with a time lapse of 15min . _ right panels _ : differences between the stokes @xmath13 profiles computed for the individual subexposures and the average stokes @xmath13 profile . , title="fig:",scaledwidth=22.0% ] profiles in the subexposures recorded on the nights of 2012 july 15 ( top ) and 18 ( bottom ) . _ left panels _ : overplotted stokes @xmath13 profiles computed for the individual subexposures obtained with a time lapse of 15min . _ right panels _ : differences between the stokes @xmath13 profiles computed for the individual subexposures and the average stokes @xmath13 profile . , title="fig:",scaledwidth=22.0% ] profiles in the subexposures recorded on the nights of 2012 july 15 ( top ) and 18 ( bottom ) . _ left panels _ : overplotted stokes @xmath13 profiles computed for the individual subexposures obtained with a time lapse of 15min . _ right panels _ : differences between the stokes @xmath13 profiles computed for the individual subexposures and the average stokes @xmath13 profile . , title="fig:",scaledwidth=22.0% ] as we mentioned above , the star pds2 was reported to show @xmath4 scuti - like pulsations on a time scale between 0.9 and 2.0h . since the full harps exposure times of about 2h on both nights are of the same order , and pulsations are known to have an impact on the analysis of the presence of a magnetic field and its strength ( e.g. , @xcite ; @xcite ) , as a first step , we verified that no change in the line profile shape or radial velocity shifts are present in the obtained spectra . in fig . [ fig : night12 ] on the left side we present overplotted stokes @xmath13 profiles computed for the individual subexposures recorded on both nights . on the right side of this figure we show differences between the stokes @xmath13 profiles computed for the individual subexposures and the average stokes @xmath13 profile . no impact of pulsations at a level higher than the spectral noise is detected in the stokes @xmath13 profiles . , @xmath17 , and @xmath27 svd profiles obtained for pds2 on two different nights . the @xmath17 and @xmath27 profiles were expanded by a factor of 30 and shifted upwards for better visibility . the red ( in the on - line version ) dashed lines indicate the standard deviations for the @xmath17 and @xmath27 spectra.,title="fig:",scaledwidth=45.0% ] , @xmath17 , and @xmath27 svd profiles obtained for pds2 on two different nights . the @xmath17 and @xmath27 profiles were expanded by a factor of 30 and shifted upwards for better visibility . the red ( in the on - line version ) dashed lines indicate the standard deviations for the @xmath17 and @xmath27 spectra.,title="fig:",scaledwidth=45.0% ] the resulting mean stokes @xmath13 , stokes @xmath17 , and null profiles obtained by using the svd method with 2094 metallic lines in the line mask are presented in fig . [ fig : svd ] . the line mask was constructed using the vald database ( e.g. @xcite ) and the respective stellar parameters of pds2 . due to the very low signal - to - noise at the blue and red ends of the harps spectra , the spectral lines used for the computation of the svd profiles have been selected in the wavelength region from 4200 to 6200 . the mean longitudinal magnetic field is estimated from the svd reconstructed stokes @xmath17 and @xmath13 using the center - of - gravity method ( see e.g. @xcite ) . a velocity range @xmath28kms@xmath6 was adopted to determine the detection probability and the longitudinal magnetic field value . for both observations the null spectra appear flat , indicating the absence of spurious polarisation . no longitudinal magnetic field is detected on the first epoch on 2012 july 15 , where we measure @xmath29 g . a definite detection of a field , @xmath0 g , with a false alarm probability ( fap ) smaller than @xmath30 , is achieved on the second epoch three nights later . in table [ tab : log_meas ] . we list for the two observations the heliocentric julian date , the @xmath12 reached in the final stokes @xmath13 profiles , the @xmath12 obtained in the svd profile , the longitudinal magnetic field @xmath19 determined with svd , and @xmath19 determined with the moment technique from iron lines . as the magnetic field strength and the magnetic field geometry in herbig stars are poorly known only about 20 late herbig be and herbig ae stars have been reported to possess large - scale organized magnetic fields we compiled for them all magnetic field measurements reported in previous spectropolarimetric studies . in table [ tab:4 ] we present the @xmath31 values selected from previous low - resolution spectropolarimetric studies with fors1/2 , where magnetic field measurements were carried out using the entire spectra , and high - resolution spectropolarimetric studies using the harps , espadons , and narval spectrographs . the rms longitudinal magnetic field , the rms standard error , and the reduced @xmath32 for these measurements have been computed following the equations of @xcite : @xmath33 table [ tab:4 ] lists for each star its name and spectral type , the number of magnetic field measurements used to calculate @xmath31 , the rms longitudinal magnetic field @xmath31 , the rms standard error , the reduced @xmath32 values , and finally the references to the measurements . [ cols="<,^ , > , > , > , > , > , < " , ] references : a09 @xcite ; a13a @xcite ; a13b @xcite ; c07 @xcite ; d97 @xcite ; h07 @xcite ; h09 @xcite ; h11a @xcite ; h11b @xcite ; h13 @xcite ; h15 this paper ; s10 @xcite ; w05 @xcite ; w07 @xcite . in fig . [ fig : rms ] , we present the distribution of the rms longitudinal magnetic field strength for all late herbig be and herbig ae stars , for which detections of a magnetic field were reported in the past . the obtained density distribution of the rms longitudinal magnetic field values reveals that only very few stars have rms fields stronger than 200 g , and half of the sample possesses magnetic fields of about 100 g and less . ) for the twenty late herbig be and herbig ae stars for which detections of a magnetic field were reported in the past . , scaledwidth=35.0% ] in this work , we present the first detection of a weak magnetic field in the herbig ae star pds2 using high - resolution spectropolarimetric observations with harps . previous observations using low - resolution spectropolarimetry with fors1 indicated @xmath11 g @xcite . apart from pds2 , the authors announced the detection of a weak longitudinal magnetic fields in six other herbig ae stars . confirmation of the definite presence of the magnetic field based on accurate high - resolution spectropolarimetry with low uncertainties is still pending for these other six stars . among these herbig ae / be stars , three show longitudinal magnetic fields below 100 g , while for the remaining three stars the magnetic field ranges from 100 to 200 g . magnetospheric accretion has been well established for ttauri stars and depends on a strong ordered predominantly dipolar field channeling circumstellar disk material to the stellar surface via accretion streams . however , no convincing scenario on how magnetospheric accretion works in herbig ae stars possessing rather weak magnetic fields currently exists . @xcite recently studied he i @xmath910830 morphology in a sample of 56 herbig ae / be stars . they suggest that herbig be stars do not accrete material from their inner disks in the same manner as ttauri stars , while late herbig be and herbig ae stars show evidence for magnetospheric accretion . further , due to their high rotation rates @xcite and weak magnetic fields , more compact magnetospheres in herbig stars are proposed . we note that since the rotation period of pds2 is currently unknown , it is not clear whether it might be a rapid rotator with a low inclination of the rotation axis . in fact , the density distribution of the rms longitudinal magnetic field strength clearly indicates that the magnetic fields in herbig ae stars are by far weaker than those measured in their lower mass counterparts , the ttauri stars , usually possessing kg magnetic fields . as is shown in fig . [ fig : rms ] , out of the sample of twenty magnetic late herbig be and herbig ae stars , only very few stars have rms fields stronger than 200 g , and half of the sample possesses magnetic fields of about 100 g and less . the obtained results seem to support the existence of a different accretion mechanism mediating the mass flow from the disk to the intermediate - mass star , compared to that working in ttauri stars . noteworthy , for the currently best studied herbig ae stars , hd101412 and v380ori with strong magnetic fields monitored over the rotation cycles , the obtained magnetic field models assuming a simple centered dipole indicate rather large obliquity @xmath34 of the magnetic axis to the rotation axis @xcite . the fact that the dipole axes are located close to the stellar equatorial plane is very intriguing in view of the generally assumed magnetospheric accretion scenario . as was shown in the past @xcite , the topology of the channeled accretion critically depends on the tilt angle between the rotation and the magnetic axis . for large inclination angles @xmath34 , many polar field lines would thread the inner region of the disk , while the closed lines cross the path of the disk matter , causing strong magnetic braking . clearly , the qualitative picture is expected to be different if the magnetic field topology was proven as more complex than a simple centered dipole model . for a better understanding of the role of magnetic fields in herbig ae / be stars , it is important to carry out additional highly accurate magnetic field measurements of a representative sample of herbig ae stars over their rotation periods using high quality , high - resolution polarimetric spectra . using multi - epoch observations , it will become possible to disclose the magnetic topology on the surface of herbig ae stars necessary to understand the interaction of the magnetic field with winds , accretion disks , convection , turbulence , and circulation . based on data obtained from the eso science archive facility under request mschoeller 77411 . based on observations made with eso telescopes at the la silla paranal observatory under programme i d 187.d-0917(c ) . we would like to thank the anonymous referee for useful comments . snik f. , jeffers s. , keller c. , piskunov n. , kochukhov o. , valenti j. , johns - krull c. , 2008 , in mclean i.s . , casali m.m . , eds . , proc . of the spie , ground - based and airborne instrumentation for astronomy ii . , vol . 7014 , 70140o

models of magnetically driven accretion and outflows reproduce many observational properties of ttauri stars , but the picture is much less clear for the herbig ae / be stars , due to the poor knowledge of their magnetic field strength and topology . the herbig ae star pds2 was previously included in two magnetic studies based on low - resolution spectropolarimetric observations . only in one of these studies the presence of a weak mean longitudinal magnetic field was reported . in the present study , for the first time , high - resolution harps spectropolarimetric observations of pds2 are used to investigate the presence of a magnetic field . a firm detection of a weak longitudinal magnetic field is achieved using the multi - line singular value decomposition method for stokes profile reconstruction ( @xmath0 g ) . to gain better knowledge of typical magnetic field strengths in late herbig be and herbig ae stars , we compiled previous magnetic field measurements , revealing that only very few stars have fields stronger than 200 g , and half of the sample possesses fields of about 100 g and less . these results challenge our current understanding of the magnetospheric accretion in intermediate - mass pre - main sequence stars as they indicate that the magnetic fields in herbig ae / be stars are by far weaker than those measured in ttauri stars . [ firstpage ] stars : pre - main sequence stars : individual ( pds2 ) stars : magnetic field stars : oscillations stars : variables : general

hydrogen is the most abundant element in the universe and therefore is an important probe for the physical conditions of intergalactic medium throughout the observable universe . high resolution spectroscopy of quasars shows a large number of absorption lines blueward of ly@xmath0 mostly due to neutral hydrogen components in intergalactic medium intervening along the line of sight . these quasar absorption systems due to hydrogen are classified according to the column densities . quasar absorption systems with a neutral column density not exceeding @xmath13 constitute the ly@xmath0 forest which is attributed to the residual hydrogen atoms contained in intergalactic filamentary structures that are highly ionized ( e.g. rauch 1998 , meiksin 2009 , kim et al . the absorption systems associated with a neutral hydrogen column density in excess of @xmath14 are called the damped lyman alpha systems ( dlas ) , which are distinguished from other quasar absorption systems in that they are dominantly neutral ( e.g. wolfe et al . 1986 , 2005 ) . a catalogue of 322 dlas was provided by curran et al . ( 2002 ) , and recently 721 dlas are listed from the sloan digital sky survey data release 7 ( khare et al . 2012 ) . the exact nature of the dlas is still controversial , but they are believed to dominate the neutral gas content in the universe , providing raw material for star formation during most of the time from the reionization era to the present ( e.g. wolfe et al . 2005 , prochaska , herbert - fort & wolfe 2005 ) . dlas are also important to trace the chemical evolution of the universe by carefully measuring the metal abundance as a function of redshift ( e.g. calura , matteucci & vladilo 2003 , rafelski et al . accurate atomic physics for ly@xmath0 is essential to obtain a reliable estimate of metallicity of a dla . recently , kulkarni et al . ( 2012 ) reported a discovery of super - damped lyman - alpha absorber at @xmath15 toward the qso q1135 - 0010 . their profile fit to the dla showed a high neutral hydrogen column density of @xmath16 . a little higher column density of @xmath17 was reported for the same object by noterdaeme et al . ( 2012 ) , who also suggested a significant star formation rate of @xmath18 based on the strength of h@xmath0 . damped ly@xmath0 absorption profiles are analyzed using the voigt function which is defined as a convolution of a lorentzian function with a gaussian function ( e.g. rybicki & lightman 1979 ) . when @xmath4 is very large , the absorption at the core part is almost complete . contributing only to the core part of the voigt function , the gaussian function does not play an important role in the analysis of high column density systems . in the wing part the voigt function coincides with the lorentzian , and in this case the damping term in the denominator of the lorentzian is quite negligible . therefore , the wing profile is essentially proportional to @xmath19 , where @xmath20 is the difference in wavelength from the ly@xmath0 line center wavelength @xmath21 . the lorentzian function , invoked to describe the wing parts of the absorption profile , is obtained when the scattering atom is regarded as a two - level atom . instead of being a two - level system , the hydrogen atom has infinitely many energy levels , and therefore the scattering cross section is expected to deviate from the lorentzian function that is symmetric with respect to the line center wavelength . peebles ( 1993 ) discussed the resonance line shape that deviates from the simple lorentzian and mentioned the marginal possibility of detecting this deviation in the absorption line profiles of dla systems ( e.g. peebles 1993 , p. 573 ) . the formula for the scattering cross section he introduced is derived in a heuristic way to illustrate the behavior of the lorentzian profile near line resonance and the classical @xmath22-dependence in the low energy regime . however , this formula is inaccurate because it fails to include the contributions from the infinitely many @xmath2 states that participate in the electric dipole interaction . the exact scattering cross section is computed by summing all the probability amplitudes contributed from the infinitely many bound and free @xmath2 states . the result is summarized in the kramers - heisenberg formula ( e.g. bethe & salpeter 1967 , sakurai 1967 ) . an expansion of the kramers - heisenberg formula around ly@xmath0 in frequency space was given by lee ( 2003 ) , in which the redward asymmetry of the scattering cross section around ly@xmath0 was briefly illustrated . however , spectroscopy is often presented in wavelength space rather than in frequency space so that it will also be useful to express the kramers - heisenberg formula in wavelength space . in this paper , we present the same expansion in wavelength space and quantify the redward shift of the center wavelength as a function of @xmath4 . in addition , we also expand the kramers - heisenberg formula in the vicinity of ly@xmath3 in order to investigate the asymmetry around ly@xmath3 . in the case of ly@xmath3 , there is an additional scattering channel , which results from radiative de - excitation into the @xmath23 state re - emitting an h@xmath0 line photon . this inelastic or raman scattering branch is proposed to be important in the formation of broad h@xmath0 wings observed in young planetary nebulae and symbiotic stars ( e.g. isliker , nussbaumer & vogel 1989 , lee 2000 , schmid 1989 ) . in this paper , we show that the cross section around ly@xmath3 is asymmetric blueward , which is in high contrast with the behavior around ly@xmath0 . a brief discussion on the observational consequences is presented . the scattering cross section is given by the kramers - heisenberg formula that is obtained from a second - order time dependent perturbation theory ( e.g. sakurai 1967 , merzbacher 1970 ) . in terms of the matrix elements of the dipole operator , the kramers - heisenberg formula can be written as @xmath24 where @xmath25 is the electron mass and @xmath26 is the classical electron radius . the polarization vectors of incident and scattered radiation are denoted by @xmath27 and @xmath28 , respectively . here , @xmath29 is the angular frequency between the intermediate state @xmath30 and the ground @xmath31 state . the intermediate state @xmath30 that participates in the electric dipole interaction of lyman photons consists of bound @xmath32 states and free @xmath33 states . in the atomic units adopted in this work , the bound @xmath32 state has the energy eigenvalue @xmath34 and correspondingly @xmath35 . similarly , for the @xmath33 state , @xmath36 and @xmath37 . the term denoted by @xmath38 represents the matrix element of the position operator between the intermediate state @xmath30 and the ground @xmath31 state . being a two - body system , the hydrogen atom admits analytically closed expressions of the wavefunctions , which enables one to compute explicitly the matrix elements of the dipole operator in terms of the confluent hypergeometric function . a typical matrix element @xmath39 for an intermediate state with @xmath40 is explicitly written as @xmath41^ * ( { \bf r}\cdot { \bf e}^{(\alpha ) } ) r_{10}(r)y_0 ^ 0(\theta,\phi ) r^2 dr \sin\theta d\theta d\phi,\ ] ] where @xmath42 is a spherical harmonic function and @xmath43 is the radial wavefunction given by an associated laguerre function . the angular integration followed by summing over magnetic substates @xmath44 of each @xmath32 state and averaging over polarization states of incident and outgoing radiation results in a numerical factor of @xmath45 , which is discussed in more detail in appendix a. the radial matrix elements of the dipole operators @xmath46 and @xmath47 are readily found in many textbooks on quantum mechanics ( e.g. berestetski , lifshitz & pitaevskii 1971 , bethe & salpeter 1967 ) . the radial matrix elements for the bound @xmath32 states are given by @xmath48^{1\over2 } a_b,\ ] ] where @xmath49 is the bohr radius . for the continuum @xmath33 states , the corresponding values are given by @xmath50}\over { [ ( n')^2 + 1]^{5}[1-\exp(-2\pi n ' ) ] } \right]^{1\over2}a_b,\ ] ] which is obtained through analytic continuation into the complex plane ( bethe & salpeter 1967 , saslow & mills 1969 ) . lee ( 2003 ) provided the expansion of the kramers - heisenberg formula for rayleigh scattering in the vicinity of ly@xmath0 in terms of @xmath51 . the result is summarized as @xmath52 where @xmath53 is the thomson scattering cross section and @xmath54 is the oscillator strength for the ly@xmath0 transition . the coefficients @xmath55 were numerically computed by lee ( 2003 ) , who gave @xmath56 in table 1 , we show these coefficients up to @xmath57 . up to the first order of @xmath58 the scattering cross section can be expressed as @xmath59 here , we introduce the characteristic cross section @xmath60 for ly@xmath0 defined as @xmath61 . the coefficient @xmath62 , being less than zero , is responsible for the redward asymmetric deviation of the scattering cross section in frequency space . astronomical spectroscopy is often presented in wavelength space , which makes it necessary to express the scattering cross section in terms of @xmath20 , the difference in wavelength from the ly@xmath0 line center . from the following relation @xmath63 we may notice that expansion in wavelength space will yield different coefficients from those obtained in expansion in frequency space . substituting eq . ( [ convert ] ) into eq . ( [ lyaeq1 ] ) , we obtain @xmath64 \nonumber \\ & = & \sigma_\alpha \left({\lambda_{\alpha}\over\delta\lambda}\right)^2 \bigg[1 + 3.792\left({\delta\lambda\over\lambda_{\alpha}}\right ) \nonumber\\ & -&20.84 \left({\delta\lambda\over\lambda_{\alpha}}\right)^2 + 83.14\left({\delta\lambda\over\lambda_{\alpha}}\right)^3+\cdots \bigg ] . \label{lyaeq2}\end{aligned}\ ] ] thus , up to first order , we have @xmath65 , \label{lya_wv}\ ] ] from which it is found that the coefficient 3.792 is significantly different from the coefficient @xmath66 in frequency space . the red asymmetry in the ly@xmath0 scattering cross section can be explained by noting the denominator @xmath67 in eq . ( 1 ) , where the dominant contribution comes from @xmath68 . the contributions from all the excited states with @xmath69 interfere positively with the dominant contribution from @xmath68 for photons on the red side whereas the interference is negative for photons on the blue side . therefore the red wing is strengthened relative to the pure lorentzian profile by the positive interference of scattering from all other levels . in a similar way , we define the difference in frequency from ly@xmath3 by @xmath70 and expand the kramers - heisenberg formula in terms of @xmath71 . we note that the terms appearing in the kramers - heisenberg formula include @xmath72 and @xmath73.\ ] ] for @xmath74 , the second term in the summation in eq . ( [ kr_hei ] ) can be written as @xmath75.\ ] ] similar expressions for the continuum states are obtained in a straightforward manner . we expand the kramers - heisenberg formula in frequency space for rayleigh scattering near ly@xmath3 , which is written as @xmath76 < r>_{n1}^2 \nonumber \\ & + & \sum_{n\neq 3 } { \delta\omega_2\omega_{n1}\over \omega_{n1}+\omega_{31 } } \left [ 1 -{\omega_{n1}\over \omega_{31 } } \sum_{k=1}^\infty \left ( { -\delta\omega_2\over\omega_{n1}+\omega_{31 } } \right)^k \right ] < r>_{n1}^2 \nonumber \\ & - & \int_0^\infty dn ' { \delta\omega_2\omega_{n'1}\over\omega_{n'1}-\omega_{31 } } \left [ 1 + { \omega_{n'1}\over \omega_{31 } } \sum_{k=1}^\infty \left ( { \delta\omega_2\over \omega_{n'1}-\omega_{31 } } \right)^k \right ] < r>_{n'1}^2 \nonumber \\ & + & \left . \int_0^\infty dn ' { \delta\omega_2\omega_{n'1}\over \omega_{n'1}+\omega_{31 } } \left [ 1 -{\omega_{n'1}\over \omega_{31 } } \sum_{k=1}^\infty \left ( { -\delta\omega_2\over\omega_{n'1}+\omega_{31 } } \right)^k \right ] < r>_{n'1}^2 \right|^2 . \label{eq_lyb}\end{aligned}\ ] ] here , angular integration has been performed and the atomic unit system is adopted , in which the bohr radius @xmath77 . an algebraic rearrangement of eq . ( [ eq_lyb ] ) can be made to express @xmath78 as @xmath79 the coefficients @xmath80 and @xmath81 are determined through following relations ; @xmath82 where @xmath83 is the oscillator strength for the ly@xmath3 transition . the coefficients @xmath84 for @xmath85 are given as @xmath86<r>_{n1}^2 \nonumber \\ & -&{1\over3}\int_{0}^\infty dn ' { \omega_{n'1}^2\over\omega_{31 } } \left [ \left({\omega_{31}\over\omega_{n'1}-\omega_{31}}\right)^k -\left({-\omega_{31}\over\omega_{n'1}+\omega_{31}}\right)^k \right]<r>_{n'1}^2 . \end{aligned}\ ] ] the numerical values of the coefficients up to @xmath87 are computed as follows ; @xmath88 in particular , the coefficient @xmath89 is positive due to the predominant contribution from the @xmath90 state . therefore , up to the first order approximation in @xmath71 , the rayleigh scattering cross section around ly@xmath3 is given by @xmath91 in wavelength space , the rayleigh scattering cross section in the vicinity of ly@xmath3 with the line center @xmath92 can be expanded as @xmath93 \nonumber \\ & = & \sigma_t\left({f_{13}\over2}\right)^2 \left({\lambda_{\beta}\over\delta\lambda_2}\right)^2 \bigg[1 - 31.64\left({\delta\lambda_2\over\lambda_{\beta}}\right ) \nonumber\\ & -&5.970\times10 ^ 2 \left({\delta\lambda_2\over\lambda_{\beta}}\right)^2 + 1.792\times10 ^ 4\left({\delta\lambda_2\over\lambda_{\beta}}\right)^3\cdots \bigg ] , \label{lybeq2}\end{aligned}\ ] ] where @xmath9 is the wavelength deviation from the ly@xmath3 center . the negative value of the coefficient @xmath94 implies that the rayleigh scattering cross section near ly@xmath3 is asymmetric to the blue of ly@xmath3 , which is in high contrast with the behavior around ly@xmath0 . in the case of ly@xmath3 , the main contributor to the kramers - heisenberg formula is the @xmath95 state and the residual contribution comes from the @xmath90 state and all the @xmath2 states lying higher than the @xmath95 state . the contribution to @xmath96 of a given @xmath32 or @xmath33 state is measured roughly by the oscillator strength inversely weighted by the energy difference from ly@xmath3 . therefore , the contribution of the @xmath90 state is more important than that from all the @xmath2 states lying higher than the @xmath95 state . hence , in the case of ly@xmath3 , the @xmath68 contribution has lower frequency and the interference with the principal @xmath97 scattering contribution is negative on the red side and positive on the blue side , which explains the blue asymmetric scattering cross section . interaction with a hydrogen atom of electromagnetic radiation around ly@xmath3 has another channel , which is inelastic or raman scattering . the scattering hydrogen atom de - excites into the @xmath23 state re - emitting an h@xmath0 photon into another line of sight , which provides an important contribution to the absorption profile around ly@xmath3 . the astrophysical importance of raman scattering can be appreciated in the emission features at 6830 and 7088 that appear in the spectra of about a half of symbiotic stars . these are formed through raman conversion of the resonance doublet @xmath98 1032 , 1038 ( schmid 1989 , nussbaumer , schmid & vogel 1989 ) . another example of raman scattering by atomic hydrogen is provided by far uv emission lines in symbiotic stars and young planetary nebulae ( e.g. birriel 2004 , lee et al . 2006 , lee 2012 ) . it has also been proposed that broad h@xmath0 wings often found in planetary nebulae and symbiotic stars are formed through raman scattering of far uv continuum around ly@xmath3 ( e.g. lee 2000 , arrieta & torres - peimbert 2003 ) . as is illustrated in sakurai ( 1967 ) , the term corresponding to the seagull graph is absent in the kramers - heisenberg formula for the case of raman scattering . this difference allows an alternate expression of the kramers - heisenberg formula given in terms of the matrix elements of the momentum operator ( see also saslow & mills 1969 , lee & lee 1997 ) . in a manner analogous to what is illustrated in appendix a , taking angular integrations , summing over magentic substates and averaging over polarizations of incident and outgoing radiation , we arrive at an explicit expression of the raman cross section given by @xmath99 here @xmath100 is the angular frequency of the raman scattered radiation . the matrix element @xmath101 associated with the momentum operator between the @xmath32 and the @xmath31 states is given by @xmath102 r^2 dr= \left [ { 2 ^ 6 n^3 ( n-1)^{2n-3}\over ( n+1)^{2n+3 } } \right]^{1/2}.\ ] ] here , an atomic unit system is adopted and the reality of the radial wavefunctions is noted . the matrix element @xmath103 corresponds to the transition between the @xmath32 and @xmath23 states , which is explicitly given by @xmath104^{1/2}.\ ] ] the contribution from the continuum @xmath33 states is obtained by considering the matrix elements of the momentum operator given by @xmath105^{1/2 } \nonumber \\ < p>_{n'2 } & = & \left [ { 2^{11 } n'^3(n'^2 + 1 ) e^{-4n'\tan^{-1}{2\over n'}}\over ( n'^2 + 4)^4(1-e^{-2\pi n ' } ) } \right]^{1/2}.\end{aligned}\ ] ] due to the vanishing matrix element @xmath103 for @xmath68 , the sum in eq . ( [ raman_kh ] ) begins from @xmath97 for the bound @xmath32 states , which implies that the @xmath90 state does not contribute to the cross section for raman scattering around ly@xmath3 . this is decisively important to the behavior of the cross section , as we discuss later in more detail . the terms involving angular frequencies can be rearranged using the following relation @xmath106 where @xmath107 is the angular frequency for h@xmath0 . use is also made of the following relations @xmath108 the kramers - heisenberg formula for raman scattering near ly@xmath3 can be expanded in frequency space as follows @xmath109 where the coefficients @xmath110 are given by @xmath111 and @xmath112 \nonumber\\ & + & \int_0^\infty dn ' { < p>_{n'2}<p>_{n'1}\over 3\omega_{31}}\bigg [ \left ( { \omega_{31}\over \omega_{n'1}-\omega_{31}}\right)^k- \left({-\omega_{31}\over \omega_{n'1}+\omega_{31}-\omega_{21 } } \right)^k \bigg],\end{aligned}\ ] ] for @xmath85 . here , @xmath113 ^ 2=0.4349 $ ] is the oscillator strength between the @xmath23 and @xmath95 states ( e.g. bethe & salpeter 1967 ) . therefore , in frequency space the raman scattering cross section is written as @xmath114 \nonumber \\ & = & \sigma_t \left({\omega_{31}\over\delta\omega_2 } \right)^2 { \omega_{32}\over\omega_{31 } } |c_0|^2 \left [ 1 - 7.832\left({\delta\omega_2\over\omega_{31}}\right ) + \cdots\right ] . \label{ram_betaf}\end{aligned}\ ] ] in wavelength space , we obtain @xmath115 \nonumber \\ & = & \sigma_t \left({\lambda_\beta\over\delta\lambda_2 } \right)^2 { 5\over 32 } |c_0|^2[1 + 5.223\times10 ^ 1(\delta\lambda_2/\lambda_\beta ) \nonumber \\ & + & 9.103\times10 ^ 2(\delta\lambda_2/\lambda_\beta)^2 -8.267\times10 ^ 3(\delta\lambda_2/\lambda_\beta)^3+\cdots ] , \label{ram_beta}\end{aligned}\ ] ] where the lower case coefficients @xmath116 are defined by @xmath117 . the numerical values of these coefficients up to @xmath118 are shown in table 1 . unlike the case for rayleigh scattering near ly@xmath3 , the raman scattering cross section shows redward asymmetry with respect to the ly@xmath3 center . this result can be traced to the fact that no contribution is made from the @xmath90 state , which played a dominant role in the case of rayleigh scattering near ly@xmath3 . in the absence of the @xmath90 contribution , all the perturbing @xmath2 states are more energetic than ly@xmath3 . this situation is exactly the same as the rayleigh scattering around ly@xmath0 resulting in redward asymmetry . the ratio @xmath119 of the cross sections for raman scattering to rayleigh scattering in the vicinity of ly@xmath3 is given by @xmath120 where the first three coefficients are explicitly @xmath121 , @xmath122 and @xmath123 . this result shows discrepancy with that provided by yoo , bak & lee ( 2002 ) , in which there is an error in their numerical calculation of the coefficients @xmath124 and @xmath125 . the leading term can also be expressed as @xmath126 , which implies that the branching ratio is determined by a combination of the oscillator strength and the phase space volume factor represented by @xmath127 . it is seen that the dominant contribution is made by the phase space volume available to scattered radiation . in fig . 1 , we show the branching ratio @xmath119 in the neighborhood of ly@xmath3 . the solid line shows the result from a direct numerical computation of the kramers - heisenberg formula . the dotted line shows the linear fit and the dot - dashed line shows the second order fit using eq . ( [ branching_eq ] ) . because the coefficient @xmath128 is large , the nonlinearity of @xmath119 is quite conspicuous in the figure . this behavior leads to a redward shift in broad h@xmath0 wings observed in young planetary nebulae and symbiotic stars which are also attributed to raman scattering of ly@xmath3 ( jung & lee 2004 ) . in this subsection , we combine the results of previous subsections to provide the expansion of the total scattering cross section around ly@xmath3 . the total scattering cross section around ly@xmath3 is the sum of eq . ( [ lybeq1 ] ) and eq . ( [ ram_betaf ] ) , which is , to the first order of @xmath71 , given by @xmath129.\ ] ] here , we introduce another parameter @xmath130 defined by @xmath131=1.180\times10^{-27}{\rm\ cm^2}.\ ] ] in wavelength space , we may combine eq . ( [ lybeq2 ] ) and eq . ( [ ram_beta ] ) to express the total scattering cross section around ly@xmath3 as @xmath132 . \label{lybeq3}\ ] ] from this result , it is seen that the ly@xmath3 absorption profiles tend to shift blueward of the ly@xmath3 line center . in fig . 2 , we show the total scattering cross section obtained from a numerical evaluation of the kramers - heisenberg formula around ly@xmath0 and ly@xmath3 in wavelength space . the vertical axis shows the logarithm to the base 10 of @xmath96 in units of @xmath133 . in order to take a clear view of the asymmetry of the scattering cross section we plot the same quantities in fig 3 as a function of the absolute value of the wavelength deviation . the cross sections redward of ly@xmath0 and ly@xmath3 are shown with solid lines in the upper panel and lower panel , respectively . the dotted lines show the cross sections blueward of ly@xmath0 and ly@xmath3 . the dotted lines are mirror images of the curves blueward of ly@xmath0 and ly@xmath3 shown in fig . 2 . in fig . 3 , we see that red ly@xmath0 photons have larger scattering cross section than blue counterparts and that the opposite is the case for ly@xmath3 . in fig . 4 , we show the transmission coefficient @xmath134 defined by @xmath135\ ] ] for various neutral hydrogen column densities . the upper panel is for ly@xmath0 and the lower panel is for ly@xmath3 . the solid line shows the result for @xmath136 , the dotted line for @xmath137 , and the dashed line for @xmath138 . in the case of @xmath139 , the asymmetry is quite noticeable in the scale shown in the figure . in this subsection , we investigate the shift of the absorption line center near ly@xmath0 and ly@xmath3 as a function of the neutral hydrogen column density . denoting by @xmath140 the line center wavelength of ly@xmath0 or ly@xmath3 , the scattering cross section is approximated to the first order of dimensionless wavelength deviation from line center @xmath141 by a function @xmath142 the equation @xmath143 has two solutions @xmath144 , of which the mean is @xmath145 . this implies that the absorption center can be meaningfully defined when we fix the value of cross section . the sign of the coefficient @xmath146 determines the direction of asymmetry , where a positive @xmath146 results in a red asymmetry . given a value of the h i column density @xmath4 we define the mean wavelength @xmath147 of the two wavelengths @xmath148 at which @xmath149 around ly@xmath0 and in a similar way we define @xmath150 for ly@xmath3 . we also introduce @xmath151 and @xmath152 as the mean value of the two wavelengths @xmath153 where we have @xmath154 around ly@xmath0 and ly@xmath3 , respectively . corresponding to these wavelengths @xmath155 , we define the velocity shift @xmath156 by the relation @xmath157 for ly@xmath0 and in a similar way @xmath158 is defined for ly@xmath3 . here , @xmath159 is the speed of light . in table 2 , we show the values of @xmath147 and @xmath160 for various neutral hydrogen column densities . also in table 3 we show the quantities corresponding to the ly@xmath3 transitions . at @xmath137 we obtain a redward center shift in the amount of @xmath161 for ly@xmath0 and and a blueward shift of @xmath162 for ly@xmath3 . in fig . [ fig_cena ] , we show @xmath163 and @xmath164 as a function of @xmath4 in the cases of ly@xmath0 ( upper panel ) and @xmath158 and @xmath165 for ly@xmath3 ( lower panel ) . the dotted line shows a fit to the data , which implies that both @xmath166 and @xmath167 are proportional to @xmath4 . the linear fit shown by the dotted line for ly@xmath0 in the figure is given by @xmath168 { \rm\ km\ s^{-1}},\ ] ] and similarly for ly@xmath3 it is given by @xmath169 { \rm\ km\ s^{-1}}.\ ] ] another way of quantifying the asymmetry is provided by fitting the absorption profiles . in this subsection , we compare the transmission coefficient @xmath134 derived from the kramers - heisenberg formula with that obtained from the lorentzian shifted by a finite amount . for simplicity , we fix the column density @xmath139 . this procedure may illustrate an error estimate in determining the redshift of a dla system with @xmath139 . in fig . 6 we show the result for ly@xmath0 . the solid line in each panel shows the transmission coefficient obtained from the kramers - heisenberg formula . the dotted line in the top panel shows the transmission coefficient from the lorentzian function , which provides an excellent fit near the line center . however , a considerable deviation in the wing part is quite noticeable . with the dotted line in the bottom panel , we show the quantities obtained by shifting the lorentzian redward by an amount of @xmath170 . improvement of the fitting in wing parts is achieved only at the expense of a poor approximation near the line center . in the middle panel , we show the lorentzian shifted by @xmath171 , in which the quality of the fit is compromised between the previous two cases . in the analysis by lee ( 2003 ) the optimal wavelength shift was proposed by @xmath172 , which is smaller than @xmath171 suggested in this work . this discrepancy is due to the fact that the fitting procedure in lee ( 2003 ) was confined to a rather narrow interval of @xmath173 excluding extreme wing parts . the procedure of fitting a dla profile using the shifted lorentzian tends to overestimate the line center wavelength of ly@xmath0 leading to corresponding overestimate of the redshift of the dla . we note that lee ( 2003 ) made a mistake in pointing out that the redshift would be _ underestimated _ , which should be corrected to be _ overestimated_. a similar analysis corresponding to ly@xmath3 is shown in fig . 7 for the same neutral hydrogen column density @xmath174 . in the figure , the dotted line in each panel shows the transmission coefficient from the lorentzian function ( top panel ) and shifted lorentzian functions ( middle and bottom panels ) , whereas the solid line shows the exact transmission coefficient computed from the kramers - heisenberg formula . the amount of wavelength shift blueward of ly@xmath3 is @xmath175 and @xmath176 for the middle and bottom panels , respectively . as in the case of ly@xmath0 illustrated in fig . 6 , the unshifted lorentzian gives an excellent fit to the core part of the absorption profile whereas the bottom panel shows an improved fit to the wing parts with the loss of fitting quality at the core part . in fig . 8 , we present the transmission coefficients using the kramers - heisenberg formula and the lorentzian functions around ly@xmath0 and ly@xmath3 in the wavelength interval between 980 and 1400 for a very thick medium with @xmath177 . this kind of an extreme neutral hydrogen column density has been found toward the gamma ray burst grb080607 ( e.g. prochaska et al . for comparison , we show the transmission coefficients obtained from the lorentzian around ly@xmath0 and ly@xmath3 by the dotted line and the dashed line , respectively . in this highly thick medium , the deviation from the lorentzian is quite severe due to the contribution from higher order terms , which prevents one from obtaining satisfactory results by fitting the absorption profiles by a voigt or equivalently a lorentzian function . in particular , in the wavelength range shown in fig . 8 , the local peak transmission is found at @xmath178 , for which @xmath179 . however , the sum of two lorentzian functions around ly@xmath0 and ly@xmath3 admits a local maximum at @xmath180 . this shows the inadequacy of using a voigt function for fitting analyses in extended wing parts in the case of very high column density systems . furthermore , at this high @xmath4 , the blue wing region of ly@xmath0 overlaps with that of the red ly@xmath3 wing , for which full quantum mechanical formula should be invoked for an accurate analysis . the kramers - heisenberg formula is expanded around ly@xmath0 and ly@xmath3 in order to investigate the asymmetric deviation of the scattering cross section . a redward asymmetry is seen around ly@xmath0 and a blueward asymmetry is found around ly@xmath3 . for red ly@xmath0 photons the perturbing transitions from @xmath181 states @xmath182 provide a positive contribution to the scattering cross section because they are in the same side as the @xmath90 state in the energy space , resulting in red asymmetry . in the case of ly@xmath3 , rayleigh scattering contributes more than raman scattering by a factor 6.452 . raman scattering around ly@xmath3 exhibits a red asymmetry like ly@xmath0 because all the perturbing transitions lie higher than the main transition . however , for rayleigh scattering around ly@xmath3 , the transition from @xmath90 state is the dominant perturbing transition which is less energetic than ly@xmath3 . this leads to a blue asymmetry in @xmath96 around ly@xmath3 . in an attempt to quantify these asymmetries we compute the mean wavelengths for which the scattering optical depth becomes a unity or one half for various values of column density @xmath4 . also we fitted the transmission coefficients for given @xmath4 by shifting the lorentzian function . peebles ( 1993 ) introduced the formula for resonance scattering cross section around ly@xmath0 @xmath183 which is often used in fitting wing profiles of ly@xmath0 ( e.g. miralda - escude 1998 ) . in particular , the red damping wing of ly@xmath0 is essential to probe the partially neutral intergalactic medium expected around the end of cosmic reionization ( gunn & peterson 1965 , scheuer 1965 , mortlock et al . 2011 ) . neglecting the damping term in the denominator , this expression yields an expansion in frequency space @xmath184.\ ] ] in this expression , the coefficient of the first order term is 4 , which differs significantly from the correct value of @xmath66 . according to this formula , the scattering cross section is larger in the blue part of ly@xmath0 than in the red part , which is incorrect . the discrepancy in the expansion may be traced to the approximation adopted in the derivation of eq . ( [ peebles ] ) , where the hydrogen atom is effectively treated as a two level system . the lorentzian or voigt profile matches the kramers - heisenberg profile excellently only in the core part . therefore , the redshift will be measured reliably when the profile fitting is more weighted toward deeply absorbed core part than far wing parts . with the accurate determination of the redshift and column density of the dla , one may obtain reliable transmission coefficients using the kramers - heisenberg formula or its first order approximation given in eq . ( [ lya_wv ] ) and eq . ( [ lybeq3 ] ) . in an analysis of a quasar spectrum , it is highly difficult to obtain the accurate continuum level due to intervening ly@xmath0 forest systems . securing the quasar continuum level around the damped ly@xmath0 center with high precision is critical to verify the asymmetry presented in this work . with the advent of extremely large telescopes in the near future equipped with a high resolution spectrometer the accurate atomic physics will shed light on the physical conditions of neutral hydrogen reservoir in the early universe . the author is very grateful to the anonymous referee whose comments greatly improved the presentation of this paper . this research was supported by the basic science research program through the national research foundation of korea ( nrf ) funded by the ministry of education , science and technology ( 2011 - 0027069 ) . we show a detailed angular integration of the matrix element that constitute the kramers - heisenberg formula . because of the selection rule of the electric dipole interaction , the relevant states are @xmath32 and @xmath31 state in the case of rayleigh scattering . in the case of raman scattering relevant to the interaction around ly@xmath3 , @xmath23 state is also involved . however , as long as the anglular and polarization average is concerned , the same calculation is performed . a typical matrix element to be summed in the kramers - heisenberg formula is @xmath185 where @xmath30 denotes an intermediate state . in particular , @xmath30 can be written as @xmath40 , where @xmath186 is the magnetic quantum number taking one of zero and @xmath187 in the case of a @xmath2-state . the spherical harmonic functions with @xmath188 are explicitly defined by @xmath189 from which we may set @xmath190 therefore given an intermediate state @xmath40 , we have @xmath191 the wavefunction @xmath192 is given by the product of the radial part @xmath193 and angular part @xmath194 , where as the @xmath31 state is characterized by the radial part @xmath195 multiplied by the trivial spherical harmonic @xmath196 . therefore , we have @xmath197y_1^m \nonumber \\ & = & < 1s|r|np>(4\pi)^{-1/2}\sqrt{2\pi\over 3}[\delta_{m,-1}-\delta_{m,1 } ] \nonumber \\ & = & < 1s|r|np>{1\over\sqrt{6}}[\delta_{m,-1}-\delta_{m,1}].\end{aligned}\ ] ] here , @xmath198 is the kronecker delta and @xmath199 is the radial expectation value between @xmath31 and @xmath32 state . in a similar way , for the operator @xmath200 and @xmath201 we have @xmath202 \nonumber \\ < 1s|z|np , m > & = & < 1s|r|np>{i\over\sqrt{3}}\delta_{m,0}.\end{aligned}\ ] ] from this we note that @xmath203 \times\left [ { 1\over\sqrt{6}}(\delta_{m,-1}-\delta_{m,1})e^{\alpha'}_x \right . \nonumber \\ & & \left . + { -i\over\sqrt{6}}(\delta_{m,-1}+\delta_{m,1})e^{\alpha'}_y + { 1\over\sqrt{3}}\delta_{m,0}e^{\alpha'}_z \right ] \nonumber \\ & = & |<1s|r|np>|^2\left[{1\over6}\delta_{m,-1}(e^{\alpha}_x+ie^\alpha_y ) ( e^{\alpha'}_x - ie^{\alpha'}_y ) \right . \nonumber \\ & & \left . + { 1\over6}\delta_{m,1 } ( -e^\alpha_x+ie^\alpha_y ) ( -e^{\alpha'}_x - ie^{\alpha'}_y ) + { 1\over3}\delta_{m,0}e^\alpha_ze^{\alpha'}_z \right]\end{aligned}\ ] ] given @xmath32 states , we sum over substates with @xmath204 to obtain @xmath205 as is well - known for thomson scattering ( e.g. pages 51 and 52 in sakurai 1967 ) , a numerical factor of @xmath206 results from averaging over polarization states for both incoming and outgoing radiation . arrieta , a. , torres - peimbert , s. , 2003 , apjs , 147 , 97 berestetskii , v.b . , lifshitz , e.m . , & pitaevskii , l.p . , 1971 , relativistic quantum mechanics , pergamon press bethe , h. a. & salpeter , e. e. 1967 , quantum mechanics of one and two electron atoms , academic press inc . , new york birriel , j. , 2004 , apj , 612 , 1136 calura , f. , matteucci , f. , vladilo , g. , 2003 , mnras , 340 , 59 curran , s. j. , webb , j. k. , murphy , m. t. , bandiera , r. , corbelli , e. , flambaum , v. v. , 2002 , pasa , 19 , 455 gunn , j. e. , peterson , b. a. , 1965 , apj , 142 , 1633 isliker , h. , nussbaumer , h. , & vogel , m. , 1989 , a & a , 219 , 271 jung , y .- c . , lee , h .- w . , 2004 , mnras , 350 , 580 khare , p. , vanden berk , d. , york , d. g. , lundgren , b. , kulkarni , v. p. , 2012 , mnras , 419 , 1028 kim , j. , park , c. , rossi , g. , lee , s. m. , gott iii , r. , 2011 , journal of the korean astronomical society , 44 , 217 kulkarni , v. p. , meiring , j. , som , d. , proux , c. , york , d. g. , khare , p. , lauroesch , j. t. , 2012 , apj , 749 , 176 lee , h. -w . , 2000 , apj , 541 , l25 lee , h. -w . , 2003 , apj , 594 , 637 lee , h. -w . , 2012 , apj , 750 , 127 lee , h. -w . , lee , k. w. , 1997 , mnras , 287 , 211 lee , h. -w . , jung , y. -c . , song , i. -o . , ahn , s. -h . , 2006 , apj , 636 , 1045 meiksin , a. a. , 2009 , reviews of modern physics , 81 , 2405 merzbacher , e. 1970 , quantum mechanics , wiley , new york miralda - escud , j. , 1998 , , 501 , 15 mortlock , d. j. et al . 2011 , nature , 474 , 616 noterdaeme , p. , lauresen , p. , petitjean , p. , vergani , s. d. , maureira , m. j. , ledoux , c. , fynbo , j. p. u. , l ' opez , s. , srianand , r. , 2012 , a & a , 540 , a63 nussbaumer , h. , schmid , h. m. & vogel , m. , 1989 , a&a , 221 , l27 peebles , p. j. e. , 1993 , principles of physical cosmology , princeton university press , princeton prochaska , j. x. , herbert - fort , s. , wolfe , a. m. , 2005 , apj , 635 , 123 prochaska , j. x. et al . , 2009 , apj , 691 , l127 rafelski , m. , wolfe , a. m. , prochaska , j. x. , neeleman , m. , medez , a. j. , 2012 , apj , 755 , 89 rauch , m. , 1998 , ara&a , 36 , 267 rybicki , g. b. , lightman , a. p. , 1979 , radiative processes in astrophysics , wiley - interscience , new york sakurai , j. j. , 1967 , advanced quantum mechanics , addison - wesley publishing company , reading , massachusetts saslow , w. m. , mills , d. l. 1969 , physical review , 187 , 1025 scheuer , p. a. g. 1965 , nature , 207 , 963 schmid , h. m. 1989,a & a , 211 , l31 wolfe , a. , turnshek , d. a. , smith , h. e. , cohen , r. d. , 1986 , apjs , 61 , 249 wolfe , a. , gawiser , e. , prochaska , j. x. , 2005 , ara&a , 43 , 861 yoo , j. j. , bak , j .- y . , lee , h .- w . , 2002 , mnras , 336 , 467 ccc ly@xmath0 & ly@xmath3 & ly@xmath3 ( raman ) @xmath207 & @xmath208 & @xmath209 @xmath210 & @xmath211 & @xmath212 @xmath213 & @xmath214 & @xmath215 @xmath216 & @xmath217 & @xmath218 @xmath219 & @xmath220 & @xmath221 ccccc log @xmath4 & @xmath147 ( ) & @xmath163 ( km s@xmath222 ) & @xmath160 ( ) & @xmath223 ( km s@xmath222 ) 19.0 & 6.10e-04 & 0.151 & 1.34e-03 & 0.331 19.7 & 3.30e-03 & 0.813 & 6.47e-03 & 1.60 20.0 & 6.47e-03 & 1.60 & 1.32e-02 & 3.25 20.7 & 3.26e-02 & 8.04 & 6.51e-02 & 16.0 21.0 & 6.51e-02 & 16.0 & 1.30e-01 & 32.1 21.7 & 3.25e-01 & 80.2 & 6.51e-01 & 1.60e+02 22.0 & 6.51e-01 & 1.60e+02 & 1.31 & 3.20e+02 22.7 & 3.25 & 8.01e+02 & 6.48 & 1.60e+03 ccccc log @xmath4 & @xmath150 ( ) & @xmath224 ( km s@xmath222 ) & @xmath152 ( ) & @xmath225 ( km s@xmath222 ) 19.0 & -1.22e-04 & -0.03568 & -2.44e-04 & -0.07136 19.7 & -7.32e-03 & -0.214 & -1.34e-03 & -0.392 20.0 & -1.34e-03 & -0.392 & -2.69e-02 & -0.785 20.7 & -6.59e-03 & -1.93 & -1.34e-02 & -3.92 21.0 & -1.34e-02 & -3.92 & -2.67e-02 & -7.81 21.7 & -6.64e-02 & -19.4 & -1.32e-01 & -38.5 22.0 & -1.32e-01 & -38.5 & -2.60e-01 & -75.9 22.7 & -6.22e-01 & -1.82e+02 & -1.16 & -3.38e+02

damped ly@xmath0 systems ( dlas ) observed in the quasar spectra are characterized by a high neutral hydrogen column density @xmath1 . the absorption wing profiles are often fitted using the voigt function due to the fact that the scattering cross section near resonant line center is approximately described by the lorentzian function . since a hydrogen atom has infinitely many @xmath2 states that participate in the electric dipole interaction , the cross section starts to deviate from the lorentzian in an asymmetric way in the line wing regions . we investigate this asymmetry in the absorption line profiles around ly@xmath0 and ly@xmath3 as a function of the neutral hydrogen column density @xmath4 . in terms of @xmath5 we expand the kramers - heisenberg formula around ly@xmath0 to find @xmath6 $ ] , where @xmath7 and @xmath8 are the oscillator strength of ly@xmath0 and the thomson scattering cross section , respectively . in terms of @xmath9 in the vicinity of ly@xmath3 , the total scattering cross section , given as the sum of cross sections for rayleigh and raman scattering , is shown to be @xmath10 $ ] with @xmath11 and the factor @xmath12 being the oscillator strength for ly@xmath3 and the ratio of raman cross section to rayleigh cross section , respectively . a redward asymmetry develops around ly@xmath0 whereas a blue asymmetry is obtained for ly@xmath3 . the absorption center shifts are found to be almost proportional to the neutral hydrogen column density .

on november 3 , 2013 , the ministry of health of saudi arabia was notified of a suspected case of mers - cov infection in a 43-year - old male patient at king abdulaziz university hospital in jeddah . the patient had cared for ill camels in his herd of 9 animals starting in early october , when the patient noted respiratory signs of illness with nasal discharge in several animals ; he continued caring for the sick animals until october 27 , the day of onset of his own illness . the patient cared for the animals for 3 hours per day 3 days per week , applying herbal remedies to the animals snouts and nostrils . he did not clean the stables or milk the animals , but he routinely consumed raw , unpasteurized camel milk from the herd . presence of mers - cov rna in the patient was confirmed at jeddah regional laboratory by using reverse transcription pcr ( rt - pcr ) targeting the upe and orfa gene fragments ( 11,12 ) . respiratory swab specimens yielded detectable signal after 28 rt - pcr cycles , indicative of an approximate viral load of 350,000 rna copies per sample . kj556336 ) , confirming the presence of a typical mers - cov whose closest relatives were in the riyadh_3 clade , as defined in ( 2 ) ( phylogeny shown in online technical appendix figure 1 , wwwnc.cdc.gov/eid/article/20/6/14-0402-techapp1.pdf ) . to identify potential sources of infection , on november 9 , the ministry of health investigated 5 close household contacts and the animal attendant on a farm owned by the patient . nasopharyngeal swab samples were taken and tested at jeddah regional laboratory by using rt - pcr . deep nasal swab specimens were taken on the same day from 3 of the 9 camels at the farm . testing of all samples by rt - pcr using the upe assay ( 11,12 ) did not detect mers - cov rna in any of the human patients , but 1 of the 3 camels ( camel g ) tested positive ( cycle threshold [ ct ] = 33 ) . on november 13 , nasal swab samples were obtained from all 9 animals . upe rt - pcr results were positive for camel g ( ct = 38 ) and a second camel ( camel b ; ct = 39 ) . samples from november 13 and a small remaining amount of rna extract from camel g from november 9 were sent to the sanger institute in cambridge , uk , and confirmation of reactivity ( ct 38 ) was obtained for pooled samples with the upe assay from camel g but not for camel b. the result for camel g was confirmed at the institute of virology in bonn , germany , for the same samples by using real - time rt - pcrs targeting the upe and 1a diagnostic target regions . a sequence of 15% of the camel - derived genome was determined from 8 rt - pcr fragments , 2 of them partially overlapping ( 4,608 nt total ) ( 13 ) . phylogenetic analyses supported the conclusion that transmission occurred between camel and patient , but no direction was implied ( e.g , camel to human vs. human to camel ; online technical appendix figure 1 ) . the human- and camel - derived sequences shared a signature of single nucleotide polymorphisms that occurred in no other known mers - cov sequences ( figure ) . single nucleotide exchanges occurred at nt positions 21945 and 29662 ; these exchanges might have arisen during virus transmission , as described ( 10 ) . however , because of the low rna concentration in the samples , reamplification of the material and investigation of possible pcr - based mutations could not be done . direct comparison of the middle east respiratory syndrome coronavirus ( mers - cov ) jeddah_1_2013 genome sequence , jeddah _ camel1_2013 fragments ( boxes at bottom ) , and representative genomes of other clade viruses : 2 additional genomes from the riyadh_3 clade , riyadh_3_2013 and taif_1_2013 ; and representative genomes from the al - hasa and hafr - al - batin_1 and buraidah_1 clades . a map of the mers - cov genome with the major open reading frames ( orfs ) indicated is shown at the top . nucleotide differences for other genomes from jeddah_1_2013 are shown by vertical colored bars : orange , change to a ; red , change to t ; blue , change to g ; violet , change to c. gaps in all full - genome sequences are indicated in gray . positions according to the mers - cov genome emc/2012 : fragment 1 , 976710354 ; fragment 2 , 1750718394 ; fragment 3 , 2108922046 ; fragment 4 , 2356924059 ; fragment 5 , 2534926056 ; fragment 6 , 2727628095 ; fragment 7 , 2959629757 . kj556337kj556340 ; others are pending ) . a serum sample taken from camel g during the initial investigation on november 9 was tested by recombinant immunofluorescence assay ( ifa ) as described ( 6,14 ) and showed reactivity to mers - cov ( titer 320 ) . to investigate signs of recent mers - cov infection in the group of camels , we obtained blood samples at short intervals from all 9 animals during november 14december 9 , 2013 . all samples were tested by elisa against recombinant mers - cov spike antigen domain s1 fused to human fc fragment , using a formulation as described ( 15 ) . serum samples from all 9 animals showed reactivity to the mers - cov antigen ; serum samples from control animals showed no reactivity ( online technical appendix figure 2 , panel a ) . elisa signals were constant over time in most animals , but a small , yet visible , change of signal over the observation period was noted for camels b and g. to clarify the reasons for this putative signal increase , the first and last serum samples ( obtained on november 14 and december 9 ) from all animals were re - tested by ifa . as summarized in the table , camels b and g showed 4-fold increases of titer for the paired first and last serum samples . in serologic tests that rely on 2-fold endpoint titrations , a titer increase > 2 dilution steps is considered a significant sign of recent acute infection . for additional confirmation of rises of titer , sequential samples from camels b and g were compared with sequential samples from camels e and i by using ifa with endpoint titration . these data confirmed the increases of titers for camels b and g ( online technical appendix figure 2 , panel b ) . because bovine cov occurs in camels , we tested for antibodies against bovine cov in camels b and g to exclude potential cross - reactions . using ifa ( 6 ) , we found no bovine cov antibodies in camel g , but camel b showed rising bovine cov antibody titers ( table ) . to obtain further differentiation , we performed neutralization assays against mers - cov and bovine cov ( 7 ) . titers in serum samples from november 14 and december 9 , respectively , were 160 and 320 for camel b and 160 and 160 for camel g. none of the animals showed serum neutralization against bovine cov . for camel g , a sample taken on november 9 was also available and yielded an immunofluorescence titer of 320 . these data add to recent findings showing high similarity of mers - covs carried by humans and camels ( 8,10 ) , supporting the hypothesis that human mers - cov infection may be acquired directly from camels . in addition , both animals that showed signs of recent infection were juvenile , which provides further support to previous findings that mainly young animals are infected by mers - cov ( 7,8 ) . given the synchronized parturition pattern of dromedary camels , with birthing in the winter months , an increase of epizootic activity might be expected after some latency during the first half of each year . antibody titers rose and viral rna concentrations were already on the decline in the camels while the patient was hospitalized with acute symptoms . assuming a time before appearance of antibodies of 1021 days , at least some of the camels would have been actively infected during middle to late october , when some animals showed signs of respiratory illness and the patient acquired his infection . nevertheless , we can not rule out other infectious causes of the animals upper respiratory signs . also , because of the retrospective nature of this investigation , we can not rule out the possibility of a third source of mers - cov infection for camels and humans . maximum - clade credibility tree of 66 human middle east respiratory syndrome coronavirus ( mers - cov ) genomes and 3 camel genomes or genome fragments and results of serologic screening of 9 dromedary camels from jeddah , saudi arabia , 2013 .

we investigated a case of human infection with middle east respiratory syndrome coronavirus ( mers - cov ) after exposure to infected camels . analysis of the whole human - derived virus and 15% of the camel - derived virus sequence yielded nucleotide polymorphism signatures suggestive of cross - species transmission . camels may act as a direct source of human mers - cov infection .

And The 'Dancing With the Stars' Results... Email This After an eventful season 11 premiere of 'Dancing With the Stars,' one star had to foxtrot home. Who was sent packing? Find out the results. (Spoiler alert!) >> After an eventful season 11 premiere of 'Dancing With the Stars,' one star had to foxtrot home. Who was sent packing? Find out the results. 2010 AOL LLC. All Rights Reserved. Copyright 2009 The Associated Press. The information contained in the AP news report may not be published, broadcast, rewritten or otherwise distributed without the prior written authority of The Associated Press. Active hyperlinks have been inserted by AOL. He was king of the beach on 'Baywatch,' but David Hasselhoff didn't fare so well on 'DWTS.' The 58-year-old entertainer was the first celebrity voted off the new season. Hasselhoff and his professional partner, Kym Johnson, were ousted from the program Tuesday after performing just one dance."It's been a great ride," Hasselhoff said after learning his fate. "I feel bad for Kym because she worked hard trying to get me where I was going. I'm so proud that my daughters are here and they got to see me come this far.""I think his daughters are more upset than he is," Johnson said after the show.Hasselhoff said he joined the hit ABC dance competition because his family are fans. Daughters Hayley and Taylor were in the audience for Tuesday's show and said they were proud of his performance.The judges, however, felt differently. They criticized Hasselhoff's cha-cha, with judge Bruno Tonioli calling it "a potpourri of insanity disguised as dance." The couple landed in last place, tied with 'Jersey Shore' star Mike " The Situation " Sorrentino and comedian Margaret Cho.Still, the other remaining contestants said they're turning their attention to perfecting next week's dance. Half the group will perform the quickstep while the other half do the jive.Bristol Palin will be learning her new dance on her home turf in Alaska, adding it was "a bummer" mom Sarah Palin wasn't able to see her 'Dancing' debut in person. "Hopefully she'll be here for the next week," Bristol Palin said.Besides Sorrentino, Palin, Warner and Cho, the remaining contestants are singer-actress Brandy ; actors Jennifer Grey, Florence Henderson and Kyle Massey; athlete Rick Fox; reality star Audrina Patridge and singer Michael Bolton. ||||| David Hasselhoff Is the Early 'DWTS' Favorite Email This We had some questions when we first heard the cast announcement for this season's 'Dancing With the Stars.' They're probably the same ones that popped into most of your heads, so we feel comfortable sharing them today after the news has sunk in. Can All of these quandaries have made us pretty psyched for the upcoming season. We spoke with some dance experts about who we can expect to do well on the reality show this time around and the surprising answer from the lot of them ... none other than the Hoff!!! "He's already established as a musical entertainer -- especially in Germany -- so he knows how to perform. I might be biased because I worked with him on 'Baywatch,' but he's obviously athletic, so he's got a real advantage over the other contestants here," says choreographer and former NFL cheerleader We had some questions when we first heard the cast announcement for this season's 'Dancing With the Stars.' They're probably the same ones that popped into most of your heads, so we feel comfortable sharing them today after the news has sunk in. Can Audrina Patridge chew gum and dance at the same time? Will David Hasselhoff perform his dance numbers in a red bathing suit in slow motion? Can a fist pump be worked into a waltz?All of these quandaries have made us pretty psyched for the upcoming season. We spoke with some dance experts about who we can expect to do well on the reality show this time around and the surprising answer from the lot of them ... none other than the Hoff!!!"He's already established as a musical entertainer -- especially in Germany -- so he knows how to perform. I might be biased because I worked with him on 'Baywatch,' but he's obviously athletic, so he's got a real advantage over the other contestants here," says choreographer and former NFL cheerleader Bonnie Jill Laflin Filed under: TV News Shauna Tysor of the Houston Ballet agrees. She and her fellow twinkle toes will be tuning in to watch them some Hoff."I'm holding out for David Hasselhoff. All that choreographed running on 'Baywatch' had to give the man some rhythm," Tysor said.Everyone's favorite drunk lifeguard aside, from a dance point of view, Tysor was a little disappointed in this season's lineup."After a stellar season last year, this year's line up looks a bit clunky. Let's see ... Audrina could be the next Kate Gosselin if Bristol Palin doesn't take the 'Iron Leg' award from her. I'm ashamed to say I've never watched the 'Jersey Shore,' but if Mike 'The Situation' is anything like Bill Hader's spoof on SNL, we may be in for some good TV. I'm envisioning plenty of shirtless, orange, Latin numbers," Tysor told us.Since Tysor has never watched 'Jersey Shore,' then she has never seen The Situation fist pump his way into the ladies' hearts. Which leads us to our final question: Can a fist pump be seamlessly incorporated into the waltz?"Oh, hell no!" Laflin exclaimed when we had the audacity to ask the question out loud. "Club dancing and professional ballroom dancing are two very different things! Thinking you are a dancer because you've had a lot to drink isn't dancing compared to what a trained dancer goes through."There you have it. The experts are saying this cycle is the Hoff's to lose, The Situation doesn't stand a chance and we're all giving Audrina some pity votes.This season would have no doubt been less clunky and a little more interesting had ABC been able to secure their dream team of contestants. The Hollywood Reporter got an exclusive list of who turned the show down this go around.According to a source involved with casting, the network approached Facebook creator Mark Zuckerberg, but was unable to secure him. The network also lobbied unsuccessfully for Sylvester Stallone, political commentator Ann Coulter, former Secretary of State Condoleezza Rice, the real Erin Brockovich, billionaire Richard Branson, comic actor Tim Allen and former TV darling Suzanne Somers.There's always cycle 12!! ||||| Infamous Cheeseburger Video the Main Meal in David Hasselhoff Comedy Roast Email This When Major media fallout followed, and the video became something of a cultural phenomenon, attracting more than a billion views on the Internet. Three year's later, the Hoff's greatest viral embarrassment, as well as his longtime struggle with alcohol, provides the fuel for the 'Comedy Central Roast of David Hasselhoff.' Scheduled to air on August 15, the roast was filmed Sunday night and is shockingly the first time Hasselhoff has ever addressed the infamous video or his reported alcohol relapses. When David Hasselhoff 's now infamous cheeseburger video hit the Internet in 2007, the shocking image of the shirtless, slurring 'Baywatch' star on the floor struggling to eat fast food was no laughing matter.Major media fallout followed, and the video became something of a cultural phenomenon, attracting more than a billion views on the Internet.Three year's later, the Hoff's greatest viral embarrassment, as well as his longtime struggle with alcohol, provides the fuel for the 'Comedy Central Roast of David Hasselhoff.'Scheduled to air on August 15, the roast was filmed Sunday night and is shockingly the first time Hasselhoff has ever addressed the infamous video or his reported alcohol relapses. "I've been waiting for a forum to talk about where I'm at," Hasselhoff said backstage at the event. "I didn't do it in the beginning because I was in a very personal matter and it involved the custody of my children."Hasselhoff has always maintained that the burger video was illegally released and has never spoken about it publicly -- despite offers from major magazines and Larry King."I wanted to address [it] the way I wanted to address it," he added. "And tonight was the way I wanted to address it."More than address it, Hasselhoff was tormented about it repeatedly during the two-hour roast by some of the sharpest tongues in the business.Those who felt the comics would keep the gloves on for the roast were immediately proven wrong during Hasselhoff's introduction, where, sprinkled among the clips from his 'Baywatch' and 'Knight Rider' days, moments from the horrifying burger video kept popping up. Taboo no more.Seth MacFarlane, the roast master for the event, launched right in and zeroed in on the video."How do you make jokes about a joke? How do you embarrass a man who so thoroughly embarrasses himself?" he asked as the crowd roared with laughter. "How do you put someone down when they are already lying shirtless on the floor?"And that was only the beginning. While fellow roasters like Hulk Hogan, Jerry Springer and Pamela Anderson looked on, Hasselhoff sat in the middle on a red, oversized lifeguard's chair. His arms were folded in front of him for much of the night, but he gamely laughed at most of the jokes that were hurled at him.It might have been his greatest acting role ever. Though during the first commercial break, he showed a little chink in the armor. "It's going to be a long night," he said in the direction of his two daughters, who were in the audience.Insult specialist and former 'Dancing with the Stars' contestant Jeffrey Ross inquired what drink Hasselhoff had in a dark red glass on his lifeguard's chair. When the Hoff insisted it was water, Ross expressed disbelief and then continued his attack."I must admit, I did love you in that cheeseburger commercial you once made," Ross mocked, insisting the motto from the burger chain must have been "Have it Floor Way!""I'm so relieved you're wearing a shirt tonight because it will be so much easier than picking the vomit out of your chest hair later," Ross continued.Even animal rights activist and 'Baywatch' co-star Pamela Anderson piled on."David, I have to say, when I saw the video of you lying on the floor -- drunk, broken down, cheeseburger meat falling from your mouth -- I felt so sad," said Anderson. "For that cow."Hasselhoff exited the show triumphantly -- we don't want to spoil the ending, but it's awesome. And he even gamely met the press backstage."Yeah, it goes too far," Hasselhoff said when asked about some of the barbs. "That's what they want to do. They want to get to everybody."He kept a fixed smile on his face throughout and insisted the event was "therapeutic." Hasselhoff had, in his mind, dealt with the video issue once and for all -- and he was still standing."No one got me," said the Hoff. "I'm still laughing. My face hurts. I'm sorry it's over."Greatest. Actor. Ever.

– Poor David Hasselhoff: He’s already the butt of so many cheeseburger-related jokes, and now he can probably expect some Dancing With the Stars jokes to come his way. Despite being the early favorite to win, last night The Hoff became the first celeb to leave the show this season, PopEater reports. Watch his (apparently sober) cha-cha, which one judge called “a potpourri of insanity disguised as dance,” in the gallery. For last night’s elimination video, click here.

the motion of particles in potentials that do not have mirror reflection symmetry has attracted much attention in the last years for several reasons . the interest extends from fundamental problems concerning the validity of the second law of thermodynamics @xcite to applications in biological @xcite and chemical systems @xcite , as well as for solid - state devices @xcite . major efforts have been devoted to an understanding of molecular motors , where proteins move in nonsymmetric potentials under the influence of stochastic and/or other forces . one specific observation for transport in nonsymmetric potentials is the possibility of rectification effects if the forces on the particles are beyond the regime where linear - response theory is applicable @xcite . rectification effects have been discussed in continuous @xcite as well as in hopping systems @xcite . if applications of effects of particle motion in nonsymmetric potentials are envisaged then the question arises as to the influence of many - particle effects . the limit of single - particle motion is rarely realized ; in real systems many particles are present that compete about the sites that can be occupied . many - particle effects have been studied in continuous nonsymmetric periocic potentials in ref.@xcite , where interesting dependencies of the current on particle concentration and size were found . in this paper we will investigate hopping motion of lattice - gas particles in nonsymmetric hopping potentials under the influence of strong bias . we utilize the simple site exclusion model where multiple occupancy of sites is excluded and direct our attention to nonlinear effects on the particle current . the stationary current of a single particle performing a hopping motion in a nonsymmetric potential under an arbitrary bias is known exactly @xcite . the calculation of the stationary current of site - exclusion lattice gases in nonsymmetric potentials that lead to rectification effects in the single - particle case is a difficult problem . extensive work has been devoted to the asymmetric site exclusion process including the totally asymmetric site exclusion process ( tasep ) where the particles can only hop in one direction , corresponding to very strong bias . the case of uniform hopping potentials is now well understood @xcite , but the case of nonuniform potentials is not generally solved . recent work has been devoted to the tasep with disordered potentials @xcite . for the general asymmetric case one has to resort to numerical simulations ; we are going to present simulation results for the stationary current of lattice - gas particles in nonsymmetric potentials , for various concentrations and values of the bias . nonetheless , some analytical treatment can be given . first , the case of very small periodic systems can be treated explicitly : the motion of 2 particles on a ring of period 4 can be solved by elementary means . although this is a very simple system , conclusions can be drawn in the limit of very strong bias that are of interest for the totally asymmetric site exclusion process . the nonlinear current of site - exclusion lattice gases in extended systems with periodic repetitions of nonsymmetric segments can be derived in a mean - field approximation for strong bias conditions . interesting symmetry properties have been pointed out for the tasep in disordered hopping potentials @xcite . while a particle - vacancy symmetry is also present in our model , the case of inversion of the bias direction is different here . in the following section the hopping motion of 2 particles on a ring of period 4 is solved and analyzed . in sec . iii a mean - field approximation for the stationary current of lattice gases under strong bias in nonsymmetric hopping potentials is presented and compared with simulation results in a sawtooth potential . the symmetry properties of the model are discussed in sec . iv and concluding remarks are given in sec . a very simple yet nontrivial model is given by a ring with 4 sites and 2 particles , cf . the basic quantities for the description of the system are the joint probabilities @xmath0 of finding one particle at site @xmath1 and the other particle at site @xmath2 , at time @xmath3 , for specified initial conditions . since the particles are considered as indistinguishable , @xmath4 . there are 6 different joint two - particle probabilities on the ring with 4 sites ( generally @xmath5 on rings with @xmath6 sites ) . higher - order joint probabilities do not occur for 2 particles . the probabilities @xmath7 of finding a particle at site @xmath1 at time @xmath3 are given by @xmath8 for two particles they are normalized to @xmath9 this condition implies @xmath10 the master equations for the joint probabilities are easily written down , @xmath11 the sum of the 6 master equations leads to the conservation law @xmath12 = 0 \:,\ ] ] consistent with the relation ( [ np2 ] ) given above . we are interested in the stationary solution of the system of master equations ( [ me ] ) . the stationary values @xmath13 will be denoted by @xmath14 . the stationary joint probabilities for adjacent sites , e.g. @xmath15 , can all be expressed by the stationary joint probabilities @xmath16 and @xmath17 . for instance , the first line of eq.([me ] ) yields @xmath18 three analogous relations follow from ( [ me ] ) ; they can be obtained by cyclically increasing the indices in eq.([elim ] ) . if the joint probabilities for adjacent sites are eliminated from the stationary master equations , two homogeneous equations remain which are equivalent . we write this equation as @xmath19 with the coefficients @xmath20 the second equation for @xmath16 and @xmath17 is obtained from the normalization condition eq.([np2 ] ) , after elimination of the joint probabilities of adjacent sites . it reads @xmath21 with the coefficients @xmath22 the solution of the two linear equations is @xmath23 since the joint probabilities for adjacent sites are obtained from the @xmath16 , @xmath17 , and the one - site stationary probabilities @xmath24 from eq.([pp ] ) , eq.([sol ] ) represents the complete solution of the stationary problem . we derive the stationary current in the system by considering the bond connecting sites 1 and 2 . the stationary current is given by @xmath25 the joint probabilities in eq.([curr1 ] ) ensure exclusion of double occupancy of sites . using eq.([pp ] ) the current is expressed in terms of the joint probabilities , @xmath26 insertion of the stationary solution for the joint probabilities gives @xmath27 the current may also be derived by considering the other bonds of the ring . two equivalent forms of the current result ; the second ( equivalent ) form reads @xmath28 it can be shown that the current vanishes if the right and left transition rates fulfill the following condition , @xmath29 corresponding to a detailed balance relation over the ring . the sawtooth potential including bias on a 4-site ring is defined by choosing @xmath30 where @xmath31 represents the bias and @xmath32 is a constant representing a transition rate to the right in the absence of a bias , cf . fig.1(b ) . note that the right transition rates are explicitly multiplied by the bias factor @xmath31 and the left transition rates by @xmath33 , respectively . physically , @xmath34 where @xmath35 represents the potential drop between two neighboring sites under the influence of the bias . for @xmath36 the system satisfies the detailed balance condition and the current @xmath37 vanishes . in what follows the current obtained in a system with @xmath38 particles will be denoted as @xmath39 . in fig . [ figk2 ] we present a plot of @xmath40 and @xmath41 as functions of the bias @xmath31 for the ring with 4 sites and @xmath42 . the result for the two - particle system was obtained using eq . ( [ curr4 ] ) , and for a single - particle system we employed the exact solution derived in ref . we can see that the behavior of the currents of one- and two - particle systems are qualitatively similar . of course , the current @xmath43 of two particles is larger than the one - particle current @xmath44 . the inset shows the behavior of the current for smaller bias . the curves for the bias to the right and to the left become equal in the limit @xmath45 , i.e. , in the linear - response regime , for two particles on the ring with 4 sites , and also for one particle on this ring . however , the two - particle current is about @xmath46 larger than the one - particle current . in the case of a strong bias to the right , @xmath47 , the two - particle current @xmath41 differs from @xmath40 by a constant factor . for the sawtooth potential this behavior can be understood as follows . if @xmath48 , only transitions to the right are important , and backward transitions can be neglected . in our model the transition rates to the right are all equal , @xmath49 for @xmath50 . hence for @xmath51 all stationary site occupation probabilities become equal , @xmath52 for the 4-site ring and @xmath53 for a ring with l sites . in the limit of a strong bias to the right all stationary joint probabilities also become equal , i.e. , @xmath54 @xmath55 for the 4-site ring and , generally , @xmath56 ( see ref . @xcite ) . using expression ( [ curr1 ] ) we thus expect that for @xmath57 @xmath58.\ ] ] for @xmath59 there is thus @xmath60 , which should be compared with the single - particle current @xmath61 . similarly , in the general case of an @xmath6-site ring we have @xmath62 for the 4-site ring this limiting behavior can be easily derived from the exact formula ( [ curr4 ] ) . actually , for @xmath59 , @xmath63 , and @xmath64 there is @xmath65 , in agreement with the above considerations . figure [ figk2 ] also shows that @xmath43 becomes almost identical to @xmath44 in the case of a strong bias to the left , @xmath66 . to understand this phenomenon assume that @xmath67 , so that @xmath68 , i.e. , site 1 acts as a `` bottle - neck '' . if @xmath66 the particles are driven against the high barrier at site 1 , which has a relatively very small transition rate @xmath69 to the left . the second particle on site 2 has to wait until the first particle has jumped over the high barrier , and only then can it make an attempt to jump over that barrier . soon after the first particle has managed to pass the bottleneck at site 1 , the second particle will jump from site 2 to 1 and the first particle will quickly line up behind the second particle , waiting for it to jump over the high barrier . consequently , the current becomes practically equal to that of a single - particle system . it is evident that in the limit of a large bias to the left the system behaves as a tasep on a ring with one defect . if the defect is characterized , in a discrete - time dynamics , by the transition probability @xmath70 , the current of @xmath38 particles on a ring with @xmath6 sites ( @xmath71 ) will approach the one - particle current . the above reasoning is confirmed by an explicit calculation of the current @xmath43 in the limit @xmath72 . using ( [ curr4 ] ) we conclude , after some algebra , that @xmath73 . since for a single - particle system the current @xmath44 , for @xmath66 , is approximately equal @xmath74 ( see ref.@xcite ) , we find that @xmath75 for @xmath76 , i.e. , for a growing asymmetry of the sawtooth potential , this limit actually approaches 1 . in particular , for the value of @xmath42 used in fig . 2 there is @xmath77 . note , however , that in contrast to the case @xmath47 , for @xmath78 the current depends on the parameter @xmath79 characterizing the inhomogeneity of the sawtooth potential . in particular , for @xmath80 , which corresponds to a fully homogeneous system , @xmath81 . actually , for @xmath82 , the ratio @xmath83 equals @xmath84 irrespective of the bias @xmath31 ( see @xcite ) . in this section lattice gases in extended potentials are considered that consist of periodic repetitions of nonsymmetric segments . first the situation of very strong bias is discussed and a mean - field approximation is given for the case where the particles experience periodically arranged high barriers . the analytical results are then compared with numerical simulations of the motion of lattice - gas particles in nonsymmetric hopping potentials for different concentrations and under various bias conditions . the hopping potential that is used in in this section is the sawtooth potential as shown in fig . 1(b ) , except that it is periodically repeated with period @xmath6 . the nearest - neighbor transition rates from site @xmath85 to @xmath86 are @xmath87 . as a short notation we use @xmath88 for the `` right '' and @xmath89 for the `` left '' transition rates . without additional bias , the transition rates between neighbor sites fulfill detailed balance . bias is introduced by multiplying all right transition rates by @xmath31 , @xmath90 , and all left transition rates by @xmath33 , @xmath91 . the linear chain on which the model is defined shall have @xmath92 sites where we consider @xmath93 in this section . periodic boundary conditions are introduced and the sites are occupied by @xmath38 particles . the concentration is then @xmath94 . multiple occupancy of the sites is excluded ; no further interactions of the particles are taken into account . for @xmath57 we can apply essentially the same reasoning as in the case of the 2-particle system considered in sec . ii . in this limit transitions to the left are so rare that they can be ignored and the system essentially behaves like a tasep with transitions @xmath95 , @xmath96 . the current for such a system reads @xcite @xmath97 for large system sizes @xmath98 this formula can be rewritten as @xmath99 for @xmath78 we can neglect transition rates to the right , and so the system behaves like a tasep with transition rates @xmath100 if @xmath101 and @xmath102 otherwise . if additionally @xmath82 , all @xmath103 are equal to each other and the current is given simply by ( [ j_tasep ] ) . a more complicated situation appears for @xmath67 , a condition which will be assumed henceforth . in this case sites @xmath104 act on the flow of particles as `` bottlenecks '' , for the mean time necessary to leave them is much larger than the time to leave any other site . therefore the system , which consists of @xmath105 similar segments of length @xmath6 , effectively behaves like a ring made up of @xmath105 similar `` boxes '' , each able to contain up to @xmath6 particles . a transition from a segment @xmath2 to @xmath106 occurs with a rate @xmath107 irrespective of the number of particles in each of the segments , provided , of course , that there is at least one particle in segment @xmath2 and at most @xmath108 particles in segment @xmath106 . let @xmath109 denote the probability that in the steady state there are @xmath110 particles in a given segment ( @xmath111 ) . let @xmath112 denote the joint probability of finding , in the steady state , @xmath113 particles at a given segment @xmath2 and @xmath114 particles at @xmath115 . of course @xmath109 and @xmath112 do not depend on @xmath2 , and the @xmath109 satisfy @xmath116 let us assume a mean - field approximation : @xmath117 . in the stationary state the mean number @xmath118 of segments occupied by @xmath110 particles does not depend on time . as the particles hop between segments , @xmath118 can decrease when one of the particles jumps from or to a segment occupied by @xmath110 particles . the corresponding rates are @xmath119 and @xmath120 , respectively . the number of segments containing @xmath110 particles can also increase owing to jumps ending at segments containing @xmath121 particles or originating at segments with @xmath122 particles ; the corresponding transition rates are @xmath123 and @xmath124 , respectively . consequently , the appropriate balance conditions read @xmath125 where @xmath126 in ( [ balance1 ] ) and in ( [ balance2 ] ) and ( [ balance3 ] ) we have taken into account the fact that neither jumps from a segment containing @xmath127 particles nor transitions to a segment with @xmath6 particles are possible . together with ( [ prob=1 ] ) and ( [ rho ] ) these relations form @xmath128 equations for @xmath129 variables @xmath109 , @xmath111 , with the concentration @xmath130 being the only free parameter . this system of equations is easily shown to have a unique solution @xmath131 where the parameter @xmath132 can be determined using @xmath133 the concentration @xmath130 is a monotonic function of @xmath132 , increasing from 0 for @xmath134 to 1 in the limit @xmath135 . the value @xmath136 corresponds to @xmath137 and , generally , @xmath138 having obtained @xmath109 we can calculate the current as @xmath139 using ( [ ro - a ] ) it is easy to see that @xmath140 because for @xmath141 eq . ( [ conda ] ) implies @xmath142 , using our formula ( [ jbleft ] ) we conclude that for small concentrations of particles the current @xmath37 grows linearly with @xmath130 , @xmath143 for @xmath144 the mean - field theory ( [ jbleft ] ) predicts @xmath145 in our simulations we used a lattice with @xmath146 sites consisting of @xmath147 segments , each of length @xmath148 . we used a sawtooth potential with @xmath149 . the number of particles in the system varied from @xmath150 to @xmath151 . we carried out our simulations for @xmath152 monte carlo time steps per particle and the results were averaged over @xmath153 different realizations of the process , which enabled us to estimate the statistical errors . we first present simulation results for the current at a fixed concentration @xmath154 , or for @xmath155 , as a function of the bias parameter @xmath31 for bias to the right , and @xmath33 for bias to the left , respectively . figure [ fig3 ] shows the current @xmath37 observed in simulations ( symbols ) together with a simple approximation obtained by multiplying a single - particle current @xmath40 @xcite by the number @xmath38 of particles in the system ( free particle approximation ) . one observes that the current in the case of a system with a hard - core interactions is reduced as compared to the case of non - interacting particles ; but the general behavior as a function of the bias parameter is practically the same . in particular , the rectification effects for particle motion in nonsymmetric potentials are qualitatively the same in both cases . the inset in fig.[fig3 ] depicts the ratio @xmath156 as a function of the bias . owing to ( [ j_tasep ] ) we expect that for @xmath57 @xmath157 . for @xmath158 we found @xmath159 , in excellent agreement with the theoretical value @xmath160 . for @xmath66 our mean - field approximation ( [ eq_34 ] ) predicts @xmath161 ; for @xmath162 our simulations yielded a slightly smaller value @xmath163 . we now discuss the dependence of the current on concentration for selected values of the bias @xmath164 , or @xmath165 , respectively , and compare the results with the theoretical considerations of sec . iiib . in fig . [ figright ] we present results of our simulations for a bias to the right ( @xmath166 , 10 and 2 ) . for a strong bias ( @xmath166 ) the agreement with the theoretical prediction , eq.([j_tasep_ro ] ) , is very good . the results obtained for a bias to the left ( @xmath167 , 0.1 , 0.5 , and 0.9 ) are depicted in fig . [ figleft ] . we can see that if the bias is strong ( @xmath168 ) , the agreement between the mean - field theory ( solid line ) and the simulation data ( circles and crosses ) is very good for concentrations close to 0 and 1 . however , for @xmath169 we observe that the mean - field theory tends to overestimate the actual value of @xmath37 by approximately 5% , which is much more than the statistical errors of our data ( the relative standard deviation at @xmath154 is about 0.33% ) . we repeated our simulations for larger number of monte - carlo time steps ( @xmath170 ) and for different values of the bias @xmath31 , but the difference between simulations and the theory remained practically the same . we thus conclude that it is not a numerical artifact . a similar discrepancy was observed by tripathy and barma @xcite , who considered a tasep with random transition rates . however , in their model the mean - field approach underestimated the magnitude of the current obtained in simulations for @xmath171 . moreover , they found that @xmath172 has quite a broad plateau around @xmath173 . this phenomenon is not observed in our case because the transition rates in our model are not random . in this section we discuss the symmetry properties of our lattice - gas model with nonsymmetric potentials , and of related models . in the simulations , as well as in the mean - field approximation , the current exhibits a particle - vacancy symmetry , @xmath174 the symmetry properties of the tasep have been analyzed in @xcite and the relation eq.([sym ] ) has been established in this context . however , the model employed in those references differs in important aspects from our model . hence a detailed discussion is in order . the particle - vacancy symmetry of the current for the tasep has been shown in refs.@xcite for disordered hopping potentials where the transition rates are associated with the bonds between the sites . if the motion of the particles is reversed ( symmetry operation t according to refs.@xcite , the particles experience the same set of transition rates as before , only the order of the rates has been changed . if the vacancies are interpreted as particles ( symmetry operation c ) , they experience the same transition rates as the particles after the operation t. the symmetry under ct is evident ; the nontrivial statement is the symmetry of the current ( up to a sign ) under the operations c , or t , separately . the class of models for the hopping potential that are considered here do not correspond to bond disorder . the set of `` right '' transition rates is different from the set of the `` left '' transition rates . if a strong bias @xmath175 to the right is applied , leading approximately to a tasep , the current is different from the case of strong bias to the left with @xmath176 . in other words , the symmetry under reversal of motion t does not exist for the class of models leading to rectification , by their definition . if the vacancies are considered as particles , they experience the same set of transition rates as the original particles , see also below . we conjecture that symmetry under the operation c also exists for our models , if the limiting case of the tasep is considered . hence we expect eq.([sym ] ) to be approximately valid for the models that lead to rectification effects , in the limit of very strong bias . the sawtooth potential that is investigated in this paper has a special symmetry which will be described now . in the limit of concentration of the lattice gas approaching one , the particle problem is equivalent to the problem of hopping motion of single , independent vacancies . the hopping transitions of an isolated vacancy are reversed in comparison to the transitions of the particle that makes an exchange with the vacancy , e.g. , @xmath177 using the rates eq.([gv ] ) it is easy to reconstruct the hopping potential for single vacancies . if this construction is done for the the extended sawtooth potential of fig.1(b ) , a sawtooth potential is obtained for the vacancy which is mirror - symmetric with respect to the original sawtooth potential , see fig . if a bias is applied to the particles , expressed by the factor @xmath31 in the transition rates to the right , the factor @xmath31 appears in the transition rates of the vacancy to the left . it is evident from this consideration that the particle current for @xmath178 is identical to the one for @xmath179 . it is obvious that a particle - vacancy symmetry pertains for the problem of motion of lattice gases in a sawtooth potential with the above symmetry property ; hence we expect eq.([sym ] ) to be valid for all values of the bias @xmath31 . we point out that the sawtooth potential represents a special case ; general nonsymmetric potentials do not provide mirror - symmetric potentials for the vacancies in the limit @xmath179 . for instance , if the potential corresponding to an ehrlich - schwoebel barrier ( see , eg . @xcite ) is transformed by using eq.([gv ] ) into the corresponding hopping potential of a single vacancy , a different potential is obtained . as a consequence , the mobility of a single particle is different from the mobility of a single vacancy . hence for this example @xmath180 for @xmath31 close to @xmath181 . this example is sufficient to show that the particle - vacancy symmetry ( [ sym ] ) can not be generally valid , for arbitrary @xmath31 . another counterexample is provided by the random - trap model , see ref.(@xcite ) . in this paper we investigated the motion of lattice - gas particles in hopping potentials that are composed of segments without mirror - reflection symmetry . we considered in particular the effects of exclusion of multiple occupancy of sites , under various bias conditions . we first studied the case of two particles on a ring of 4 sites with a sawtooth potential . the explicit solution of this simple system can be given , and interesting conclusions emerge in the limits of large bias to the right , or to the left . we point out that the ring with 4 sites is a model case for the treatment of 2 site - exclusion particles on a finite ring ; larger systems can be solved in a similar manner , e.g. , by using symbolic formula manipulation programs . we then investigated the case of many particles on extended systems which consist of periodic repetitions of sawtooth potentials . these systems behave , for strong bias in one direction , as uniform systems where the result for the current of lattice gases is known . for strong bias in the reverse directions , the extended sawtooth potential acts as a periodic arrangement of weak links . a mean - field expression for the current can be derived for this case from the cluster dynamics of the particles on the segments , which shows similarities to the cluster dynamics of the bosonic lattice gases of ref.@xcite . good agreement with the numerical simulations was found for both cases under strong bias ; deviations appear for smaller bias values . the results for the current exhibit a particle - vacancy symmetry as a consequence of a special particle - hole symmetry of the hopping processes in the sawtooth potential used . generally , the current per particle of a site - exclusion lattice gas shows the same qualitative behavior as a function of the strength and the direction of the bias parameter , as the current of independent particles . this observation is important for possible applications , for instance for transport through channels in membranes or through layered structures with suitable potential structures . it means that qualitative or even semiquantitative predictions of the effects of strong bias on the current can already be obtained from the single - particle description . we thank g. schtz for discussions on the tasep . z.k . gratefully acknowledges partial support by the polish kbn grant nr 2 p03b 059 12 . r. p. feynman , r. b. leighton , and m. sands , _ the feynman lectures in physics _ ( addison wesley , reading , ma , 1966 ) , vol . 1 , chap . 46 . m. o. magnasco , phys . lett . * 71 * , 1477 ( 1993 ) . j. e. hall , c. a. mead , and g. szabo , j. membrane biol . * 11 * , 75 ( 1973 ) . g. stark , biochimica and biophysica acta * 298 * , 323 ( 1973 ) . m. m. millonas and d. r. chialvo , phys . * 76 * , 550 ( 1996 ) . a. lorke , s. wimmer , b. jager , j.p . kotthaus , w. wegscheider , and m. bichler , physica b * 249 - 251 * , 312 ( 1998 ) . a.m. song , a. lorke , a. kriele , j.p . kotthaus , w. wegscheider , and m. bichler , phys.rev.lett . * 80 * , 3831 ( 1998 ) . for a review and references schtz , to be published in _ phase transitions and critical phenomena _ , c. domb and j.l . lebowitz ( eds . ) , academic , london . s.a . janowsky and j.l . lebowitz , phys.rev.a . * 45 * , 618 ( 1992 ) . schtz , j.stat.phys . * 71 * , 471 ( 1993 ) . g. tripathy and m. barma , phys.rev.lett . * 78 * , 3029 ( 1997 ) . g. tripathy and m. barma , phys.rev.e * 58 * , 1911 ( 1998 ) . s. goldstein and e.r . speer , phys.rev.e * 58 * , 4226 ( 1998 ) . k.m . kolwankar and a. punnoose , cond - mat/9807246 ( 1998 ) .

the hopping motion of lattice gases through potentials without mirror - reflection symmetry is investigated under various bias conditions . the model of 2 particles on a ring with 4 sites is solved explicitly ; the resulting current in a sawtooth potential is discussed . the current of lattice gases in extended systems consisting of periodic repetitions of segments with sawtooth potentials is studied for different concentrations and values of the bias . rectification effects are observed , similar to the single - particle case . a mean - field approximation for the current in the case of strong bias acting against the highest barriers in the system is made and compared with numerical simulations . the particle - vacancy symmetry of the model is discussed .

SECTION 1. MENTAL HEALTH AND STUDENT SERVICE PROVIDERS. Title X of the Elementary and Secondary Education Act of 1965 (20 U.S.C. 8001 et seq.) is amended by adding at the end the following: ``PART L--MENTAL HEALTH AND STUDENT SERVICE PROVIDERS ``SEC. 10993. FINDINGS. ``Congress finds the following: ``(1) Although 7,500,000 children under the age of 18 require mental health services, fewer than 1 in 5 of these children receive the services. ``(2) Across the United States, counseling professionals are stretched thin, and often students do not get the help the students need. The current national average ratio of students to counselors in elementary and secondary schools is 513:1. ``(3) United States schools need more mental health professionals, and the flexibility to hire the professionals that will best serve their students. ``(4) The maximum recommended ratio of-- ``(A) students to counselors is 250:1; ``(B) students to psychologists is 1,000:1; and ``(C) students to social workers is 800:1. ``(5) In States like California or Minnesota, 1 counselor typically serves more than 1,000 students. In some schools, no counselor is available to assist students in times of crisis, or at any other time. In Colorado, the average student-to- counselor ratio is 645:1. ``(6) The number of students is expected to grow significantly over the next few years. During this time, many school-based mental health professionals who currently serve our Nation's youth will retire. Not counting these retirements, over 100,000 new school counselors will be needed to decrease the student-to-counselor ratio to 250:1 by the year 2005. ``(7) The Federal support for reducing the student-to- counselor ratio would pay for itself, through reduced incidences of death, violence, and substance abuse, and through improvements in students' academic achievement, graduation rates, college attendance, and employment. ``SEC. 10993A. PURPOSE. ``The purpose of this part is to help States and local educational agencies recruit, train, and hire 141,000 additional school-based mental health personnel, including 100,000 additional counselors, 21,000 additional school psychologists, and 20,000 additional school social workers over a 5-year period-- ``(1) to reduce the student-to-counselor ratios nationally, in elementary and secondary schools, to an average of-- ``(A) 1 school counselor for every 250 students ``(B) 1 school psychologist for every 1,000 students; and ``(C) 1 social worker for every 800 students; as recommended in a report by the Institute of Medicine of the National Academy of Sciences relating to schools and health, issued in 1997; ``(2) to help adequately address the mental, emotional, and developmental needs of elementary and secondary school students; ``(3) to remove the emotional, behavioral, and psycho- social barriers to learning so as to enhance the classroom preparedness and ability to learn of students; ``(4) to support school staff and teachers in improving classroom management, conducting behavioral interventions to improve school discipline, and developing the awareness and skills to identify early warning signs of violence and the need for mental health services; and ``(5) to support parents in improving the school behavior and academic success of their children. ``SEC. 10993B. DEFINITIONS. ``In this part: ``(1) Mental health and student service provider.--The term `mental health and student service provider' includes a qualified school counselor, school psychologist, or school social worker. ``(2) Mental health and student services.--The term `mental health and student services' includes direct, individual, and group services provided to students, parents, and school personnel by mental health and student service providers, or the coordination of prevention strategies in schools or community-based programs. ``(3) Poverty line.--The term ``poverty line'' means the poverty line (as defined by the Office of Management and Budget, and revised annually in accordance with section 673(2) of the Community Services Block Grant Act (42 U.S.C. 9902(2)) applicable to a family of the size involved. ``(4) School counselor.--The term `school counselor' means an individual who has documented competence in counseling children and adolescents in a school setting and who-- ``(A) possesses State licensure or certification granted by an independent professional regulatory authority; ``(B) in the absence of such State licensure or certification, possesses national certification in school counseling or a specialty of counseling granted by an independent professional organization; or ``(C) holds a minimum of a master's degree in school counseling from a program accredited by the Council for Accreditation of Counseling and Related Educational Programs or the equivalent. ``(5) School psychologist.--The term `school psychologist' means an individual who-- ``(A) possesses a minimum of 60 graduate semester hours in school psychology from an institution of higher education and has completed 1,200 clock hours in a supervised school psychology internship, of which 600 hours shall be in the school setting; ``(B) possesses State licensure or certification in the State in which the individual works; or ``(C) in the absence of such State licensure or certification, possesses national certification by the National School Psychology Certification Board. ``(6) School social worker.--The term `school social worker' means an individual who holds a master's degree in social work and is licensed or certified by the State in which services are provided or holds a school social work specialist credential. ``(7) State.--The term `State' means each of the several States of the United States, the District of Columbia, and the Commonwealth of Puerto Rico. ``SEC. 10993C. ALLOTMENTS TO STATES. ``(a) Allotments.--From the amount appropriated under section 10993H for a fiscal year, the Secretary-- ``(1) shall make a total of 1 percent available to the Secretary of the Interior (on behalf of the Bureau of Indian Affairs) and the outlying areas for activities that achieve the purposes of this part; and ``(2) shall allot to each eligible State the same percentage of the remaining funds as the percentage the State received of funds allocated to States for the previous fiscal year under part A of title I, except that such allotments shall be ratably decreased as necessary. ``(b) State-Level Expenses.--Each State may use not more than \1/2\ of 1 percent of the amount the State receives under this part, or $50,000, whichever is greater, for a fiscal year, for the administrative costs of the State educational agency in carrying out this part. ``SEC. 10993D. STATE APPLICATIONS. ``(a) In General.--To be eligible to receive an allotment under section 10993C, a State shall submit an application to the Secretary at such time, in such manner, and containing such information as the Secretary may require, including an assurance that the State will provide the State share of the cost described in section 10993G. ``(b) Approval.--In approving the applications, the Secretary shall, to the extent practicable, approve applications to fund, in the aggregate, 100,000 additional counselors, 21,000 additional school psychologists, and 20,000 additional school social workers. ``SEC. 10993E. ALLOCATIONS TO LOCAL EDUCATIONAL AGENCIES. ``(a) Within State Distribution.-- ``(1) In general.--After using funds in accordance with section 10993C(b), each State that receives an allotment under section 10993C shall allocate to eligible local educational agencies in the State the total of-- ``(A) the amount of the allotted funds that remain; and ``(B) the State share of the cost described in section 10993G for the local educational agencies. ``(2) Allocation.--From the total described in paragraph (1), the State shall allocate to each local educational agency an amount equal to the sum of-- ``(A) an amount that bears the same relationship to 80 percent of such total as the number of children in poverty who reside in the school district served by the local educational agency bears to the number of such children who reside in all the school districts in the State; and ``(B) an amount that bears the same relationship to 20 percent of such total as the number of children enrolled in public and private nonprofit elementary schools and secondary schools in the school district served by the local educational agency bears to the number of children enrolled in all such schools in the State. ``(3) Data.--For purposes of paragraph (2), the State shall use data from the most recent fiscal year for which satisfactory data are available, except that the State may adjust such data, or use alternative child poverty data, to carry out paragraph (2) if the State demonstrates to the Secretary's satisfaction that such adjusted or alternative data more accurately reflect the relative incidence of children who are living in poverty and who reside in the school districts in the State. ``(b) Definitions.--In this section: ``(1) Child.--The term `child' means an individual who is not less than 5 and not more than 17. ``(2) Child in poverty.--The term `child in poverty' means a child from a family with an income below the poverty line. ``SEC. 10993F. LOCAL APPLICATIONS. ``To be eligible to receive an allocation under section 10993E, a local educational agency shall submit an application to the State at such time, in such manner, and containing such information as the State may require, including an assurance that the agency will provide the local share of the cost described in section 10993G. ``SEC. 10993G. USE OF FUNDS. ``(a) In General.--A local educational agency that receives an allocation under section 10993E shall use the funds made available through the allocation to pay for the local share of the cost of recruiting, hiring, and training mental health and student service providers to provide mental health and student services, to students in elementary schools and secondary schools, for a 1-year period. ``(b) Federal, State, and Local Shares.-- ``(1) Federal share.--The Federal share of the cost shall be 33\1/3\ percent. ``(2) State share.--The State share of the cost shall be 33\1/3\ percent. ``(3) Local share.--The local share of the cost shall be 33\1/3\ percent. ``(4) Non-federal share.--The non-Federal share of the cost may be provided in cash or in kind, fairly evaluated, including plant, equipment or services. ``SEC. 10993H. AUTHORIZATION OF APPROPRIATIONS. ``To carry out this part, there are authorized to be appropriated $340,000,000 for each of fiscal years 2000 through 2004.''.

Directs the Secretary of Education, after reserving certain funds for schools in outlying areas and schools run by the Bureau of Indian Affairs, to make program allotments to States according to a specified formula. Requires States to allocate Federal and State shares of program costs to LEAs according to specified formulas. Sets forth requirements for State and LEA applications and LEA use of funds. Requires Federal, State, and local shares of program costs to each equal one-third, but allows State and local shares to be in cash or in kind. Authorizes appropriations.

SECTION 1. SHORT TITLE. This Act may be cited as the ``United Nations Accountability Act of 1997''. SEC. 2. PROHIBITION OF PAYMENT OF ARREARAGES TO UNITED NATIONS. Until a certification by the President of reforms in the United Nations under section 3 is transmitted to the Congress and the certification is approved by the Congress through enactment of a joint resolution in accordance with section 4, and notwithstanding any other provision of law, funds appropriated or otherwise made available for any fiscal year under ``Contributions to International Organizations'', ``Contributions for International Peacekeeping'', or any other account shall not be available for the payment of any assessed contribution of the United States for prior years to the United Nations. SEC. 3. CERTIFICATION BY THE PRESIDENT OF UNITED NATIONS REFORMS. The certification referred to in section 2 is a certification (with supporting documentation) by the President to the Congress that the United Nations has implemented all of the following reforms: (1) Assessed payment reformulation.-- (A) The assessed payment of the United States to the United Nations for each year has been lowered to 20 percent of the budget of the United Nations, or (B) The United Nations has reformulated each member state's assessed level to reflect each state's share of the total world gross national product. (2) Code of conduct.--The United Nations has implemented a code of conduct for all employees of the United Nations. The code of conduct shall specify that no United Nations official, including the Secretary General, shall be permitted to engage in business activities outside the United Nations, or provide any relative with access to United Nations procurement contracts, or take bribes, directly or indirectly, from individuals or corporations doing business with the United Nations or from United Nations member states or their representatives. (3) Inspector general of the united nations.--The Office of Inspector General of the United Nations has been strengthened as follows: (A) The United Nations has a truly independent office of inspector general to conduct and supervise objective audits, inspections, and investigations relating to programs and operations of the United Nations. The office shall be financed under a separate line item in the budget of the United Nations and shall function independently of the Secretary General. (B) The United Nations has an inspector general who is selected and elected by the General Assembly for a term of 3 years and whose appointment was made principally on the basis of the appointee's integrity and demonstrated ability in accounting, auditing, financial analysis, law, management analysis, public administration, or investigation. The inspector general may be removed only for cause by the Secretary General with the approval of the General Assembly. (C) The inspector general is authorized to-- (i) make investigations and reports relating to the administration of the programs and operations of the United Nations; (ii) have access to all relevant records, documents, and other available materials relating to those programs and operations; and (iii) have direct and prompt access to any official of the United Nations. (D) The United Nations has fully implemented, and made available to all member states, procedures designed to protect the identity of, and prevent reprisals against, any employee of the United Nations making a complaint or disclosing information to, or cooperating in any investigation or inspection by, the inspector general. (E) The United Nations has fully implemented procedures designed to ensure compliance with recommendations of the inspector general. (F) The United Nations has required the inspector general to issue an annual report and has ensured that the annual report and all other relevant reports of the inspector general are made available to the member governments of the United Nations General Assembly without modification. (G) The United Nations is committed to providing sufficient budgetary resources to ensure the effective operation of the office of the inspector general. (4) Employee protection.--The existing United Nations grievance system has been thoroughly reformed to permit United Nations employees to hire outside counsel for taking their grievances up the United Nations grievance ladder to the top United Nations grievance appeals level. It should also be made amply clear for civil lawyers and judges in each member state that United Nations officials' immunity from civil process applies only to actions performed in the strict fulfillment of United Nations official duties and never to abuses in violation of an extensive United Nations code of conduct, United Nations employees having the right and option in such cases any time to exit the United Nations grievance process and sue in a civil court. (5) Procurement reforms.-- (A) The United Nations has implemented a system requiring at least 30 days prior notification for the submission of all qualified bid proposals on all United Nations procurement opportunities of more than $100,000 and a public announcement of the award of any contract of more than $100,000 (except in justified and documented emergencies). (B) To the extent practicable, notifications and announcements under subparagraph (A) are made in the Commerce Business Daily. (C) The procurement regulations of the United Nations prohibit punitive actions such as the suspension of contract eligibility for contractors who challenge contract awards or complain about delayed payments. (6) Whistleblower protection.--The United Nations has implemented whistleblower protection for employees of the United Nations that-- (A) protects employees who allege or report instances of fraud or mismanagement, and (B) the independent Office of the Inspector General has reviewed the policies and regulations under subparagraph (A) and determined, in writing, that they offer adequate safeguards against retaliation for such employees, and that the United Nations employee grievance system outlined in paragraph (4)(C)(ii) has been reformed and the reforms implemented. (7) No growth budget.--The United Nations has adopted a calendar year 2000-2001 biennial budget that requires no nominal growth, in dollars, in expenditures. (8) Downsizing.--The United Nations has continued to downsize the number of authorized employment positions, including a reduction of not less than 10 percent in the number of full-time permanent authorized employment positions from the number of such positions authorized on January 1, 1997. Acceptable downsizing may not include early detachment from United Nations service with full pay until retirement age is reached, nor may it include the hiring of consultants to replace employees detached early with full pay or those replaced by temporary employees on short-term contracts. (9) Salaries.--The United Nations has imposed a freeze on salaries of employees of the United Nations which allows only for annual increases not greater than any annual increase in the United States consumer price index. (10) Representation on advisory committee on administrative and budget questions.--The 8 member states which are the highest contributors to the budget of the United Nations shall be permanent members of the Advisory Committee on Administrative and Budget Questions. (11) Access to documents.--Require access by any member state of the United Nations Budget Committee (also known as the Fifth Committee) to any document concerning any United Nations program that involves expenditures. (12) Annual reauthorization of peace-keeping missions.--The United Nations requires an annual review and reauthorization of any peacekeeping missions by the United Nations Security Council. (13) Reimbursement for united states department of defense peacekeeping expenditures.--The United Nations has reimbursed the United States Department of Defense for voluntary contributions to United Nations peacekeeping missions and the United Nations and the United States have entered into an agreement that calls for United Nations reimbursement for any future voluntary contributions by the United States Department of Defense, whether they be financial, logistical, or material. (14) United states arrearages.--The United Nations and the United States have mutually determined an amount that will satisfy any and all arrearages of the United States in assessed contributions for prior years. (15) Nominations to security council.--All member states of the United Nations belong to a regional group that allows each member state to be nominated to the Security Council. (16) United nations taxes.--The United Nations has abandoned any effort to establish an international tax or any other international fee or assessment imposed by the United Nations (other than the assessed contributions of member states of the United Nations and associated organs). (17) Noninterference with religious belief, culture, or tradition.--Neither the United Nations nor any affiliated agency or entity is engaged in any program or activity that threatens to interfere with the religion, moral values, culture, or traditions of any person or group, except insofar as is strictly necessary for the protection of fundamental and internationally recognized human rights. SEC. 4. CONGRESSIONAL APPROVAL OF PRESIDENTIAL CERTIFICATION. (a) Terms of the Resolution.--For purposes of section 2, the term ``joint resolution'' means only a joint resolution which is enacted within the 30-legislative day period beginning on the date on which the President transmits the certification (and supporting documentation) to the Congress under this Act, and-- (1) which does not have a preamble; (2) the matter after the resolving clause of which is as follows: ``That Congress approves the certification of the President regarding reforms in the United Nations.''; and (3) the title of which is as follows: ``Joint resolution approving the certification of the President regarding reforms in the United Nations.''. (b) Referral.--A resolution described in subsection (a) that is introduced in the House of Representatives shall be referred to the Committee on International Relations and the Committee on Appropriations of the House of Representatives. A resolution described in subsection (a) introduced in the Senate shall be referred to the Committee on Foreign Relations and the Committee on Appropriations of the Senate. (c) Discharge.--If the committee to which a resolution described in subsection (a) is referred has not reported such resolution (or an identical resolution) by the end of the 15 legislative-day period beginning on the date on which the President transmits the certification to the Congress under section 2, such committee shall be, at the end of such period, discharged from further consideration of such resolution, and such resolution shall be placed on the appropriate calendar of the House involved. (d) Consideration.--(1) On or after the third legislative day after the date on which the committee to which such a resolution is referred has reported, or has been discharged (under subsection (c)) from further consideration of, such a resolution, it is in order (even though a previous motion to the same effect has been disagreed to) for any Member of the respective House to move to proceed to the consideration of the resolution. A Member may make the motion only on the legislative day after the legislative day on which the Member announces to the House concerned the Member's intention to make the motion, except that, in the case of the House of Representatives, the motion may be made without such prior announcement if the motion is made by direction of the committee to which the resolution was referred. All points of order against the resolution (and against consideration of the resolution) are waived. The motion is highly privileged in the House of Representatives and is privileged in the Senate and is not debatable. The motion is not subject to amendment, or to a motion to postpone, or to a motion to proceed to the consideration of other business. A motion to reconsider the vote by which the motion is agreed to or disagreed to shall not be in order. If a motion to proceed to the consideration of the resolution is agreed to, the respective House shall immediately proceed to consideration of the joint resolution without intervening motion, order, or other business, and the resolution shall remain the unfinished business of the respective House until disposed of. (2) Debate on the resolution, and on all debatable motions and appeals in connection therewith, shall be limited to not more than 2 hours, which shall be divided equally between those favoring and those opposing the resolution. An amendment to the resolution is not in order. A motion further to limit debate is in order and not debatable. A motion to postpone, or a motion to proceed to the consideration of other business, or a motion to recommit the resolution is not in order. A motion to reconsider the vote by which the resolution is agreed to or disagreed to is not in order. (3) Immediately following the conclusion of the debate on a resolution described in subsection (a) and a single quorum call at the conclusion of the debate if requested in accordance with the rules of the appropriate House, the vote on final passage of the resolution shall occur. (4) Appeals from the decisions of the Chair relating to the application of the rules of the Senate or the House of Representatives, as the case may be, to the procedure relating to a resolution described in subsection (a) shall be decided without debate. (e) Consideration by Other House.--(1) If, before the passage by one House of a resolution of that House described in subsection (a), that House receives from the other House a resolution described in subsection (a), then the following procedures shall apply: (A) The resolution of the other House shall not be referred to a committee and may not be considered in the House receiving it except in the case of final passage as provided in subparagraph (B)(ii). (B) With respect to a resolution described in subsection (a) of the House receiving the resolution-- (i) the procedure in that House shall be the same as if no resolution had been received from the other House; but (ii) the vote on final passage shall be on the resolution of the other House. (2) Upon disposition of the resolution received from the other House, it shall no longer be in order to consider the resolution that originated in the receiving House. (f) Rules of the Senate and House.--This section is enacted by Congress-- (1) as an exercise of the rulemaking power of the Senate and House of Representatives, respectively, and as such it is deemed a part of the rules of each House, respectively, but applicable only with respect to the procedure to be followed in that House in the case of a resolution described in subsection (a), and it supersedes other rules only to the extent that it is inconsistent with such rules; and (2) with full recognition of the constitutional right of either House to change the rules (so far as relating to the procedure of that House) at any time, in the same manner, and to the same extent as in the case of any other rule of that House. (g) Legislative Day Defined.--For the purposes of this section, the term ``legislative day'' means any calendar day other than a day on which either House is not in session.

United Nations Accountability Act of 1997 - Prohibits the payment of arrearages of U.S. contributions to the United Nations (UN) until the President certifies to, and a joint resolution is approved by, the Congress that the UN has implemented specified reforms, including: (1) a reformulation of the assessed U.S. payment to the UN; (2) implementation of a code of conduct for UN employees; (3) strengthening of the powers of the Office of Inspector General of the UN; (4) reform of the UN grievance system to permit UN employees to hire outside counsel; (5) implementation of certain reforms to UN procurement procedures; (6) whistleblower protection for UN employees; (7) adoption of a no growth biennial budget; (8) acceptable downsizing; (9) a freeze on UN employee salaries; (10) making the eight member states with the highest contributions to the UN permanent members of the Advisory Committee on Administrative and Budget Questions; (11) providing access by Budget Committee member states to certain expenditure documents; (12) requiring an annual review and reauthorization of any peacekeeping missions by the UN Security Council; (13) UN reimbursement for Department of Defense contributions to UN peacekeeping missions; (14) satisfaction of U.S. arrearages in contributions to the UN; (15) allowance of all member states to be nominated to the Security Council; (16) abandonment of UN efforts to establish an international tax; and (17) UN noninterference with any people's religion, moral values, culture, or traditions.

we should like to thank a. hoang and a. leike for useful discussions . 10 x. calmet and h. fritzsch , phys . b * 496 * , 161 ( 2000 ) [ hep - ph/0008243 ] , x. calmet , phys . b * 510 * , 221 ( 2001 ) [ hep - th/0008189 ] , x. calmet and h. fritzsch , hep - ph/0103333 . s. l. glashow , nucl . phys . * 22 * , 579 ( 1961 ) , s. weinberg , phys . rev . * 19 * , 1264 ( 1967 ) , a. salam , elementary particle physics , in proceedings of the 8th nobel symposium , 1968 . k. osterwalder and e. seiler , annals phys . * 110 * ( 1978 ) 440 , e. fradkin and s. h. shenker , phys . * d19 * ( 1979 ) 3682 , phys . lett . * b164 * ( 1985 ) 121 . g. t hooft , in erice 1998 , from the planck length to the hubble radius , 216 - 236 , hep - th/9812204 , hep - th/9812204 , g. t hooft , in `` recent developments in gauge theories '' , carges 1979 , ed . t hooft et al . plenum press , new york , 1980 , lecture ii , p.117 , see also t. banks and e. rabinovici , nucl . phys . * b160 * ( 1979 ) 349 , s. dimopoulos , s. raby and l. susskind , nucl . * b173 * ( 1980 ) 208 . m. veltman , acta phys . b * 12 * , 437 ( 1981 ) , g. passarino and m. veltman , nucl . b * 160 * , 151 ( 1979 ) . j. fleischer and f. jegerlehner , phys . d * 23 * , 2001 ( 1981 ) . e. ma , phys . d * 47 * , 2143 ( 1993 ) [ hep - ph/9209221 ] . m. sher , phys . rept . * 179 * , 273 ( 1989 ) , m. sher , phys . lett . b * 317 * , 159 ( 1993 ) [ b * 331 * , 448 ( 1993 ) ] [ hep - ph/9307342 ] , j. r. espinosa and m. quiros , phys . b * 353 * , 257 ( 1995 ) [ hep - ph/9504241 ] , j. a. casas , j. r. espinosa and m. quiros , phys . b * 342 * , 171 ( 1995 ) [ hep - ph/9409458 ] . t. kawamoto , contributed to 36th rencontres de moriond on qcd and hadronic interactions , les arcs , france , 17 - 24 mar 2001 , hep - ex/0105032 . x. calmet and h. fritzsch , phys . * b496 * , 190 ( 2000 ) [ hep - ph/0008252 ] .

we compute the higgs mass in a model for the electroweak interactions based on a confining theory . this model is related to the standard model by the complementarity principle . a dynamical effect due to the large typical scale of the higgs boson shifts its mass above that of the w - bosons . we obtain @xmath0 gev . @sh[#1]#2 fmsl@sh fmsl@sh fmsl@sh fmsl@sh#1#2#3@th hep - ph/0107085 + lmu 01/10 + xavier calmet + and harald fritzsch + _ ludwig - maximilians - university munich , sektion physik _ + _ theresienstrae 37 , d-80333 munich , germany _ recently we have proposed a model for the electroweak interactions based on a confining @xmath1 theory @xcite . it was shown that , at least at low energies , this model is complementary or dual to the electroweak standard model @xcite . the complementarity principle states that there is no phase transition between the higgs and the confinement phase if there is a higgs boson in the fundamental representation of the gauge group @xcite . the lagrangian of the theory under consideration is exactly that of the standard model before gauge symmetry breaking . however the sign of the higgs boson squared mass is changed , i.e. it is positive , and the gauge symmetry is thus unbroken . we have the following fundamental left - handed dual - quark doublets , which we denote as d - quarks : + [ cols= " < , < , < " , ] + the right - handed particles are those of the standard model . as the gauge symmetry is unbroken , physical particles must be singlets under @xmath1 transformation , and we thus get the following particle spectrum @xmath2 where @xmath3 is the coupling constant of the gauge group @xmath4 and @xmath5 is the corresponding covariant derivative . we have used the unitary gauge @xmath6 where @xmath7 is the parameter appearing in the expansion of the bound states ( [ def2 ] ) . matching the expansion of the higgs boson to the standard model we get @xmath8 gev @xcite . using this expansion , we can associate a certain scale , which is proportional to @xmath7 , to each particle . the scale of the @xmath9-bosons is then @xmath10 gev . as can be seen from the expansion for the higgs boson ( [ def2 ] ) , there is a factor four between the expansion parameter of the higgs boson and that of the w - bosons , thus one finds @xmath11 gev . this factor four is dictated by the algebraic structure of the underlying gauge theory . in the confinement phase the higgs boson is the @xmath12-wave of the @xmath1 theory , whereas the @xmath9-bosons are the corresponding @xmath13-waves . thus one expects the higgs boson to be lighter than the @xmath9-bosons . but , as we shall show , a dynamical effect shifts the higgs boson mass above that of the @xmath9-bosons mass . the reason for this phenomenon is the large higgs boson scale compared to that of the @xmath9-bosons . the masses of the physical higgs and w - bosons , being bound states consist of a constituent mass @xmath14 , where @xmath15 is the mass of the scalar @xmath16-quark and of dynamical contributions . we have to consider two types of diagrams : the one - particle reducible diagrams ( 1pr ) and the one - particle irreducible diagrams ( 1pi ) . for the higgs boson mass , we have to take the self - interaction and the contribution of the @xmath17 and @xmath18-bosons into account ( see figures [ fig1 ] , [ fig2 ] and [ fig3 ] ) . the fermions couple via yukawa coupling to the higgs boson , and as this interaction is not confining , fermions can not contribute to the dynamical mass of the higgs boson . the first task is to extract the constituent mass from the experimentally measured @xmath9-bosons mass . the fermions contribute to the dynamical mass of the @xmath9-bosons as they couple via @xmath1 couplings to the electroweak bosons but the divergence is only logarithmic @xcite and we shall only keep the quadratic divergences . [ fig3 ] ] [ fig3 ] ] [ fig3 ] ] [ fig6 ] ] [ fig6 ] ] [ fig6 ] ] we have considered the tadpoles and the one - particle - irreducible contributions at the one loop order ( the diagrams contributing to the @xmath9-bosons mass are similar to those contributing to the higgs - boson mass ) . using the duality described in @xcite , these duality diagrams can be related to the feynman graphs of figures [ fig4 ] , [ fig5 ] and [ fig6 ] . the feynman graphs have been evaluated in ref . @xcite as a function of a cut - off parameter and we will only keep the dominant contribution which is quadratically divergent . we obtain : @xmath19 this equation can be solved for @xmath20 : @xmath21 we can now compute the dynamical contribution to the higgs boson mass . the exact one loop , gauge invariant counterterm has been calculated in refs . @xcite , @xcite and @xcite . using the results of ref . @xcite , where this counterterm was calculated as a function of a cut - off , we obtain : @xmath22 the unknown of this equation is the higgs boson s mass @xmath23 . this equation can be solved by numerical means . we obtain two positive solutions : @xmath24=14.1 gev and @xmath25=129.6 gev . the first solution yields an imaginary constituent mass and is thus also discarded . the second solution is the physical higgs boson mass . we thus obtain @xmath26=129.6 gev in the one loop approximation . the constituent mass is then @xmath27=78.8 gev . as expected the dynamical contribution to the @xmath9-bosons masses is small and the higgs boson mass is shifted above that of that of the @xmath9-bosons mass because of the large higgs boson scale . note that our prediction @xmath26=129.6 gev is in good agreement with the requirement of vacuum stability in the standard model which requires the mass of the higgs boson to be in the range 130 gev to 180 gev if the standard model is to be valid up to a high energy scale @xcite . we can thus deduce that the duality we have described @xcite must also be valid up to some high energy scale . our result is also in good agreement with the expectation @xmath28 gev based on electroweak fits @xcite . this has also consequences for the model proposed in @xcite , where we assumed that the higgs boson does not couple to @xmath29-quarks . because of the dynamical effect we have discussed , the higgs boson is relatively heavy and should decay predominantly into electroweak bosons .

SECTION 1. EXTENSION OF SUSPENSION OF DUTY ON CERTAIN CHEMICALS. Each of the following headings of the Harmonized Tariff Schedule of the United States is amended by striking ``12/31/92'' and inserting ``12/31/94''. (1) 9902.29.04 (relating to p-Toluenesulfonyl chloride). (2) 9902.29.13 (relating to 2,6-Dichlorobenzaldehyde). (3) 9902.29.28 (relating to &lt;greek-a&gt;,&lt;greek-a&gt;,&lt;greek-a&gt;- Trifluoro-o-toluidine). (4) 9902.29.30 (relating to 8-Amino-1-naphthalenesulfonic acid and its salts). (5) 9902.29.31 (relating to 5-Amino-2-(p- aminoanilino)benzenesulfonic acid). (6) 9902.29.33 (relating to 1-Amino-8-hydroxy-3,6- naphthalenedisulfonic acid; and 4-Amino-5-hydroxy-2,7- naphthalenedisulfonic acid, monosodium salt (H acid, monosodium salt)). (7) 9902.29.35 (relating to 6-Amino-4-hydroxy-2- naphthalenesulfonic acid (Gamma Acid)). (8) 9902.29.38 (relating to 3,3'-Dimethoxybenzidine (o- Dianisidine) and its dihydrochloride). (9) 9902.29.40 (relating to 2-Amino-5-nitrophenol). (10) 9902.29.43 (relating to 1-Amino-2,4- dibromoanthraquinone). (11) 9902.29.44 (relating to 1-Amino-4-bromo-2- anthraquinonesulfonic acid (Bromamine acid) and its sodium salt). (12) 9902.29.47 (relating to 4-Methoxyaniline-2-sulfonic acid). (13) 9902.29.51 (relating to N-(7-Hydroxy-1-naphthyl acetamide). (14) 9902.29.57 (relating to N,N-bis(2-cyanoethyl)aniline). (15) 9902.29.64 (relating to 6-(3-Methyl-5-oxo-1- pyrazolyl)-1,3-naphthalenedisulfonic acid (amino-J-pyrazolone) (CAS No. 7277-87-4); and 3-Methyl-1-phenyl-5-pyrazolone (Methylphenylpyrazolone)). (16) 9902.29.69 (relating to 3-Methyl-5-pyrazolone). (17) 9902.29.79 (relating to 2-Amino-N- ethylbenzenesulfonoanilide). (18) 9902.30.15 (relating to 7-Hydroxy-1,3- naphthalenedisulfonic acid, dipotassium salt (CAS No. 842-18- 2)). (19) 9902.30.18 (relating to 1,4-Dihydroxyanthraquinone (CAS No. 81-64-1)). (20) 9902.30.31 (relating to 2-Chloro-4-nitroaniline (CAS No. 121-87-9)). (21) 9902.30.32 (relating to 4-Chloro-&lt;greek-a&gt;-&lt;greek-a&gt;- &lt;greek-a&gt;-trifluoro-o-toluidine (CAS No. 445-03-4)). (22) 9902.30.34 (relating to 5-Amino-2-naphthalenesulfonic acid (CAS No. 119-79-9)). (23) 9902.30.35 (relating to 7-Amino-1,3- naphthalenedisulfonic acid, monopotassium salt (CAS No. 842-15- 9)). (24) 9902.30.36 (relating to 4-Amino-1-naphthalenesulfonic acid, sodium salt (CAS No. 130-13-2)). (25) 9902.30.37 (relating to 8-Amino-2-naphthalenesulfonic acid (CAS No. 119-28-8)). (26) 9902.30.38 (relating to mixtures of 5- and 8-amino-2- naphthalenesulfonic acid (CAS No. 119-28-8)). (27) 9902.30.39 (relating to 1-Naphthylamine (CAS No. 134- 32-7)). (28) 9902.30.40 (relating to 6-Amino-2-naphthalenesulfonic acid (CAS No. 93-00-5)). (29) 9902.30.43 (relating to 2,4-Diaminobenzenesulfonic acid (CAS No. 88-63-1)). (30) 9902.30.48 (relating to 2-Amino-4-chlorophenol (CAS No. 95-85-2)). (31) 9902.30.47 (relating to 1-Amino-2-methoxybenzene (o- Anisidine) (CAS No. 90-04-0)). (32) 9902.30.51 (relating to 7-Anilino-4-hydroxy-2- naphthalenesulfonic acid (CAS No. 119-40-4)). (33) 9902.30.52 (relating to 1,4-Diamino-2,3- dihydroanthraquinone (CAS No. 81-63-0)). (34) 9902.30.55 (relating to 1-Amino-2-bromo-4- hydroxyanthraquinone (CAS No. 116-82-5)). (35) 9902.30.67 (relating to 4-Aminoacetanilide (CAS No. 122-80-5)). (36) 9902.30.75 (relating to 2-[(4- Aminophenyl)sulfonyl]ethanol, hydrogen sulfate ester (CAS No. 2494-89-5)). (37) 9902.30.80 (relating to 2,5-Dichloro-4-(3-methyl-5- oxo-2-pyrazolin-1-yl)-benzenesulfonic acid (CAS No. 84-57-1)). (38) 9902.30.89 (relating to 1,3,3-Trimethyl-2- methyleneindoline (CAS No. 118-12-7)). (39) 9902.30.94 (relating to 7-Nitronaphth[1,2]-oxadiazole- 5-sulphonic acid (CAS No. 84-91-3)). SEC. 2. EFFECTIVE DATE. (a) In General.--The amendments made by section 1 apply with respect to goods entered, or withdrawn from warehouse for consumption on or after the 15th day after the date of the enactment of this Act. (b) Retroactive Provision.--Notwithstanding section 514 of the Tariff Act of 1930 or any other provision of law, upon a request filed with the appropriate customs officer on or before the 90th day after the date of the enactment of this Act, any entry or withdrawal from warehouse for consumption of goods to which the amendment made by section 1 applies and that was made-- (1) after December 31, 1992; and (2) before the 15th day after the date of the enactment of this Act; and with respect to which there would have been a lower duty if the amendment made by section 1 had applied to such entry or withdrawal, shall be liquidated or reliquidated as though such entry or withdrawal had occurred on such 15th day.

Amends the Harmonized Tariff Schedule of the United States to suspend, through December 31, 1994, the duty on certain organic chemicals.

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abstractdirect sersbased quantification of inorganic metal species has been a problem , because they have a small raman crosssection or even no vibrational mode . here , we report a new strategy for sersbased quantification of such metal species , as exemplified by inorganic mercury ( hgii ) in waters . stepbystep design and synthesis from azathioethers [ 3 , 9dithia6monoazaundecane ( dma ) and 3,6,12,15tetrathia9monoazaheptadecane ( ttm ) ] to an azathiacrown [ 7aza1,4,10,13tetrathiacyclohexadecane ( ns4 ) ] demonstrate an improved spulling effect and sizefit specificity towards hgii to form hgs bonds . modification of ns4 on the surface of au@sio2 by using a 4(bromomethyl)benzoic linker enabled direct sersbased specific quantification of hgii for the first time , in which the ultrathin layer ( ca . 2 nm ) that covered the au core ( 55 nm ) could be a barrier preventing the au core from having direct interaction with the hgii , and with phenyl serving as an internal standard ( is ) . the ratio of the hgs sers band intensity at 270 cm1 to that of is [ ( cc+ccc ) at 1046 cm1 ] was practically proportional to the concentration of hgii , eliminating the inevitable uncertainties encountered in sersbased measurements . such a methodology is expected to pave a new way for sersbased quantification of inorganic metal species when specific complexing substrates and suitable iss are designed .

recently , the central exclusive production of @xmath3 charmonia has attracted a lot of attention from both experimental @xcite and theoretical @xcite sides . at the moment , such a process provides the unique opportunity to test the qcd diffractive kaidalov - khoze - martin - ryskin ( kkmr ) mechanism @xcite based on the @xmath2-factorisation incorporating nonperturbative small-@xmath6 gluon dynamics described by the unintegrated gluon distribution functions ( ugdfs ) against accessible data . the final hadronic central system is , however , rather complicated and composed of three spin states @xmath7 , and there is no yet any reliable way to measure them separately . such a measurement would significantly reduce an overall theoretical uncertainty , as different @xmath3 spin contributions come from different phase space regions @xcite . indeed , in the asymptotical forward limit @xmath5 are strongly suppressed with respect to @xmath8 due to the @xmath9 selections rule @xcite . however , corrections to this asymptotics turn out to be important in the total cross section leading to a noticeable contribution of the @xmath5 states to the observable signal from radiative @xmath3 decays @xcite . generally , separate measurements of @xmath3 states in diffractive production would impose more strict bounds on the production mechanism under consideration and extract some new information on the underlying qcd dynamics @xcite . one of the ways is to measure the characteristic differential distributions like meson @xmath10 distributions or angular correlations of the outgoing protons . however , such distributions are rather sensitive to ugdfs and cuts on kinematical variables @xcite , and existing experimental techniques do not allow to reconstruct such observables with sufficient precision . another possible way is to look at observables related with meson polarisations and their decay distributions . the goal of the present paper is to analyze polarisation effects in the central exclusive production of @xmath3 charmonia . such effects can be potentially identified by measuring the angular distribution of @xmath4 mesons from radiative decays of @xmath11 giving more detailed information on the partial meson helicity contributions . moreover , certain combinations of polarisation observables can be less sensitive to unknown nonperturbative effects leading to unique opportunities for model - independent analysis of diffractive processes . the paper is organized as follows . in section ii we give general expressions for the amplitude of the central exclusive @xmath5 production with all necessary notations . section iii contains discussion of the rapidity dependence of the hard subprocess amplitudes for different @xmath3 polarisations . in sections iv and v we derive the angular dependence of outgoing @xmath4 mesons in the helicity frame in terms of the diffractive @xmath3 production density matrix @xmath12 . sections vi and vii are devoted to discussion of gluon off - shell effects and absorptive corrections . section viii contains the presentation of the main results , including differential distributions of polarised @xmath5 and angular correlations of the outgoing @xmath4 mesons . finally , in section ix we give a set of concluding remarks and present a discussion of the final results and theoretical uncertainties . according to the kaidalov - khoze - martin - ryskin approach ( kkmr ) @xcite , we write the amplitude of the exclusive double diffractive color singlet production @xmath13 as @xmath14 where @xmath15 are the off - diagonal unintegrated gluon distributions for `` active '' gluons with momenta @xmath16 and color indices @xmath17 , and the screening soft gluon with small fraction @xmath18 , @xmath19 and @xmath20 are the spin and helicity of a produced meson with momentum @xmath21 and mass @xmath22 in the center - of - mass frame of colliding protons and @xmath23 axis directed along the meson momentum @xmath24 , respectively . @xmath25 here is the hard @xmath26 production amplitude for charmonium with quantum numbers @xmath27 . the structure of @xmath28 in eq . ( [ ampl ] ) ( we omit here the color and polarisation indices for simplicity ) is determined by gauge invariant amplitude @xmath29 for the off - shell gluon fusion process , and given in terms of its projection onto the gluon polarisation vectors as @xcite @xmath30 in order to define the polarisation states of @xmath5 mesons , one has to fix a specific frame , in which those are uniquely identified and can be measured experimentally . the commonly used polarisation frames are the helicity , target , gottfried - jackson and collins - soper frames ( see , e.g. @xcite ) . in this work we primarily focus on polarisation effects in the helicity frame . according to refs . @xcite , in the considered frame we introduce the time - like basis vectors @xmath31 satisfying @xmath32 ( with @xmath33 ) with collinear @xmath34 and @xmath24 vectors ( so , we have @xmath35 ) , and @xmath36 then the hard production amplitudes for the axial - vector @xmath37 ( @xmath38 ) and tensor @xmath39 ( @xmath40 ) charmonia in the helicity frame read ( for more details , see refs . @xcite ) @xmath41\times{\bf n}_1|\,\mathrm{sign}(q^y)\,\mathrm{sign}(\cos\psi)\biggr]+\label{v - fin - chic1}\\ & & ( 1-|\lambda|)(q_{1,t}^2+q_{2,t}^2)\,|[{\bf q}_{1,t}\times{\bf q}_{2,t}]\times{\bf n}_3|\,\mathrm{sign}(q^y)\,\mathrm{sign}(\sin\psi)\biggr\},\nonumber\end{aligned}\ ] ] @xmath42\times{\bf n}_1|\,(1-|\lambda|)\,\mathrm{sign}(\sin\psi)\,\mathrm{sign}(\cos\psi)+\nonumber\\ & & 2\,|[{\bf q}_{1,t}\times{\bf q}_{2,t}]\times{\bf n}_3|\,(2-|\lambda|)\big\}-\big[2q_{1,t}^2q_{2,t}^2+(q_{1,t}^2+q_{2,t}^2)(q_{1,t}q_{2,t})\big]\times\nonumber\\ & & \big\{3m^2(\cos^2\psi+1)\lambda(1-|\lambda|)+6me\sin(2\psi)\,\lambda(2-|\lambda|)\ , \mathrm{sign}(\sin\psi)\,\mathrm{sign}(\cos\psi)+\nonumber\\ & & \sqrt{6}\,(m^2 + 2e^2)\sin^2\psi\,(1-|\lambda|)(2-|\lambda|)\big\}\biggr ] \ ; , \nonumber\end{aligned}\ ] ] where @xmath43 are the @xmath44-components of the gluon transverse momenta @xmath45 in considered coordinates , @xmath46 $ ] is the polar angle between @xmath24 and the c.m.s . beam axis , and @xmath47\times{\bf n}_1|=\sqrt{q_{1,t}^2q_{2,t}^2-(q_{1,t}q_{2,t})^2}\,|\cos\psi|,\\ & & |[{\bf q}_{1,t}\times{\bf q}_{2,t}]\times{\bf n}_3|=\frac{e}{m}\sqrt{q_{1,t}^2q_{2,t}^2-(q_{1,t}q_{2,t})^2}\,|\sin\psi|,\\ & & |{\bf p}_t|^2=|{\bf q}_{1,t}|^2 + |{\bf q}_{2,t}|^2 + 2|{\bf q}_{1,t}||{\bf q}_{2,t}|\cos\phi,\\\end{aligned}\ ] ] where @xmath48 is the angle between fusing gluons . amplitudes ( [ v - fin - chic1 ] ) and ( [ v - fin - chic2 ] ) explicitly obey gauge invariance and bose symmetry properties with respect to the gluon momenta interchange @xmath49 . another important feature is that the amplitude of axial - vector charmonia production turns to zero for on - shell gluons , i.e. when @xmath50 due to the landau - yang theorem ( see , e.g. ref . the gluon virtualities ( transverse momenta ) provide a leading effect in the diffractive @xmath0 production , and , therefore , can not be neglected @xcite . this is the striking difference between the @xmath2-factorisation approach under consideration and collinear factorisation which forbids production of axial - vector states @xcite . as was demonstrated in refs . @xcite amplitudes for diffractive @xmath5 turn to zero in the forward limit , i.e. when @xmath51 , due to symmetry relations . this is a direct consequence of @xmath9 selection rule @xcite saying that cep of higher spins @xmath52 is strongly suppressed in the forward limit . like the gluon virtualities in the @xmath0 case , the off - forward corrections provide a leading effect in the case of @xmath5 production , and can not be neglected in the integrated cross section . in particular , they lead to a substantial contribution of @xmath1 meson cep @xcite , close to that from @xmath53 mesons . let us now turn to the discussion of the polarisation effects in diffractive @xmath54 charmonia production and first start from analytic investigation of helicity amplitudes . for the purpose of illustration amplitudes squared , not the diffractive @xmath56 amplitude squared . ] , it is interesting to look at the @xmath44-dependence of the @xmath57 ( hard ) subprocess amplitudes ( [ v - fin - chic1 ] ) and ( [ v - fin - chic2 ] ) for different meson helicities @xmath58 and @xmath59 , respectively . it is convenient to express them in terms of the transverse 3-momenta of fusing off - shell gluons @xmath60 and @xmath61 , and the angle between them @xmath48 in the center - of - mass frame of colliding nucleons with the @xmath23-axis fixed along meson momentum @xmath24 . in this case , summing the matrix element squared @xmath62 over meson polarisations @xmath20 up to some constant normalization factor @xmath63 we get : @xmath64 } { ( |{\bf q}_{1,t}|^2+|{\bf q}_{2,t}|^2+m^2)^4},\\ s^{j=2}&=&n^{j=2}\frac{|{\bf q}_{1,t}|^2|{\bf q}_{2,t}|^2 \big[3m_{\perp}^2m^2+\left(|{\bf q}_{1,t}|^2\cos\phi+|{\bf q}_{1,t}|^2\cos\phi+2|{\bf q}_{1,t}||{\bf q}_{2,t}|\right)^2\big ] } { ( |{\bf q}_{1,t}|^2+|{\bf q}_{2,t}|^2+m^2)^4 } \label{tot - sum}\end{aligned}\ ] ] these sums are proportional to the ones derived by kniehl et al . in ref . @xcite ( see right below eq . ( 27 ) ) . the distinction is only due to different normalizations of gluon polarisation vectors @xmath65 used in ref . @xcite and light - cone vectors @xmath66 used in our calculation . the sums ( [ tot - sum ] ) are @xmath44-independent . then , for partial polarisations of the @xmath0 meson we have @xmath67}{(m_{\perp}^2\cosh^2y - m^2)({\cal b}m^2+{\cal a } ) } , \label{y - dep - chic1}\end{aligned}\ ] ] where latexmath:[\ ] ] where @xmath141 are positive numbers satisfying @xmath142 to be determined experimentally . in ref . @xcite these values were extracted from the fermilab e835 data on fractional amplitudes of the electric dipole ( e1 ) , magnetic quadrupole ( m2 ) , and electric octupole ( e3 ) transitions in the exclusive reactions @xmath143 , with @xmath83 . they are listed here @xmath144 the corresponding values for a pure e1 transitions read @xmath145 , and @xmath146 . having these values we only need to calculate the independent components of @xmath85 to determine the @xmath4 angular distribution @xmath147 completely . analogously to eq . ( [ prod - cross ] ) , we can represent the angular distribution function as @xmath148 such a representation will allow us to calculate correlations between kinematical variables of the central system as a whole ( for example , rapidity @xmath44 , momentum transfers @xmath149 and angle between outgoing protons @xmath150 ) and angular variables of produced @xmath4 meson . distributions @xmath151 contain all the information about diffractive @xmath3 production mechanism , meson polarisations and decay process . let us comment now on the importance of gluon virtualities ( transverse momenta ) in the hard subprocess vertex @xmath152 implied by the genuine @xmath2-factorisation scheme . this question was originally investigated in ref . @xcite when considering the central exclusive production of @xmath8 meson . in particular , it was found that the on - shell approximation ( @xmath153 ) relying on the neglecting terms of the order of @xmath154 is too crude for the production of low mass systems with mass being of the order of a few gev . in the @xmath8 cep case , inclusion of the gluon virtualities @xmath155 in the hard matrix element leads to a noticeable decrease of the total ( bare ) cep cross section by a factor of 2 4 depending on the model of ugdf used . this off - shell effect is even more pronounced in the case of the axial - vector @xmath0 production , as it is dominated mostly by relatively large gluon virtualities and vanishes in the strict on - shell case . even when included in the numerator of the vertex ( see , e.g. , eq . ( [ v - fin - chic1 ] ) ) the `` small '' terms @xmath155 are sometimes neglected in its denominator . such an approximation @xmath153 increases the total @xmath0 cep cross section by almost a factor of 7 in absolute normalization making a large effect in the @xmath156 ratio in the observable radiative decay channel @xcite ( see also table [ table : dy0 ] below ) . this resulted in a large discrepancy ( in both normalisation of the total cross sections and relative spin contributions into observable signal ) between our previous results in refs . @xcite , where the exact hard matrix elements with off - shell gluons were used , and hkrs results in refs . @xcite , where gluon on - shell approximation @xmath153 was adopted . unlike the absolute normalisation of the cross section , the shapes of the differential distributions are not strongly affected by such an approximation . one should note here that the description of the tevatron data on the central exclusive @xmath3 production with updated results , including off - shell effects , becomes more difficult as the total cross section in the radiative decay channel @xmath157 gets underestimated by about a factor of two with respect to the tevatron data @xcite , if one uses values for the gap survival factors calculated in refs . . however , such results are still within an overall theoretical uncertainty from the soft physics involved , ugdf models in the qcd mechanism under consideration @xcite , and also from unknown nlo corrections to the @xmath158 vertex , which are implicitly , but only partly , taken into account by the @xmath2-factorisation approach used . in refs . @xcite , for simplicity the whole analysis of observables has been performed adopting an approximation when all soft rescattering effects are effectively absorbed into the effective gap survival factor @xmath159 taken into account multiplicatively . however , it is known from earlier analysis of the central exclusive higgs production @xcite ( and later for unpolarized @xmath3 production @xcite ) that the soft rescattering may change angular distributions crucially , so it is not enough to include the gap survival factor as a constant normalization of the cross section . in order to get some insight on the soft rescattering effects and include them dynamically , in the first approximation we use the simple one - channel model for the eikonal part of the survival probability calculated as @xmath160 where @xmath161 are the transverse momenta of the final protons , @xmath162 is the `` bare '' amplitude for the @xmath3 cep , defined in eq . ( [ ampl ] ) , and @xmath163 is the rescattering correction which can be written in the form ( see , e.g. , eq . ( 13 ) in ref . @xcite ) @xmath164 where @xmath165 ( the real part is small in the high energy limit ) , @xmath166 is the @xmath167-slope of the elastic @xmath168 differential cross section , and @xmath169 is the @xmath167-slope of the proton form factor . at the tevatron energy we have @xmath170 mb and @xmath171 . in table [ table : dy0 ] we have collected results for differential cross section @xmath172 for different spin states , as well as their contributions to the radiative @xmath173 decay channel @xmath174 at tevatron . for illustration , here we use only the perturbatively modeled kmr ugdf @xcite , which include the sudakov form factor and grv94ho gluon pdf @xcite . the results are presented for both versions of the absorptive corrections by using the one - channel approximation according to the eikonal model , we are grateful to l. harland - lang for providing us with a grid for its numerical calculation as a function of transverse momenta . ] ( [ seik ] ) , ( [ res ] ) , and in the factorized form with @xmath175-averaged ( effective ) gap survival factors @xmath176 obtained recently in ref . @xcite : @xmath177 where it is assumed that the enhanced suppression factor @xmath178 is the same for all spin states . .[table : dy0 ] differential cross section @xmath172 ( in nb ) of the exclusive diffractive production of @xmath7 mesons and their partial and total signal in radiative @xmath173 decay channel @xmath174 at tevatron ( @xmath179 tev ) for the kmr ugdf @xcite , different cuts on the transverse momentum of the gluons in the loop @xmath180 , with the on - shell gluons approximation @xmath153 in the hard subprocess part ( denoted as `` on - shell '' ) and without it ( `` off - shell '' ) . nlo correction factors to the hard part @xmath181 @xcite and absorptive corrections in factorized ( [ s2eff ] ) and in one - channel model ( [ seik ] ) , ( [ res ] ) forms are included . contributions of all polarisations are incorporated here . [ cols="^,^,^,^,^,^,^,^,^,^,^ " , ] in tables [ tab : chic1 ] and [ tab : chic2 ] we present the integrated elements of the diffractive @xmath5 production helicity matrix @xmath182 . only independent , both diagonal ( purely real ) and non - diagonal ( complex ) , non - zeroth elements are listed . rapidity dependence of the non - diagonal terms ( their real and imaginary parts ) in the axial - vector @xmath37 cep case is presented for illustration in fig . [ fig : chic1-ndiag ] . ( real and imaginary parts ) for the central exclusive axial - vector @xmath0 meson production.__,width=377 ] as was already pointed out , the total cep cross section is dominated by the maximal helicities . the subleading contribution of states with @xmath183 in the total cep cross section is about 5 - 6% for both @xmath0 and @xmath1 mesons . measure of such subleading polarisation contribution is given by the ratio @xmath184 ( see , last columns in tables [ tab : chic1 ] and [ tab : chic2 ] ) . we calculated these ratios for two typical ugdf models : kmr @xcite and kutak - stato @xcite . we see that the ratios @xmath185 are the same for both mesons , they are almost independent on ugdf models as the most of theoretical uncertainties ( including soft rescattering effects ) are canceled out inside them . thus , @xmath186 can be considered as a good model - independent observable for tests of underlined qcd production mechanism of @xmath3 mesons . _ angular distribution @xmath108 of @xmath4 meson from radiative decay of centrally produced @xmath0 ( left panel ) and @xmath1 ( right panel ) mesons in polar @xmath102 and azimuthal @xmath48 angles in the helicity frame . full phase space for central exclusive @xmath3 production is included , kmr ugdf @xcite was used._,scaledwidth=100.0% ] _ angular distribution @xmath108 of @xmath4 meson from radiative decay of centrally produced @xmath0 ( left panel ) and @xmath1 ( right panel ) mesons in polar @xmath102 and azimuthal @xmath48 angles in the helicity frame . full phase space for central exclusive @xmath3 production is included , kmr ugdf @xcite was used._,scaledwidth=100.0% ] as it was demonstrated in ref . @xcite , relative contributions of different spins @xmath19 are rather sensitive to the model of ugdf . this is due to the fact that the central exclusive production of @xmath0 is more sensitive to small gluon @xmath187 than @xmath1 production . moreover , non - diagonal elements @xmath188 have much stronger sensitivity to ugdf model , than the diagonal ones . therefore , experimental access to different elements of the production density matrix @xmath85 ( or @xmath189 ) would provide an opportunity for strong experimental constraints on the unintegrated gluon distributions at small @xmath6 and small gluon transverse momenta @xmath187 . now let us turn to the discussion of observable signal in radiative decay channel @xmath190 . as one of the important characteristics of the production process @xmath191 , the angular distribution of the @xmath4 meson @xmath108 in the helicity frame is shown in fig . [ fig : w ] as a function of polar @xmath102 and azimuthal @xmath48 angles for both @xmath5 mesons . _ angular distribution of @xmath4 meson averaged over azimuthal angle @xmath48 as function of polar angle @xmath102 ( in radians ) for @xmath0 meson ( solid line ) and @xmath1 meson ( dashed line ) . left panel corresponds to rapidity interval @xmath192 , right panel to @xmath193._,scaledwidth=130.0% ] _ angular distribution of @xmath4 meson averaged over azimuthal angle @xmath48 as function of polar angle @xmath102 ( in radians ) for @xmath0 meson ( solid line ) and @xmath1 meson ( dashed line ) . left panel corresponds to rapidity interval @xmath192 , right panel to @xmath193._,scaledwidth=130.0% ] the function @xmath108 is a periodic one in both the angles @xmath102 and @xmath48 . from eqs . ( [ jpsi-1 ] ) and ( [ jpsi-2 ] ) it follows that the dependence on polar angle @xmath102 is determined mostly by the diagonal terms of the production density matrix @xmath194 , whereas @xmath48-dependence is given by real and imaginary parts of non - diagonal terms . moreover , in the angular distribution @xmath195 averaged over @xmath48 all the terms with non - diagonal elements @xmath196 are dropped out for both @xmath5 mesons . the @xmath48-dependence of @xmath4 meson from the @xmath0 cep turned out to be much stronger than that from @xmath1 cep as it is seen from fig . [ fig : w ] . as for the @xmath102-dependence , periods of oscillations for @xmath0 and @xmath1 mesons are shifted by @xmath197 with respect to each other , as demonstrated in fig . [ fig : wav ] for distribution @xmath198 averaged over @xmath48 . also , from this figure we see that the amplitudes of variations in @xmath102 become smaller and the dominance of the maximal helicity gets weaker and can be eliminated when one shrinks the rapidity interval in the phase space integral . this is a direct consequence of the specific rapidity dependence of the production density matrix elements in the central rapidity region @xmath199 . _ angular differential distribution of @xmath4 meson averaged over azimuthal angle @xmath48 as function of polar angle @xmath102 ( in radians ) and @xmath3 meson rapidity @xmath44 for @xmath0 ( left panel ) and @xmath1 mesons ( right panel ) . kmr ugdf @xcite was used._,scaledwidth=100.0% ] _ angular differential distribution of @xmath4 meson averaged over azimuthal angle @xmath48 as function of polar angle @xmath102 ( in radians ) and @xmath3 meson rapidity @xmath44 for @xmath0 ( left panel ) and @xmath1 mesons ( right panel ) . kmr ugdf @xcite was used._,scaledwidth=100.0% ] now the main question is how to measure experimentally the kinematical effects in the central exclusive @xmath5 production reflected in the maxima / minima of rapidity distributions @xmath200 for different meson helicities @xmath20 . kinematical effects under consideration are natural in the helicity frame , in which we actually work . such a frame can be used in a real experiment . in principle , analogous calculations in other frames of reference can also be useful . as was already mentioned above , the total ( summed over all meson helicities @xmath20 ) cross section is regular around @xmath199 and does not contain information about rapidity dependence of the partial helicity contributions . instead , for the purpose of experimental identification of the kinematical effects and separation of the meson helicity contributions it is instructive to look at the correlation function @xmath201 in both variables polar angle of @xmath4 meson and rapidity @xmath44 of @xmath3 meson ( or , equivalently , @xmath173 system ) . we present such a function for each @xmath123 meson in fig . [ fig : wav - y ] . maxima / minima in differential distributions @xmath200 are then reflected in @xmath44-dependence of the correlation function @xmath202 at fixed @xmath102 . in principle , one can write formulae analogous to eqs . ( [ jpsi-1 ] ) and ( [ jpsi-2 ] ) in another frame , where the `` peaks '' in rapidity near @xmath199 can be eliminated . but then one looses some information about non - maximal helicity projections of the production density matrix . since helicity has different meaning in different frames , our effect is purely of kinematical nature and thus should also be different in different frames . our results can be summarized as follows : we have calculated differential cross sections for central exclusive @xmath5 meson production for different spin polarisations in the helicity frame . the integrated cross section for the maximal helicity state is approximately an order of magnitude greater than that for the non - maximal ones . we have shown that this effect has a kinematical nature : heavy ( non - relativistic , @xmath203 ) meson is dominantly produced in the @xmath183 state , massless ( relativistic , @xmath204 ) meson is produced mostly in the @xmath79 states . in the total cross section integrated over the meson rapidity @xmath44 the second effect turns out to be dominated , i.e. relativistic with @xmath204 @xmath3 mesons with maximal helicity ( @xmath79 for @xmath0 and @xmath80 for @xmath1 ) are preferably produced in the exclusive process @xmath205 . we used two different models for the @xmath187-dependent unintegrated gluon distributions from the literature conventional kmr distribution which includes sudakov form factor @xcite and the nonlinear kutak - stato model @xcite based on unified bfkl - dglap evolution . the contributions of the minimal helicity state @xmath183 given by the diagonal elements of the production density matrix @xmath185 are close both @xmath5 mesons and amount to @xmath206 % . they are only weekly dependent on ugdf ( but rather strongly dependent on cuts in rapidity @xmath44 ) . such quantities @xmath185 are , therefore , good model - independent observables , which can be used to constrain the underlying qcd diffractive production mechanism of heavy quarkonia . we have calculated , in addition , angular distributions of @xmath4 meson @xmath108 from radiative decays @xmath207 in the helicity frame , both analytically and numerically . the function @xmath147 contains an important information about all independent elements of the production density matrix @xmath85 , both diagonal and non - diagonal . azimuthal angle @xmath48 dependence of outgoing @xmath4 mesons is given by the real and imaginary parts of the non - diagonal elements @xmath196 , which are very sensitive to the ugdf model used . a specific shape of the rapidity dependence of the @xmath4 meson correlation function @xmath208 shown in fig . [ fig : wav - y ] is a result of the `` peaked '' shape of the @xmath3 production density matrix around central rapidity region @xmath199 . measurements of such a differential distribution @xmath208 averaged over azimuthal angle @xmath48 would allow to separate different helicity contributions and to identify the kinematical effects under discussion . distributions based on general correlation function @xmath147 can , in principle , be measured at the tevatron and lhc . they could also provide an independent check of the discussed diffractive qcd mechanism . this work was partly supported by the carl trygger foundation , the rfbr ( grants no . 09 - 02 - 01149 and 09 - 02 - 00732 ) and the polish grant of mnisw no . n202 2492235 . we are grateful to sergey baranov and valery khoze for valuable and stimulating discussions . we are especially indebted to lucian harland - lang for the exchange of fortran codes , making possible a direct comparison of our calculations and to find out the reasons of differences between them . m. g. albrow _ et al . _ [ fp420 r and d collaboration ] , jinst * 4 * , t10001 ( 2009 ) [ arxiv:0806.0302 [ hep - ex ] ] . t. aaltonen _ et al . _ [ cdf collaboration ] , phys . lett . * 102 * , 242001 ( 2009 ) [ arxiv:0902.1271 ] . m. g. albrow , t. d. coughlin and j. r. forshaw , arxiv:1006.1289 [ hep - ph ] . l. a. harland - lang , v. a. khoze , m. g. ryskin and w. j. stirling , eur . j. c * 65 * , 433 ( 2010 ) [ arxiv:0909.4748 [ hep - ph ] ] . l. a. harland - lang , v. a. khoze , m. g. ryskin and w. j. stirling , arxiv:1005.0695 [ hep - ph ] . khoze , a.d . martin and m.g . ryskin , phys . b * 401 * , 330 ( 1997 ) ; + v.a . khoze , a.d . martin and m.g . ryskin , eur . j. c * 23 * , 311 ( 2002 ) ; + a.b . kaidalov , v.a . khoze , a.d . martin and m.g . ryskin , eur . j. c * 31 * , 387 ( 2003 ) [ arxiv : hep - ph/0307064 ] ; + a.b . kaidalov , v.a . khoze , a.d . martin and m.g . ryskin , eur . j. c * 33 * , 261 ( 2004 ) ; + v.a . khoze , a.d . martin , m.g . ryskin and w.j . stirling , eur . j. c * 35 * , 211 ( 2004 ) . r. s. pasechnik , a. szczurek and o. v. teryaev , phys . b * 680 * , 62 ( 2009 ) [ arxiv:0901.4187 [ hep - ph ] ] . r. s. pasechnik , a. szczurek and o. v. teryaev , phys . d * 81 * , 034024 ( 2010 ) [ arxiv:0912.4251 [ hep - ph ] ] . r. s. pasechnik , a. szczurek and o. v. teryaev , phys . d * 78 * , 014007 ( 2008 ) [ arxiv:0709.0857 [ hep - ph ] ] . c. s. lam and w. k. tung , phys . d * 18 * , 2447 ( 1978 ) . v. a. khoze , a. d. martin and m. g. ryskin , eur . j. c * 19 * , 477 ( 2001 ) [ erratum - ibid . c * 20 * , 599 ( 2001 ) ] [ arxiv : hep - ph/0011393 ] . b. a. kniehl , d. v. vasin and v. a. saleev , phys . d * 73 * , 074022 ( 2006 ) [ arxiv : hep - ph/0602179 ] . b. a. kniehl , g. kramer and c. p. palisoc , phys . d * 68 * , 114002 ( 2003 ) [ arxiv : hep - ph/0307386 ] . m. a. kimber , a. d. martin and m. g. ryskin , phys . rev . d * 63 * , 114027 ( 2001 ) [ arxiv : hep - ph/0101348 ] ; + a. d. martin and m. g. ryskin , phys . d * 64 * , 094017 ( 2001 ) [ arxiv : hep - ph/0107149 ] . m. glck , e. reya and a. vogt , z. phys . c * 67 * , 433 ( 1995 ) ; + m. glck , e. reya and a. vogt , eur . j. c * 5 * , 461 ( 1998 ) . r. barbieri , m. caffo , r. gatto and e. remiddi , nucl . b * 192 * , 61 ( 1981 ) ; + w. kwong , p. b. mackenzie , r. rosenfeld and j. l. rosner , phys . d * 37 * , 3210 ( 1988 ) ; + m. l. mangano and a. petrelli , phys . b * 352 * , 445 ( 1995 ) [ arxiv : hep - ph/9503465 ] .

we discuss exclusive elastic double diffractive axial - vector @xmath0 and tensor @xmath1 mesons production for different meson polarisations in proton-(anti)proton collisions at the tevatron energy . the amplitude for the process is derived within the @xmath2-factorisation approach using unintegrated gluon distributions ( ugdfs ) . differential cross sections for different @xmath3 polarisations are calculated . angular distributions of @xmath4 meson from the radiative @xmath5 decays are derived . prospects for experimental selection of different spin states of @xmath3 mesons are discussed .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Small Public Housing Authorities Paperwork Reduction Act''. SEC. 2. PUBLIC HOUSING AGENCY PLANS FOR CERTAIN QUALIFIED PUBLIC HOUSING AGENCIES. (a) In General.--Section 5A(b) of the United States Housing Act of 1937 (42 U.S.C. 1437c-1(b)) is amended by adding at the end the following: ``(3) Exemption of certain phas from filing requirement.-- ``(A) In general.--Notwithstanding paragraph (1) or any other provision of this Act-- ``(i) the requirement under paragraph (1) shall not apply to any qualified public housing agency; and ``(ii) except as provided in subsection (e)(4)(B), any reference in this section or any other provision of law to a `public housing agency' shall not be considered to refer to any qualified public housing agency, to the extent such reference applies to the requirement to submit an annual public housing agency plan under this subsection. ``(B) Civil rights certification.--Notwithstanding that qualified public housing agencies are exempt under subparagraph (A) from the requirement under this section to prepare and submit an annual public housing plan, each qualified public housing agency shall, on an annual basis, make the certification described in paragraph (16) of subsection (d), except that for purposes of such qualified public housing agencies, such paragraph shall be applied by substituting `the public housing program of the agency' for `the public housing agency plan'. ``(C) Definition.--For purposes of this section, the term `qualified public housing agency' means a public housing agency that-- ``(i) administers-- ``(I) 500 or fewer public housing dwelling units; or ``(II) any number of vouchers under section 8(o) of the United States Housing Act of 1937 (42 U.S.C. 1437f(o)); and ``(ii) is not designated under section 6(j)(2) as a troubled public housing agency.''. (b) Resident Participation.--Section 5A of the United States Housing Act of 1937 (42 U.S.C. 1437c-1) is amended-- (1) in subsection (e), by inserting after paragraph (3) the following: ``(4) Qualified public housing agencies.-- ``(A) In general.--Except as provided in subparagraph (B), nothing in this section may be construed to exempt a qualified public housing agency from the requirement under paragraph (1) to establish 1 or more resident advisory boards. Notwithstanding that qualified public housing agencies are exempt under subsection (b)(3)(A) from the requirement under this section to prepare and submit an annual public housing plan, each qualified public housing agency shall consult with, and consider the recommendations of the resident advisory boards for the agency, at the annual public hearing required under subsection (f)(5), regarding any changes to the goals, objectives, and policies of that agency. ``(B) Applicability of waiver authority.--Paragraph (3) shall apply to qualified public housing agencies, except that for purposes of such qualified public housing agencies, subparagraph (B) of such paragraph shall be applied by substituting `the functions described in the second sentence of paragraph (4)(A)' for `the functions described in paragraph (2)'. ``(f) Public Hearings.--''; and (2) in subsection (f) (as so designated by the amendment made by paragraph (1)), by adding at the end the following: ``(5) Qualified public housing agencies.-- ``(A) Requirement.--Notwithstanding that qualified public housing agencies are exempt under subsection (b)(3)(A) from the requirement under this section to conduct a public hearing regarding the annual public housing plan of the agency, each qualified public housing agency shall annually conduct a public hearing-- ``(i) to discuss any changes to the goals, objectives, and policies of the agency; and ``(ii) to invite public comment regarding such changes. ``(B) Availability of information and notice.--Not later than 45 days before the date of any hearing described in subparagraph (A), a qualified public housing agency shall-- ``(i) make all information relevant to the hearing and any determinations of the agency regarding changes to the goals, objectives, and policies of the agency to be considered at the hearing available for inspection by the public at the principal office of the public housing agency during normal business hours; and ``(ii) publish a notice informing the public that-- ``(I) the information is available as required under clause (i); and ``(II) a public hearing under subparagraph (A) will be conducted.''

Small Public Housing Authorities Paperwork Reduction Act - Amends the United States Housing Act of 1937 to exempt a qualified public housing agency from the requirement to prepare an annual public agency plan if the agency: (1) administers 500 or fewer public housing dwelling units, or section 8 vouchers; and (2) is not designated as a troubled agency. Requires an agency to: (1) continue to make an annual civil rights certification and establish, and consult with, one or more resident advisory boards; and (2) conduct a public hearing to discuss changes to agency goals and policies and make the information available to the public at the agency's principal office.

Dow Jones is reporting that Apple will unveil its 2017 iPhone lineup at a special event scheduled for Tuesday, September 12. While Apple has yet to issue official invites for the event, the September 12th date does align with previous rumors that recently emerged over the past few days. Assuming that the September 12 date is in fact accurate, Apple in just about two weeks will introduce a brand new iPhone 7s and an iPhone 7s Plus. Of course, it goes without saying that the main attraction at Apple’s upcoming event will be the highly anticipated iPhone 8, a device which may very well usher in the largest iPhone refresh Apple has ever seen. At this point, it’s no secret what the iPhone 8 will bring to the table. According to a number of credible sources, the iPhone 8 will feature a edgeless OLED display and will incorporate advanced facial recognition technology. What’s interesting, though, is that the inclusion of facial recognition technology might see Apple remove Touch ID altogether. From what we can gather so far, Apple initially wanted to embed the Touch ID sensor underneath the OLED display itself, only to abandon this approach after encountering a yield issues during initial production runs. As for other iPhone 8 features we can expect to see, Apple’s next-gen device will likely incorporate a new wireless charging feature. Though Android smartphones have had wireless charging for quite some time, it’s nice to see Apple finally deciding to join the party. On a related note, a recent iPhone 8 rumor claims that wireless charging on Apple’s next-gen device will not be up to par with what some Android smartphone owners already enjoy. As we covered earlier, rumor has it that the iPhone 8 — along with Apple’s iPhone 7s lineup — will only support Qi’s slower wireless charging standard. As for some other iPhone 8 tidbits worth mentioning, it’s believed that the entry-level iPhone 8 will sport 64GB of storage, with more premium models offering users 256GB and 512GB of storage. Price wise, The New York Times recently published a report indicating that the entry-level iPhone 8 will start at $999, easily making it the most expensive iPhone model ever released. Lastly, we’ve also seen rumors claiming that pre-orders for the iPhone 8 will open up on Friday, September 15 ahead of a worldwide launch on Friday, September 22, two dates which fit in nicely with the aforementioned September 12th unveiling. New iPhones aside, Apple on September 12 will also unveil a revamped version of the Apple Watch along with a brand new 4K capable Apple TV. Update: The Wall Street Journal also has a report corroborating the September 12th date, adding that the event will be held in the 1,000-seat Steve Jobs Theater located at the company’s new spaceship campus. Developing… ||||| Apple Inc. has scheduled a product-announcement event on Sept. 12, according to people briefed on its plans, reinforcing expectations that the technology giant will release new iPhones and a smartwatch well ahead of the holiday shopping season. The company is expected to unveil three iPhones, according to other people familiar with its plans. Those include a showcase iPhone to mark the product’s 10th anniversary that is larger and pricier and features an edge-to-edge display and facial-recognition technology, as well as updates...

– Those waiting to upgrade their iPhones can expect to see the new options on Sept. 12. The Wall Street Journal reports that as the date for the next Apple product unveiling. Assuming that's the case—last-minute production glitches could throw off the schedule—customers should be able to order about 10 days afterward. Apple is expected to offer updated versions of the iPhone 7 and iPhone 7 Plus, but most eyes will be on the new iPhone 8, rumored to be an ambitious upgrade to mark the phone's 10th anniversary. "At this point, it's no secret what the iPhone 8 will bring to the table," notes a post at BGR, ticking off features such as an OLED display, advanced facial recognition, and wireless charging. In addition to the phones, Apple also is expected to unveil an upgraded Apple Watch and Apple TV. (Expect to pony up for the iPhone 8—it's expected to be the most expensive iPhone yet, with some reports suggesting a price of up to $1,400.)

Yemeni forces raided an al-Qaida hideout and set off a gunbattle Wednesday as the government vowed to eliminate the group that claimed it was behind the Christmas bombing attempt on a U.S. airliner. This image provided by IntelCenter Wednesday Dec. 30, 2009 and taken from a video released Jan. 23, 2009 by al-Malahim Media Foundation, the media arm of Al-Qaida in the Arabian Peninsula shows men whom... (Associated Press) This image provided by IntelCenter Wednesday Dec. 30, 2009 and taken from a video released Jan. 23, 2009 by al-Malahim Media Foundation, the media arm of Al-Qaida in the Arabian Peninsula shows a man... (Associated Press) This image provided by IntelCenter, Wednesday Dec. 30, 2009, and taken from a video released Jan. 23, 2009 by al-Malahim Media Foundation, the media arm of Al-Qaida in the Arabian Peninsula, shows a man... (Associated Press) This image provided by IntelCenter Wednesday Dec. 30, 2009 and taken from a video released Jan. 23, 2009 by al-Malahim Media Foundation, the media arm of Al-Qaida in the Arabian Peninsula, shows a man... (Associated Press) The fighting took place in an al-Qaida stronghold in western Yemen, haven for a group that attacked the U.S. Embassy here in 2008, killing 10 Yemeni guards and four civilians. A government statement said at least one suspected militant was arrested during the clashes. "The (Interior) Ministry will continue tracking down al-Qaida terrorists and will continue its strikes against the group until it is totally eliminated," Deputy Interior Minister Brig. Gen. Saleh al-Zawari told senior military officials at a meeting in Mareb, another province believed to shelter al-Qaida fighters. Al-Qaida in the Arabian Peninsula, an offshoot of Osama bin Laden's group, claimed it was behind the attempt to bomb a Detroit-bound airliner. Nigerian Umar Farouk Abdulmutallab, a 23-year-old passenger, was arrested Friday after he allegedly tried to bring down the Northwest Airlines flight, carrying 289 people. U.S. investigators said Abdulmutallab told them he received training and instructions from al-Qaida operatives in Yemen. Yemen's government has said Abdulmutallab spent two periods in the country, from 2004 to 2005 and from August to December of this year, just before the attempted attack. Abdulmutallab's Yemen connection has drawn attention to al-Qaida's growing presence in the impoverished and lawless country, which is located on the tip of the Arabian Peninsula across the Gulf of Aden from Somalia. Wednesday's clashes took place in Hudaydah province, an al-Qaida stronghold along the Red Sea coast. A security official said the target was a house owned by an al-Qaida sympathizer. The official said the owner was arrested, a suspected al-Qaida member was injured and several militants who fled were being pursued. He spoke on condition of anonymity because he was not authorized to speak to the press. Before Wednesday's clashes, Yemeni forces backed by U.S. intelligence carried out two major strikes against al-Qaida hideouts this month, reportedly killing more than 60 militants. The U.S. has increasingly provided intelligence, surveillance and training to Yemeni forces during the past year, and has provided some firepower, according to a senior U.S. defense official, who requested anonymity because he was not authorized to discuss the subject. Defense Department spokesman Bryan Whitman said Yemen received $67 million in training and support under the Pentagon's counterterrorism program last year, second only to some $112 million spent in Pakistan. He said the program was not a new one. "We are going to work with allies and partners to seek out terrorist activity, al-Qaida, wherever they operate, plan their operations, seek safe harbor," he said. "This is an effort that is years old now." In Holland, the Dutch government issued a preliminary report Wednesday calling the airliner plot professional, but describing the execution as "amateurish." Dutch Interior Minister Guusje Ter Horst told a news conference Abdulmutallab apparently assembled the explosive device, including 80 grams of PETN, in the aircraft toilet, then planned to detonate it with a syringe of chemicals. She said the explosives appeared to have been professionally prepared and then given to Abdulmutallab. President Barack Obama has demanded a preliminary report by Thursday on what went wrong in the Detroit case. Obama said the intelligence community should have been able to piece together information that would have raised "red flags" and possibly prevented Abdulmutallab from boarding the airliner. Abdulmutallab had been placed in one broad database, but he never made it onto more restrictive lists, despite his father's warnings to U.S. Embassy officials in Nigeria last month. Abdulmutallab attended a two-week seminar in Houston in August 2008 that was conducted by the AlMaghrib Institute, a Web-based Islamic education center, said Waleed Basyouni, vice president of the institute. The institute is cooperating with authorities, he said. Meanwhile, officials told The Associated Press on Wednesday that a man tried to board a commercial airliner in the Somali capital of Mogadishu last month carrying powdered chemicals, liquid and a syringe in a case bearing chilling similarities to the Detroit airliner plot. The Somali man _ whose name has not yet been released _ was arrested by African Union peacekeeping troops before the Nov. 13 Daallo Airlines flight took off. It had been scheduled to travel from Mogadishu to the northern Somali city of Hargeisa, then to Djibouti and Dubai. The aborted attack in Detroit was launched almost a year after al-Qaida's operations in Yemen and Saudi Arabia united to form Al-Qaida in the Arabian Peninsula, making Yemen its base. Shortly after Al-Qaida in the Arabian Peninsula was formed, Saudi Arabia announced a list of 85 most wanted militants outside its borders. It said 11 of them were former Guantanamo detainees who had gone through its rehabilitation program. Three were confirmed to have gone to Yemen. They included Abu al-Hareth Muhammad al-Oufi, who later surrendered in Yemen and was handed over to Saudis, Said al-Shihri, the group's No. 2 and Youssef al-Shihri, who was killed in a clash with Saudis in southern Saudi Arabia. The Yemeni roots of the attack threaten to complicate U.S. efforts to empty the U.S. prison at Guantanamo Bay, where nearly half the remaining detainees are from Yemen. Finding a home for them is key to Obama's pledge to close the prison, but emerging details of the plot are renewing concerns about Yemen's capacity to contain militants and growing al-Qaida safe havens. Rep. Mike Castle, R-Del., noted that of the 90 men remaining at Guantanamo, more than 60 have been identified as dangerous by the Pentagon. "Yet, in the past few weeks, the Obama Administration has overseen the repatriation of six Yemenis from Guantanamo back to their home country," he said. "As we learn more about Abdulmutallab's ties to Yemen and AQAP, it is increasingly clear that the transfer of detainees from Guantanamo is a flawed process demanding immediate review." Abdulmutallab spent about five months in Yemen leading up to the airliner attack and a year before that in 2004-2005, Yemeni officials said. Administrators at the San'a Institute for the Arabic Language said he was enrolled at the school during both periods to study Arabic. But staff and students said he spent at most one month at the school starting in late August. His time through December is unaccounted for. Acquaintances described the strict Islamic life he led, rejecting music, TV and mixing with women. All of them expressed surprise that the quiet man they knew would even consider to carry out such an act. "I saw him once tenderly kiss a baby," said Ahmed Mohammed, a teacher at the institute. "Today, he's turned into a monster who would have killed children if the operation had succeeded." ___ Abu-Nasr contributed from Riyadh, Saudi Arabia, and Adam Schreck from Dubai, United Arab Emirates. ||||| The US is planning retaliatory strikes in Yemen against al-Qaida over its attempt to blow up a transatlantic flight on Christmas Day. American officials say intelligence efforts are focused on identifying and tracking down those who plotted to put Umar Farouk Abdulmutallab on the plane with enough explosive in his underwear to bring down the Northwest Airlines flight from Amsterdam. But they warn that finding those responsible is unlikely to be swift and say that identifying other "high-value" al-Qaida targets for retaliatory attack would also be a priority. "First we have to find out who put Abdulmutallab on the plane with the bomb," said a US official working alongside intelligence organisations. "He's providing some leads and we're not dealing with an unknown quantity here. We've been watching and listening to what goes on in Yemen and we may have pieces of the puzzle already and just need to fit it together. "If and when we identify them then we plan how to deal with them. Who they are is one thing, where they are is another.If they're still in Yemen and we can get a lock on them then it won't be too difficult to know what to do. But they know who they are and won't be standing out. After that we can move with the president's authorisation. I don't think there's much doubt that authorisation will be forthcoming, but no one should think all of this is going to happen overnight." The official acknowledged that there was likely to be political and public pressure on Barack Obama to strike back at al-Qaida, particularly with Republican opponents breaking with the usual solidarity on national security issues to accuse him of weakness and making America vulnerable to attack. "The people we want are the ones who put Abdulmutallab on the plane. Until we can get them there are other high-value targets that will make the point that attacking America does not go unpunished," said the official. But given the regular attacks against al-Qaida in Yemen, these may have a greater impact on American public opinion than on the extremist group. The US has been conducting a covert assault with drone attacks on al-Qaida bases for about a year, while CIA agents inside the country help direct ground operations. American special forces have been training the Yemeni military and may have been involved in raids. General David Petraeus, the American regional commander, and John Brennan, the president's counterterrorism adviser, both visited Yemen this year. Joe Lieberman, chairman of the Senate's homeland security committee, who visited Yemen in August, described the country this week as a focus of the assault on al-Qaida. "Yemen now becomes one of the centres of that fight. We have a growing presence there – and we have to – of special operations, Green Berets, intelligence," he said. Yesterday, Yemeni forces targeted Nasser Ahmed al-Ahdal, a former prisoner released after renouncing violence but believed to have renewed links to al-Qaida. One man was injured and captured but Ahdal and two others escaped. Several al-Qaida members killed in raids by Yemeni forces in the past fortnight had been released or had escaped from prison. Others who have left jail to rejoin the fight include Nasser al-Wahayshi, the Yemeni leader of al-Qaida, who escaped along with 22 others from prison in Yemen in 2006. His deputy, Saeed al-Shihri, joined al-Qaida in Yemen last year after being released to Saudi Arabia from Guantánamo. While intelligence officials plan how to hit back abroad, they are under pressure at home after Obama blamed intelligence failings for Abdulmutallab being allowed to board a plane to the US. The president has ordered that a preliminary report be delivered to him today tomorrow explaining how the young Nigerian managed to smuggle the explosives on to the flight. The criticism is focused on the CIA and the national counterterrorism centre (NCC) established after 9/11. The CIA is under scrutiny because it picked up intelligence from Yemen that a Nigerian was involved in a forthcoming attack at about the same time that Abdulmutallab's father told US diplomats in the Nigerian capital, Abuja, that his son had become radicalised in Yemen and was a possible threat. That information was shared with CIA officials in Abuja who passed it on to the NCC, but it was apparently not matched with the intelligence from Yemen. On Tuesday Obama condemned the failure to share information and other intelligence failings as "totally unacceptable".

– The US is planning fresh drone strikes on al-Qaeda leaders in Yemen in the wake of the attempted Detroit Christmas bombing. Officials say they are working to identify the militant leaders responsible for the "underwear bomber," and will strike any militant leaders are soon as they are located, the Guardian reports. "The people we want are the ones who put Abdulmutallab on the plane," said one official. "Until we can get them, there are other high-value targets that will make the point that attacking America does not go unpunished." Yemen's government has vowed to wipe out the country's al-Qaeda offshoot group. Security forces raided an al-Qaeda hideout in western Yemen today and killed at least one militant, AP reports.

the apparent success of the one - body picture in explaining the quasi - elastic @xmath9 results was put in a different perspective when the longitudinal and transverse response functions were experimentally separated . in the one - body picture the virtual photon is assumed to couple with the individual nucleons in the target nucleus , the whole process exhibiting hardly any medium dependence . notwithstanding the extensive amount of work which has been devoted to a theoretical understanding of the separated @xmath9 data , a full explanation of both response functions in a consistent model has not yet been accomplished @xcite . recent coincidence @xmath1 measurements have established the significant role played by multinucleon mechanisms in the quasi - elastic @xcite , dip @xcite and @xmath10-excitation domain @xcite . the existence of multinucleon mechanisms was evidenced through a rise in the measured transverse @xmath1 response functions at high missing energies e@xmath11=@xmath12-t@xmath13 in the ( a-1 ) system @xcite . this excess strength has been shown to be unlikely due to rescattering effects , since a comparable rise of the longitudinal strength would then be expected , an effect which has not been observed experimentally . it is worth mentioning that recent measurements of the separate @xmath1 structure functions indicate that a similar situation seems to occur as for the inclusive @xmath9 cross sections : whereas the one - body picture gives a fair account of the complete quasi - elastic @xmath1 cross sections for reactions in which the residual nucleus is created in a hole state @xcite , discrepancies turn up when it comes to comparing the separated structure functions @xcite . in a recent paper we have illustrated the particular sensitivity of the longitudinal - transverse @xmath1 response function to multihadron currents related to pion - exchange and @xmath10 excitation @xcite . whereas the gathered evidence for electron scattering reactions proceeding in part via multinucleon components is relatively new , over the years overwhelming evidence for the occurrence of multinucleon components in real photon reactions has been produced . rather than attempting to be complete we mention some illustrative examples . 1 . using the tagged photon technique , a glasgow - edinburgh - mainz collaboration succeeded in measuring the @xmath3c photoproton cross section up to high excitation energies in the residual nucleus @xcite . just as for the @xmath3c@xmath1 results of refs . @xcite , the @xmath3c@xmath0 results of ref . @xcite reported excess strength at high missing energies , which was shown to be unlikely due to one - body knockout from the deep - lying hole states . in the meantime , the findings of ref . @xcite have been confirmed by several independent measurements @xcite . strong indications for the occurrence of multinucleon mechanisms have also been obtained for the exclusive regime . for a long time it has been realized that exclusive @xmath4 reactions at high photon energies are good candidates to reveal information about the role of multihadron currents in photoinduced reactions . only one experiment of this type has been reported up to now . exclusive @xmath5o@xmath6o@xmath14 measurements at mit - bates @xcite confirmed the similarity of @xmath15 and @xmath16 angular cross sections for photon energies ranging from just above the particle emission threshold , which are typically probing the giant resonance region , to the @xmath10-production region . this is rather surprising given the uncharged nature of the neutron and the fact that the squared ratio of the respective magnetic moments @xmath17 equals 2.13 . 3 . as a third illustrative example of obvious multinucleon components showing up in photonuclear reactions , we mention the high - resolution @xmath3c@xmath0 measurements of refs . @xcite and the high - resolution @xmath18ca@xmath0 measurements of ref . @xcite . in these experiments a strong feeding of states with a 2hole-1particle ( @xmath19 ) character has been observed . in a recent publication @xcite we have pointed out that the angular cross section for these transitions can be naturally explained by assuming direct proton emission following the absorption on the pion - exchange currents . a similar strong feeding of the @xmath19 states has been observed in the recent @xmath3c@xmath1 measurements at high missing momenta at nikhef - amsterdam @xcite . clearly , photonuclear reactions offer a good testing ground for any model that aims at describing the multihadron mechanisms in electromagnetically induced nucleon emission reactions . in addition , the similarities in some of the qualitative features of @xmath0 and @xmath1 are so obvious that a combined analysis is likely to result in a better insight in both types of reactions . this procedure might be particularly useful to arrive at a better quantitative understanding of the physics of the dip and the @xmath10 region , for which the @xmath1 spectra exhibit similar qualitative features as their @xmath0 counterparts @xcite . the multinucleon mechanisms in photonuclear reactions have been customary interpreted in terms of the phenomenological quasideuteron ( qd ) model @xcite in which the photon is assumed to be predominantly absorbed by @xmath20 pairs . this model gives a natural explanation of the measured excess strength in the @xmath0 and @xmath4 spectra at high missing energies . in the qd phenomenology the measured nucleon is not exclusive and is accompanied by an other nucleon which remains either undetected or gets reabsorbed . the quasideuteron phenomenology has been confirmed by double coincidence measurements of the type @xmath21 @xcite . in line with the predictions of the quasideuteron model , the @xmath21 data were shown to scale with the missing momentum @xmath22 , the p dependence being determined by the probability of finding in the target nucleus a @xmath20 pair with total momentum @xmath23 and zero separation . in this paper we present a non - relativistic microscopic model for the calculation of cross sections for one and two - nucleon knockout processes following photoabsorption on finite nuclei . our main focus will be on estimating the effect of two - nucleon emission processes to @xmath2 cross sections starting from principal grounds . this involves a microscopic model for the photoabsorption mechanism and a treatment of the final state interaction between the escaping nucleons and the residual nucleus . concerning the final state interaction , we rely on a shell - model approach to deal with the distortions that the struck nucleons undergo in their way out of the nucleus . by doing this we do not have to worry about spurious contributions to the cross sections due to non - orthogonality problems . within this shell - model framework for the treatment of the final state interaction we explore the relevance of pionic and @xmath10 degrees of freedom in inclusive and exclusive photonucleon processes . the plan of this paper is as follows . in sect . ii the formalism is sketched this includes a model for the calculation of @xmath24 cross sections and their contribution to the @xmath2 spectra . in sect . iii the numerical results of the @xmath2 and @xmath24 cross sections are presented . in particular , sect iiia deals with the contributions stemming from pionic and @xmath10 degrees of freedom to exclusive @xmath5o@xmath6o(g.s . ) processes at higher photon energies . in sect . iiib we summarize some results of calculations aiming at estimating the influence of two - nucleon knockout on the @xmath2 processes leaving the residual nucleus in a continuum state above the two - particle emission threshold . in sect . iiic the results of the @xmath5o@xmath24 calculations are compared with the data . we conclude with a summary and some outlooks in sect . iv . in line with the above discussion , photonucleon spectra reflect multinucleon components in both the discrete ( exclusive @xmath2 ) and the continuous part of their spectrum . as explained before there are strong indications that the continuum strength can be attributed to @xmath21 processes . consequently , a model for two - nucleon emission is essential to calculate @xmath2 spectra above the two - particle emission threshold . in this section we will first sketch an unfactorized model for the calculation of @xmath24 cross sections . this model does account for the distortions which the outgoing nucleon pair undergoes in its way out of the target nucleus and has been described in more detail in ref . @xcite . in the process of calculating the two - nucleon knockout cross sections , the nuclear structure of the target and the residual nucleus reflects itself in the two - hole spectral function . a schematic model for these spectral functions will be presented . subsequently , by integrating the derived @xmath24 cross sections over one of the nucleon coordinates , we will obtain an expression for the inclusive @xmath2 cross section . lastly , we will elaborate upon the two - body currents on which the initial photoabsorption is assumed to take place . in the laboratory frame , the coincidence angular cross section for a @xmath25 reaction ( figure [ pnsch ] ) is given by ( @xmath26=c=1 ) : @xmath27 where the feynman amplitude @xmath28 reads : @xmath29 here , @xmath30 is a shorthand notation for all quantum numbers specifying the eigenstates of the ( a-2 ) system and @xmath31 denotes the positive excitation energy measured with respect to the ground state of the residual ( a-2 ) nucleus . in the cross section of eq . ( [ cross ] ) we have summed over the spin projections of the escaping nucleons @xmath32 and averaged over the initial photon polarization @xmath33 . the sum over @xmath30 extends over the discrete and the continuum states of the residual ( a-2 ) nucleus . we assume that for the present purposes the target and residual nucleus can be well described with the aid of slater determinants of the independent - particle model . further , we discard all effects due the rescattering ( multi - step mechanisms ) . within these assumptions the main contribution to the @xmath24 cross sections is supposed to come from direct two - nucleon knockout following the photoabsorption on a two - body current . in such a reaction picture the residual nucleus will be created in a 2 hole @xmath34 state relative to the ground state @xmath35 of the target nucleus : @xmath36 by analogy with the partial - wave expansion techniques which are commonly employed in a shell - model approach to one - nucleon emission processes and which are extensively described in ref . @xcite , a double partial wave expansion has recently been suggested for the two - nucleon emission case @xcite . here , the proper asymptotic behaviour of the a - body wave function @xmath37 is determined by : @xmath38 \ ; , \label{abod}\end{aligned}\ ] ] and is reached through an expansion in terms of the continuum states @xmath39 of the mean - field potential : @xmath40 where @xmath41 , @xmath42 , @xmath43 is the nucleon mass , @xmath44 is the central phase shift and @xmath45 the coulomb phase shift of the continuum single - particle state @xmath46 . in eq . ( [ abod ] ) the operator @xmath47 makes sure that the total a - body wave function is properly antisymmetrized and @xmath48 is a measure for the radius of the target nucleus . asymptotic wave functions of the type ( [ abod ] ) refer to a situation in which the detected nucleon pair has the momentum - spin characteristics @xmath49 and in which the residual nucleus is created in the @xmath50 state @xmath51 . the sum over the partial waves @xmath52 runs over all continuum states of the single - particle mean - field potential at a particular excitation energy @xmath53 , the latter being set by the kinetic energy of the escaping nucleon under consideration . the wave function of eq . ( [ wave ] ) has been derived under the following normalization convention for the continuum single - particle states : @xmath54 in order to calculate the feynman amplitude of eq . ( [ feynman ] ) it is convenient to expand the nuclear current operator in terms of its multipole components . this is commonly done with the aid of the electric and magnetic transition operators @xcite : @xmath55 inserting the eqs . ( [ wave ] ) and ( [ multi ] ) in the feynman amplitude ( [ feynman ] ) and performing some basic manipulations we obtain the following expression : @xmath56 \ ; , \label{feynb}\end{aligned}\ ] ] where the function @xmath57 is equal to the joint probability of removing two nucleons remaining in the states @xmath58 and @xmath59 from the ground state of the target nucleus and of finding the resulting system ( with ( a-2 ) nucleons ) with an excitation energy in the interval ( e , e+de ) . the function @xmath57 is commonly referred to as the two - hole spectral function @xcite and is defined according to : @xmath60 in the actual calculations we have adopted a very schematic model for the two - hole spectral functions . under the assumption that the removal of a nucleon does not affect the subsequent removal of a second nucleon , the function @xmath61(e ) can be approximated by the product of two probabilities : the probability to remove a nucleon in the state h and create the ( a-1 ) system at an excitation energy @xmath62 and the probability to remove a nucleon in the state @xmath59 from the ( a-1 ) system and create the ( a-2 ) nucleus at an excitation energy e , or formally : @xmath63 where the hole spectral function @xmath64 is given by : @xmath65 in the optical model the hole spectral function is distributed according to a breit - wigner law , centered on the quasi - particle energy @xmath66-@xmath67 ( here , @xmath68 denotes the fermi energy ) and with a full width at half maximum given by 2w(e ) @xcite : @xmath69 parametrizations for the imaginary part of the optical potential w(e ) are obtained from compilations of experimental data and can e.g. be found in ref . @xcite . in this work we have adopted the parametrization by jeukenne and mahaux @xcite : @xmath70 in fig . [ 2hspec ] some two - hole spectral functions for @xmath5o obtained in the outlined model are shown . in line with the results of the quasi - elastic @xmath5o@xmath1 measurements regarding the spreading of the hole strength in @xmath71n @xcite , the quasi - particle energies @xmath72 were determined to be 6 mev for the @xmath73 and 30 mev for the @xmath74 hole state . for all results of this paper the two - hole spectral functions @xmath61 have been renormalized to unity : @xmath75 . for many years , the @xmath2 process for transitions in which the residual nucleus is created at high excitation energies , has been interpreted as the qd region with an undetected nucleon of opposite nature . here , we will work out a microscopic model which will put us in the position to calculate cross sections for these inclusive processes starting from principal grounds . in line with the basic assumption of the qd model , we can assume that an important part of the @xmath76 cross section at excitation energies above the two - particle emission threshold can be attributed to @xmath25 processes . another mechanism which could be expected to contribute to @xmath2 transitions at high excitation energies in the residual nucleus , is the exclusive process with excitation of the deep lying hole strength . accordingly , we write the @xmath2 cross section above the two - particle emission threshold as the sum of a one - nucleon and a two - nucleon knockout piece : @xmath77 } + \left . \frac{d^2 \sigma ^{lab } } { d \omega _ a dk_a } \right|_{[2 ] } \ ; , \label{split}\ ] ] where the two - nucleon piece is determined according to : @xmath78 } = \int d\omega_b \int_{0}^{\infty } dk_b \frac{d^4 \sigma ^{lab } } { d \omega _ a d \omega _ b dk_a dk_b}(\gamma , n_a n_b ) \;.\ ] ] in the calculation of the two - nucleon knockout contribution , the @xmath25 cross section is determined within the model outlined in the previous subsection . since we are working in coordinate space the integration over the solid angle of the undetected nucleon can be performed analytically . after some basic manipulations we find with the aid of the eq . ( [ feynb ] ) that : @xmath79 } = \sum_{hh ' } \int dk_b \int de_x s_{hh'}(e_x ) \delta ( e_{a-2}+e_a+e_b - e_a - e_{\gamma } ) \nonumber \\ & & \qquad \qquad \times \sum_{j_r } \sum_{lj } \sum_{l_1 ' j_1 ' } \sum_{l'j ' } \sum_{j_1 j_1 ' } \sum_{j , j ' \geq 1 } \sum_{j_2 } \frac{a-2}{a } \frac{k_a e_b}{4m_n^2 } \frac{\pi}{e_{\gamma } } ( -i)^{l'-l_1'+j - j ' } \widehat{j } \widehat{j ' } \widehat{j ' } \widehat{j_1 ' } \widehat{j_1 } \widehat{j_1 ' } \nonumber \\ & & \qquad \qquad \times p_{j_2}(cos\theta_a ) ( -1)^{j-1/2+j_r+j'-j_1 ' } e^{-i(\delta_{l'}+\sigma_{l'}-\delta_{l_1 ' } -\sigma_{l_1 ' } ) } \frac{1}{2 } \left [ 1 + ( -1)^{l'+l_1'+j_2 } \right ] \nonumber \\ & & \qquad \qquad \times < j ' \ ; -1 \ ; j \ ; 1 \mid j_2 \ ; 0 > < j'\;1/2\;j_1'\;-1/2 \mid j_2 0 > \left\ { \begin{array}{lll } j_1 ' \ ; j_1 ' \ ; j \nonumber \\ j_1 \ ; j ' \ ; j_2 \end{array } \right\ } \left\ { \begin{array}{lll } j_1 \ ; j \ ; j_r \nonumber \\ j ' \ ; j_1 ' \ ; j_2 \end{array } \right\ } \nonumber \\ & & \qquad \qquad \times \left\ { \left ( 1+(-1)^{j+j'+j_2 } \right ) \left [ { \cal m}_{pp';hh'}^{el}(j_1,j , j_r ) \left ( { \cal m}_{pp_1';hh'}^{el}(j_1',j',j_r)\right ) ^ * \nonumber \right . \right . \\ & & \qquad \qquad \left . \qquad \qquad \qquad \qquad \qquad \qquad + { \cal m}_{pp';hh'}^{mag}(j_1,j , j_r ) \left ( { \cal m}_{pp_1';hh'}^{mag}(j_1',j',j_r)\right ) ^ * \right ] \nonumber \\ & & \qquad \qquad + \left ( 1+(-1)^{j+j'+j_2 + 1 } \right ) \left [ { \cal m}_{pp';hh'}^{el}(j_1,j , j_r ) \left ( { \cal m}_{pp_1';hh'}^{mag}(j_1',j',j_r)\right ) ^ * \nonumber \right . \\ & & \qquad \qquad \left . \qquad \qquad \qquad \qquad \qquad + { \cal m}_{pp';hh'}^{mag}(j_1,j , j_r ) \left ( { \cal m}_{pp_1';hh'}^{el}(j_1',j',j_r)\right ) ^ * \right ] \right\ } \ ; , \label{gncross}\end{aligned}\ ] ] where @xmath80 , the @xmath81 are the familiar legendre polynomials of degree j , @xmath31 is the excitation energy in the ( a-2 ) nucleus and the two - body matrix elements @xmath82 have been defined according to : @xmath83 where @xmath84 . the one - nucleon knockout contribution to the cross sections ( [ split ] ) is calculated with a coupled - channel continuum rpa technique . for an elaborate description of this model the interested reader is referred to ref . @xcite . in brief , the rpa model involves a coupled - channel calculation for all one - nucleon emission channels ( @xmath0 and @xmath4 ) leaving the residual nucleus in a hole state relative to the ground state of the target nucleus . an obvious shortcoming of the standard rpa is that it does not account for the spreading of the single - particle hole strength in the residual nucleus . essentially , in the calculation of the cross sections for a particular reaction channel @xmath85 ( in the rpa formalism a channel @xmath85 is characterized by the quantum numbers of the hole state excited in the residual nucleus and the momentum of the outgoing nucleon @xmath86 ) , it is assumed that all hole strength is concentrated in the residual nucleus at an excitation energy @xmath87 . here , @xmath88 is the hartree - fock single - particle energy of the considered state . in order to account for the spreading of the deep - lying hole strength in the residual nucleus , we have folded the calculated @xmath2 angular cross sections with excitation of particular hole state @xmath58 ( denoted by @xmath89 ) , with the hole spectral function @xmath90 as defined in the preceeding subsection . the single - nucleon knockout contribution to the eq . ( [ split ] ) is then given by : @xmath91 } = \sum_{h } s_h ( e_x ) \left . \frac { d \sigma^{lab } } { d \omega _ a } \right|_{rpa(h)}\ ] ] where the sum extends over all occupied single - particle states in the residual nucleus and the excitation energy in the residual nucleus @xmath31 is determined by @xmath92 . the next step is to provide a model for the dominant mechanisms in the photoabsorption process . since our main focus will be on photon energies below 200 mev , we assume the photon to couple predominantly with the pion dominated nucleon - nucleon correlations in the target nucleus . these correlations include terms with and without an intermediate @xmath10 excitation , as indicated in fig . [ absor ] . for the terms with no @xmath10 lines we have considered the currents associated with the one - pion exchange potential ( opep ) @xmath93 where @xmath94 is the pion mass and @xmath95 the pseudovector pion - nucleon coupling constant , @xmath96 . the one - pion exchange current originating from the coupling of an external electromagnetic field with two nucleons interacting through the potential ( [ opep ] ) can be found in many textbooks and is a sum of the seagull ( diagram ( a ) ) and the pion - in - flight term ( diagram ( b ) ) @xcite . in the evaluation of the @xmath10 propagators in the diagrams ( c ) and ( d ) we have introduced an energy - dependent @xmath10 decay width @xmath97 , such that the propagators read @xmath98 with @xmath99=1232 mev . the @xmath100-decay width @xmath97 is considered to be exclusively the result of @xmath101 decay and has been determined according to the expression given in ref . @xcite : @xmath102 in coordinate space , the @xmath10-isobar current corresponding to the diagrams ( c ) and ( d ) is then : @xmath103 + 1 \longleftrightarrow 2 \right\}\frac { e^{-m_{\pi } \mid { \bf r}_2 - { \bf r}_1 \mid } } { 4 \pi \mid { \bf r}_2 - { \bf r}_1 \mid}\ ; , \label{eq : pidelta}\end{aligned}\ ] ] with @xmath104 . in the absence of a convincing microscopic theory , we are forced to treat the @xmath105 vertex in a phenomenological way . in this paper we shall resort to the widely used monopole form : @xmath106 with a cutoff parameter @xmath107=1.2 gev , a value obtained in investigations in which nucleon - nucleon scattering data are fitted in terms of the bonn one - boson exchange potential . all results presented below have been obtained with single - particle wave functions obtained from a hartree - fock ( hf ) calculation with an effective interaction of the skyrme type : ske2 @xcite . apart from the bound state wave functions , the hf calculation determines the distorting potential in which the partial waves and phase shifts for the escaping nucleons are calculated . all results presented below were checked not to depend dramatically on this particular choice for generating the mean - field characteristics of the target nucleus . this observation can be understood by considering that the two - body matrix elements are not very sensitive to the high - momentum components in the mean - field wave functions . figure [ gn0 ] contains the calculated exclusive @xmath5o@xmath110n cross sections at three different values of the photon energy , all lying above the pion threshold . the results are obtained in a direct knockout reaction formalism including the diagrams as listed in fig . [ diahole ] . given the uncharged nature of the neutron , the one - body component is restricted to the magnetization current . the two - body components involve the currents of sect . [ sec : absor ] . inspecting fig . [ gn0 ] it is clear that the calculations meet our expectations in the sense that the one - body mechanism represents but a fraction of the measured strength and that the angular cross sections are determined by neutron emission following the absorption on the two - body currents . at forward neutron angles a destructive interference effect between the one - body and the mec contribution is noticed . consequently , the cross section is dominated by the resonant @xmath10 term at forward neutron angles . remark further that the @xmath10 contribution gains in importance with increasing photon energies . whereas at e@xmath111=150 and 200 mev a fair description of the data can still be obtained with the one - body and the nonresonant mec contribution , the @xmath10 produces the major contribution at e@xmath111=250 mev . all curves drawn in fig . [ gn0 ] are obtained for a spectroscopic factor of 0.5 . this corresponds with the ground state in @xmath71o exhausting 50 % of the total @xmath112 hole strength . the results of our model calculations for the @xmath3c@xmath4 reaction above the @xmath8 emission threshold are summarized in fig . [ abogn ] . in all figures of this subsection , the missing energy is defined according to @xmath114 , with @xmath115 the kinetic energy of the detected nucleon in the lab system . in fig . [ abogn ] we have plotted the calculated contributions from both one- and two - nucleon knockout . the contribution from exclusive one - neutron knockout ( at the considered missing energies dominated by @xmath116-shell removal ) is calculated in the rpa formalism as outlined in ref . @xcite . in previous papers , it was illustrated that the rpa gives a fairly realistic account of the exclusive @xmath2 data below 100 mev photon energy @xcite . for the spreading of the single - hole strength in the residual nucleus we used the hole spectral function of eq . ( [ sh ] ) in combination with the parametrization of eq . ( [ shpar ] ) . in line with the @xmath3c@xmath117 results @xcite which find the s - shell knockout strength being distributed in the form of a wide peak between 10 and 30 mev excitation energy , the quasi - particle energy @xmath118 was fixed at 20 mev . the neutron separation energy @xmath119 being 18.7 mev , the peak of the @xmath120-shell removal strength corresponds with a missing energy of about 39 mev . accordingly , the s - shell knockout strength is concentrated just above the @xmath8 threshold ( s@xmath121=27.4 mev ) in the @xmath4 spectrum . it should be stressed that the missing - energy dependence of the @xmath116 strength is mainly determined by the hole spectral function @xmath90 . whereas , at e@xmath111=75 mev the @xmath116 @xmath2 strength is still substantial in comparison with the @xmath8 strength , it is hardly visible at e@xmath111=100 mev . generally , for e@xmath122 100 mev the rpa predicts the one - body knockout contributions from the deep - lying hole states to be a negligible fraction of the measured @xmath2 strength in the continuum . the calculated @xmath21 contributions are predicted to be substantially larger but are observed not to fully exhaust the measured strength . nevertheless the calculations seem to account for the overall missing energy behaviour of the data . this is particularly the case when the @xmath21 contribution is arbitrarily renormalized with a factor of two . the results of the @xmath3c(@xmath123 calculations are shown in figs . [ abogp1 ] , [ abogp2 ] and [ emdepen ] and compared with unpublished results of a glasgow - mainz collaboration @xcite . the calculations have been performed at two photonenergies , one at each side of the pion production threshold : @xmath124 and 150 mev . the missing energy dependencies at different values of the proton angle are drawn in figs . [ abogp1 ] and [ abogp2 ] , whereas in fig . [ emdepen ] the full angular cross sections are shown for different values of the proton energy . the proton kinetic energies were chosen such that they span the whole missing - energy spectrum . from figs . [ abogp1 ] and [ abogp2 ] it emerges that the @xmath21 calculations give a reasonable description of the photoproton spectra , particularly for the backward proton angles . nevertheless , in line with the @xmath3c@xmath4 findings presented earlier , the @xmath8 calculations tend to underestimate the measured photonucleon cross sections . in particular , this seems to be the case at forward proton angles and large missing energies . the excess strength at higher missing energies , which corresponds with slow detected protons , is likely to be due to other mechanisms , like three - nucleon emission ( s@xmath125=34.0 mev , s@xmath126=35.8 mev ) which are totally discarded in our calculations . a striking feature of the data is the considerable amount of experimental strength which is observed for the forward proton angles in the region of the @xmath8 threshold . right at the threshold this strength is unlikely to be due to two - nucleon knockout . furthermore , exclusive proton removal from the @xmath74 shell as calculated in the rpa , was found to represent but a very small fraction of the measured strength for the two considered photon energies . regarding the missing - energy behaviour , similar features as for the @xmath3c@xmath0 are found in @xmath18ca . the missing energy behaviour of the @xmath18ca@xmath0 cross sections for a fixed value of @xmath127 is presented in fig . [ carol ] . obviously , the predicted @xmath21 strength does not account for the experimental strength at forward proton angles , whereas a better description is reached at backward angles . remark further the considerable amount of measured photoproton strength in the region of the @xmath8 threshold at @xmath128 . in the process of calculating the contribution of exclusive one - nucleon knockout to the @xmath18ca@xmath0 spectrum , we considered removal from the @xmath116 and @xmath129 shell in addition to the 1d@xmath130 orbit . the effect of the final state interaction of the struck nucleons with the residual nucleus has been estimated by doing the @xmath3c@xmath0 calculations at @xmath127=150 mev , with a plane wave description for the outgoing nucleon pair and comparing the results with the full distorted - wave cross sections . in the formalism outlined in sect . ii , a plane wave description can be simply achieved by replacing the partial waves @xmath39 by properly normalized spherical bessel functions . in passing it is worth mentioning that the plane wave ( pw ) description does no longer guarantee the orthogonality between the inital and final states , such that spurious contributions could enter the cross sections . from fig . [ emdepen ] it becomes obvious that the effect of the distortions on the angular cross sections is not too dramatic , but for the region just above the threshold ( t@xmath131=100 mev ) . this particular behaviour can be easily explained by considering that from energy - conservation arguments a fast moving proton will be necessarily accompanied by a slow neutron , and therefore one of the outgoing nucleons will be subject to strong interactions with the residual system . in fig . [ emdepen ] the effect of different absorption mechanisms is also studied . from the curves drawn in fig . [ emdepen ] it is clear that even at photonenergies as low as 150 mev a considerable fraction of the @xmath8 strength at backward proton angles is related to the resonant terms in the nuclear current . in passing it is worth mentioning that strictly speaking also the @xmath7 channel could be expected to contribute to the @xmath0 spectra . within our model assumptions , the @xmath7 channel can only be fed through the @xmath10 diagrams of fig . [ absor ] . the other diagrams are closed for two - proton emission since they involve a charge - exchange mechanism . in line with the experimental observations @xcite , however , the calculated @xmath7 strength represents but a small fraction of the photoabsorption strength emerging in the @xmath8 channel @xcite . as will become clear in the fortcoming subsection , this finding even holds in the region of the @xmath10 resonance . from the results presented in previous subsection , it emerged that there are strong indications that at high excitation energies in the residual nucleus the measured @xmath2 cross sections should not be interpreted as the result of an exclusive process but reflect substantial two - nucleon knockout contributions . in this sense , the @xmath2 spectra above the two - nucleon emission threshold , could be expected to be largely set by the physics of @xmath25 processes . the latter type of reactions , however , offer some supplementary degrees of freedom which might be worth exploiting in order to reach a better understanding of two - nucleon mechanisms in finite nuclei . at present , a full determination of the fivefold differential cross sections @xmath132 is clearly at the edge of experimental feasibility . recently , however , several labs have produced double coincidence data at fixed kinematical conditions for one of the outgoing nucleons @xcite . to calculate the measured cross sections , we can employ eq . ( [ gncross ] ) . this expression was derived by integrating the full coincidence @xmath25 cross section over one of the outgoing nucleon coordinates and produced the predictions for the two - nucleon components in the @xmath2 spectra . in order to get some idea regarding the realistic character of the proposed @xmath24 model , it is worth checking its predictions against the data . here , we present some calculations under the kinematical conditions of the measurements of ref . @xcite . the results of the @xmath5o@xmath21 and @xmath5o@xmath133 calculations at @xmath127=281 mev and different values of the proton energy are summarized in figs . [ gpn1 ] and [ gpn2 ] . at this photonenergy the cross sections are dominated by the @xmath10 current . the @xmath21 and @xmath133 cross sections are found to exhibit similar characteristics . for the high kinetic energies , the angular cross sections are clearly forwardly peaked . with decreasing proton kinetic energy flatter distributions are obtained . the data compromise the proton energy dependence of the cross section at a fixed proton angle ( @xmath134 ) . the comparison with the data is shown in fig . [ gpn3 ] . at low proton energies , the calculated @xmath133 and @xmath21 clearly underestimate the data . this region is usually interpreted as being dominated by pion production . our calculations seem to suggest that even at low proton kinetic energies there is a considerable background of direct two - nucleon emission . apart from the pion knockout , also three and more nucleon knockout processes will preferentially feed the low proton energy domain of the spectrum . for lack of a microscopic theory for three and more nucleon ejection processes , explicit @xmath135 measurements will be needed to gain insight into the pionproduction channels . at higher kinetic energies , the calculations give a reasonable account of the @xmath7 and @xmath8 emission channel . the dashed curve for the @xmath133 channel is the cross section obtained with a plane - wave description for the escaping protons . it is clear that the distortion effects from the fsi reduce the peak of the cross section and are substantial in explaining the data . remark further how the background of @xmath7 strength at low proton energies can be partly ascribed to fsi effects . the @xmath7 cross sections are about one order of magnitude smaller than the @xmath8 cross sections , a feature which is nicely reproduced by the calculations . summarizing , we have presented a microscopic study of multinucleon mechanisms in photoinduced nucleon - knockout processes . our study encompasses both inclusive and exclusive photonucleon processes in addition to two - nucleon knockout reactions . in the exclusive regime , we have reported on @xmath5o@xmath16 results above the pion - production threshold . here , the predominant role of pionic degrees of freedom , including the @xmath10 excitation , in photonucleon processes is striking . our main focus has been on the contribution from two - nucleon knockout to the inclusive photonucleon spectra . the description relies on an unfactorized approach to two - nucleon knockout reactions . the fair description of the @xmath5o@xmath21 and @xmath5o@xmath133 data , makes us feel rather confident about the realistic character of the employed two - nucleon knockout formalism . regarding the @xmath2 processes , we have shown that at higher missing energies the @xmath8 emission strength largely exceeds the strength related to one - nucleon removal from the deep - lying hole states . we find our model , which accounts for photoabsorption on the resonant and non - resonant pion currents , to give a reasonable description of the general features of the @xmath2 spectra at high excitation energies in the residual nucleus . nevertheless , the calculations tend to selectively underestimate the available @xmath3c@xmath0 and @xmath3c@xmath4 spectra above the @xmath8 threshold . this is particularly the case at forward nucleon angles and higher missing energies . this feature , together with the observation that quite some strength resides in the region of the @xmath8 threshold , points towards other mechanisms , besides @xmath8 emission , contributing to the photonucleon processes with excitation of the residual nucleus in a continuum state . it would be worth investigating this in more detail , particularly in view of the fact that recent calculations predict the short - range effects to occur mainly at high excitation energies @xcite . finally , we stress that the techniques adopted in this paper can be easily applied to @xmath136 and @xmath137 processes . it is to be hoped that a combined analysis of the @xmath0 and @xmath1 spectra , together with new data from @xmath24 and @xmath137 measurements , will lead to a better insight into the nature of the multinucleon mechanisms in electromagnetically induced nucleon knockout . given their particular sensitivity to multinucleon mechanisms , reactions with real photons will play a substantial role in this program . one of us ( j.r . ) is indebted to d. van neck for useful discussions on two - hole spectral functions . the authors would like to thank p. harty and c. van den abeele for giving us the permission to show their data prior to publication . we are also indebted to k. heyde for valuable discussions and a careful reading of the manuscript . this work was supported by the national fund for scientific research and in part by the nato through the research grant nato - crg920171 . weinstein and w. bertozzi , _ in _ proc . of the fourth workshop on perspectives in nuclear physics at intermediate energies ( trieste , 1988 ) , s. boffi , c. ciofi degli atti and m. giannini , ( world scientific , singapore , 1989 ) . et al . _ , 59 * , 2259 ( 1987 ) . et al . _ , lett . * 64 * , 1646 ( 1990 ) . et al . _ , phys . rev . 2364 ( 1986 ) . h. baghaei _ et al . _ , phys . rev . * c39 * , 177 ( 1989 ) . t. takaki , phys . rev . * c39 * , 359 ( 1989 ) . a.e.l . dieperink and p.k.a . de witt huberts , annu . nucl . part . sci . * 40 * , 239 ( 1990 ) . spaltro , h.p . blok , e. jans , l. lapiks , m. van der schaar , g. van der steenhoven and p.k.a . de witt huberts , nikhef - k preprint . v. van der sluys , j. ryckebusch and m. waroquier , submitted for publication . mcgeorge , g.i . crawford , r.o . owens , m.r . sen , d. branford , a.c . shotter , b. schoch , r. beck , p. jennewein , f. klein , j. vogt and f. zettl , phys . b179 * , 212 ( 1986 ) . harty , m.n . thompson , g.j . okeefe , r.p . rassool , k. mori , y. fujii , t. suda , i. nomura , o. konno , t. terasawa and y. torizuka , phys . rev . * c37 * , 13 ( 1988 ) . l. van hoorebeke _ et al . _ , phys . rev . * c42 * , r1179 ( 1990 ) . beise , g. dodson , m. garon , s. hoibr@xmath138ten , c. maher , l.d . pham , r.p . redwine , w. sapp , k.e . wilson and s.a . wood , phys . lett . * 62 * , 2593 ( 1989 ) . springham , d. branford , t. davinson , a.c . shotter , j.c . mcgeorge , j.d . kellie , s.j . kellie , s.j . hall , r. beck , p. jennewein and b. schoch , nucl . a517 * , 93 ( 1990 ) . c. van den abeele _ et al . _ , b296 * , 302 ( 1992 ) . j. ryckebusch , k. heyde , l. machenil , d. ryckbosch , m. vanderhaeghen and m. waroquier , phys . * c46 * , r829 ( 1992 ) . c. mahaux and h. weidenmller , _ in _ a shell model approach to nuclear reactions ( north holland , amsterdam , 1969 ) . t. de forest and j.d . walecka , adv . * 15 * , 1 ( 1966 ) . j. ryckebusch , m. waroquier , k. heyde , j. moreau and d. ryckbosch , nucl . * a476 * , 237 ( 1988 ) . s. frullani and j. mougey , adv . * 14 * , 1 ( 1984 ) . towner , phys . 155 * , 263 ( 1987 ) . e. oset , h. toki and w. weise , phys . * 83 * , 281 ( 1982 ) . m. waroquier , j. ryckebusch , j. moreau , k. heyde , n. blasi , s.y . van der werf and g. wenes phys * 148 * , 249 ( 1987 ) . g. jacob and th.a.j . marius , rev . * 45 * , 6 ( 1973 ) . harty , i.j.d . macgregor , j.c . mcgeorge , s.n . dancer and r.o . owens , phys . c * 47 * , 2185 ( 1993 ) . p. harty , private communication c. van den abeele , private communication . doran , i.j.d . macgregor , j.r.m . annand , i. anthony , s.n . dancer , s.j . hall , j.d . kellie , j.c . mcgeorge , g.j . miller , r.o . owens , p.a . wallace , b. schoch , h. schmieden and s. klein , nucl . phys . * a559 * , 347 ( 1993 ) . j. arends , p. detemple , n. floss , s. huthmacher , g. kaul , b. mecking , g. nldike and r. stenz , nucl . a526 * , 479 ( 1991 ) . c. ciofi degli atti , s. simula , l.l . frankfurt and m.i . strikman , phys . c * 44 * , r7 ( 1991 ) . h. mtter and w.h . dickhoff , preprint .

the similarities in the experimental indications for multinucleon mechanisms in @xmath0 and @xmath1 processes are pointed out . for both types of reactions , the substantial role of two - nucleon emission processes for transitions to high excitation energies in the residual nucleus is stressed . a microscopic model for the calculation of the two - body knockout contributions to the inclusive @xmath2 reaction is presented . it is based on an unfactorized formalism for the calculation of electromagnetically induced two - nucleon emission cross sections . the model is shown to yield a reasonable description of the overall behaviour of the @xmath3c@xmath0 and @xmath3c@xmath4 data at high excitation energies in the residual nucleus . in the calculations , effects from non - resonant and resonant pion exchange currents are included . photoabsorption on these currents are predicted to produce the major contributions to the exclusive @xmath5o@xmath6o process at photonenergies above the pion threshold . double differential cross sections for photon induced @xmath7 and @xmath8 emission from @xmath5o are calculated and compared with the data .

SECTION 1. SHORT TITLE. This Act may be cited as the ``TARP Recipient Ownership Trust Act of 2009''. SEC. 2. AUTHORITY OF THE SECRETARY OF THE TREASURY TO DELEGATE TARP ASSET MANAGEMENT. Section 106(b) of the Emergency Economic Stabilization Act of 2008 (12 U.S.C. 5216(b)) is amended by inserting before the period at the end the following: ``, and the Secretary may delegate such management authority to a private entity, as the Secretary determines appropriate, with respect to any entity assisted under this Act''. SEC. 3. CREATION OF MANAGEMENT AUTHORITY FOR DESIGNATED TARP RECIPIENTS. (a) Federal Assistance Limited.--Notwithstanding any provision of the Emergency Economic Stabilization Act of 2008, or any other provision of law, no funds may be expended under the Troubled Asset Relief Program, or any other provision of that Act, on or after the date of enactment of this Act, until the Secretary of the Treasury transfers all voting, nonvoting, and common equity in any designated TARP recipient to a limited liability company established by the Secretary for such purpose, to be held and managed in trust on behalf of the United States taxpayers. (b) Appointment of Trustees.-- (1) In general.--The President shall appoint 3 independent trustees to manage the equity held in the trust, separate and apart from the United States Government. (2) Criteria.--Trustees appointed under this subsection-- (A) may not be elected or appointed Government officials; (B) shall serve at the pleasure of the President, and may be removed for just cause in violation of their fiduciary responsibilities only; and (C) shall each be paid at a rate equal to the rate payable for positions at level III of the Executive Schedule under section 5311 of title 5, United States Code. (c) Duties of Trust.--Pursuant to protecting the interests and investment of the United States taxpayer, the trust established under this section shall, with the purpose of maximizing the profitability of the designated TARP recipient-- (1) exercise the voting rights of the shares of the taxpayer on all core governance issues; (2) select the representation on the boards of directors of any designated TARP recipient; and (3) have a fiduciary duty to the American taxpayer for the maximization of the return on the investment of the taxpayer made under the Emergency Economic Stabilization Act of 2008, in the same manner and to the same extent that any director of an issuer of securities has with respect to its shareholders under the securities laws and all applications of State law. (d) Liquidation.-- (1) In general.--The trustees shall liquidate the trust established under this section, including the assets held by such trust, not later than December 24, 2011, unless-- (A) the trustees submit a report to the Congress that liquidation would not maximize the profitability of the company and the return on investment to the taxpayer; and (B) within 15 calendar days after the date on which the Congress receives such report, there is enacted into law a joint resolution described in paragraph (2). (2) Contents of joint resolution.--For purposes of this subsection, the term ``joint resolution'' means only a joint resolution-- (A) that is introduced not later than 3 calendar days after the date on which the report referred to in paragraph (1)(A) is received by the Congress; (B) which does not have a preamble; (C) the title of which is as follows: ``Joint resolution relating to the approval of the continuation of the TARP management trust''; and (D) the matter after the resolving clause of which is as follows: ``That Congress approves the continuation of the TARP management trust established under the TARP Recipient Ownership Trust Act of 2009.''. (3) Fast track consideration in house of representatives.-- (A) Reconvening.--Upon receipt of a report under paragraph (1)(A), the Speaker, if the House would otherwise be adjourned, shall notify the Members of the House that, pursuant to this subsection, the House shall convene not later than the second calendar day after receipt of such report. (B) Reporting and discharge.--Any committee of the House of Representatives to which a joint resolution is referred shall report it to the House not later than 5 calendar days after the date of receipt of the report described in paragraph (1)(A). If a committee fails to report the joint resolution within that period, the committee shall be discharged from further consideration of the joint resolution and the joint resolution shall be referred to the appropriate calendar. (C) Proceeding to consideration.--After each committee authorized to consider a joint resolution reports it to the House or has been discharged from its consideration, it shall be in order, not later than the sixth day after Congress receives the report described in paragraph (1)(A), to move to proceed to consider the joint resolution in the House. All points of order against the motion are waived. Such a motion shall not be in order after the House has disposed of a motion to proceed on the joint resolution. The previous question shall be considered as ordered on the motion to its adoption without intervening motion. The motion shall not be debatable. A motion to reconsider the vote by which the motion is disposed of shall not be in order. (D) Consideration.--The joint resolution shall be considered as read. All points of order against the joint resolution and against its consideration are waived. The previous question shall be considered as ordered on the joint resolution to its passage without intervening motion except two hours of debate equally divided and controlled by the proponent and an opponent. A motion to reconsider the vote on passage of the joint resolution shall not be in order. (4) Fast track consideration in senate.-- (A) Reconvening.--Upon receipt of a report under paragraph (1)(A), if the Senate has adjourned or recessed for more than 2 days, the majority leader of the Senate, after consultation with the minority leader of the Senate, shall notify the Members of the Senate that, pursuant to this subsection, the Senate shall convene not later than the second calendar day after receipt of such message. (B) Placement on calendar.--Upon introduction in the Senate, the joint resolution shall be placed immediately on the calendar. (C) Floor consideration.-- (i) In general.--Notwithstanding Rule XXII of the Standing Rules of the Senate, it is in order at any time during the period beginning on the 4th day after the date on which Congress receives a report of the plan of the Secretary described in paragraph (1)(A) and ending on the 6th day after the date on which Congress receives a report of the plan of the Secretary described in paragraph (1)(A) (even though a previous motion to the same effect has been disagreed to) to move to proceed to the consideration of the joint resolution, and all points of order against the joint resolution (and against consideration of the joint resolution) are waived. The motion to proceed is not debatable. The motion is not subject to a motion to postpone. A motion to reconsider the vote by which the motion is agreed to or disagreed to shall not be in order. If a motion to proceed to the consideration of the resolution is agreed to, the joint resolution shall remain the unfinished business until disposed of. (ii) Debate.--Debate on the joint resolution, and on all debatable motions and appeals in connection therewith, shall be limited to not more than 10 hours, which shall be divided equally between the majority and minority leaders or their designees. A motion further to limit debate is in order and not debatable. An amendment to, or a motion to postpone, or a motion to proceed to the consideration of other business, or a motion to recommit the joint resolution is not in order. (iii) Vote on passage.--The vote on passage shall occur immediately following the conclusion of the debate on a joint resolution, and a single quorum call at the conclusion of the debate if requested in accordance with the rules of the Senate. (iv) Rulings of the chair on procedure.-- Appeals from the decisions of the Chair relating to the application of the rules of the Senate, as the case may be, to the procedure relating to a joint resolution shall be decided without debate. (5) Rules relating to senate and house of representatives.-- (A) Coordination with action by other house.--If, before the passage by one House of a joint resolution of that House, that House receives from the other House a joint resolution, then the following procedures shall apply: (i) The joint resolution of the other House shall not be referred to a committee. (ii) With respect to a joint resolution of the House receiving the resolution-- (I) the procedure in that House shall be the same as if no joint resolution had been received from the other House; but (II) the vote on passage shall be on the joint resolution of the other House. (B) Treatment of joint resolution of other house.-- If one House fails to introduce or consider a joint resolution under this subsection, the joint resolution of the other House shall be entitled to expedited floor procedures under this subsection. (C) Treatment of companion measures.--If, following passage of the joint resolution in the Senate, the Senate then receives the companion measure from the House of Representatives, the companion measure shall not be debatable. (D) Consideration after passage.-- (i) In general.--If Congress passes a joint resolution, the period beginning on the date the President is presented with the joint resolution and ending on the date the President takes action with respect to the joint resolution shall be disregarded in computing the 15-calendar day period described in paragraph (1)(A). (ii) Vetoes.--If the President vetoes the joint resolution-- (I) the period beginning on the date the President vetoes the joint resolution and ending on the date the Congress receives the veto message with respect to the joint resolution shall be disregarded in computing the 15- calendar day period described in paragraph (1)(A); and (II) debate on a veto message in the Senate under this subsection shall be 1 hour equally divided between the majority and minority leaders or their designees. (E) Rules of house of representatives and senate.-- This paragraph, and paragraphs (2), (3), and (4) are enacted by Congress-- (i) as an exercise of the rulemaking power of the Senate and House of Representatives, respectively, and as such it is deemed a part of the rules of each House, respectively, but applicable only with respect to the procedure to be followed in that House in the case of a joint resolution, and it supersedes other rules only to the extent that it is inconsistent with such rules; and (ii) with full recognition of the constitutional right of either House to change the rules (so far as relating to the procedure of that House) at any time, in the same manner, and to the same extent as in the case of any other rule of that House. SEC. 4. DEFINITIONS. As used in this Act-- (1) the term ``designated TARP recipient'' means any entity that has received, or will receive, financial assistance under the Troubled Asset Relief Program or any other provision of the Emergency Economic Stabilization Act of 2008 (Public Law 110- 343), such that the Federal Government holds or controls, or will hold or control at a future date, not less than a 15 percent ownership stake in the company as a result of such assistance; (2) the term ``Secretary'' means the Secretary of the Treasury or the designee of the Secretary; and (3) the terms ``director'', ``issuer'', ``securities'', and ``securities laws'' have the same meanings as in section 3 of the Securities Exchange Act of 1934 (15 U.S.C. 78c).

TARP Recipient Ownership Trust Act of 2009 - Amends the Emergency Economic Stabilization Act of 2008 (EESA) to authorize the Secretary of the Treasury to delegate to a private entity management authority over troubled assets with respect to any entity assisted under the Troubled Asset Relief Program (TARP). Prohibits any expenditure of TARP funds until the Secretary transfers all voting, nonvoting, and common equity in any designated TARP recipient to a limited liability company, to be held and managed in trust on behalf of U.S. taxpayers. Requires the trustees to liquidate the trust and its assets by December 24, 2011, unless: (1) the trustees report to Congress that liquidation would not maximize profitability of the company and the return on investment to the taxpayer; and (2) Congress enacts into law a joint resolution approving continuation of the TARP management plan established under this Act.

the presence of a very compact infrared source in the nucleus of the seyfert galaxy ngc4151 was first suggested by the observations of @xcite , who reported photometric variations of the galaxy nucleus both in the optical and in the near - infrared ( hereafter near - ir ) . a close inspection of the light curves shown by @xcite suggests a delay between the near - ir and optical variations , recently confirmed by @xcite , who could better quantify its value as 48@xmath5 days . these authors concluded that the @xmath6band emission is dominated by thermal radiation from hot dust located at @xmath70.04pc from the nucleus . a similar intepretation was previously proposed by @xcite , via models fitted to a large aperture ( @xmath88 ) nuclear optical and near - ir spectrum , concluding that in the near - ir the emission is dominated by thermal reradiation by hot dust with temperature @xmath9k . @xcite have reported neutral hydrogen absorption in vla radio observations with subparsec linear resolution , close to the systemic velocity of the galaxy , interpreted as due to a clumpy gas layer suggested to be associated to a circumnuclear obscuring torus . according to @xcite , this absorption is observed along the line of sight towards the first component of the radio counterjet , at @xmath100.1pc from the nucleus , thus consistent with the estimated inner radius of @xmath70.04pc derived by @xcite . the interpretation put forth by @xcite that the obscuring torus is not in front of the active galactic nucleus ( agn ) is necessary in order to reconcile the radio observations with the uv / optical observations which show a blue nuclear continuum and broad emission lines , indicating that both the nuclear source and the broad - line region are visible . the presence of a dusty torus around the nucleus of ngc4151 was disputed by @xcite on the basis of interferometric observations at 2.2@xmath11 m using the two 10 m keck telescopes . these authors found a marginally resolved nuclear source @xmath100.1pc in diameter consistent with the observations of both @xcite and @xcite , but favor an origin for this emission in thermal gas from the accretion disk , arguing that previous nuclear spectra of ngc4151 did not show an `` infrared bump '' , in apparent contradiction with the previous study by @xcite . such a bump is expected if a dusty torus is present , due to reprocessing of uv / optical radiation from the central engine ( e.g. * ? ? ? ? * ; * ? ? ? the alternative interpretation proposed by @xcite seems nevertheless to be in line with recent results presented by @xcite , who studied the distribution of [ oiii]@xmath125007 and [ oii]@xmath123727 emission in the narrow line region ( nlr ) of ngc4151 . these authors pointed out that there does not seem to be a region of complete shadow around the apex of the bicone , as significant ionized gas emission is found there , although with a lower ionization parameter , consistent with a weaker ionizing flux . @xcite propose that the attenuation of the nuclear radiation could be due to low - ionization absorbers swept out by a wind originating in the accretion disk , suggesting that there is no need for a `` classical , doughnut - shaped '' torus in order to explain the observed light distributions , in agreement with recent modelling for the obscuring region around an agn @xcite . in this work , we present new observations of the nucleus of ngc4151 with the gemini near infrared integral field spectrograph ( nifs ) at an angular resolution of 0@xmath112 corresponding to a spatial resolution of a few pc at the galaxy which is much improved relative to previous spectroscopic studies . our observations clearly reveal the presence of an unresolved nuclear source in the near - ir . we have already used the nifs data to map the excitation ( * ? ? ? * hereafter paper i ) and kinematics @xcite of the nlr . in the present paper , we use the nuclear spectrum , combined with surrounding extranuclear spectra and a _ space telescope imaging spectrograph _ ( stis ) optical spectrum , in order to isolate the emission of the infrared nuclear source , which is consistent with that predicted for the torus postulated in the unified model of agns @xcite . we adopt a distance to ngc4151 of 13.3mpc , corresponding to a scale at the galaxy of 65pcarcsec@xmath13 @xcite . this paper is organized as follows . in section2 , we present a summary of the observations , in section3 we present the results and in section4 we present and discuss our conclusions . two - dimensional spectroscopic data were obtained on the gemini north telescope with the instrument nifs @xcite operating with the adaptive optics module altair on the nights of december 12 and 13 , 2006 . the observations covered the spectral bands z , j , h and k , at spectral resolutions of 4990 , 6040 , 5290 and 5290 , respectively , resulting in a wavelength coverage from 0.94@xmath11 m to 2.40@xmath11 m . more details of the observations and reduction procedures can be found in @xcite . in the present paper we concentrate on the analysis of the nuclear continuum . the spatial profiles of the nuclear region of the galaxy in the k and j bands are shown in fig.[psf ] , in comparison with stellar profiles . the nuclear source which has a full width at half maximuum ( fwhm ) of 012@xmath14002 in the k - band and 016@xmath14002 in the j - band corresponding to [email protected] and [email protected] at the galaxy , respectively is unresolved by our observations , in spite of the fact that their spatial profiles are marginally broader than those of the stars in fig.[psf ] . as discussed in @xcite , this is due to the much shorter exposures of the stellar observations . in order to include as much as possible of the nuclear source , we have chosen an extraction aperture of 03 radius which includes the nuclear flux down to 10% of the peak value in the k - band , as illustrated by the dashed lines in fig.[psf ] . m.the spectra are shown in arbitrary flux units and are shifted by a constant for clarity . ] the nuclear spectrum is shown in the fig.[spec ] , together with extranuclear spectra obtained through similar 0@xmath13 apertures at distances of 09ne , 09sw , 18ne , and 18sw from the nucleus , normalized to the flux of the nuclear spectrum at @xmath15 m . fluxes of more than 50 emission lines have been measured and listed in table 1 of paper i for the nuclear and two extranuclear spectra . from fig.[spec ] , as well as from spectra shown in paper i , we observe that the extranuclear spectra are blue at all locations around the nucleus . as this blue continuum is observed up to at least 2arcsec from the nucleus , it can not be due to the agn and can thus be attributed to a young stellar population surrounding the nucleus . absorption features from stellar co bands are indeed observed in the k band , marked by vertical dotted lines in fig.[spec ] . only right at the nucleus the continuum is clearly very red . similar red nuclear continua have been observed for other agns and attributed to emission from hot dust , possibly from a dusty torus around the supermassive black hole , with temperature close to the dust sublimation temperature @xcite . in order to better constrain the nuclear spectral energy distribution ( sed ) , we have used an optical stis spectrum of the nucleus extracted within a similar aperture to that of our near - ir spectrum , obtained from the atlas of agn spectra compiled by @xcite . this spectrum was extracted within an aperture of 02@xmath1601 and covers the spectral range 0.31@xmath11 m . we have used the continuum region from 9780 to 9820 to normalize the optical spectrum to the same flux as our near - ir spectrum ( which extends down to the z - band ) as there is a flux difference of @xmath730% between the stis spectrum and our nuclear spectrum . the small difference between the apertures is not important because the stellar contribution , when compared to the nuclear one , is small , as discussed below . we show the optical plus near - ir spectrum in fig.[fit ] . the optical continuum is very blue and can be well reproduced by a power - law up to @xmath71@xmath11 m , where there is a change in slope and a red component begins to appear in the near - ir . although the near - ir emission is dominated by this component , the contribution of the power - law in the near - ir is not negligible in the z , j and h bands , as discussed below . we have modelled the optical@xmath17near - ir nuclear continuum of ngc4151 by the sum of two components : a power law , which seems to dominate in the optical , plus a blackbody function , which dominates in the near - ir , as illustrated in fig.[fit ] . the fit was performed using the _ nfit1d _ task from the stsdas iraf package , which allows the selection of limited spectral intervals for the fit . we have excluded the spectral interval between 0.6 and 0.9@xmath11 m from the fit as we have estimated that the contribution of the paschen continuum in this interval ( @xmath18ergs@xmath19s@xmath13a@xmath13 at 8200 ) , is not negligible when compared to the total flux observed in the continuum . moreover , the quality of the optical spectrum in its red end is quite poor , and should not be used to constrain the sed . excluding the above spectral region , the best fit was obtained for a power law @xmath20 and a blackbody function of temperature @xmath0k , which peaks at @xmath21 m . the fit of the two functions combined is shown in fig.[fit ] as a continuous line , while the black body component is shown as a dashed line and the power law as dotted line . we have next evaluated the effect of the underlying stellar population in the fit above . a stellar population spectrum was extracted from our near - ir datacubes within a ring around the nucleus with inner radius of 06 and outer radius of 09 . we have then normalized the flux of this extranuclear spectrum to 15% of the peak nuclear flux in the k band , which is the maximum contribution of the stellar population estimated from a spatial profile through the nucleus . under the assumption that the underlying stellar population in the nuclear spectrum is the same as the one from the ring ( which is supported by other spectra from the nuclear vicinity ) , we have then subtracted the extranuclear spectrum from the nuclear one . as we do not have an extranuclear optical spectrum , we repeated the fit for the near - ir only , comparing the temperature of the uncorrected to the corrected spectrum , concluding that , within the uncertainties ( @xmath750k ) , the blackbody temperature is the same . the reddening may also affect the results of the fit . an estimate of the reddening in the near - ir can be obtained from the emission lines of the narrow - line region . we have used the [ feii]@xmath22m/@xmath23 m line ratio to calculate the reddening ( as described in paper i , but using the present nuclear spectrum , for an aperture of radius 0@xmath13 ) , resulting in e(b - v)@xmath24 . it is not clear that this reddening applies to the optical continuum . if it does , it would result in a very steep power law for the corrected nuclear continuum : using the extinction curve of @xcite , we obtain @xmath25 . nevertheless , the presence of broad lines in the spectra and the already very blue continuum suggests that the reddening of the optical spectrum is much smaller ; we may be seing the nuclear source through a low extinction window to the nucleus . this may apply also to the near - ir nuclear source , but , even if the extinction applies , the correction in the near - ir is small . a reddening correction of only the near - ir spectrum for e(b - v)=0.6 , keeping the power - law index the same , results in a revised blackbody temperature of @xmath3k . following @xcite and @xcite we can estimate the mass of the hot dust producing the unresolved near infrared emission . firstly , we obtain the infrared spectral luminosity of each dust grain , in ergs@xmath13hz@xmath13 , assuming that the dust is composed of graphite grains , by @xmath26 where @xmath27 is the grain radius , @xmath28 is the absorption efficiency and @xmath29 is its spectral distribution assumed to be a planck function with temperature @xmath30 . the number of dust grains ( @xmath31 ) can be estimated from the ratio between the total luminosity of the hot dust ( @xmath32 ) and the total luminosity of one dust grain ( @xmath33 ) as @xmath34 . @xmath32 was obtained by integrating the flux under the planck function fitted to the nuclear spectrum and adopting a distance to ngc4151 of @xmath35mpc , while @xmath33 was obtained by the intregration of equation[lgr ] for a temperature of @xmath36k . finally , the mass of the emitting hot dust is obtained by : @xmath37 assuming a graphite density of @xmath38g@xmath39 @xcite , we obtain @xmath40 . if we assume that the near - ir nuclear source is subject to reddeninng , we should then use the temperature @xmath41k , which will lead to a smaller dust mass of @xmath4 . [ cols="<,<,<",options="header " , ] [ hd_mass ] in table[hd_mass ] , we present a comparison of the mass of hot dust obtained here for ngc4151 with the ones derived for other agns in previous works . this comparison reveals that the hot dust mass for ngc4151 is similar to the ones obtained for ngc1068 by @xcite , for ngc4593 by @xcite and for ngc1566 by @xcite and is smaller than the masses derived for other galaxies such as ngc7582 , mrk1239 , mrk766 , ngc7469 , ngc3783 and fairall9 by @xcite , @xcite , @xcite,@xcite , @xcite and @xcite , respectively . as discussed in the introduction , @xcite observed ngc4151 at 2.2@xmath11 m and have marginally resolved a nuclear source @xmath100.1pc in diameter , concluding that the emission was due to thermal gas from the central accretion disk instead of a dusty torus , as they claimed that previous observations did not show the bump . our near - ir nuclear spectrum ( fig.[spec ] ) clearly shows this bump and favours emission by hot dust as the dominant mechanism for its origin , in agreement with previous studies using larger aperture data @xcite . a more recent near - ir spectrum obtained by @xcite , although with lower spatial resolution than ours , also suggests the presence of the bump . the modern view of the torus @xcite is not of a static doughnut shape structure but of a clumpy wind of dusty and optically thick clouds originating in the black - hole accretion disk , a view which has recently been favored also in the case of ngc4151 by @xcite , and which is in partial agreement with the proposition by @xcite . being clumpy , the dusty wind allows the view of the nuclear source through low - extinction holes . the presence of such holes is also supported by the observation of ionized gas close to the apex of the bicone , beyond its presumed walls . this more updated view is also consistent with our data and results from previous papers discussed above , if we consider that the near - ir nuclear source can be identified with the hottest part of the dusty wind , which is the one closest to the nucleus and which emits most of the near - ir radiation . according to our data , the temperature of this dust is @xmath42k and its mass is @xmath2 , obtained by fitting the optical and near - ir spectrum . the observation of the nuclear continuum and of the broad emission lines suggest that we are looking to the nuclear source through a low extinction window , in spite of the fact that the estimated reddening from the emission lines of the narrow - line region is e(b - v)=0.6 . if we assume that this reddening is also affecting the nuclear source , we obtain @xmath43k for the dust temperature and mass @xmath4 . the temperatures obtained are in good agreement with those previously obtained by @xcite . comparison between our near - ir flux values with theirs shows that the nucleus was 34 times brighter than in the epoch of our observations , suggesting that the temperature of the hot dust does not depend on the agn luminosity . regarding the location of the hot dust , our spatial resolution allows us to put only an upper limit to the radius of the infrared source of 4pc ( half the fwhm of the nuclear source ) . similar scales have been probed by @xcite , who found a heavily obscured starburst closer than 9pc from the nucleus in ngc1097 and argued that it could be located in the outskirts of the torus . @xcite using mid - ir interferomentric observations constrained the dust emission in ngc1068 to originate in a region of only 1pc diameter . in the case of ngc4151 , optical and near - ir monitoring observations of @xcite provide a better constraint on the location of the inner radius of the torus at @xmath70.04pc from the nucleus . the nlr of ngc4151 has an approximate biconical morphology with projected opening angle of @xmath875@xmath44 and with its axis oriented along a pa @xmath860/240@xmath44 ( ne sw ) . the sw side of the bicone is tilted toward us , making an angle of 45@xmath44 with the line - of - sight , according to @xcite , who gives also an opening angle of the cone of 66@xmath44 , which puts our line - of - sight just outside the cone wall . if the torus is oriented perpendicularly to the cone , we are looking down into the torus hole . this allows us to constrain the half - height of the torus to less than 0.04pc for a `` doughnut shape '' opaque torus . this torus should extend to at least 0.1pc from the nucleus , in order to contain the neutral hydrogen clouds observed by @xcite . as proposed by these authors , the ne part of the radio jet would be behind the torus , while the sw part would be in front of it . we thank the referee dr . george rieke for valuable suggestions which helped to improve the present paper . this work is based on observations obtained at the gemini observatory , which is operated by the association of universities for research in astronomy , inc . , under a cooperative agreement with the nsf on behalf of the gemini partnership : the national science foundation ( united states ) , the science and technology facilities council ( united kingdom ) , the national research council ( canada ) , conicyt ( chile ) , the australian research council ( australia ) , ministrio da cincia e tecnologia ( brazil ) and ministerio de ciencia , tecnologa e innovacin productiva ( argentina ) . this work has been partially supported by the brazilian intitution cnpq and australian research council .

we have used a near - infrared nuclear spectrum ( covering the z , j , h and k bands ) of the nucleus of ngc4151 obtained with the gemini near - infrared integral field spectrograph ( nifs ) and adaptive optics , to isolate and constrain the properties of a near - ir unresolved nuclear source whose spectral signature is clearly present in our data . the near - ir spectrum was combined with an optical spectrum obtained with the space telescope imaging spectrograph which was used to constrain the contribution of a power - law component . after subtraction of the power - law component , the near - ir continuum is well fitted by a blackbody function , with @xmath0k , which dominates the nuclear spectrum within an aperture of radius 0@xmath13 in the near - ir . we attribute the blackbody component to emission by a dusty structure , with hot dust mass @xmath2 , not resolved by our observations , which provide only an upper limit for its distance from the nucleus of 4pc . if the reddening derived for the narrow - line region also applies to the near - ir source , we obtain a temperature @xmath3k and a mass @xmath4 for the hot dust . this structure may be the inner wall of the dusty torus postulated by the unified model or the inner part of a dusty wind originating in the accretion disk .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Department of Homeland Security Headquarters Consolidation Accountability Act of 2015''. SEC. 2. INFORMATION ON DEPARTMENT OF HOMELAND SECURITY HEADQUARTERS CONSOLIDATION PROJECT. (a) In General.--Not later than 120 days after the date of enactment of this Act, the Secretary, in coordination with the Administrator, shall submit to the appropriate committees of Congress information on the implementation of the enhanced plan for the Department headquarters consolidation project within the National Capital Region, approved by the Office of Management and Budget and included in the budget of the President for fiscal year 2016 (as submitted to Congress under section 1105(a) of title 31, United States Code), that includes the following: (1) A proposed occupancy plan for the consolidation project that includes specific information about which Department-wide operations, component operations, and support offices will be located at the site, the aggregate number of full time equivalent employees projected to occupy the site, the seat-to-staff ratio at the site, and schedule estimates for migrating operations to the site. (2) A comprehensive assessment of the difference between the current real property and facilities needed by the Department in the National Capital Region in order to carry out the mission of the Department and the future needs of the Department. (3) A current plan for construction of the headquarters consolidation at the St. Elizabeths campus that includes-- (A) the estimated costs and schedule for the current plan, which shall conform to relevant Federal guidance for cost and schedule estimates, consistent with the recommendation of the Government Accountability Office in the September 2014 report entitled ``Federal Real Property: DHS and GSA Need to Strengthen the Management of DHS Headquarters Consolidation'' (GAO-14-648); and (B) any estimated cost savings associated with reducing the scope of the consolidation project and increasing the use of existing capacity developed under the project. (4) A current plan for the leased portfolio of the Department in the National Capital Region that includes-- (A) an end-state vision that identifies which Department- wide operations, component operations, and support offices do not migrate to the St. Elizabeths campus and continue to operate at a property in the leased portfolio; (B) for each year until the consolidation project is completed, the number of full-time equivalent employees who are expected to operate at each property, component, or office; (C) the anticipated total rentable square feet leased per year during the period beginning on the date of enactment of this Act and ending on the date on which the consolidation project is completed; and (D) timing and anticipated lease terms for leased space under the plan referred to in paragraph (3). (5) An analysis that identifies the costs and benefits of leasing and construction alternatives for the remainder of the consolidation project that includes-- (A) a comparison of the long-term cost that would result from leasing as compared to consolidating functions on Government-owned space; and (B) the identification of any cost impacts in terms of premiums for short-term lease extensions or holdovers due to the uncertainty of funding for, or delays in, completing construction required for the consolidation. (b) Comptroller General Review.-- (1) Review required.--The Comptroller General of the United States shall review the cost and schedule estimates submitted under subsection (a) to evaluate the quality and reliability of the estimates. (2) Assessment.--Not later than 90 days after the submittal of the cost and schedule estimates under subsection (a), the Comptroller General shall report to the appropriate committees of Congress on the results of the review required under paragraph (1). (c) Definitions.--In this Act: (1) The term ``Administrator'' means the Administrator of General Services. (2) The term ``appropriate committees of Congress'' means the Committee on Homeland Security and the Committee on Transportation and Infrastructure of the House of Representatives and the Committee on Homeland Security and Governmental Affairs of the Senate. (3) The term ``Department'' means the Department of Homeland Security. (4) The term ``National Capital Region'' has the meaning given the term under section 2674(f)(2) of title 10, United States Code. (5) The term ``Secretary'' means the Secretary of Homeland Security. Speaker of the House of Representatives. Vice President of the United States and President of the Senate.

(This measure has not been amended since it was reported to the Senate on March 14, 2016. Department of Homeland Security Headquarters Consolidation Accountability Act of 2015 (Sec. 2) This bill directs the Department of Homeland Security (DHS), in coordination with the General Services Administration (GSA), to submit information on the implementation of the enhanced plan for the DHS headquarters consolidation project within the National Capital Region, approved by the Office of Management and Budget and included in the budget of the President for FY2016, that includes: a proposed occupancy plan that includes specific information about which DHS-wide operations, component operations, and support offices will be located at the site, the aggregate number of full time equivalent employees projected to occupy the site, the seat-to-staff ratio at the site, and schedule estimates for migrating operations to the site; a comprehensive assessment of the difference between the current real property and facilities needed by DHS in the Region to carry out its mission and its future needs; an analysis of the difference between the current and needed capital assets and facilities of DHS; a current plan for construction of the headquarters consolidation at the St. Elizabeths campus that includes the estimated costs and schedule for the current plan and any estimated cost savings associated with reducing the scope of the project and increasing the use of existing capacity developed under the project; a current plan for the leased portfolio of DHS in the Region that includes an end-state vision that identifies which DHS-wide operations, component operations, and support offices do not migrate to the St. Elizabeths campus and continue to operate at a property in the leased portfolio, the number of full-time equivalent employees who are expected to operate at each property, component, or office for each year until the consolidation project is completed, the anticipated total rentable square feet leased per year between the date of this Act's enactment and the date on which the consolidation project is completed, and the timing and anticipated lease terms for leased space; and an analysis that identifies the costs and benefits of leasing and construction alternatives for the remainder of the consolidation project, including a comparison of the long-term cost that would result from leasing to the cost of consolidating functions on government-owned space and the identification of any cost impacts in terms of premiums for short-term lease extensions or holdovers due to the uncertainty of funding for, or delays in, completing construction required for the consolidation. The bill directs the Government Accountability Office to evaluate the quality and reliability of the cost and schedule estimates submitted and report on the results.

analysis of the large scale structure of the universe allows us to probe the universe throughout its expansion history and provides the most robust route to measuring the late - time evolution of the universe . over the last decade , large sky - area galaxy surveys such as the sloan digital sky survey ( sdss ; @xcite ) , 2df galaxy redshift survey ( 2dfgrs ; @xcite ) , 6df galaxy redshift survey ( 6dfgrs , @xcite ) and wigglez survey @xcite have allowed us to probe this large scale structure and have provided us with a wealth of cosmological information . in particular measurements of the baryon acoustic oscillation scale ( bao ; @xcite ) provide us with a standard ruler , allowing us to measure the accelerated expansion of the universe , whilst redshift space distortions ( rsd ; @xcite ) provide a direct probe of the growth of structure and the fidelity of general relativity . these probes have become more and more accurate in recent years , with @xcite providing a 1% measurement of the distance scale to @xmath3 , the most precise from a galaxy survey to date . however , these measurements , and their errors , require intimate knowledge of the statistical and systematic distributions from which they are drawn . this need will only be exacerbated as future surveys , such as the large sky synoptic telescope ( lsst ; @xcite ) and euclid @xcite , strive for even greater precision . under the assumption of gaussian - distributed errors , the statistical errors inherent in large scale clustering measurements are encapsulated by the covariance matrix . although this can be calculated analytically in the linear regime @xcite , the non - linear galaxy covariance matrix is a complex function of non - linear shot - noise , galaxy evolution and the unknown relationship between the galaxies and the underlying dark matter . in any real application this is further compounded by the effect of rsd . as such , a much more common solution is to use a set of detailed galaxy simulations , otherwise known as mock catalogues ( mocks ) , to either fully estimate the covariance matrix or as the basis for an empirically motivated analytic fit @xcite . ideally these simulations would take the form of fully realised n - body simulations , with accurate small scale clustering , covering the whole volume of the galaxy survey . however , for current surveys , recent studies @xcite show that we require 1000 mocks to obtain an accurate numerical estimate of the covariance matrix with sub - dominant errors compared to the statistical errors themselves . higher precision measurements in the future may require many more . instead there have been many studies looking at fast methods of producing simulations that enable us to produce mocks hundreds of times faster than an tree - pm n - body simulation , at the cost of reduced small scale clustering accuracy . past measurements of the large scale structure have used lognormal models to generate realizations of the galaxy overdensity field and estimate the covariance matrix @xcite . however this approach does not accurately capture the non - gaussian behaviour of gravitational collapse . recently , @xcite and @xcite have used an implementation of the more accurate pthalos method @xcite to generate mock catalogues for the data releases 9 and 10 of the baryon oscillation spectroscopic survey ( boss ; @xcite + @xcite ) . in addition to this there is a wealth of alternative methods such as pinocchio @xcite , quick particle mesh simulations ( qpm ; @xcite ) , augmented lagrangian perturbation theory ( alpt ; @xcite ) , effective zeldovich approximation mocks ( ezmocks ; @xcite ) and the comoving lagrangian acceleration method ( cola ; @xcite , @xcite ) which can all be used to produce mock catalogues comparable in accuracy to , if not better than , 2lpt and with similar speed . in this paper we present a stand - alone parallel implementation of the latter of these , with emphasis on maximising speed , memory conservation and ease of use . this code , which we dub l - picola , combines a range of features that will be of increasing interest for the next generation of galaxy surveys , including the ability to produce lightcone simulations , replicate the simulation at runtime and include primordial non - gaussianity based on a generic input bispectrum , as per @xcite . on top of this the cola method itself is able to reproduce the dark matter field with much greater accuracy on small , non - linear scales than the pthalos method , at only a moderate increase in computational cost . as such , we expect our implementation to be suitable for both current and future surveys , being able to both capture non - linear evolution with a precision necessary to reach the required covariance matrix accuracy for these surveys and scalable up to very large numbers of particles and volumes . in fact , we have already used this code to measure the bao and rsd signals from a subset of luminous red galaxies drawn from the sloan digital sky survey data release 7 main galaxy sample @xcite . additionally , manera et al . , ( in prep . ) describe an application of l - picola to the dark energy survey ( des ; @xcite ) , making use of the fast lightcone algorithm that we will discuss in this paper . it should be noted that in previous studies using this code , we named the code picola . however , very recently , @xcite present an extension to the cola method that allows one to decouple the short and long range gravitational forces _ spatially _ in addition to temporally . this allows the user to calculate the non - linear displacements for only a small subsection of the full simulation volume and still recover reasonable accuracy across the whole simulation . in this work they also present a code pycola , a shared - memory python implementation of the extended cola method . to avoid confusion in the names of these codes , and highlight the additional features we have implemented since the first application of our code , we have renamed it l - picola . this paper is structured as follows : in section 2 we provide a brief description of the theory behind the 2lpt and cola methods . section 3 introduces l - picola , with section 4 detailing the steps we have taken to parallelise the cola method for a distributed - memory machine . sections 5 and 6 detail the additional features we have included in l - picola , beyond the standard snapshot simulations . in particular , in section 6 we validate the need for lightcone simulations and perform a rigorous test of our implementation . in sections 7 we compare the accuracy of l - picola to 2lpt and a full n - body simulation . in this section we also test the effect on the clustering accuracy of several of the free parameters that can be used to speed up the convergence of the cola method . in section 8 we compare the speed of l - picola with the 2lpt and n - body simulations , and look at the scaling of different segments of l - picola itself . finally in section 9 we conclude and discuss further improvements that can be made to the code . included in the appendix are details of the memory footprint of l - picola . unless otherwise stated , we assume a fiducial cosmology given by @xmath4 , @xmath5 , @xmath6 , @xmath7 , and @xmath8 . also , unless otherwise stated , all simulations presented use a number of mesh cells equal to the number of particles , the cola method with modified cola timestepping , @xmath9 and 10 linearly spaced timesteps . these l - picola - specific parameters are stated here for completeness but are explained within this paper . in the following section we describe the cola method for evolving a system of dark matter particles under gravity , as first introduced by @xcite . we begin with a summary of the theoretical underpinnings of the algorithm , including a brief overview of second order lagrangian perturbation theory ( 2lpt ) , before moving onto the algorithmic implementation . as described in @xcite ( see also @xcite and @xcite ) , cold dark matter particles evolving over cosmological time in an expanding universe follow the equation of motion ( eom ) @xmath10 where @xmath11 is the gravitational potential , @xmath12 is the conformal hubble parameter and @xmath13 is the scale factor . @xmath14 is the displacement vector of the particle and relates the particle s eulerian position @xmath15 to its initial , lagrangian position , @xmath16 , via @xmath17 by taking the divergence of the equation of motion and using the poisson equation , we find @xmath18 here @xmath19 is the matter density at @xmath20 , whilst @xmath21 is the local overdensity . lagrangian perturbation theory seeks to solve this equation by perturbatively expanding the displacement vector , @xmath22 if we then apply the continuity equation , @xmath23 , which states that a mass element @xmath24 centred at @xmath16 at time zero becomes a mass element @xmath25 , centred at @xmath26 , at time @xmath27 , we find that , to first order @xmath28 this is the well known zeldovich appoximation ( za ; @xcite ) . here @xmath29 is the linear growth factor , @xmath30 is the linear overdensity field and we have rewritten the divergence as a function of @xmath16 by using the fact that they are related via the jacobian of the transformation from @xmath26 to @xmath16 , i.e. , @xmath31 . solving to second order introduces corrections to the first order displacement of the form @xmath32 where , for brevity , we have defined @xmath33 . @xcite provide a good approximation for @xmath34 , the second order growth factor , for a flat universe with non - zero cosmological constant @xmath35 for further computational ease , we can define two langragian potentials , @xmath36 , such that eq . ( [ lagrangian ] ) becomes @xmath37 and the lagrangian potentials are obtained by solving the corresponding pair of poisson equations derived from eq . ( [ za ] ) and eq . ( [ 2lpt ] ) respectively , @xmath38 @xmath39 the cola method @xcite provides a much more accurate solution to eq.([eom ] ) than 2lpt , at only a moderate ( @xmath40 ) reduction in speed . it does this by utilising the first and second - order lagrangian displacements , which provide an exact solution at large , quasi - linear scales , and solving for the resultant , non - linear component . by switching to a frame of reference comoving with the particles in lagrangian space , we can split the dark matter equation of state as follows , @xmath41 + t[{d}_{1}]\boldsymbol{\psi}_{1 } + t[{d}_{2}]\boldsymbol{\psi}_{2 } + \nabla \phi = 0 , \label{eq : cola}\ ] ] where , @xmath42 = \frac{d^{2}x}{d\tau^{2 } } + \mathcal{h}\frac{dx}{d\tau}.\ ] ] @xmath43 is the remaining displacement when we subtract the quasi - linear 2lpt displacements from the full , non - linear displacement each particle should actually feel . the reason this method is so useful is because we only need to calculate the lagrangian displacements once , at redshift @xmath0 , and scale them by the appropriate derivatives of the growth factor . in fact , as we will see in later sections , it is common practice in many n - body simulations to use 2lpt to generate the initial positions of the particles at a suitably high redshift , where the results are exact . in l - picola , ( [ eq : cola ] ) is solved as a whole ( as opposed to evaluating @xmath44 individually ) by discretising the operator ` t ' using the kick - drift - kick algorithm @xcite , such that at each iteration the velocity and position of each particle is updated based on the gravitational potential @xmath11 _ and _ the stored 2lpt displacements . the well - known particle - mesh algorithm , with forward ( fft ) and inverse ( ifft ) fourier transforms , is used to evaluate the gradient of @xmath11 using the particle density . i.e , @xmath45\right]\ ] ] the following sections detail the kick - drift - kick method and the particle - mesh algorithm used in l - picola and how these are easily modified to solve eq . ( [ eq : cola ] ) as opposed to the standard dark matter equation of motion . . [ eq : cola ] is discretised using the kick - drift - kick / leapfrog + method @xcite . the modified , cola dark matter eom is solved iteratively , and at each iteration the particle velocities and positions are updated based on the gravitational potential felt by each particle . particle velocities are calculated from the displacements and updated to the nearest half - integer timestep . the particle positions are then updated to the nearest integer timestep using the previous velocity . in this way the particle velocities and positions are never ( except at the beginning and end ) calculated for the same point in time but rather ` leapfrog ' over each other with the next iteration of the velocity dependent on the position from the previous iteration and so on . in the standard , non - cola method , the dark matter eom can be solved via . @xmath47 encapsulates the time interval and appropriate numerical factors required to convert the displacement to a velocity and the velocity to a position . @xcite evaluate these as @xmath48 the equations for updating the particle positions and velocities can be modified to solve the cola eom in the following way @xmath49\delta a_{1 } , \label{eq : vcola } \\ & \boldsymbol{r}_{i+1 } = \boldsymbol{r}_{i } + \boldsymbol{v}_{i+1/2}\delta a_{2 } + \delta d_{1}\boldsymbol{\psi}_{1 } + \delta d_{2}\boldsymbol{\psi}_{2 } \label{eq : rcola}\end{aligned}\ ] ] here @xmath50 denotes the change in the first and second order growth factors over the timestep . the modified kick - drift - kick equations are derived under the condition that , for eq . ( [ eq : cola ] ) to be valid , the displacements felt by each particle must be computed in the 2lpt reference frame . in other words , the acceleration each particle feels due to the the gravitational potential must be modified , and the 2lpt contribution to the acceleration removed . the new gravitational potential is then , by design , @xmath51 $ ] . the exact procedure used to calculate @xmath52 is not important and as such any code that updates the particle velocities and positions iteratively based on the gravitational potential , i.e. , a tree - pm code , can be modified in the above way to include the cola mechanism . an important point of note in enforcing the change of reference frame is that particle velocities at the beginning of the simulation , after creation of the 2lpt initial conditions but before iterating , must be identically 0 . at this point the velocity a particle has is exactly equal to the velocity of the reference frame we are moving too . however when the particles are output at the end of the simulation we want the particle velocities in _ eulerian _ coordinates . this means that the initial particle velocities must be removed and stored at the beginning of the timestepping and then added back on at the end of the simulation . when implementing the modified cola timestepping , the time intervals , @xmath47 , for each timestep do not get explicitly changed and as such can remain the same as the those presented in @xcite . however , @xcite present a second , cola specific , formulation which gives faster convergence , hence allowing us to recover our evolved dark matter field to greater accuracy in fewer time steps . in their method , @xmath53 where they find the best results using a value @xmath54 . as the choice of @xmath47 is somewhat arbitrary l - picola retains both methods as options . this choice ( and @xmath55 ) should be treated formally as an extra degree of freedom in the code . in fact we find that the value of @xmath55 used in the code can affect the final shape of the power spectrum recovered from cola due to the way different growing modes are emphasised by different values . this is pointed out in @xcite and means that for a given set of simulation parameters one would ideally experiment to find the type of timestepping that recovers the required clustering in the fewest timesteps possible . this is demonstrated further in section [ sec : accuracy ] . for the timestepping method presented here and adopted in l - picola , the only remaining piece of the puzzle is the calculation of @xmath56 = -t[{d}_{1}]\boldsymbol{\psi}_{1 } - t[{d}_{2}]\boldsymbol{\psi}_{2 } - \nabla \phi$ ] . as the za and 2lpt displacements have been stored we only need a method of evaluating @xmath57 . in l - picola this is done using the particle - mesh algorithm , though could be done using a method such as the tree - pm algorithm . the evaluation of @xmath58 $ ] and @xmath59 $ ] can be performed numerically for a given cosmological model very easily , although a suitable approximation for @xmath60 must be adopted . for flat cosmologies one could use eq ( [ eq:2lptgrowth ] ) , however in l - picola we adopt the expression of @xcite which is also accurate for non - flat cosmologies . here we provide a brief overview of the particle - mesh ( pm ) algorithm ( see @xcite for a good review of this method ) . our implementation is based on the publicly available pmcode @xcite , and as such we refer the reader to the associated documentation for full details on the set of equations we solve to get the displacement . in the pm method we place a mesh over our dark matter particles and solve for the gravitational forces at each mesh point . we then interpolate to find the force at the position of each particle and use this to calculate the gravitational potential each particle feels . this gravitational potential is then related to the additional velocity , and resultant displacement , for each particle as per the this is performed iteratively over a series of small timesteps . for @xmath61 mesh points and @xmath62 particles , this means that at each iteration we only need to perform @xmath61 force calculations , which is much faster than a direct summation of the contribution to the gravitational force from each individual particle ( at least for all practical applications , where @xmath63 ) . at each iteration we perform the following steps to calculate the displacement : 1 . use the cloud - in - cell linear interpolation method to assign the particles to the mesh , thereby calculating the mass density , @xmath64 , at each mesh point . 2 . use a fast fourier transform ( fft ) to fourier transform the density and solve the comoving poisson equation in fourier space . @xmath65 3 . use the gravitational potential and an inverse - fft to generate the force in each direction in real - space . here we also deconvolve the cloud - in - cell window function . @xmath66 4 . calculate the acceleration each particle receives in each direction , again using the cloud - in - cell interpolation method to interpolate from the mesh points . as suggested by the name , l - picola is a parallel implementation of the cola method described in the previous section . we have designed the code to be ` stand alone ' , in the sense that we can generate a dark matter realisation based solely on a small number of user defined parameters . this includes preparing the initial linear dark matter power spectrum , generating an initial particle distribution with k - space distribution that matches this power spectrum , and evolving the dark matter field over a series on user specified timesteps until some final redshift is reached . at any point in the simulation the particle position and velocities can be output , allowing us to capture the dark matter field across a variety of epochs in a single simulation . in order to make l - picola as useful as possible we have also implemented several options that modify how l - picola is actually built at compile time . on top of allowing variations in output format and memory / speed balancing we also allow the user to create ( and then evolve ) initial particle distributions containing primordial non - gaussianity . another significant improvement , and one that will be extremely important for future large scale structure surveys , is the option to generate a lightcone simulation , which contains variable clustering as a function of distance from the observer , as opposed to a snapshot simulation at one fixed redshift . although lightcone simulations can be reconstructed from a series of snapshots @xcite , l - picola can produce lightcone simulations ` on - the - fly ' in a short enough time to be suitable for generating significant numbers of mock galaxy catalogues . these additions will be detailed and tested in later sections . [ picolachart ] shows a simple step - by - step overview of how l - picola works . the different coloured boxes highlight areas where the structure of the code actually changes depending on how it is compiled . the blue box shows where the different types of non - gaussianity can be included . the red boxes show where significant algorithmic changes occur in the code if lightcone simulations are requested . these will we detailed in the following sections , along with an explanation of how we parallelise the cola method . l - picola is publicly available under the gnu general public license at https://cullanhowlett.github.io/l-picola . in this section we will detail the steps we have taken to parallelise the cola method . all parallelisation in the code uses the message passing interface ( mpi ) library . see @xcite for a comprehensive guide to the usage and syntax of mpi . in the following subsections we provide an overview to the parallelisation and detail the three main parallel algorithms in the code : parallel cloud - in - cell interpolation , parallel fft s and moving particles between processors . parallelisation of l - picola has been performed with the goal that each processor can run a small section of the simulation whilst needing minimal knowledge of the state of the simulation as a whole . we have separated both the mesh and particles across processors in one direction . in this way each processor gets a planar portion of the mesh , and the particles associated with that portion . we have tried to balance the load on each processor as much as possible whilst adhering to the fact that each processor must have an integer number of mesh cells in the direction over which we have split the full mesh . this process is enabled by use of the publicly available fftw - mpi libraries , which also serve to perform the fast fourier transforms when the mesh is split over different processors . in a simulation utilising @xmath67 processors and consisting of a cubic mesh of size @xmath68 , each processor gets @xmath69 slices of the mesh where each slice consists of @xmath70 cells . the extra @xmath71 cells in each slice are required as buffer memory for the fftw routines . depending on the ratio of @xmath72 to @xmath67 this may give too many slices in total , so then we work backwards , removing slices until the total number of slices is equal to @xmath72 . the number of particles each processor has is related to the number of mesh cells on that processor as each processor only requires knowledge of any particles that interact with its portion of the mesh . hence , as the particles are originally spaced equally across the mesh cells , each processor initially holds @xmath73 particles , multiplied by the number of slices it has . as each processor only contains particles which belong to the mesh cells it has , and our interpolation assigns particles to the mesh by rounding down to the nearest mesh cell , the density assignment step proceeds as per the standard cloud - in - cell interpolation method , except near the ` left - hand ' edge of the processor . here the density depends on particles on the preceding processor . figure [ cloudincell ] shows a 2-d graphical representation of this problem . which are then transferred and added to the left most slice on processor @xmath74.,width=317 ] in order to compensate for this we assign an extra mesh slice to the ` right - hand ' edge of each processor . this slice represents the leading slice on the neighbouring processor and by assigning the particles to these where appropriate and then transferring and adding the ` slices ' to the appropriate processors , each portion of the mesh now contains an estimate of the density which matches the estimate as if all the mesh were contained on a single processor . it should also be noted that a reverse of this process must also be done after calculating the forces at each mesh point , as the displacement of a particle near the edge of a processor is reliant on the force at the edge of the neighbouring processor . to take the fourier transform of our mesh once it is split over many processors we use the parallel fftw - mpi routines available alongside the aforementioned fftw libraries . this is intimately linked to the way in which the particles and mesh are actually split over processors and routines are provided in this distribution that enable us to perform this split in the first place . the fftw routines use a series of collective mpi communications to transpose the mesh and perform a multi - dimensional real - to - complex discrete fourier transformation of the density , assigning the correct part of the transformed mesh to each processor . in terms of implementing this , all that is required is for us to partition the particles and mesh in a way that is compatible with the fftw routines , create a fftw plan for the arrays we wish to transform and perform the fourier transformation once we have calculated the required quantity at each mesh point . the fftw libraries perform all mpi communications and operations internally . one final modification to the particle - mesh algorithm is to compensate for the fact that , over the course of the simulation , particles may move outside the physical area contained on each processor . their position may now correspond to a portion of the mesh that the processor in question does not have . as such , after each timestep we check to see which particles have moved outside the processor boundaries and move them to the correct processor . this is made particularly important as the cola method converges in very few timesteps , meaning the particles can move large distances in the space of a single timestep . in the case where we have a high particle density or small physical volume assigned to each processor , a single particle can jump across several neighbouring processors in a single timestep . so , when moving the particles , we iterate over the maximum number processors any single particle has jumped across . however the number of particles that need to be moved is unknown _ a priori _ and so to be conservative and make sure that we do not overload the buffer memory set aside for the transfer , not all the particles that are moving are transferred simultaneously ( i.e. via a collective mpi - alltoall command ) . rather , all the particles that have moved from processor n to n@xmath751 are moved first then all the particles that have moved from processor n to n@xmath752 are transferred . although this requires iterating over the particles on processor n multiple times , in the majority of cases there are no particles moving to any processors beyond n@xmath751 and so only one iteration is required . as the simulation progresses the particles will not remain homogeneously spread over the processes , so we assign additional buffer memory to each processor to hold any extra particles it acquires . this is utilised during the moving of the particles and all particles a processor receives are stored in this buffer . however , in order to make sure this buffer is not filled too quickly we also use the fact that each processor is likely to lose some particles . when a particle is identified as having left a particular processor the particle is moved into temporary memory and the gap is filled with a particle from the end of the processors main particle memory . in this way we collect all remaining particles together before moving the new particles across , ensuring a contiguous , compact particle structure . this is shown in figure [ moveparticles ] . in order to allow l - picola to run a simulation from scratch we have integrated an initial conditions generator into the code . this means that we can simply store the first and second order lagrangian displacements for each particle as they are calculated rather than assume some initial positions for the particles and reconstruct them . we use the latest version of the parallelised 2lptic code @xcite to generate the initial conditions , with some modifications to allow a more seamless combination of the two codes , especially in terms of parallelisation . for compatibility with l - picola we have removed the warm dark matter and non - flat cosmology options from the 2lpt initial conditions generator , though these are improvements that could easily be added in the future . the particles are initially placed uniformly , in a grid pattern throughout the simulation volume , so rather than creating the particles at this stage , we also conserve memory by only generating the 2lpt displacements at these points and creating the particles themselves just before timestepping begins . because of this addition , l - picola can be used very effectively to create the initial conditions for other n - body simulations , as well as evolving the dark matter field itself . in fact in a single run we can output both the initial conditions and the evolved field at any number of redshifts between the redshift of the initial conditions and the final redshift , which allows easy comparison between picola and other n - body codes . a final point is that because the 2lpt section is based on the latest version of the 2lptic code , we are also able to generate , and then evolve , initial conditions with local , equilateral , orthogonal or generic primordial non - gaussianity . local , equilateral and orthogonal non - gaussianity can be added simply by specifying the appropriate option before compilation and providing a value for @xmath76 . we can also create primordial non - gaussianity for any generic bispectrum configuration using a user - defined input kernel , following the formalism in the appendix of @xcite . the final large modification we have made to the code , and one which will be very useful for future large scale structure surveys , is the ability to generate lightcone simulations in a single run , as opposed to running a large number of snapshots and piecing them together afterwards . snapshot simulations , generated at some effective redshift , have been widely used in the past to calculate the covariance matrix and perform systematic tests on data @xcite . however , as future surveys begin to cover larger and larger cosmological volumes with high completeness across all redshift ranges it is no longer good enough to produce a suite of simulations at one redshift . lightcone simulations mimic the observed clustering as a function of redshift and so introduce a redshift dependence into the covariance matrix . on top of this , once a full redshift range has been simulated we can apply identical cuts to the mock galaxy catalogues and the data . as such , in the case when we make measurements at multiple effective redshifts with a single sample , we may need less simulations in total , especially if multiple runs would be required to produce the snapshots at multiple redshifts . figure [ lightcone_pk ] demonstrates the effect of simulating a lightcone using the power spectrum . we populate a @xmath77 box with @xmath78 particles , place the observer at ( 0,0,0 ) , and using a flat , @xmath79 cosmology ( all other parameters match our fiducial cosmology ) , simulate an eighth of the full - sky out to a maximum redshift of 0.75 . the power spectrum is then calculated using the method of @xcite for three redshift slices between 0.0 , 0.25 , 0.5 and 0.75 , using a random , unclustered catalogue to capture the window function . as expected we see a significant evolution of the clustering as a function of redshift that would not be captured in a single snapshot simulation . the overall clustering amplitude increases as we go to lower redshifts with additional non - linear evolution on small scales at later times . to further compare the clustering of this lightcone simulation with the expected clustering , we overlay the power spectrum from a snapshot simulation at the effective redshift of each lightcone slice . we define the effective redshift of each slice , bounded by the redshifts @xmath80 and @xmath81 , using the formulation of @xcite where @xmath82 for our simulations the number density , @xmath83 , is constant and the weighting factors , @xmath84 and @xmath85 @xcite cancel . this in turn reduces the effective redshift to @xmath86 where @xmath87 is the comoving distance , @xmath88 is the speed of light and @xmath89 is the hubble parameter . we can see good agreement on all scales between the snapshot and lightcone power spectra for each of the redshift slices . the window function causes noise on the largest scales , especially for the lowest volume slice , however the redshift - dependent amplitude is captured very well within a single lightcone simulation . in the following subsections we will provide a detailed description of how lightcone simulations are produced in l - picola , test the accuracy of our implementation and also looking at how we can replicate the simulations volume to fill the full lightcone during run - time . in order to simulate the past lightcone , we require the properties of each particle in the simulation at the moment when it leaves a lightcone shrinking towards the observer . as has been done in several studies @xcite , we can interpolate these particle properties using a set of snapshot simulations , however this requires significant post - processing and more storage space than generating a lightcone simulation at run - time . as such , in order to provide a useful tool for future cosmology surveys , we have implemented the latter into l - picola . this is done as follows : the user specifies an initial redshift , at which we begin the simulation , and an origin , the point at which the observer sits . each of the output redshifts is then used to set up the timesteps we will use in the simulation , with the first output denoting the point at which we start the lightcone and the final output corresponding to the final redshift of the simulation . any additional redshifts in between these two can be used to set up variable timestep sizes . if we imagine the lightcone as shrinking towards the origin as the simulation progresses , then for every timestep between these two redshifts we output only those particles that have left the lightcone . this is shown pictorally in figure [ lightcone ] . slice of a l - picola dark matter field simulated on the past lightcone with an observer situated at the ( 0,0,0 ) . as the lightcone shrinks with each timestep ( the lightcone radius is denoted by the black lines ) we only output the particles that have left the lightcone that timestep , with their position interpolated to the exact point at which they left . this means that the particles shown in the diagram were output in stages with the particles between lines t0 and t1 output first . between output stages the particles evolve as normal , resulting in clustering that is dependent on the distance from the observer.,width=317 ] mathematically , it is simple to identify whether the particle should be output between timesteps @xmath90 and @xmath74 by looking for particles which satisfy both @xmath91 and @xmath92 where @xmath93 is the comoving distance between the particle and the lightcone origin at scale factor @xmath94 and @xmath95 is the comoving radius of the lightcone at this time . however , we really wish to output a given particle at the exact moment it satisfies the equation , @xmath96 from the cola method we have @xmath97 where @xmath98 is the position of the lightcone origin and the ` @xmath99 ' terms are dependent on the value of @xmath100 . the comoving lightcone radius at @xmath100 is simply the comoving distance @xmath101 equating these should allow us to solve for @xmath100 . once this is known we can calculate the properties of each particle we wish to output . however , this equation can not be solved analytically and so requires us to numerically solve it for each individual particle that we wish to output . this would be prohibitively time - consuming and instead we approximate the solution by linearly interpolating both the lightcone radius and the particle position between the times @xmath102 and @xmath103 . substituting the linear interpolation into eq.([eq : lightcone ] ) and rearranging we find @xmath104 this is trivial to calculate as we already need to know @xmath93 and @xmath105 in order to update the particle during timestepping anyway , and @xmath95 and @xmath106 are needed to identify which particles have left the lightcone in the first place . in fact the whole procedure can be performed with minimal extra runtime , as we simply modify the ` drift ' part of the code . the only extra computations are to check the particle s new position against the lightcone and interpolate if necessary . once we know the exact time the particle left the lightcone we can update the particle s position , using eq.(16 ) , to the position it had when it left the lightcone and output the particle . in l - picola lightcone simulations we do not interpolate the velocity , using instead the velocity at time @xmath107 . we make this choice as it mimics the inherent assumption of the kick - drift - kick method , that the velocity is constant between @xmath102 and @xmath103 . to properly interpolate the velocity in the same way as the particle position would require us to evaluate the velocity at times @xmath102 and @xmath103 which in turn would require us to measure the particle density at half timestep intervals . one could also imagine assuming that the non - linear velocity is constant and interpolating the za and 2lpt velocities ( which must be added back on before outputting to move back to the correct reference frame ) . however , we find that the assumption of constant velocity between @xmath102 and @xmath103 is a reasonable one . to test the numerical interpolation against the analytic expectations , and provide a graphical representation of the particle positions and velocities output during lightcone simulations , we compare particles output during the final timestep of a lightcone simulation to the same particles output from snapshot simulations evaluated at the beginning and end of that timestep ( the corresponding redshifts are @xmath108 and @xmath109 in this case ) . the particles are matched based on a unique identification number which is assigned when the particle are created and as such is consistent between the three simulations . for both the particle positions and velocities we look at the difference between the lightcone properties and the properties of the @xmath108 snapshot , normalised by the same difference between the @xmath109 and @xmath108 snapshots . we plot this in figure [ picola_interp_vel ] as a function of the distance from the observer ( also normalised , using the comoving distance to @xmath109 ) . if we were to interpolate the particle positions after runtime using the two snapshots we would expect the particles to lie exactly on the diagonal in figure [ picola_interp_vel ] . we find that the particle positions interpolated _ during _ the simulation also lie close to the diagonal , which validates the accuracy of our numerical interpolation . the small scatter in both of these plots is due to floating - point errors and the normalisation in the particle positions . particles that do not move much between the two snapshots will have a normalisation close to zero , which in turn makes our choice of plotting statistic non - optimal . the particle velocities show no trend as a function of distance to the observer or when they were output . in this case the velocities in each direction are all situated close to the mid point between the two simulations . this validates the kick - drift - kick assumption , that the velocities evolve approximately linearly between two timesteps , such that the velocity at time @xmath107 is half way between that at time @xmath102 and @xmath103 , although there is some scatter and offset due to the true non - linear nature of the velocity . on top of comparing the numerical interpolation during runtime to the analytic interpolation between two snapshots , we also check the assumption that we can use linear interpolation between two timesteps _ at all_. as mentioned previously , the exact time the particle leaves the lightcone , which we ll call @xmath110 , is given by numerically solving eq.([eq : lightcone ] ) , but solving this for each particle is extremely time consuming and so we linearly interpolate instead . to test this we find the exact solution for a subset of the particles in the @xmath111 simulation and compare this to the approximate solution , @xmath112 . this is shown in figure [ picola_interp_a ] . we find that the linear interpolation slightly overestimates the value of @xmath100 , with a common trend across all timesteps , however this effect is less than 0.5% across all times for this simulation . the two solutions agree almost perfectly close to the timestep boundaries , denoted by the dashed vertical lines . this is because the particle positions and lightcone radius are known exactly at these points . further away from the timestep boundaries inaccuracies are introduced as the assumption that the particle position and lightcone radius are linear functions of the scale factor is less accurate . and the value recovered using eq.([eq : lightconeinterp ] ) , as a function of the true scale factor . the dashed lines show the scale factor at which we evaluate the timesteps of the simulations , and hence know the exact positions of the particles and the lightcone radius.,width=317 ] and those recovered using eq.([eq : lightconeinterp ] ) , as a function of the distance from the observer , normalised by the maximum lightcone radius of the simulation . we plot the magnitude of the difference vector between the two methods . we see good agreement , with a maximum difference of @xmath113 , across all scales.,width=317 ] we can further quantify the reliability of the linear interpolation by looking at the positions of the particles output in both these simulations . this is shown in figure [ picola_interp_pos2 ] , where we plot the difference in particle position ( we take the magnitude of the difference vector ) as a function of the distance between the particle and the observer , normalised to the maximum lightcone radius for the simulation . we can see that the linear interpolation is indeed very accurate , and even at large radii , where the comoving distance between timesteps is largest , the particle positions are equivalent to within @xmath114 . this is well below the mesh scale of this simulation , and is subdominant compared to the errors caused by the finite mesh size and the large timesteps . on top of the lightcone interpolation we have accounted for the fact that lightcones built from snapshot simulations often replicate the simulation output to reach the desired redshift . l - picola has the ability to replicate the box as many times as required in each direction during runtime . this is done by simply modifying the position of each particle as if it was in a simulation box centred at some other location . in this way we can build up a large cosmological volume whilst still retaining a reasonable mass and force resolution . however it is important to note that this can have undesired effects on the power spectrum and covariance matrix calculated from the _ full _ replicated simulations volume , which will be detailed subsequently . figure [ lightcone_replicate ] highlights the replication process . here we run a similar lightcone to that used in figure [ lightcone ] , however the actual simulation contains 64 times less particles in a volume 64 times smaller and is replicated 64 times . in this way we can cover the full volume and mass range required but the cpu and memory requirements are much smaller . to help identify the replication we have used the friends - of - friends algorithm @xcite to group the particles into halos and plotted the centre - of - mass position of each halo . this results in obvious points where the same halo is reproduced after more particles have accreted onto that halo , and the halo has evolved in time . but using 64 times less particles and in a volume 64 times smaller . we then replicate the box 64 times at runtime as shown by the dashed lines ( we only show 1 replicate in the z direction ) . to aid visualisation we also over plot the halos recovered from this simulation using a friends - of - friends algorithm.,width=317 ] the downside of the replication procedure is that in repeating the same structures we are not be sampling as many independent modes as would be expected from an unreplicated simulation of the same volume . rather we are just sampling the same modes multiple times . this affects both the power spectrum and the covariance matrix . to test the effects of replication we use a set of 500 lightcone simulations , containing @xmath78 particles in a box of edge length @xmath115 we then compare this to another set of 500 simulations with @xmath116 particle in a @xmath117 box , which is then replicated 8 times . we calculate the power spectra for both using the method of @xcite , in bins of @xmath118 , estimating the expected overdensity from the total number of simulation particles and the box volume . this works for the lightcone simulations as the maximum lightcone radius is larger than the diagonal length of the cubic box , such that the simulation still fills volume . particle lightcone simulations in a @xmath115 box and @xmath116 particle lightcone simulations in a @xmath119 box . the lines correspond to the average power spectra from 500 independent realisations and the errors are those on a single realisation calculated from the diagonal of the covariance matrix constructed from the 500 realisations . the blue line represents the average power spectrum when we replicate the @xmath116 particle simulation 8 times so that it has the same volume and number of particles as the larger simulation , and as expected is virtually indistinguishable from the large , unreplicated simulation . the amplitude of power spectra match the order of the legend.,width=317 ] the average power spectra are shown in figure [ replicate_pk ] , where the errors come from the diagonal elements of the covariance matrix and are those for a single realisation . as the simulations are periodic in nature we expect the power spectra for the two box sizes to be almost identical except for the fact that the larger simulation volume has a greater effective redshift and hence a power spectrum with lower amplitude and less non - linear evolution . we see that this holds true for our lightcone simulations , and that the difference in the replicated and unreplicated @xmath78 simulations is , at least on linear scales , equal to the difference in the linear growth factor between the effective redshifts of the two sets of simulations . however , in order to produce the replicated power spectrum , it is necessary to correct for the replication procedure . when we replicate a simulation , we are changing the fundamental mode of the simulation but without adding any additional information , either in the number of independent modes we sample , or on scales beyond the box size of the unreplicated simulation . this in turn creates ringing on the order of the unreplicated box size . this can demonstrated using a simple toy model . in figure [ replicate_pk_toy ] we show a small @xmath120 overdensity field before and after taking the discrete fourier transform . then , if we replicate the @xmath120 overdensity field 4 times and take the discrete fourier transform , we assign the fourier components to a grid 4 times larger than for the unreplicated field as the fundamental mode of the simulation should be twice as small . however we have not added any information beyond that contained in the original @xmath120 grid and as such every other component of the fourier transformed replicated field is zero , creating ringing within the power spectrum . this also highlights the correction we perform to remove this affect . after fourier transforming the replicated overdensity field we simply remove the zero components and place the remaining non - zero components in the same size grid as that used for the unreplicated box , correcting for the differences in normalisation between the two fields . we then compute the power spectrum using this smaller grid . this removes the ringing on the order of the box size and returns the power spectrum as seen in figure [ replicate_pk ] . it is important to note that this procedure still lacks the k - space resolution one would naively expect due to the fact our simulation box is larger . neither our replication method nor our correction for ringing adds in modes larger than the unreplicated box size ( there are , however , methods that do do this , see e.g. @xcite ) this is an important correction and one that should be used whenever a simulation is replicated . it is important to note however that we believe such a correction to only be necessary when looking at a portion of a replicated simulation with volume equal to or greater than the unreplicated simulation . for most practical applications , the unreplicated simulation would be much larger than that used here , and the lightcone simulations themselves would undergo significant post - processing , such as the application of a survey window function and cutting into redshift slices . in this case the volume of each redshift slice will most likely be less than the original unreplicated simulation volume and so no correction will be necessary . utilising our 500 realisations for both sets of simulations we also look at the effect of replication on the covariance matrix . this is shown in figure [ replicate_cov ] . assuming gaussian covariance , .i.e . , @xcite , we would expect the covariance to scale as the inverse of the simulation volume . our two sets of unreplicated simulations show this behaviour , with the larger volume simulation having a covariance 8 times smaller than the smaller simulation , at least on linear scales . but , as with the power spectrum , artificially increasing the simulation volume by replication does not add in any extra unique modes and so does not increase the variance . this in turn means that the covariance matrix of the replicated simulation does not display the expected volume dependence . particle lightcone simulations in a @xmath115 box and @xmath116 particle lightcone simulations in a @xmath119 box . the errors are derived from bootstrap resampling with replacement over the 500 realisations . the dashed line shows the covariance of the replicated simulations after dividing by the difference in volume between the two sets of unreplicated simulations . the amplitude of the covariance matches the order of the legend.,width=317 ] knowing the expected volume dependence , however , we can correct for this effect . this correction is shown in [ replicate_cov ] as the dashed blue line . the corrected , replicated covariance agrees very well with the unreplicated covariance , however there is some residual differences on small scales . we hypothesise that this arises due to the absence of modes larger than the unreplicated box size , which would otherwise couple with the small scale modes within the simulation and increase the small scale covariance . this coupling is referred to as the super - sample covariance by @xcite and @xcite , who also explore corrections for this effect that could be applied to replicated simulations . however as , like the power spectrum , most applications of l - picola will involve some manipulation of the final simulation output , we would not expect to see this incorrect volume dependence unless the comoving volume of the region we were analysing was close to the unreplicated simulation size . on the other hand , with this in mind , we still recommend that for any usage of l - picola involving replication of the simulation region , the effects on the power spectrum and covariance matrix are throughly tested . this could be done using a procedure similar to that shown here , comparing replicated and unreplicated simulations after applying any survey geometry and data analysis effects . obviously replication will only be necessary if maintaining both the full volume and number density is unfeasible , however as these effects arise due to the simulation volume rather than the particle number density one would be able to test this without simulating the full number of particles in the unreplicated volume . in l - picola , lightcone simulations are performed in such a way as to add no additional memory requirements to the run , however the amount of time to drift the particles will increase proportionally to the number of replicates . in order to speed this up we identify , each timestep , which replicates are necessary to loop over . any replicates that have all 8 vertices inside the lightcone at the end of the timestep will not have particles leaving the lightcone and so can be ignored for the current iteration . furthermore , for replicates not fully inside the lightcone , we calculate the shortest distance between the replicate and the origin by first calculating the distance to each face of the replicate then the shortest distance to each line segment on that face . if the shortest distance to the origin is larger than the lightcone radius then the replicate has completely exited the lightcone and will no longer be required for the duration of the simulation . overall , this means that even if the simulation box is replicated @xmath121 times in each direction we will only need to look at a small fraction of the replicates ( @xmath122 in each direction unless the simulation box is so small that the lightcone radius changes by more than the boxsize in a single timestep ) . in this section we compare the accuracy of l - picola to a full n - body simulation using the tree - pm code gadget-2 @xcite and to the results returned using only 2lpt , which has been used to generate mock catalogues for the boss survey @xcite . in all cases we use a simulation containing @xmath123 particles in a box of edge length @xmath124 , starting at an initial redshift of 9.0 and evolving the dark matter particles to a final redshift of 0.0 . we use our fiducial cosmology and a linear power spectrum calculated at redshift 0.0 from camb @xcite . in all cases , unless this choice itself is being tested , we set @xmath125 . the memory requirements for this simulation are given in appendix a , where this simulation is used as an example . we first look at how well l - picola recovers the two - point clustering of the dark matter field compared to the n - body simulation , which we treat as our fully correct solution . in all cases we estimate the power spectrum within our cubic simulations using the method of @xcite . in figure [ picola_accuracy1 ] we show the ratio of the power spectra recovered from the approximate simulations and from the gadget-2 run . we plot the results recovered using 2lpt and l - picola runs with 10 timesteps and 50 timesteps , and for a set of runs with the cola modification turned off and the same numbers of timesteps . the act of turning the cola method off reduces l - picola to a standard particle - mesh code . we also plot the cross correlation , @xmath126 , between the approximate dark matter field , @xmath127 , and the full non - linear field from our n - body run , @xmath128 , defined as @xmath129 we neglect the contribution from shot - noise here as for dark matter particles and our simulation specifications this will be very sub - dominant on all scales we consider . we see that the cola method creates a much better approximation of the full non - linear dark matter field than 2lpt and the particle - mesh algorithms alone for a small number of timesteps . the agreement between the cola and n - body fields is remarkable , with the power spectra agreeing to within @xmath1 up to @xmath130 , which covers all the scales currently used for bao and rsd measurements . an @xmath131 agreement remains even up to scales of @xmath132 . this level of conformity is mirrored in the cross correlation , which for the cola run remains above 98% for all scales plotted . further to this , where the cross - correlation is 1 , we would not expect this to deviate between realisations . it is non - stochastic . as such we would expect that where the cross - correlation is 1 , the covariance of the l - picola and gadget-2 simulations would be identical ( at the level of noise caused by using a finite number of realizations ) . figure [ picola_accuracy1 ] indicates that the real - space covariance matrix recovered from l - picola is exact on all scales of interest to bao and rsd measurements . even where the cross - correlation between the l - picola and gadget-2 simulations deviates from 1 , it still remains very high , such that the covariance matrix recovered from l - picola would match extremely well that from a full ensemble of n - body realisations even up to @xmath132 in the same number of timesteps the particle - mesh algorithm can not match the accuracy of cola on any scales . even on large scales there is a discrepancy between the pm and gadget runs , as there are not enough timesteps for the pm algorithm to fully recover the linear growth factor . this validates the reasoning behind the cola method as the 2lpt solution provides the solution on linear scales but performs much worse than the pm algorithm on smaller scales . the time taken for a single timestep under both the cola and pm methods is identical and as such the cola method gives much better results for a fixed computational time . interestingly , however , the cola and the standard pm algorithm converge if a suitable number of timesteps is used ( 50 in this case ) . when this many timesteps are used the pm code can accurately recover the linear growth factor and the non - linear clustering is greatly improved . using a larger number of timesteps for the cola run only affects the non - linear scales as the linear and quasi - linear scales are already fully captured . using larger and larger numbers of timesteps has a diminishing effect on both algorithms , as the small scale accuracy becomes bounded by the lack of force resolution below the mesh scale . as the cola method is already quite accurate for a few timesteps increasing the number of timesteps for a fixed mesh size does not add as much accuracy as for the pm method alone . incorporating the cola mechanism into a tree - pm code would negate this effect and we expect that increasing the number of timesteps used would then continue to increase the small scale accuracy beyond that achieved using the pm algorithm only . figure [ picola_accuracyrsd ] compares the real and redshift - space cross correlation for the cola and pm runs using 10 timesteps . the additional displacement each particle receives due to redshift space distortions , @xmath133 , is evaluated using @xmath134 where @xmath135 is the line of sight velocity of each particle for an observer situated in the centre of the simulation box . in all cases we see that the accuracy of the simulation in redshift - space is worse than in real space . the @xmath136 cross correlation continues only up to @xmath137 . however , this is to be expected as , in addition to slightly under - predicting the spatial clustering of the dark matter particles , the approximate methods do not recover the full non - linear evolution of the particle s velocities as a function of time . the agreement in redshift space between the cola method and the gadget-2 run is still very good on all scales of interest to bao and rsd measurements and the cola method still outperforms the pm algorithm . similarly we would expect the redshift - space covariance matrix to remain extremely accurate on these scales of interest . we also look at the accuracy with with l - picola recovers the three - point clustering of the dark matter field . in particular we use the reduced bispectrum , @xmath138 where @xmath139 is the bispectrum for our periodic , cubic simulation . in order to explore the agreement between gadget-2 and l - picola across a wide range of bispectrum configurations we plot the reduced bispectrum ratio for l - picola and gadget-2 as a function of the ratios @xmath140 and @xmath141 for a variety of different values of @xmath142 . this is shown in figure [ reduced_bispectrum2 ] . for clarity in this figure and to avoid double plotting the same configurations we enforce the conditions @xmath143 and @xmath144 . from figure [ reduced_bispectrum2 ] we find that l - picola is able to reproduce the reduced bispectrum to within 6% for _ any _ bispectrum configuration up to @xmath145 . we can also identify the configurations that l - picola reproduces with greatest and least accuracy . regardless of the scale we find that the bispectrum in the squeezed , elongated or folded limit is reproduced extremely well , to within @xmath1 on all scales . this is because these configurations contain large contributions from triangles with one or two large scale modes , which we expect l - picola to reproduce exactly . the least accurate regime is the equilateral configuration , with accuracy decreasing as we go to smaller scales ( larger @xmath142 ) . this is because these triangles contain the biggest contribution from small scale modes in the simulation , which are not reproduced quite as accurately in l - picola . it should be noted that the convergence time of cola depends intimately on the choice of timestepping and mesh size used and the accuracy after a given number of timesteps can vary based on the exact choices made . the representative run in figure [ picola_accuracy1 ] uses the modified cola timestepping and the value of @xmath9 suggested by @xcite and a number of mesh cells equal to the number of particles . figure [ picola_accuracymesh ] shows how the accuracy of cola is reduced when lower force resolutions ( less mesh cells ) are used . we look at the case where the number of mesh points is equal to 1 , 1/2 and 1/4 times the number of particles . we do not consider a number of mesh cells larger than the number of particles as , from the nyquist - shannon sampling theorem , we do not expect any improvement in the clustering at early times , when the particle distribution is approximately grid based . furthermore @xcite and @xcite advocate that there is little justification in using a force resolution higher than the mean particle separation due to the inevitable differences in clustering between different simulations caused by using a finite number of particles . for most practical applications of l - picola it also becomes computationally infeasible to use a number of mesh cells much larger than the number of particles , due to the large increase in computational time for the fourier transforms . as expected we find a reduction in the non - linear clustering accuracy as each mesh cell becomes larger , corresponding to a larger force smoothing . the large scales are still well recovered for all mesh sizes tested . using smaller mesh sizes results in faster simulations and so for a given application of l - picola a balance between mesh size and speed should be carefully considered based on the accuracy required and at which scales . in figure [ picola_accuracy2 ] we look at the effect of using timesteps linearly and logarithmically spaced in @xmath13 and also the effect of using the modified timestepping ( with @xmath9 still ) compared to the standard @xcite method . and using the modified method of @xcite in place of the standard @xcite timestepping . we also compare the cola runs to standard pm runs using linearly and logarithmically spaced timesteps . in all cases we run the simulation for 10 timesteps . the order of the legend matches the amplitude of the lines at large @xmath146.,width=317 ] in all cases we see that the cola method still outperforms the standard particle - mesh algorithm , although to differing degrees . in the case of identical timestepping choices between the cola and pm runs we see that the large scale and quasi - linear power is recovered much better . one point of interest is that using linearly spaced timesteps in the pm method reduces the accuracy on large scales below that of the logarithmically - spaced pm run , but greatly improves the non - linear accuracy , beyond even that of cola with logarithmic steps . this is because using timesteps logarithmically spaced in @xmath13 means the code takes more timesteps at higher redshift , where the evolution of the dark matter field is more linear . this means that the pm algorithm recovers the linear growth factor more accurately . using linear timesteps results in more ` time ' spend at low redshifts , where the evolution is non - linear and so the non - linear growth is captured more accurately , at the expense of the large scale clustering . as the cola method gets the large scale clustering correct very quickly , using linear timesteps to increase the non - linear accuracy is much more beneficial . indeed , we find even more improvement using the modified timestepping method , eq.([eq : modifiedt ] ) , which emphasises the non - linear modes and corroborates the claims of @xcite . it should be noted , however , that using the modified timestepping value puts additional emphasis on different growing modes , based on the value of @xmath55 , which can change the shape of the power spectrum . this is shown in figure [ picola_accuracy3 ] where we plot the power spectrum ratio between the n - body and l - picola runs for different values of @xmath55 , exciting different combinations of decaying and growing modes , which are dominant at different cosmological times . we indeed see that different values produce slightly different power spectra . however the cross - correlations for these runs are all very similar , indicating that the difference is non - stochastic and can not vary from realisation to realization . as such , though the ` correct ' choice depends on the exact scales and statistics we wish to reproduce with our mock realisations , this is not very important . the results can be calibrated afterwards simply by comparing two different simulations with different values of @xmath55 . we find that for our case a value @xmath9 shows reasonable behaviour on all scales . throughout this section we have shown that the dark matter clustering recovered by l - picola is extremely accurate on all scales of interest to bao and rsd measurements . it is important to note however that when producing mock catalogues it is a representative galaxy field that is needed . in order to produce these l - picola can be combined with other codes for identifying halos and populating the dark matter field with galaxies . using the friends - of - friends algorithm @xcite and halo occupation distribution model @xcite , @xcite generated mock catalogues from l - picola fields . in this case no modification of the friends - of - friends linking length or the hod model was needed . other methods such as those presented by @xcite , @xcite or @xcite could also be used . we have shown that the cola method itself outperforms both the 2lpt and particle - mesh algorithms in terms of the accuracy with which it reproduces the ` true ' clustering recovered from a tree - pm n - body simulations . in this section we highlight the transformation of the cola method into a viable code for use with current and next generation large scale structure surveys by demonstrating the speed of l - picola and showing how long it takes to produce a dark matter realisation compared to 2lpt and gadget-2 . we run a series of simulations with differing numbers of particles , box sizes and numbers of processors and look at the time taken in both the strong and weak scaling regimes . strong scaling is defined as the change in the runtime of the code for different numbers of processors for a fixed simulation size , whereas weak scaling is the change in runtime for a fixed simulation size _ per processor_. for the strong scaling test we use the same simulation specifications as for our accuracy tests , with numbers of processors equal to \{8 , 16 , 32 , 64 , 128 , 256}. the simulations we use for the weak scaling are similar to those used for the strong scaling with additional details listed in table [ tab : speedweak ] . in all cases we fix the number of mesh cells to the number of particles . .the specifications of the l - picola , gadget-2 and 2lpt runs used in our weak scaling tests . in all cases we fix the number of mesh cells to the number of particles . all other simulation parameters are as used for the strong scaling runs and accuracy tests of section [ sec : accuracy ] . [ cols="^,^,^ " , ] all the run times are shown in figure [ picola_scaling ] , for both the strong and weak scaling . in both cases we have plotted the cpu time in such a way that perfect scaling will result in a constant horizontal line ( total cpu time summed across all processors for strong scaling and cpu time per processor for weak scaling ) . the top panel of this figure shows the full cpu time taken for each run . we find that our l - picola runs generally take about 3 times longer to run that a simple 2lpt realisation , however this is a relatively small cost compared to the difference in the accuracy of the methods . + + + in terms of the actual scaling we find that although l - picola does not scale perfectly in either the strong or weak regimes , the increase in runtime with number of processors is still reasonable . we use a simple least squares fitting method to fit a linear trend to the cpu time as a function of the number of processors . we find gradients of 0.41 and 0.30 , compared to the ideal value of 0 , for l - picola in the strong and weak scaling regimes respectively . we find that this trend can be extrapolated well beyond our fitting range . , i.e. , for a @xmath147 particle simulation in a ( @xmath148 box run on 1024 processors we find a cpu time per processor of 348 seconds , which matches very well our predicted value of 345 seconds . there exists some scatter in the runtimes for our simulations . this generally stems from the fourier transforms involved , the efficiency of which depends on the way the mesh in partitioned across the processors . in the case where we have a number of mesh cells ( in the x - direction ) that is not a multiple of the number of processors ( .i.e , the @xmath149 , strong - scaling run ) the time taken for the calculation of the 2lpt displacements and the interparticle forces during timestepping is increased . we investigate this further in the second and third rows of figure [ picola_scaling ] . here we show the time taken for different contributions to the full run and to each timestep therein . this highlights the fact that the scatter occurs mainly during the 2lpt and force calculation parts of l - picola as expected if it is due to the fourier transform efficiency . additionally this also suggests that the non - optimal strong and weak scaling does not stem from any particular part of the code , but rather due to the extra mpi communications needed when we use larger numbers of processors . looking at the contributions from the 2lpt , timestepping and output stages , we see that there is some evolution with processor number in the 2lpt stage from the fact that the fourier transforms require extra communications between different processors to transform the full mesh . we also see an increasing contribution from the output stage of the code as we go to larger numbers of processors . this is because of an option in the code to limit the number of processors outputting at once , stopping all processors outputting simultaneously . we set this to 32 processors and as expected we see an increase in the time taken to output the data once we run simulations with more than 32 processors due to the need for some processors to wait before they can output . looking at the contributions to an individual timestep we find that the drift , kick and displacement parts of the code are reasonably constant when the number of particles per processor remains constant . these consist mainly of loops over each particle and so this is too be expected . the density calculation and force calculation steps contain the fourier transforms required for each timestep and as such are the biggest contributions to the time taken for a timestep . looking at the strong scaling case we see an increase in both of these as a function of the number of processors , which indicates they are dominated by the mpi communications as expected . for the weak scaling we also see a large jump in the cpu time for both of these after 16 processors . this is another indication that the mpi communications are the cause of the scaling trends we see , as the architecture of the high performance computer we use is such that 16 processors are located on a single node and intra - node communication is much faster than inter - node . once we start to require inter - node communication to compute the fourier transforms the cpu time increases . finally we see that the move particles section of the code does not contribute much to the total time for each timestep , except where the number of inter - processor communications becomes large . this is due to the effort taken to produce a fast algorithm to pass the particles , whereas a simpler algorithm would result in a larger amount of time and memory needed to identify and store the particles that need transferring . in this paper we have introduced and tested a new code l - picola , which , due to its fast nature , can be used to generate large numbers of accurate dark matter matter simulations . the code is available under the gnu general public license at https:/cullanhowlett.github.io / l - picola . the main points of the paper are summarised as follows : * l - picola is a memory conservative , planar parallelisation of the 2lpt and cola algorithms . this is enabled by parallel algorithms for cloud - in - cell interpolation , fast fourier transforms , and fast movement of particles between processors after each timestep . * we have included additional features in l - picola such as the fast creation of initial conditions for other simulation codes , with optional primordial non - gaussianity , and the ability to produce lightcone simulation , with optional replication of the simulation volume at run - time . these will be of particular use to future large scale structure surveys . * we have quantified the accuracy of the method l - picola uses to produce lightcone simulations , verifying that it s accuracy is not unduly affected by the approximations made to ensure a fast algorithm . * we have investigated the effect of replicating the simulation volume on both the power spectrum and covariance matrix using a set of 500 individual lightcone realisations . we find that , due to the fact the replication procedure modifies the simulation volume without adding additional information , the power spectrum can suffer from ringing on the scale of the unreplicated box size and that the covariance matrix demonstrates the volume dependence of the unreplicated box size as opposed to the replicated volume . we show simple corrections for both of these effects and hypothesise that this is only a problem when analysing regions of the simulation larger than the unreplicated box size . * we have compared the accuracy of l - picola to the approximate 2lpt and pm methods and to a fully non - linear tree - pm gadget-2 simulation . we find that l - picola performs much better than the 2lpt and pm algorithms , and that the power spectra from l - picola agree with that from our gadget-2 simulations to within @xmath1 on all scales of interest to bao and rsd measurements and to within @xmath150 up to @xmath132 . the reduced bispectrum from l - picola also shows remarkable agreement with our gadget-2 simulation , to within 6% for all configurations up to @xmath145 . we do however find that this agreement has some dependence on the exact type of timestepping used in the code . * we have compared the speed of l - picola to the 2lpt and gadget-2 simulations . we find that the remarkable accuracy of l - picola comes at only a small cost to speed compared to 2lpt . l - picola exhibits reasonable scaling properties in the strong and weak scaling regimes , even up to large numbers of processors . we find that these trends are dominated by the need for extra inter - processor communication when using large numbers of processors . still , there are several improvements that could be made to l - picola in the future . in terms of parallelisation , splitting the mesh into blocks rather than slices could improve both the speed and scalability of the code to large numbers of processors , however the need for additional mpi communication during the fast fourier transforms means that the level of improvement is indeterminate at this time . furthermore one could imagine hybridising the code , using open - mp and mpi such that communication between ` local ' processors does not rely on slower mpi communication . in terms of the physics behind l - picola it would be simple to add in support for warm dark matter . another obvious addition to the code would be to implement the spatial extension of the cola method , presented by @xcite . such an improvement would allow us to simulate a large cosmological volume whilst only spending computational time evaluating the non - linear displacements for a small portion of that volume . lightcone simulations within l - picola in particular would greatly benefit from this as we would be able to simulate a small pencil - beam region of the full lightcone and scale this up to the required simulation volume . also , as this extended cola method still requires us to calculate the 2lpt displacements for all the particles within the full volume , implementing this into our distributed - memory code would allow us to simulate much larger cosmological volumes and higher particle densities than the current shared - memory implementation . additional small scale accuracy could be achieved by a suitable scaling of the mesh during the simulation , such as using a finer mesh at late times when the particles become more clustered . this would be particularly easy to implement as , in the optimal memory case , the mesh is deallocated and reallocated each time step anyway . using an adaptive mesh for high density portions of the simulation , or the tree - pm algorithm instead of the pm algorithm , could also be implemented though these methods would come at a cost to speed . furthermore , as l - picola is so fast , we find that for current applications , the total cpu time taken to produce a mock galaxy catalogue is dominated by outputting and post - processing of ( mainly reading in ) the dark matter field , especially the creation of dark matter halos . this is exacerbated even more for lightcone simulations with replication as we are effectively outputting the simulation multiple times , resulting in large increases to the amount of time taken to output and process the data . this could be vastly improved by adding in a halo finder into l - picola , either by identifying shell - crossing as it occurs during the simulation , or via the fof algorithm . this would mean that the amount of time taken to output the data , and read it in for post - processing could be reduced drastically . we would like to thank angela burden , gary burton , james briggs and john pennycook for their help and insightful comments throughout the development and testing of l - picola . we make special acknowledgement to the facilities and staff of the uk sciama high performance computing cluster supported by the icg , sepnet and the university of portsmouth . code development and testing , mock catalogue generation , power spectrum estimation , and other analysis all made use of the computing and storage offered therein . this research would not have been possible without this support . ch is grateful for funding from the united kingdom science & technology facilities council ( uk stfc ) grant + st / k502248/1 . wjp acknowledges support from the uk stfc through the consolidated grant st / k0090x/1 , and from the european research council through grants 202686 ( mdepugs ) and 614030 ( _ darksurvey _ ) . this work used the dirac data analytic system at the university of cambridge , operated by the university of cambridge high performance computing service and the cosma data centric system at durham university , operated by the institute for computational cosmology , both on behalf of the stfc dirac hpc facility ( www.dirac.ac.uk ) . this equipment was funded by bis national e - infrastructure capital grants + st / k001590/1 and st / k00042x/1 , stfc capital grants + st / h008861/1 and st / h00887x/1 , and stfc dirac operations grants st / k00333x/1 and st / k00087x/1 . dirac is part of the national e - infrastructure . this work was also undertaken on the cosmos shared memory system at damtp , university of cambridge operated on behalf of the stfc dirac hpc facility . this equipment is funded by bis national e - infrastructure capital grant + st / j005673/1 and stfc grants st / h008586/1 , st / k00333x/1 . this research has made use of nasa s astrophysics data system bibliographic services . 99 ahn , c. p. , alexandroff , r. , allende prieto , c. , et al . 2012 , apjs , 203 , 21 ahn , c. p. , alexandroff , r. , allende prieto , c. , et al . 2014 , apjs , 211 , 17 anderson , l. , aubourg , . , bailey , s. , et al . 2014 , mnras , 441 , 24 angulo , r. e. , baugh , c. m. , frenk , c. s. , & lacey , c. g. 2014 , mnras , 442 , 3256 berlind , a. a. , & weinberg , d. h. 2002 , apj , 575 , 587 bouchet , f. r. , colombi , s. , hivon , e. , & juszkiewicz , r. 1995 , a&a , 296 , 575 chuang , c .- h . , kitaura , f .- s . , prada , f. , zhao , c. , & yepes , g. 2015 , mnras , 446 , 2621 cole , s. 1997 , mnras , 286 , 38 cole , s. , percival , w. j. , peacock , j. a. , et al . 2005 , mnras , 362 , 505 coles , p. , & jones , b. 1991 , mnras , 248 , 1 colless , m. , dalton , g. , maddox , s. , et al . 2001 , mnras , 328 , 1039 colless , m. , peterson , b. a. , jackson , c. , et al . 2003 , arxiv : astro - 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picola as much as possible , including the introduction of a compilation option to conserve as much memory as possible . when this option is used the memory consumption for a l - picola run is reduced significantly and the mean memory per processor can be calculated reasonably simply . here we detail the calculation of the memory needed for an l - picola simulation under these optimum conditions . with the optimal memory setting we use floating point precision for the particles and double precision for the mesh . the information for each particle consists of x , y and z coordinates , velocities in those same directions , and the za and 2lpt displacements in those directions , resulting in @xmath151 per particle . the main contributions to the memory arise from the particles and the mesh and the key parameters are the number of mesh cells , @xmath72 , number of particles , @xmath67 and the amount of buffer memory allocated to each processor to account for the non - uniformity of the particle distribution over processors at late times , @xmath152 . the code can be split into six distinct sections : the calculation of the initial 2lpt potentials ; the calculation of the initial 2lpt displacements ; the initialisation of the particles ; the moving of particles across processors each timestep ; the evaluation of the interparticle mesh - based force each timestep ; and the calculation of the particle displacements for each timestep . the corresponding memory requirements are : @xmath153 @xmath154 @xmath155 @xmath156 @xmath157 @xmath158 the maximum memory required for an l - picola simulation is the largest of these 6 contributions . a utility for calculating the memory requirements , even when using suboptimal ( in terms of memory ) compilation options is provided with the public release of the code . . the solid lines show the contributions from different sections of the code for varying numbers of processors , whilst the intersection of the dashed line with the solid lines gives the minimum number of processors required to run the simulation assuming there is 4 gb of memory available per processor.,width=317 ] as an example figure [ picola_mem ] shows the memory requirements as a function of number of processors for the l - picola simulations used in section [ sec : accuracy ] . we can see that if we have 4 gb of memory available per processor , this simulation can be run using only 25 processors if the optimal compilation options are used ( 32 were used for the simulations in this paper ) .

robust measurements based on current large - scale structure surveys require precise knowledge of statistical and systematic errors . this can be obtained from large numbers of realistic mock galaxy catalogues that mimic the observed distribution of galaxies within the survey volume . to this end we present a fast , distributed - memory , planar - parallel code , l - picola , which can be used to generate and evolve a set of initial conditions into a dark matter field much faster than a full non - linear n - body simulation . additionally , l - picola has the ability to include primordial non - gaussianity in the simulation and simulate the past lightcone at run - time , with optional replication of the simulation volume . through comparisons to fully non - linear n - body simulations we find that our code can reproduce the @xmath0 power spectrum and reduced bispectrum of dark matter to within @xmath1 and @xmath2 respectively on all scales of interest to measurements of baryon acoustic oscillations and redshift space distortions , but 3 orders of magnitude faster . the accuracy , speed and scalability of this code , alongside the additional features we have implemented , make it extremely useful for both current and next generation large - scale structure surveys . l - picola is publicly available at https://cullanhowlett.github.io/l-picola . large - scale structure of universe - methods : numerical

the magnetohydrodynamic ( mhd ) waves and oscillations in the solar and probably in the stellar atmospheres are assumed to be generated by coupling of complex magnetic field and plasma . these mhd waves and oscillations are one of the important candidates for heating the solar / stellar coronae and accelerating the supersonic winds . in the sun , magnetically structured flaring loops , anchored into the photosphere , exhibit various kinds of mhd oscillations ( e.g. fast sausage , kink and slow acoustic oscillations ) . the idea of exploiting such observed oscillations as a diagnostic tool for deducing physical parameters of the coronal plasma was first suggested by roberts et al . wave and oscillatory activity of the solar corona is now well observed with modern imaging and spectral instruments ( e.g. instruments on - board /it soho , trace , hinode and norh ) in the visible , euv , x - ray and radio bands , and interpreted in terms of mhd wave theory ( nakariakov & verwichte 2005 ) . stellar mhd seismology is also a new developing tool to deduce the physical properties of the atmosphere of magnetically active stars , and it is based on the analogy of the solar coronal seismology ( nakariakov 2007 ) . the first stellar x - ray flare oscillations in at mic have been reported by mitra - kraev et al . ( 2005 ) and it was interpreted as a signature of slow magneto - acoustic oscillation . mathioudakis et al . ( 2006 ) have reported the fast sausage oscillations of @xmath2 s in the flaring stars eq peg b. mullan et al . ( 1992 ) have also found the oscillations on the scale of few minutes and interpreted as a transient oscillations in the stellar loops . in this letter , we find the observational signature of the fast kink oscillations in the magnetically active star @xmath0 boo ( v = 4.55 mag ) . in the case of solar corona , such type of modes are important to probe the local plasma conditions ( e.g. , van doorsselaere et al . therefore , such modes may also be useful to diagnose the stellar coronae . @xmath0 boo is a nearby ( 6.0 pc ) visual binary , comprising a primary g8 dwarf and a secondary k4 dwarf with an orbital period of 151 yr . in terms of the outer atmospheric emission , uv and x - ray observations show that the primary dominates entirely over the secondary ( e.g. laming & drake 1999 ) . the observations , data reduction , results and discussion along with the conclusions are given in the forthcoming sections . the star @xmath0 boo was observed by rgs and epic - mos on boards xmm - newton satellite ( jansen et al . 2001 ) on 2001 january 19 at 19:25:06 ut and lasted for 59 ks . the detailed method of epic - mos data reduction , and the timing , spectroscopic and flare analysis are given in pandey & singh ( 2008 ) . here , we used the 0.3 - 10.0 kev x - ray data observed from epic - mos1 . the x - ray light curve of @xmath0 boo is shown in figure [ fig : lc ] , where flare regions are represented by f1 and f2 , and the quiescent state is represented by q. the light curve was binned with 40s . in the x - ray light curve of @xmath0 boo , a period of heightened coronal emission u was identified after the flare f2 , where the average flux was 1.8 times more than the quiescent state . we have chosen the u region for our wavelet and periodogram analyses because of the stable evolution of the integrated 0.3 - 10 kev light curve after the flare f2 . to study the emission in the u regions only , we fitted the spectral data using 1-temperature plasma model apec ( smith et al . 2001 ) , with the quiescent emission taken into account by including its best - fit 2-temperature model as a frozen background contribution . the best fit temperature and emission measure during the u part of the light curve are @xmath3 mk and @xmath4 @xmath5 , respectively with reduced @xmath6 per degree of freedom of 0.99 . during the flare f2 , the average values of temperature and emission measures were found to be @xmath7 mk and @xmath8 @xmath5 , respectively . line fluxes and positions were measured using the xspec package by fitting simultaneously the rgs1 and rgs2 spectra with a sum of narrow gaussian emission lines convolved with the response matrices of the rgs instruments . the continuum emission was described using bremstrahlung models at the temperatures of the plasma components inferred from the analysis of epic - mos1 data . the emission measure derived from the analysis of the epic data was used to freeze the continuum normalization . for the present purpose we give the line fluxes of he - like triplets from o vii in table 1 . cccc [ tab : flux ] 22.08(f)&@xmath9 & 22.08(f)&@xmath10 + 21.78(i)&@xmath11 & 21.77(i)&@xmath12 + 21.58(r)&@xmath13 & 21.57(r)&@xmath14 + & & & + the he - like transitions , consisting of the resonance line ( r ) 1s@xmath15 @xmath16s@xmath17 - 1s2p @xmath16p@xmath18 , the intercombination line ( i ) 1s@xmath15 @xmath16s@xmath17 - 1s.2p @xmath19p1 , and the forbidden line ( f ) 1s@xmath15 @xmath16s@xmath17 - 1s.2s @xmath19s@xmath18 are density- and temperature - dependent ( e.g. gabriel & jordan 1969 ) . the intensity ratio g = ( i+f)/r varies with temperature and the ratio r = f / i varies with electron density due to collisional coupling between the metastable @xmath20s upper level of forbidden line and the @xmath20p upper level of the intercombination line . in the rgs wavelength , the o vii lines are clean , resolved and potentially suited to diagnose electron density and temperature ( see fig . these lines at 21.60(r ) , 21.80(i ) and 22.10(f ) have been used to obtain the temperature and density values from the g- and r - ratio using chianti database ( version 5.2.1 ; landi et al . the g - ratio for @xmath0 boo implies a temperature of @xmath21 and @xmath22 mk during the quiescent and flare states , respectively . for these temperatures , we derive electron densities of @xmath23 @xmath5 for the quiescent state ( q ) and @xmath24 @xmath5 for flare state ( f2+u ) . the electron density was slightly higher during the flare state . however , this increase is well within the @xmath25 level . [ fig : rif ] the length of the stellar loops associated with the observed flaring activity can be estimated from the various loop models . below we derive loop length from four different models . the details of this method are given in pandey & singh ( 2008 ) . the derived loop length for the flare f2 is found to be of @xmath26 cm . however , the value of @xmath27 ( = 2 ; slope of density temperature diagram ) is outside the domain of the validity of the method . therefore , the estimated loop length from this method may not be actual . alternatively , reale ( 2007 ) derived the loop length ( @xmath28 ) from the rise phase and peak phase of the flare . the loop length of the flare f2 from this approach is estimated to be @xmath29 cm . shibata & yokoyama ( 2002 ) assume that the gas pressure is balanced by the magnetic pressure and give the equation for the magnetic field ( @xmath30 ) and the loop length(@xmath28 ) : @xmath31 @xmath32 where @xmath33 is the density outside the flaring loop . by applying the average values of em and t during the flare , we obtained a magnetic field strength of @xmath34 g and a loop length of @xmath35 cm for the flare f2 . the approach is described in hawley et al . ( 1995 ) . in this approach , the loop length has been derived by solving the time - dependent energy equation in rise and decay phase separately in different limits : strong evaporation driven by heating in the rise phase and strong condensation driven by radiation in the decay phase . the time rate change of the loop pressure ( _ p _ ) for the spatial average is given by @xmath36 where @xmath37 is the volumetric flaring heating rate , and @xmath38 is the optically thin cooling rate . the rise phase is dominated by strong evaporative heating , i.e. , @xmath39 , while the decay phase is dominated by cooling and strong condensation , i.e. , @xmath40 . at the loop top , there is an equilibrium , i.e. , @xmath41 and the loop length can be given as @xmath42 where @xmath43 is the decay time , @xmath44 is the rise time , @xmath45 is the temperature at flare apex , and @xmath46 . @xmath47 ( = 3.16 counts / s ) and @xmath48 ( = 1.24 counts / s ) are count rate at the peak of the flare and the count rate during the quiescent state , respectively . using this approach , the loop length for the flare f2 is estimated to be @xmath49 cm . the values of @xmath43(=9885 s ) , @xmath44 (= 3351 s ) , and @xmath45 ( = 13.3 mk ) are taken from pandey & singh ( 2008 ) . given an estimate of two measured quantities , the emission measure ( em ) and the decay time scale of the flare ( @xmath43 ) haisch s approach ( haisch 1983 ) leads to the following expression for the loop length ( @xmath28 ) @xmath50 using this approach , we obtained a loop length of @xmath51 cm . the minimum magnetic field strength is estimated from the condition @xmath52 , where @xmath53 is boltzmann s constant . the minimum magnetic field strength thus obtained was 36 gauss . this lies in the upper limit of the magnetic field determined by the pressure balance method . the loop length derived from the above all four methods is consistent with each other . we have used the wavelet analysis idl code randomlet " developed by e. oshea . the program executes a randomization test ( linnell nemec & nemec 1985 ; oshea et al . 2001 ) which is an additional feature along with the standard wavelet analysis code ( torrence & compo 1998 ) to examine the existence of statistically significant real periodicities in the time series data . the advantage of using this test is that it is distribution free or non parametric , i.e. , it is not constrained by any specific noise model such as poisson , gaussian , etc . using this technique , many important results have been published by analyzing approximately evenly sampled data ( e.g. , banerjee et al . 2001 ; oshea et al . 2001 , 2007 ; srivastava et al . 2008a , b ; oshea & doyle 2009 ; gupta et al . 2009 ) . [ fig : period ] the wavelet power transforms of the u part of the x - ray light curve of cadence 40 s ( see the top - left panel of fig . 3a ) are shown in the middle left panel of fig . 3a , where the darkest regions show the most enhanced oscillatory power in the intensity wavelet spectrum . the cross - hatched areas are the cone of influence ( coi ) , the region of the power spectrum where edge effects , due to the finite lengths of the time series , are likely to dominate . the maximum allowed period from coi , where the edge effect is more effective , is @xmath54s . in our wavelet analysis , we only consider the power peaks and corresponding real periods ( i.e. probability @xmath55 95% ) below this threshold . the period with maximum power detectable outside the coi is @xmath562883 s with a probability of @xmath5694% and the repetition of only @xmath57 cycles in the time series . however , another peak is visible at a period of @xmath561019 s with a probability of @xmath5699% and the repetition of @xmath5611 cycles . therefore , only the periodicity of @xmath561019 s satisfies the recently reported more strict criteria of oshea & doyle ( 2009 ) , i.e. at least four cycle of repetition over the life time of the oscillations . the middle - right panel in fig . 3a shows the global wavelet power spectra of the time series from which the statistically significant period ( @xmath561019s ) is selected . in fig . 3a , the bottom panel shows the probabilities of the presence of two specific frequencies ( or periods ) corresponding to the first and second highest peaks shown in the middle - left panel as functions of the time after the start of the observations . the solid line represents the probability corresponding to the major power peak of time series data , while the dotted line corresponds to the secondary power peak . wavelet analysis was also performed in the decay phase of the flare f2 , and no significant periodicity was found . we have also performed the periodogram analysis ( scargle 1982 ) in the u part of the x - ray light curve ( see fig . 3b ) . in the power spectrum , the highest peak corresponds to a period of @xmath561005 s ( probability @xmath58% ) , which is consistent with that obtained from wavelet analysis . therefore , only the period of @xmath56 1019 s appears to be statistically significant in our analyses . llcccc [ tab : comp ] hydrodynamic & @xmath59&@xmath60 & @xmath61 & @xmath62 & + rise and decay & @xmath63&@xmath64 & @xmath65 & @xmath66 & + pressure balance & @xmath67&@xmath68 & @xmath69 & @xmath70&1019 + haisch s approach & @xmath71&@xmath72 & @xmath73 & @xmath74 & + & & & & & + the observed periodicity may be the likely signature of mhd oscillations associated with the stellar flare loops . the overdense magnetic loops are pressure balanced structures and may contain fast - kink and sausage oscillation modes with phase speed greater than the local alfvnic speed ( @xmath75 ) , and slow acoustic modes with sub - alfvnic speed ( @xmath76 ) under coronal conditions . the expressions for the oscillation periods of slow ( @xmath77 ) , fast - kink ( @xmath78 ) , and fast - sausage ( @xmath79 ) modes are given as follows ( edwin & roberts , 1983 ; roberts et al . , 1984 ; aschwanden et al . , 1999 ) : @xmath80^{1/2 } \approx 1300 \frac{l_{10 } } { \sqrt t_{6 } } s\ ] ] @xmath81 @xmath82 where @xmath28 , @xmath83 , @xmath84 , and @xmath30 are the loop length , the loop width , the ion mass density and magnetic field , respectively . the @xmath85 , where @xmath86 and @xmath87 are the sound and alfvnic speeds respectively . the @xmath88 is the phase speed . under coronal conditions , @xmath89 , @xmath90 , @xmath91 , and @xmath92 . the subscripts @xmath93 and @xmath94 stands for inside , and outside of the loop . the @xmath95 is the number of nodes in fast - kink and slow oscillations , and is equal to 1 for the fundamental mode . the approximate relation in equations 6 - 8 are given in coronal conditions for the fundamental oscillation periods of different modes in magnetic loops . therefore , these approximate equations are also valid for the stellar loops in the coronae of magnetically active sun - like stars . the parameters are expressed in units of @xmath96 , @xmath97 , @xmath98 , @xmath99 , and @xmath100 . the loop width was determined by assuming @xmath101 ( shimizu 1995 ) for a single loop . using the observationally estimated loop length and width , density , magnetic field , and equations ( 6)-(8 ) , the estimated periods for different oscillation modes are given in table 2 . the observationally derived oscillation period @xmath102 s approximately matches with the theoretically derived oscillation period for a fundamental fast kink mode . we found the first signature of fundamental kink oscillations with period of @xmath1 s in the magnetically active star @xmath0 boo observed by epic - mos of _ xmm - newton _ , which may be formed either by the superposition of oppositely propagating fast kink waves or due to flare generated disturbances near the loop apex . the flaring activity may be the possible mechanism of the generation of such oscillations in the stellar loops . recently , cooper et al . ( 2003 ) have found that the transverse kink modes of fast magneto - acoustic waves may modulate the emission observable with imaging telescopes despite their incompressible nature . this is possible only when the axis of an oscillating loop is not orientated perpendicular to the observer s line of sight . resonant absorption is the most efficient mechanism theorized for the damping of a kink mode in which energy of the mode is transferred to the localized alfvnic oscillations of the inhomogeneous layers at the loop boundary ( lee & roberts 1986 ) . intensity oscillations due to the fast - kink mode of magneto - acoustic waves do not show any decay of the amplitude during the initial 250 minutes in the post - flare phase observations of @xmath0 boo . this is probably due to an impulsive driver , which forces such kind of oscillations and dominates over the dissipative processes during the flare f2 of @xmath0 boo . in conclusion , we report the first observational evidence of fundamental fast - kink oscillations in stellar loops during a post - flare phase of heightened emission in the cool active star @xmath0 boo . these oscillations are a unique tool for the estimation of several key parameters of coronae , which are not directly measurable , e.g. , the magnetic field . some of the seismological techniques developed for the solar corona , e.g. , based upon the ratio of the periods of kink modes , do not require the spatial resolution , and hence can be applied to estimate the density scale heights of the stellar coronae . therefore , based on the solar analogy , such observations may shed new lights on the dynamics of the magnetically structured stellar coronae and its local plasma conditions . however , a future multiwavelength observational search is required to investigate various kinds of mhd modes to probe the local conditions of plasma in magnetically active stars . we thank referee for his valuable comments and suggestions . we thank e. oshea for randomlet. we also thank m. j. aschwanden , v. m. nakariakov , l. ofman , r. sagar , and t. v. zaqarashvili for carefully reading the manuscript and valuable suggestions . the research is based on observations obtained with _ xmm - newton _ , an esa science mission with instruments and contributions directly funded by esa member states and nasa . 99 aschwanden , m. j. , fletcher , l. , schrijver , c. j. , & alexander , d. 1999 , , 520 , 880 banerjee , d. , oshea , e. , doyle , j. g. , & goossens , m. 2001 , , 377 , 691 cooper , f. c. , nakariakov , v. m. , & tsiklauri , d. 2003 , , 397 , 765 edwin , p. m. , & roberts , b. 1983 , , 88 , 179 gabriel , a. h. , & jordan , c. 1969 , , 221 , 947 gupta , a. c. , srivastava , a. k. , & wiita , p. j. 2009 , , 690 , 216 haisch , b. m. 1983 , in proc . iau colloq . 71 , activity in red - dwarf stars , vol . 102 ( dordrecht : reidel ) , 255 hawley , s. l. , et al.1995 , , 453 , 464 jansen , f. , et al . 2001 , , 365 , l1 laming , j. m. , & drake , j. j. 1999 , , 516 , 324 landi , e. , del zanna , g. , young , p. r. , dere , k. p. , mason , h. e. , & landini , m. 2006 , , 162 , 261 lee , m. a. , & roberts , b. 1986 , , 301 , 430 linnell nemec , a. f. , & nemec , j. m. 1985 , , 90 , 2317 mathioudakis , m. , bloomfield , d. s. , jess , d. b. , dhillon , v. s. , & marsh , t. r. 2006 , , 456 , 323 mitra - kraev , u. , harra , l. k. , williams , d. r. , & kraev , e. 2005 , , 436 , 1041 mullan , d. j. , herr , r. b. , & bhattacharyya , s. 1992 , , 391 , 265 nakariakov , v. m. , & verwichte , e. 2005 , living reviews in solar physics , 2 , 3 nakariakov , v. m. 2007 , advances in space research , 39 , 1804 oshea , e. , & doyle , j. g. 2009 , a&a , 494 , 355 oshea , e. , srivastava , a. k. , doyle , j. g. , & banerjee , d. 2007 , , 473 , l13 oshea , e. , banerjee , d. , doyle , j. g. , fleck , b. , & murtagh , f. 2001 , , 368 , 1095 pandey , j. c. , & singh , k. p. 2008 , , 387 , 1627 reale , f. 2007 , , 471 , 271 roberts , b. , edwin , p. m. , & benz , a. o. 1984 , , 279 , 857 scargle , j. d. 1982 , , 263 , 835 shibata , k. , & yokoyama , t. 2002 , , 577 , 422 smith , r. k. , brickhouse , n. s. , liedahl , d. a. , & raymond , j. c. 2001 , , 556 , l91 shimizu t. , 1995 , pasj , 47 , 251 srivastava , a. k. , zaqarashvili , t. v. , uddin , w. , dwivedi , b. n. , & kumar , p. 2008a , , 388 , 1899 srivastava , a. k. , kuridze , d. , zaqarashvili , t. v. , & dwivedi , b. n. 2008b , , 481 , l95 torrence , c. , & compo , g. p. 1998 , bulletin of the american meteorological society , 79 , 61 van doorsselaere t. , nakariakov v. m. , verwichte e. , 2008 , apj , 676 , l73

we report the observations of x - ray oscillations during the flare in a cool active star @xmath0 boo for the first time . @xmath0 boo was observed by epic / mos of _ xmm - newton _ satellite . the x - ray light curve is investigated with wavelet and periodogram analyses . both analyses clearly show oscillations of the period of @xmath1 s. we interpret these oscillations as a fundamental fast - kink mode of magnetoacoustic waves .

SEOUL South Korea's military on Monday threatened retaliation against North Korea after accusing the North of planting land mines inside the Demilitarised Zone border that wounded two soldiers last week, in what it called a cowardly act of provocation. There was evidence to conclude that soldiers from the North crossed the Military Demarcation Line recently to plant the mines, and Pyongyang would be made to "pay a severe price", the South's military told a news briefing. "We strongly condemn this cowardly act, which would be unthinkable for a normal military," Major General Ku Hong-mo of South Korea's Joint Chiefs of Staff said, calling it a violation of the armistice agreement that ended the 1950-53 Korean War. The denunciation is likely to provoke an angry response from the North and further raise tensions on the Korean peninsula. Later on Monday, as part of its countermeasures, the South Korean military used loudspeakers to blare anti-Pyongyang rhetoric across the border, a defense ministry official said, resuming broadcasts that had been suspended since 2004. The United Nations Command, headed by the U.S. military and which oversees the armistice, also condemned what it called the North's violation of the truce. It said it would call for a meeting with North Korea's military. The area around last Tuesday's blast had been swept for mines and the terrain made it impossible for mines planted elsewhere to have drifted due to rain or shifting soil, South Korea's military said. Fragments from the exploded mines also had paint typically used by the North, it said. Two soldiers who were part of a team conducting a routine search operation inside the heavily fortified DMZ near the town of Paju, about 50 km (30 miles) north of Seoul, were seriously wounded in the blast. (Reporting by Ju-min Park; Editing by Jack Kim and Clarence Fernandez) ||||| Seoul, South Korea (CNN) South Korea says it will resume broadcasting propaganda messages over its heavily armed border with North Korea in retaliation for landmine blasts that wounded two of its soldiers. The use of loudspeakers to blare government messages into North Korean territory is a form of psychological warfare that the South Korean Defense Ministry stopped more than a decade ago during a thaw in relations between the two sides. Restarting the broadcasts is all but certain to infuriate North Korea, which has threatened in the past to destroy the groups of huge speakers that the South set up at the demilitarized zone that separates the two countries. But the South Korean government is upset over the serious leg injuries suffered by two soldiers who stepped on landmines last week in the demilitarized zone, which is considered to be the most heavily fortified border in the world. South Korea and the U.S.-led United Nations Command in Korea said Monday that the North Korean military planted the mines in the southern half of the zone along a route patrolled by South Korean troops. Wounded soldiers forced to have amputations One of the soldiers had to have part of each leg amputated, and the other had to have one foot removed at the ankle, the South Korean Defense Ministry said. Before South Korea announced the resumption of propaganda broadcasts, Maj. Gen. Koo Hong-mo, director of operations of the South's Joint Chiefs of Staff, warned that North Korea would "pay a harsh price" for laying the mines. He demanded that Pyongyang apologize for planting the landmines and severely punish whoever is responsible. There was no immediate comment on the matter Monday in North Korean state media. The South Korean Defense Ministry declined to specify when exactly the propaganda broadcasts would resume. It said sound from the the giant loudspeakers can travel about 24 kilometers (15 miles) at night and about 12 kilometers on weekdays. Professor Lee Jung-hoon said we have not heard the end of the tensions. "When we have the psychological warfare -- the leaflets or the loudspeakers -- basically the message is: the current leader is doing a very bad job, that their human rights are being violated, and that there's a much better world outside that they should be aware of," said Lee, an associate professor of international relations at Yonsei University in Seoul. He said North Korea will not take kindly to criticism against Kim. "For them Kim Jong Un, as his father and his father's father was, is not just a political leader, he's a deity figure," he said. "For the leadership, just the fact that there's the public condemnation and criticism of this godlike figure is just totally unacceptable." And North Korea, he said, will have some sort of reaction. "Absolutely they will respond," he said. "I can't say in what way." U.N. Command condemns truce violations The U.S.-led United Nations Command in Korea said that its investigation into the explosions found that the North's Korean People's Army had breached several parts of the armistice on the Korean Peninsula by planting landmines along a South Korean patrol route in the southern half of the demilitarized zone. "The United Nations Command condemns these violations of the Armistice Agreement, and will call for a general officer level-dialog with the Korean People's Army," the U.N. Command statement said. The U.N. Command, which monitors the armistice, said that the investigation had found that the wooden box landmines were recently planted, ruling out the possibility that they were old mines that might have been displaced by rain or other elements over the years. Staff members from South Korea, the United States, New Zealand and Colombia took part in the investigation, the U.N. Command said. Previous border tensions The demilitarized zone has divided North and South Korea since the Korean War ended in 1953 with an armistice rather than a formal peace treaty. As a result, the two countries technically remain at war. Tension has flared in the past around sensitive points on the their de facto border, including North Korea's shelling of an island in 2010 that killed two South Korean marines. Roughly 28,000 U.S. troops are based in South Korea.

– Two South Korean soldiers maimed near the border with North Korea last Tuesday were victims of a North Korean attack, officials say. The South Korean Defense Ministry claims North Korean soldiers crept across the 2.5-mile-wide Demilitarized Zone to plant mines outside the South's guard post near Paju, reports the New York Times. A soldier lost both legs in an explosion involving two mines when he opened the gate of a barbed-wire fence, investigators say. A colleague triggered a second blast and lost a leg when he tried to help, reports CNN. Investigators say the land mines, which used wood boxes, were typical of those from the North and targeted the South's troops. Military officials tell Reuters this is a "cowardly act, which would be unthinkable for a normal military," and "swear a severe retaliation." Investigators believe the mines were planted between July 22—when the gate was last used—and the day of the attack, the first of its kind in 48 years, South Korean officials say. They find it especially concerning that the infiltrators went undetected, despite closed-circuit and heat-detecting cameras around posts; leafy forests may have shielded them from view. Though hundreds of thousands of land mines were planted around the Demilitarized Zone during and following the Korean War, investigators confirm the ones that caused the recent blasts were newly planted. The South has now resumed broadcasting government messages up to 15 miles into the North via loudspeakers along the border; it had ended the practice a decade ago in an attempt to improve relations.

medical microbiologists and infection control practitioners in all 91 hospitals in the netherlands were contacted and asked to collect data concerning mrsa outbreaks and the results of subsequent contact screening retrospectively during june an index case - patient was defined as a hospitalized patient colonized or infected with mrsa and treated without use of barrier precautions . age , sex , and number of days hospitalized from mrsa detection through discharge were obtained . according to the guidelines in the netherlands , identification of a mrsa index case - patient initiates contact screening among contact patients and health care workers ( hcws ) ( 13 ) . the numbers of screened patients and hcws and the number of secondarily colonized patients and hcws were obtained . a secondary case - patient was defined as a patient with mrsa with a spa type identical or related to that from the index case - patient , detected during contact screening of a patient or hcw . newly identified mrsa carriers with mrsa spa types that were unrelated to that of an index case - patient were considered incidental findings . the study was approved by the medical research ethics committee of the university medical center utrecht . for all mrsa isolates , single - locus dna sequencing of the repeat region of staphylococcus protein a gene ( spa typing ) was performed by the national reference laboratory of the netherlands ( national institute for public health and the environment [ rivm ] ) , as described ( 14 ) , by use of the ridom staphtype program ( www.ridom.de ) to allocate spa types . mrsa isolates were considered to be associated with livestock if they had a livestock - associated spa type : t011 , t034 , t108 , t567 , t571 , t588 , t753 , t753 , t779 , t898 , t899 , t943 , t1184 , t1197 , t1254 , t1255 , t1451 , t1456 , t1457 , t2123 , t2287 , t2329 , t2330 , t2383 , t2582 , t2748 , t2971 , t2974 , t3013 , t3014 , t3053 , t3146 , or t3208 ( 1517 ) . all other spa types were considered to not be associated with livestock . to identify potentially unknown livestock spa types , we used bionumerics 5.1 ( applied - maths , sint maartens - latem , belgium ) to create a spa - based minimal spanning tree of spa types considered livestock - associated and the spa types of index cases ( technical appendix figure ) . genes encoding for panton - valentine leukocidin ( pvl ) , luks - pv , and lukf - pv were identified by the reference laboratory , as described ( 18 ) . to estimate the strain - specific transmission capacity ra value , we used a previously described mathematical model based on queueing theory ( 19 ) . ra is defined as the average number of secondary cases caused by 1 primary case ( the index case ) when other patients are susceptible during a single hospital admission of the primary case - patient ( 20 ) . in this model , 3 rates determine the spread of mrsa in the hospital setting : the rate at which the mrsa strain spreads , the rate at which mrsa colonization of a patient is detected ( e.g. , microbiological cultures ) , and the rate at which a colonized patient can no longer be detected . the model predicts that the distribution of the number of patients colonized at the time of detection of the index case is geometrically distributed . the parameter of the geometric distribution of detected outbreak sizes was determined by using maximum - likelihood estimations . small detected outbreak sizes could correspond to either low transmission potential or high detection rate . patients with mrsa remain colonized during their hospital stay ; therefore , the infectious period ends at the time of discharge . genotype - specific discharge rates were calculated from admission and discharge data for index case - patients admitted to participating hospitals during the study period . the detection rate was based on all blood , respiratory tract , and wound cultures conducted during 2011 at the university medical center utrecht . the upper detection limit consists of all these cultures divided by the total number of patient days in 2011 . by combining the detection and discharge rate with the parameter of geometric distribution , we could calculate ra . categorical variables were assessed 2-sided by using or fisher exact tests , as appropriate ; a cutoff value of p < 0.05 was applied for significance . confidence intervals were calculated by using the profile - likelihood method . to test whether our assumption of a geometrical distribution of the detected outbreak sizes is justified by the data medical microbiologists and infection control practitioners in all 91 hospitals in the netherlands were contacted and asked to collect data concerning mrsa outbreaks and the results of subsequent contact screening retrospectively during june an index case - patient was defined as a hospitalized patient colonized or infected with mrsa and treated without use of barrier precautions . age , sex , and number of days hospitalized from mrsa detection through discharge were obtained . according to the guidelines in the netherlands , identification of a mrsa index case - patient initiates contact screening among contact patients and health care workers ( hcws ) ( 13 ) . the numbers of screened patients and hcws and the number of secondarily colonized patients and hcws were obtained . a secondary case - patient was defined as a patient with mrsa with a spa type identical or related to that from the index case - patient , detected during contact screening of a patient or hcw . newly identified mrsa carriers with mrsa spa types that were unrelated to that of an index case - patient were considered incidental findings . the study was approved by the medical research ethics committee of the university medical center utrecht . for all mrsa isolates , single - locus dna sequencing of the repeat region of staphylococcus protein a gene ( spa typing ) was performed by the national reference laboratory of the netherlands ( national institute for public health and the environment [ rivm ] ) , as described ( 14 ) , by use of the ridom staphtype program ( www.ridom.de ) to allocate spa types . mrsa isolates were considered to be associated with livestock if they had a livestock - associated spa type : t011 , t034 , t108 , t567 , t571 , t588 , t753 , t753 , t779 , t898 , t899 , t943 , t1184 , t1197 , t1254 , t1255 , t1451 , t1456 , t1457 , t2123 , t2287 , t2329 , t2330 , t2383 , t2582 , t2748 , t2971 , t2974 , t3013 , t3014 , t3053 , t3146 , or t3208 ( 1517 ) . all other spa types were considered to not be associated with livestock . to identify potentially unknown livestock spa types , we used bionumerics 5.1 ( applied - maths , sint maartens - latem , belgium ) to create a spa - based minimal spanning tree of spa types considered livestock - associated and the spa types of index cases ( technical appendix figure ) . genes encoding for panton - valentine leukocidin ( pvl ) , luks - pv , and lukf - pv were identified by the reference laboratory , as described ( 18 ) . to estimate the strain - specific transmission capacity ra value , we used a previously described mathematical model based on queueing theory ( 19 ) . ra is defined as the average number of secondary cases caused by 1 primary case ( the index case ) when other patients are susceptible during a single hospital admission of the primary case - patient ( 20 ) . in this model , 3 rates determine the spread of mrsa in the hospital setting : the rate at which the mrsa strain spreads , the rate at which mrsa colonization of a patient is detected ( e.g. , microbiological cultures ) , and the rate at which a colonized patient can no longer be detected . the model predicts that the distribution of the number of patients colonized at the time of detection of the index case is geometrically distributed . the parameter of the geometric distribution of detected outbreak sizes was determined by using maximum - likelihood estimations . small detected outbreak sizes could correspond to either low transmission potential or high detection rate . patients with mrsa remain colonized during their hospital stay ; therefore , the infectious period ends at the time of discharge . genotype - specific discharge rates were calculated from admission and discharge data for index case - patients admitted to participating hospitals during the study period . the detection rate was based on all blood , respiratory tract , and wound cultures conducted during 2011 at the university medical center utrecht . the upper detection limit consists of all these cultures divided by the total number of patient days in 2011 . by combining the detection and discharge rate with the parameter of geometric distribution categorical variables were assessed 2-sided by using or fisher exact tests , as appropriate ; a cutoff value of p < 0.05 was applied for significance . confidence intervals were calculated by using the profile - likelihood method . to test whether our assumption of a geometrical distribution of the detected outbreak sizes is justified by the data a total of 62 ( 69% ) of the 91 hospitals in the netherlands participated in the study , yielding data for 372 months of mrsa policy . during the 6-month study period , 158 mrsa index case - patients were identified in 57 hospitals , and none were identified in the other 5 hospitals . these numbers imply that , on average , in each hospital an index case was detected every 2.5 months . two index case - patients were excluded because subsequent contact screening was not performed , and 15 index case - patients were excluded because barrier precautions were implemented on the day of admission . for these 15 index case - patients , contact screenings of 55 patients and 293 hcws had identified 1 mrsa - colonized hcw with an unrelated mrsa genotype . for the remaining 141 index case - patients , 9,361 contacts ( 2,101 patients and 7,260 hcws ) were screened . in total , 65 spa types were identified among the 141 index cases ; the most common were t011 ( n = 25 [ 18% ] ) , t008 ( n = 12 [ 9% ] ) , and t002 ( n = 7 [ 5% ] ) . a total of 40 ( 29% ) isolates had spa types indicative of la - mrsa ; the most prevalent were t011 ( n = 25 ) , t034 ( n = 6 ) , and t108 ( n = 6 ) ( table 1 ) . * pvl , panton - valentine leukocidin ; la - mrsa : livestock - associated methicillin - resistant staphylococcus aureus . pvl positive : t022 , t040 , t044 , t054 , t131 , t311 , t318 , t437 , t657 , t690 , t791 , t852 , t2815 , t3523 , t7277 ; spa types causing outbreaks : t003 , t088 , t311 , t1399 , t7277 , t9634 . luk - pv genes , indicative of pvl , were detected in 24 ( 18% ) of 131 isolates investigated , all categorized as not being la - mrsa strains . among 12 mrsa spa type t008 isolates , pvl positivity was detected in 8 ( 67% ) ( table 1 ) , and among 10 ( 7% ) mrsa isolates , the presence of pvl was undetermined . mean age among all index case - patients was 53 years . among patients with la - mrsa and other mrsa genotypes , no significant differences were found except for sex ( table 2 ) . among index case - patients with la - mrsa genotypes , 83% were male , compared with 56% case - patients with other mrsa ( p = 0.004 ) . no statistically significant differences were found in length of hospital stay ( p = 0.222 ) and number of days in hospital without barrier precautions ( p = 0.503 ) between index case - patients with la - mrsa and patients with other mrsa genotypes ( table 2 ) . * la - mrsa : livestock - associated methicillin resistant staphylococcus aureus ; ra , single - admission reproduction number ; na , not applicable . among 141 postexposure screenings , mrsa carriers were identified for 18 ( 13% ) case - patients , yielding 39 newly identified colonized patients and 34 newly identified colonized hcws with mrsa . screening of index case - patients with la - mrsa identified 15 ( 21% ) carriers , and screening of index case - patients with other mrsa identified 58 ( 79% ) carriers . of these 73 mrsa carriers , 47 ( 64% ) were colonized with a mrsa spa type that was identical to that of the corresponding index case - patient ; 3 patients had spa types matching those of 2 index case - patients with la - mrsa , and 44 had spa types matching those of 16 index case - patients with other mrsa . transmission of mrsa ( i.e. , outbreaks ) was documented for 18 index patients ; the largest outbreak consisted of 12 secondary cases ( 8 patients and 4 hcws , spa type t1081 ) , and most outbreaks ( 11 [ 61% ] of 18 ) consisted of only 1 secondary case ( figure ) . contact screening for 1 index case - patient with la - mrsa ( t011 ) revealed 1 outbreak consisting of 3 patients with a mrsa genotype ( t067 ) that was not la - mrsa . these newly identified cases of mrsa carriage were considered to be not associated with the index case with an la - mrsa genotype . number of outbreaks and outbreak sizes ( number of cases , excluding the index case ) . la - mrsa , livestock - associated methicillin - resistant staphylococcus aureus ; other mrsa , mrsa not associated with livestock . during 2011 , a total of 6,819 blood , 4,828 respiratory tract , and 1,132 wound cultures were performed . for the upper limit of detection , we used only 1 culture per patient per day , yielding 11,903 relevant cultures , divided by the number of patient - days ( 241,319 ) ( technical appendix table a ) . the ratio between detection and discharge rates did not differ much between patients with la - mrsa and other mrsa ( technical appendix table a ) . the parameter for geometric distribution for la - mrsa and other mrsa is also provided in the online technical appendix . there was no reason to reject the hypothesis of a geometrically distributed outbreak size for la - mrsa ; but the hypothesis was rejected for other mrsa ( p<0.05 ) . based on the genotype - specific ratio between detection and discharge rates , ra values were 0.43 ( 95% ci 0.320.56 ) , 0.12 ( 95% ci 0.030.31 ) , and 0.52 ( 95% ci 0.380.69 ) for all 27 genotypes , la - mrsa , and other mrsa , respectively . according to these ra - values , the transmissibility of la - mrsa was considered 4.4 times lower than that of other mrsa ( 0.12/0.52 ) . the ra value for pvl - positive strains was 0.31 ( 95% ci 0.140.58 ) . using data from 62 hospitals in the netherlands , comprising 372 months of mrsa policy , we determined that livestock - associated mrsa genotypes , compared with other mrsa genotypes , are 4.4 times less likely to spread in the hospital . our findings in this study add substantial knowledge to findings from our previous study of hospitals in the netherlands in 2005 ( 10,11 ) . the current study included a larger cohort of hospitals and genotyping of all isolates . in our previous study , we compared smai non - typeable mrsa to other mrsa genotypes without further genotyping . moreover , in the current study , we collected more detailed patient information , such as admission and discharge dates and the number of days that index and secondary case - patients were treated without barrier precautions , which enabled more precise estimation of parameters . absence of significant differences in age , length of hospital stay , or number of days not spent in isolation between index case - patients with la - mrsa and those with other mrsa reduces the possibility that the differences in transmission capacity resulted from differences in patient characteristics . the only difference was that la - mrsa index case - patients were more likely to be male , reflecting sex distributions among pig farmers and veal calf farmers . both are at risk for colonization with mrsa ; however , infectious period and infectivity may differ . second , all carriers were assumed to be equally infectious ; whereas , superspreaders could play a major role in the transmission of mrsa in certain outbreaks . the consequences of these assumptions have been discussed in detail elsewhere ( 10 ) . , mrsa outbreaks must be rare and rigorous screening must be performed after the identification of an index case . if multiple outbreaks of the same genotype occur on the same ward , ra would be an overestimation . here , spa typing was used to identify cases of transmission between index and secondary case - patients . among la - mrsa , 63% were spa type t011 ; whereas , other mrsa consist of many different spa types . the high prevalence of la - mrsa in pig - dense areas combined with the homogeneity of spa types could lead to an actual overestimation of these transmission events ( and the estimated ra values of la - mrsa ) . la - mrsa comprise a well - defined set of spa types , most commonly t011 , t034 , and t108 ; whereas , other mrsa comprise a highly heterogeneous group with hospital - associated genotypes and pvl - positive , community - associated genotypes ( 21 ) . almost 25% of all other mrsa were pvl positive , which is considered a characteristic of community - associated mrsa . although 25% seems high , the actual incidence of index case - patients with pvl - positive mrsa was 24 in 379 hospital months , comprising an average of 1 index case per 16 months per hospital . in contrast to la - mrsa and hospital - associated mrsa , there are no established risk factors in the netherlands for colonization with ca - mrsa , and unknown carriers of these genotypes will not be screened when admitted to hospital ( 13 ) . although another study from the netherlands reported a high number of pvl - positive isolates in mrsa - colonized patients without risk factors as described in the national guidelines ( 13,22 ) , our findings demonstrate that pvl - positive strains do not constitute a major risk for health care settings in the netherlands because the introduction rate and the ra in the absence of barrier precautions ( ra for pvl - positive strains 0.31 , 95% ci 0.140.58 ) are low . nevertheless , if admission rates increase , outbreaks could emerge despite ra values < 1 ( 20 ) . spa type t1081 was associated with the highest number of outbreaks and with most secondary cases . this spa type has also been associated with outbreaks in nursing homes across the netherlands . for spa type t1081 , the mic for cefoxitin ( data not shown ) is low ( 3 mg / l [ range 38 mg / l ] ) , hampering laboratory detection during routine procedures , which might have contributed to the high number of secondary cases found with this spa type . whole - genome analyses of multiple sequence type 398 s. aureus strains suggests that la - mrsa originated from methicillin - susceptible s. aureus that crossed species barriers from humans to livestock , where it acquired resistance traits ( 23 ) . it has been hypothesized that the transition from humans to animals was associated with the loss of several human immune evasion genes , carried on phage sa3 , which may prevent human niche adaptation of la - mrsa ( 24 ) . the epidemiology of ca - mrsa in europe differs markedly from that in the united states ; > 50% of community - acquired s. aureus infections in europe are caused by a few pvl - positive clones ( 25 ) . there is a paucity of data on the nosocomial transmission capacity of ca - mrsa . in hospitals in the netherlands , though , the estimated ra of ca - mrsa , consisting of a heterogeneous group of genotypes , was estimated to be 0.07 ( 95% ci 0.000.28 ) ( 26 ) , and in the hospitals participating in the present study , the ra value of pvl mrsa strains was 0.31 , 95% ci 0.140.58 . the differences between europe and the united states regarding the epidemiology of pvl - positive ca - mrsa , therefore , remain unexplained . current guidelines in the netherlands recommend mrsa screening for all patients with professional exposure to livestock , and many hospitals treat such patients in isolation while screening results are pending ( i.e. , preemptive isolation ) . in a previous multicenter study in the netherlands , we demonstrated the cost - effectiveness and safety of not preemptively isolating patients when using rapid diagnostic testing ( 27 ) . the confirmation of the lower transmissibility of la - mrsa ( in combination with the low ra value ) and the results of the previous study provide evidence that preemptive isolation may not be necessary for la - mrsa , which would substantially enhance the feasibility of this highly successful infection control policy . statistical methods used to calculate single - admission reproduction number for livestock - associated methicillin - resistant staphylococcus aureus in 62 hospitals in the netherlands .

previous findings have suggested that the nosocomial transmission capacity of livestock - associated methicillin - resistant staphylococcus aureus ( la - mrsa ) is lower than that of other mrsa genotypes . we therefore performed a 6-month ( june 1november 30 , 2011 ) nationwide study to quantify the single - admission reproduction number , ra , for la - mrsa in 62 hospitals in the netherlands and to compare this transmission capacity to previous estimates . we used spa typing for genotyping . quantification of ra was based on a mathematical model incorporating outbreak sizes , detection rates , and length of hospital stay . there were 141 index cases , 40 ( 28% ) of which were la - mrsa . contact screening of 2,101 patients and 7,260 health care workers identified 18 outbreaks ( 2 la - mrsa ) and 47 secondary cases ( 3 la - mrsa ) . ra values indicated that transmissibility of la - mrsa is 4.4 times lower than that of other mrsa ( not associated with livestock ) .

SECTION 1. SHORT TITLE. This Act may be cited as the ``District of Columbia Mental Health Civil Commitment Modernization Act of 2004''. SEC. 2. COMPOSITION, APPOINTMENT, AND ORGANIZATION OF COMMISSION ON MENTAL HEALTH. (a) In General.--Section 21-502, District of Columbia Official Code, is amended to read as follows: ``Sec. 21-502. Commission on Mental Health; composition; appointment and terms of members; organization; chairperson; salaries ``(a) The Commission on Mental Health is continued. The Chief Judge of the Superior Court of the District of Columbia shall appoint the members of the Commission, and the Commission shall be composed of 9 members and an alternate chairperson. One member shall be a magistrate judge of the Court appointed pursuant to title 11, District of Columbia Official Code, who shall be a member of the bar of the Court and has engaged in active practice of law in the District of Columbia for a period of at least 5 years prior to his or her appointment. The magistrate judge shall be the Chairperson of the Commission and act as the administrative head of the Commission. The Chairperson shall preside at all hearings and direct all of the proceedings before the Commission. Eight members of the Commission shall be psychiatrists or qualified psychologists, as those terms are defined in section 21-501, who have not had less than 5 years of experience in the diagnosis and treatment of mental illness. ``(b)(1) Appointment of members of the Commission shall be for terms of 4 years. ``(2) The initial appointment of a psychiatrist or a qualified psychologist shall be for a probationary period of one year. After the initial one-year probationary appointment, subsequent appointments of the psychiatrist or qualified psychologist shall be for terms of 4 years. ``(c) The psychiatrist or qualified psychologist members of the Commission shall serve on a part-time basis and shall be rotated by assignment of the Chief Judge of the Court, so that at any one time the Commission shall consist of the Chairperson and 2 members, each of whom is either a psychiatrist or a qualified psychologist. Members of the Commission who are psychiatrists or qualified psychologists may practice their professions during their tenures of office, but may not participate in the disposition of a case of a person in which they have rendered professional service or advice. ``(d) The Chief Judge of the Court shall appoint a magistrate judge of the Court to serve as an alternate Chairperson of the Commission. The alternate Chairperson shall serve on a part time basis and act as Chairperson in the absence of the permanent Chairperson. ``(e) The rate of compensation for the members of the Commission who are psychiatrists or qualified psychologists shall be fixed by the Executive Officer of the Court.''. (b) Clerical Amendment.--The item relating to section 21-502 in the table of sections for subchapter I of chapter 5 of title 21, District of Columbia Official Code, is amended to read as follows: ``21-502. Commission on Mental Health; composition; appointment and terms of members; organization; chairperson; salaries.''. (c) Effective Date; Transition for Current Members.--The amendments made by this section shall take effect on the date of the enactment of this Act, except nothing in this section or the amendments made by this section may be construed to affect the appointment or term of service of any individual who serves as a member or alternate member of the Commission on Mental Health (including an individual who serves as the Chairperson or alternate Chairperson of the Commission) on such date. SEC. 3. COMMISSION MEMBERS DEEMED COMPETENT AND COMPELLABLE WITNESSES AT MENTAL HEALTH PROCEEDINGS. Section 21-503(b), District of Columbia Official Code, is amended by striking ``The Commission, or any of the members thereof,'' and inserting ``Commission members who are psychiatrists or qualified psychologists''. SEC. 4. DETENTION FOR EMERGENCY OBSERVATION AND DIAGNOSIS. Section 21-526, District of Columbia Official Code, is amended by adding at the end the following new subsections: ``(c) The maximum period of time for detention for emergency observation and diagnosis may be extended for up to 21 days, if judicial proceedings under subchapter IV of this chapter have been commenced before the expiration of the order entered under section 21- 524 and a psychiatrist or qualified psychologist has examined the person who is the subject of the judicial proceedings and is of the opinion that the person being detained remains mentally ill and is likely to injure himself or others as a result of the illness unless the emergency detention is continued. For good cause shown, the Court may extend the period of detention for emergency observation and diagnosis. The period of detention for emergency observation and diagnosis may be extended pursuant to section 21-543(b) or following a hearing before the Commission pursuant to subsections (d) and (e) of this section. ``(d) If the Commission, at the conclusion of its hearing pursuant to section 21-542, has found that the person with respect to whom the hearing was held is mentally ill and, because of the mental illness, is likely to injure himself or others if not committed, and has concluded that a recommendation of inpatient commitment is the least restrictive alternative available to prevent the person from injuring himself or others, the detention for emergency observation and diagnosis may be continued by the Department or hospital-- ``(1) pending the conclusion of judicial proceedings under subchapter IV of this chapter; ``(2) until the Court enters an order discharging the person; or ``(3) until the Department or hospital determines that continued hospitalization is no longer the least restrictive form of treatment appropriate for the person being detained. ``(e) If the Commission, at the conclusion of its hearing, finds that the person is mentally ill, is likely to injure himself or other persons as a result of mental illness if not committed, and that outpatient treatment is the least restrictive form of commitment appropriate, then, within 14 days of the date of the hearing, the person shall be discharged from inpatient status and shall receive outpatient mental health services or mental health supports as an emergency nonvoluntary patient consistent with this subchapter, pending the conclusion of judicial proceedings under subchapter IV of this chapter.''. SEC. 5. REPRESENTATION BY COUNSEL OF PERSONS ALLEGED TO BE MENTALLY ILL. Section 21-543, District of Columbia Official Code, is amended-- (1) in subsection (a) (as redesignated by section 2(r)(1) of the Mental Health Civil Commitment Act of 2002), by striking the last sentence; and (2) by adding at the end the following new subsection: ``(b) The Commission may not grant a continuance for counsel to prepare his case for more than 5 days. The Commission may grant continuances for good cause shown for periods of up to 14 days. If the Commission grants a continuance, the emergency observation and detention of the person about whom the hearing is being held shall be extended for the duration of the continuance.''. SEC. 6. HEARING AND DETERMINATION ON QUESTION OF MENTAL ILLNESS. (a) In General.--Section 21-545, District of Columbia Official Code, is amended-- (1) in subsection (a), by striking ``jury trial'' each place it appears and inserting ``jury trial or a trial by the Court''; (2) by amending subsection (b) to read as follows: ``(b)(1) If the Court or jury finds that the person is not mentally ill or is not likely to injure himself or others as a result of mental illness, the Court shall dismiss the petition and order the person's release. ``(2) If the Court or jury finds that the person is mentally ill and, because of that mental illness, is likely to injure himself or others if not committed, the Court may order the person's commitment to the Department or to any other facility, hospital, or mental health provider that the Court believes is the least restrictive alternative consistent with the best interests of the person and the public. An order of commitment issued pursuant to this paragraph shall be for a period of one year.''; and (3) by adding at the end the following new subsections: ``(c) The psychiatrists and qualified psychologists who are members of the Commission shall be competent and compellable witnesses at a hearing or trial held pursuant to this chapter. ``(d) The jury to be used in any case where a jury trial is demanded under this chapter shall be impaneled, upon order of the Court, from the jurors in attendance upon other branches of the Court, who shall perform the services in addition to and as part of their duties in the Court.''. (b) Effective Date.--The amendments made by this section shall apply with respect to trials under section 21-545, District of Columbia Code, which are initiated on or after the date of the enactment of this Act. SEC. 7. RENEWAL OF COMMITMENT STATUS BY COMMISSION. (a) In General.--Subchapter IV of chapter 5 of title 21, District of Columbia Official Code, is amended by inserting after section 21-545 the following new section: ``Sec. 21-545.01. Renewal of commitment status by commission; review by Court ``(a) At least 60 days prior to the expiration of an order of commitment issued pursuant to section 21-545 or this section, the chief clinical officer of the Department, or the chief of service of the facility, hospital, or mental health provider to which the person is committed may petition the Commission for a renewal of the order of commitment for that person. For good cause shown, a petition of commitment may be filed within the last 60 days of the one-year period of commitment. The petition for renewal of commitment shall be supported by a certificate of a psychiatrist or qualified psychologist stating that he has examined the person and is of the opinion that the person is mentally ill, and, because of the illness, is likely to injure himself or other persons if not committed. The term of the renewed commitment order shall not exceed one year. ``(b) Within 3 days of the filing of a petition under subsection (a) of this section, the Commission shall send a copy of the petition and supporting certificate by registered mail to the person with respect to whom the petition was filed and by regular mail to the person's attorney. ``(c) The Commission shall promptly examine a person for whom a petition is filed under subsection (a) of this section, and, in accordance with the procedures described in sections 21-542 and 21-543, shall thereafter promptly hold a hearing on the issue of the person's mental illness and whether, as a result of a mental illness, the person is likely to injure himself or other persons if not committed. ``(d) If the Commission finds, after a hearing under subsection (c) of this section, that the person with respect to whom the hearing was held is no longer mentally ill, or is not mentally ill to the extent that the person is likely to injure himself or other persons if not committed, the Commission shall immediately order the termination of the commitment and notify the Court of that fact in writing. ``(e) If the Commission finds, after a hearing under subsection (c) of this section, that the person with respect to whom the hearing was held remains mentally ill to the extent that the person is likely to injure himself or others if not committed, the Commission shall order the renewal of the commitment of the person for an additional term not to exceed one year and shall promptly report that fact, in writing, to the Court. The report shall contain the Commission's findings of fact and conclusions of law. A copy of the report shall be served by registered mail on the person with respect to whom the hearing was held and by mail on the person's attorney. ``(f) If a petition for a renewal of an order of commitment is pending at the expiration of the commitment period ordered under section 21-545 or this section, the Court may, for good cause shown, extend the period of commitment pending resolution of the renewal petition. ``(g) Within the last 30 days of the period of commitment, the chief clinical officer of the Department, or the chief of service of the facility, hospital, or mental health provider to which a person is committed, shall notify the Court which ordered the person's commitment pursuant to section 21-545 or this section of the decision not to seek renewal of commitment. Notice to the Court shall be in writing and a copy of the notice shall be mailed to the person who was committed and the person's attorney. ``(h)(1) A person for whom the Commission orders renewed commitment pursuant to subsection (e) of this section may seek a review of the Commission's order by the Superior Court of the District of Columbia, and the Commission, orally and in writing, shall advise the person of this right. ``(2) A review of the Commission's order of renewed commitment, in whole or in part, may be made by a judge of the appropriate division sua sponte and shall be made upon a motion of one of the parties made pursuant to procedures established by rules of the Court. The reviewing judge shall conduct such proceedings as required by the rules of the Court. ``(3) An appeal to the District of Columbia Court of Appeals may be made only after a judge of the Court has reviewed the Commission's order of renewed commitment.''. (b) Clerical Amendment.--The table of sections of subchapter IV of chapter 5 of title 21, District of Columbia Official Code, is amended by inserting after the item relating to section 21-545 the following: ``21-545.01. Renewal of commitment status by Commission; review by Court.''. Speaker of the House of Representatives. Vice President of the United States and President of the Senate.

District of Columbia Mental Health Civil Commitment Modernization Act of 2004 - (Sec. 2) Amends the District of Columbia Code to modify the composition of, appointment to, and organization of the Commission on Mental Health. (Sec. 3) Limits to Commission members who are psychiatrists or qualified psychologists (currently, the Commission or any of its members) the competency to be witnesses at any mental health proceeding. (Sec. 4) Authorizes Superior Court extension for up to 21 days, under certain conditions, of the period for which an individual may be detained for emergency observation and diagnosis in a facility, hospital, or mental health provider. (Sec. 5) Authorizes the Commission to grant a continuance of up to 14 days beyond the current allowed recess of five days for the counsel of persons alleged to be mentally ill to prepare a case. Requires extension of the emergency observation and detention period for the subject of the hearing for the duration of the continuance. (Sec. 6) Revises procedures on hearings and determination of mental illness. Limits to the least restrictive alternative the kind of facility to which a Court may order a person's commitment, consistent with the best interests of the person and the public. (Sec. 7) Authorizes a one-year renewal of commitment status by the Commission, subject to judicial review, of a person in a facility, hospital, or mental health provider.

the lower esophageal sphincter is a circular smooth muscle barrier between the stomach and the esophagus . the main function of this sphincter is to prevent gastric contents from regurgitating into the esophagus and pharynx . reduced pressure and consequent reduction in the gastro - esophageal pressure gradient ( gepg ) may promote gastro - esophageal reflux , which increases the chances of aspiration , and thus contribute to aspiration pneumonia , pneumonitis , and associated morbidity . many sedatives and anesthetics reduce lower esophageal sphincter pressure ( lesp ) , but lesp per se is difficult to measure [ 24 ] . the relationship between sedation level and lower esophageal sphincter functionality is of considerable clinical interest . the most widely used and best validated monitor of hypnotic state during sedation and anaesthesia is the bispectral index ( bis ) , a measure derived from processed electroencephalographic signals . an alternative in sedated subjects is the observer s assessment of alertness and sedation ( oaa / s ) score , a well - established and commonly used tool for evaluating sedative drugs . previous studies have shown a good correlation between anesthetic dose and reduced lesp [ 24 ] , suggesting that there may also be an association between sedation level and lesp . we thus evaluated the association between lower esophageal sphincter pressure and 2 measures of sedation : bis and the responsiveness component of the observer s assessment of alertness score . we report a new analysis of results obtained during a previously published study in which we evaluated the effects of 2 different drugs and different doses on lower esophageal sphincter pressures . after obtaining approval from the university of louisville institutional review board , and informed consent of volunteers exclusion criteria were obesity with body mass index more than 30 kg / m , pregnancy , drug or alcohol abuse , heartburn reported to occur more than once per week , history of gastro - esophageal reflux disease , or a history of any esophagus or stomach surgery . volunteers were randomly allocated to propofol or dexmedetomidine sedation on 2 separate study days according to a computer - generated randomization . propofol and dexmedetomidine were given via target - controlled infusion using a harvard infusion pump ( harvard clinical technology , inc . , south natick , ma ) driven by stanpump software ( available at http://www.opentci.org ) using the schnider model . propofol was given in increasing steps to target effect - site concentration of 1 , 2 , and 4 g / ml ; dexmedetomidine was given to target plasma concentration of 0.6 , 1.2 , and 2.4 ng / ml . volunteers were monitored through the study period for electrocardiogram , non - invasive blood pressure , heart rate , pulse oximeter saturation ( spo2 ) and end - tidal pco2 . bis ( bispectral index , bis xp 3.4 monitor , aspect medical systems , newton , ma , usa ) was recorded continuously and sedation level was evaluated every 5 minutes with the oaa / s score . an esophageal manometry probe was passed transnasally , and lower - esophageal sphincter ( les ) was identified using the station pull - through technique at 1-cm intervals as described by mittal et al . pressures were again recorded after 20 and 40 minutes of sedative infusion at each concentration . esophageal and gastric pressures were evaluated by an investigator blinded to drug and dose allocations . first , exploratory graphical analyses were performed to informally assess bivariate relationships between lesp and bis and between lesp and oaa / s . these graphical analyses are useful for visually evaluating overall trends , but do not yield a formal measure of association and do not account for potential intra - subject correlation exhibited by repeated measurements within a volunteer . thus , in order to formally estimate the degree of the relationship between lesp and a given predictor of interest ( for instance , bis ) , a generalized estimating equation ( gee ) model was developed . this model appropriately accounts for the intra - subject correlation while estimating the slope ( our model incorporated an exchangeable correlation structure ) . in the gee model , we considered the potential for the relationship between bis and lesp to depend on the type of sedative drug administered by testing the interaction between type of sedative and bis ( generalized score test ) ; if this interaction term was statistically significant at the 0.10 level , separate slopes were estimated for each drug ; otherwise , a common slope was estimated after adjusting for type of sedative . the same gee modeling approach was used to characterize the relationship between oaa / s and lesp . for each predictor of interest , a ( wald ) chi - squared test for gee model terms was used to test the significance of the relationship with lesp . since there were 2 predictors of interest ( bis and oaa / s ) , we used an outcome - specific significance level of 0.025 , which reflects the bonferroni correction for 2 comparisons . if a significant interaction term was found , we similarly employed the bonferroni correction to test the drug - specific slope measuring the dependence of lesp on the relevant predictor at the 0.0125 significance level . in addition to estimating the relationships between the respective exposures and lesp , we considered the ability of each exposure to explain observed variance among lesp measurements that is , over and above that explained by type of sedative drug administered alone . the likelihood ratio r statistic for gee models is a quantity ranging from 0 to 1 , where a value of 0 represents independence between drug - adjusted lesp and the relevant predictor ( for instance , bis ) and a value of 1 represents perfect explanatory capability of the predictor . this likelihood ratio r statistic is thus analogous to a partial r from a standard linear regression model ; the only difference is that it adjusts for the intra - subject correlation exhibited by repeated measures on a volunteer . r software version 2.12.1 ( the r foundation for statistical computing , vienna , austria ) and sas software version 9.2 ( sas institute , cary , nc , usa ) were used for the statistical analysis . of course it is always ideal in any study if the relationship of interest can be visualized graphically we considered using different symbols for each of the volunteers but this would make the scatterplot more confusing . connecting them with lines would be more confusing , since patients may not have smoothly transitioned down the bis and oaa / s scales with decreasing lesp ( for example , there might be a line going from ( lesp=30 , bis=80 ) to ( 20,60 ) to ( 10,80 ) ) . it is hoped that readers will recognize the summary nature of the figures and regard to the gee analysis as the formal evaluation of the hypotheses . after obtaining approval from the university of louisville institutional review board , and informed consent of volunteers , we studied 11 healthy volunteers aged 18 to 40 years . exclusion criteria were obesity with body mass index more than 30 kg / m , pregnancy , drug or alcohol abuse , heartburn reported to occur more than once per week , history of gastro - esophageal reflux disease , or a history of any esophagus or stomach surgery . volunteers were randomly allocated to propofol or dexmedetomidine sedation on 2 separate study days according to a computer - generated randomization . propofol and dexmedetomidine were given via target - controlled infusion using a harvard infusion pump ( harvard clinical technology , inc . , south natick , ma ) driven by stanpump software ( available at http://www.opentci.org ) using the schnider model . propofol was given in increasing steps to target effect - site concentration of 1 , 2 , and 4 g / ml ; dexmedetomidine was given to target plasma concentration of 0.6 , 1.2 , and 2.4 ng / ml . volunteers were monitored through the study period for electrocardiogram , non - invasive blood pressure , heart rate , pulse oximeter saturation ( spo2 ) and end - tidal pco2 . bis ( bispectral index , bis xp 3.4 monitor , aspect medical systems , newton , ma , usa ) was recorded continuously and sedation level was evaluated every 5 minutes with the oaa / s score . an esophageal manometry probe was passed transnasally , and lower - esophageal sphincter ( les ) was identified using the station pull - through technique at 1-cm intervals as described by mittal et al . pressures were again recorded after 20 and 40 minutes of sedative infusion at each concentration . esophageal and gastric pressures were evaluated by an investigator blinded to drug and dose allocations . first , exploratory graphical analyses were performed to informally assess bivariate relationships between lesp and bis and between lesp and oaa / s . these graphical analyses are useful for visually evaluating overall trends , but do not yield a formal measure of association and do not account for potential intra - subject correlation exhibited by repeated measurements within a volunteer . thus , in order to formally estimate the degree of the relationship between lesp and a given predictor of interest ( for instance , bis ) , a generalized estimating equation ( gee ) model was developed . this model appropriately accounts for the intra - subject correlation while estimating the slope ( our model incorporated an exchangeable correlation structure ) . in the gee model , we considered the potential for the relationship between bis and lesp to depend on the type of sedative drug administered by testing the interaction between type of sedative and bis ( generalized score test ) ; if this interaction term was statistically significant at the 0.10 level , separate slopes were estimated for each drug ; otherwise , a common slope was estimated after adjusting for type of sedative . the same gee modeling approach was used to characterize the relationship between oaa / s and lesp . for each predictor of interest , a ( wald ) chi - squared test for gee model terms was used to test the significance of the relationship with lesp . since there were 2 predictors of interest ( bis and oaa / s ) , we used an outcome - specific significance level of 0.025 , which reflects the bonferroni correction for 2 comparisons . if a significant interaction term was found , we similarly employed the bonferroni correction to test the drug - specific slope measuring the dependence of lesp on the relevant predictor at the 0.0125 significance level . in addition to estimating the relationships between the respective exposures and lesp , we considered the ability of each exposure to explain observed variance among lesp measurements that is , over and above that explained by type of sedative drug administered alone . the likelihood ratio r statistic for gee models is a quantity ranging from 0 to 1 , where a value of 0 represents independence between drug - adjusted lesp and the relevant predictor ( for instance , bis ) and a value of 1 represents perfect explanatory capability of the predictor . this likelihood ratio r statistic is thus analogous to a partial r from a standard linear regression model ; the only difference is that it adjusts for the intra - subject correlation exhibited by repeated measures on a volunteer . r software version 2.12.1 ( the r foundation for statistical computing , vienna , austria ) and sas software version 9.2 ( sas institute , cary , nc , usa ) were used for the statistical analysis . of course it is always ideal in any study if the relationship of interest can be visualized graphically we considered using different symbols for each of the volunteers but this would make the scatterplot more confusing . connecting them with lines would be more confusing , since patients may not have smoothly transitioned down the bis and oaa / s scales with decreasing lesp ( for example , there might be a line going from ( lesp=30 , bis=80 ) to ( 20,60 ) to ( 10,80 ) ) . it is hoped that readers will recognize the summary nature of the figures and regard to the gee analysis as the formal evaluation of the hypotheses . eleven volunteers participated ; they were aged 244 years , had a body weight of 7012 kg , and were 1755 cm tall . fifty observations on these volunteers were available for analysis . without considering the intra - subject correlation , an overall slightly - declining relationship between lesp and deepening sedation as measured by bis was noted , and this relationship appeared not to differ between propofol and dexmedetomidine ( figure 1 ) . indeed , the interaction term in the gee model that adjusted for the intra - subject correlation was not statistically significant ( p=0.14 , generalized score test ) . but after adjusting for the main effect of type of sedative drug administered , we found a significant relationship between lesp and bis ( p=0.0043 , chi - squared test ) : a deepening of sedation as measured by a decrease in bis of 10% was associated with a decrease [ bonferroni - adjusted 95% confidence interval ] in lesp of 1.34 [ 2.39 , 0.29 ] mmhg . bis explained an additional 10.4% of variability in lesp over and above that explained by type of sedative drug administered , as given by the likelihood ratio r. box plots characterizing the distribution of lesp for each drug - oaa / s combination are given in figure 2 . due to the fact that sedation is generally deeper with propofol than with dexmedetomidine , we only had 3 measurements where the oaa / s score was less than 3 . based on a visual inspection of the box plots , a moderately declining relationship was observed among measurements obtained under propofol sedation , while a flat - to - increasing relationship was observed among the dexmedetomidine measurements . in the gee analysis for oaa / r , however , there was no such evidence of differing slopes for the 2 sedative drugs ( generalized score test p=0.22 for the interaction ) . after adjusting for the type of sedative drug administered , lesp significantly declined with declining oaa / r ( p=0.001 , chi - squared test ) : a unit decrease of oaa / s was associated with a decrease [ bonferroni - adjusted 95% confidence interval ] in lesp of 2.01 [ 3.20 , 0.81 ] mmhg . oaa / s scores explained 20.9% of the observed variability in lesp , over and above that explained by type of sedative drug administered . most anesthetic and sedation techniques reduce les tone , thus presumably increasing the chance of patients regurgitating gastric content into the esophagus and consequent risk of aspiration . aspiration is relatively rare , but the associated morbidity and mortality is devastating , and includes detrimental aspiration pneumonitis and pneumonia . microaspirations from the stomach and oropharynx are believed to play a major role in etiology of nosocomial and ventilator - associated pneumonia . preventing aspiration thus likely reduces the risk of ventilator - associated pneumonia which justifies careful consideration of preventive strategies and bundled - care approach . propofol and dexmedetomidine are frequently used sedative agents in the perioperative setting and also in the icu . in our previous study , both agents caused dose - dependent reductions in lower esophageal sphincter pressures . there is no simple way to determine or estimate lesp ; measurement of the sphincter pressure is a complicated process requiring expertise and special equipment . the bispectral index ( bis ) is an empirically calibrated value derived from processed adult eeg data , which correlates with depth of the hypnotic component of general anesthesia in adults . bis is frequently used in the perioperative setting and also has been validated in some groups of icu patients to determine the depth of sedation [ 1315 ] . our results demonstrate that bis measurements correlate significantly with lesp . that there is a correlation between bis and lesp is unsurprising , considering that previous studies have also demonstrated a dose - dependent action of different anesthetics on lesp . for example thrn et al . showed that inhalation induction with sevoflurane titrated to a bis of 40 resulted in significant decreases in lesp and barrier pressure , although the barrier pressure was kept positive in all patients . there is also a slight relationship between the frequency of spontaneous esophageal contractions and end - tidal halothane concentration , suggesting that anesthetic depth and esophageal muscle tone are related . although we found a statistically significant relation between the bis and lesp measurements , the strength of the correlation was marginal . furthermore , the strength of correlation may vary in different patient populations under different sedation regimens . for example , it may be much greater in critical care patients compared to the healthy volunteers studied in this trial . it is thus reasonable to conclude that deeper hypnotic planes ( lower bis ) are very likely to be associated with further reduced lesp . while there was a weak relationship between oaa / s sedation scores and lesp for propofol , there was no relationship with dexmedetomidine sedation . the difference may be a consequence of distinct clinical profiles of the 2 drugs . both provide good clinical sedation ; but unlike patients given propofol , those given dexmedetomidine remain arousable . a corollary is that oaa / s may not be the appropriate clinical scale for use in evaluating dexmedetomidine sedation . but even with propofol , the strength of the correlation between oaa / s and lesp was too weak to reliably predict lesp as a function of bis , or to reliably use oaa / s to titrate to safe esophageal sphincter pressures . another explanation would simply be the major difference between bis and oaa / s as the sedation assessment tools . one of them is a passive measure , which records eeg waveforms from a probe placed on forehead ( bis ) . the other is an active assessment tool , which requires an observer to physically stimulate the subject to monitor the response ( oaa / s ) . in spite of many obvious and subtle differences in these sedation assessment systems , we concluded that oaa / s like bis is related to lesp ( at least with propofol ) , but that the strength of the correlation only permits the general conclusion that deeper sedative and hypnotic planes reduce lesp , and presumably augment aspiration risk . we found that there is significant correlation between bis , oaa / s scale and lesp . sedation should be carefully titrated and maintained at the lightest effective level in patients at risk of aspiration .

summarybackgroundmany anesthetics reduce lower esophageal sphincter pressure ( lesp ) and consequently the gastro - esophageal pressure gradient ( gepg ) ; thus they may promote gastro - esophageal reflux and contribute to aspiration pneumonia . our goals were to evaluate the association between lesp and 2 measures of sedation : bispectral index ( bis ) and the responsiveness component of the observer s assessment of alertness score ( oaa / s).material / methodseleven healthy volunteers were each sedated on 2 separate days . subjects were given sedative infusions of increasing target plasma concentrations of dexmedetomidine or propofol . lesp and gepg were recorded after starting each infusion phase . generalized estimating equation modeling was used to assess the relationship between lesp and , respectively , bis and oaa / s . the existence of a drug - dependent association was evaluated within these models by testing an interaction term . wald tests were used to evaluate the relationships within the models.resultswe found a significant relationship between lesp and bis ( p=0.0043 ) after adjusting for the main effect of sedative type a deepening of sedation as measured by a decrease in bis of 10% was associated with a decrease [ bonferroni - adjusted 95% ci ] in lesp of 1.34 [ 2.39 , 0.29 ] mmhg . after adjusting for the main effect of sedative drug , lesp significantly declined with declining oaa / s ( p=0.001 ) ; a unit decrease of oaa / s was associated with a decrease [ bonferroni - adjusted 95% ci ] in lesp of 2.01 [ 3.20 , 0.81 ] mmhg.conclusionsdeeper sedation , as measured by either bis or oaa / s , significantly reduces lesp .

Story highlights Manning tweets out confirmation: "I'm OK" Manning remains under close observation (CNN) U.S. Army soldier Chelsea Manning, imprisoned for leaking classified documents, has tweeted a message confirming her health and safety following a suicide attempt. "I am okay. I'm glad to be alive. Thank you all for your love. I will get through this," she wrote on the social media site, adding the hashtag, #standwithchelsea I am okay. I'm glad to be alive. Thank you all for your love <3 I will get through this. #standwithchelsea — Chelsea Manning (@xychelsea) July 12, 2016 Although she does not have any Internet access in prison, Manning joined Twitter in April 2015 . She uses a voice phone to dictate her tweets to a communications firm, which posts them on her behalf. Her legal representatives released a statement Monday, confirming that she had attempted to take her own life. "After not connecting with Chelsea for over a week, we were relieved to speak with her this morning," the statement read. JUST WATCHED Chelease Manning: Punished for Caitlyn Jenner magazine Replay More Videos ... MUST WATCH Chelease Manning: Punished for Caitlyn Jenner magazine 00:45 Read More ||||| July 11, 2016 Today, Chelsea Manning spoke with her attorneys for the first time since her hospitalization last week. They have released the following statement on her behalf: For Immediate Release: July 11, 2016 Contact: Christina DiPasquale, 202.716.1953, [email protected] Chelsea Manning Confirms Health Status Through Her Attorneys Today, Chelsea Manning’s attorneys Chase Strangio, Vincent Ward and Nancy Hollander released the following statement jointly: “After not connecting with Chelsea for over a week, we were relieved to speak with her this morning. Though she would have preferred to keep her private medical information private, and instead focus on her recovery, the government’s gross breach of confidentiality in disclosing her personal health information to the media has created the very real concern that they may continue their unauthorized release of information about her publicly without warning. Due to these circumstances, Chelsea Manning requested that we communicate with the media and her friends and supporters on her behalf. “Last week, Chelsea made a decision to end her life. Her attempt to take her own life was unsuccessful. She knows that people have questions about how she is doing and she wants everyone to know that she remains under close observation by the prison and expects to remain on this status for the next several weeks. For us, hearing Chelsea’s voice after learning that she had attempted to take her life last week was incredibly emotional. She is someone who has fought so hard for so many issues we care about and we are honored to fight for her freedom and medical care.” ### You can write to Chelsea with your messages of support. Mail must be addressed as follows: CHELSEA E. MANNING 89289 1300 NORTH WAREHOUSE ROAD FORT LEAVENWORTH, KANSAS 66027-2304

– Chelsea Manning's attorneys confirmed Monday that she had indeed tried to commit suicide last week, but Manning herself sent a message out Monday night to reassure those worried about her, CNN reports. "I am okay. I'm glad to be alive. Thank you all for your love, I will get through this," she tweeted, including a heart symbol with her note. Meanwhile, Manning's lawyers issued a joint statement Monday that noted, "She knows that people have questions about how she is doing and she wants everyone to know that she remains under close observation by the prison and expects to remain on this status for the next several weeks." Manning, 28, who's serving a 35-year sentence in Kansas' Fort Leavenworth for sharing government documents with WikiLeaks, isn't allowed to use the Internet in prison: Instead, she dictates her tweets into a phone, and a communications company posts the tweets for her. (Manning was disciplined last year for having old toothpaste.)

gorham 's disease also called as vanishing bone disease , acute spontaneous absorption of bone , hemangiomatosis , lymphangiomatosis , is a rare disease characterized by proliferation of thin - walled vascular channels which leads to destruction and resorption of osseous matrix . numerous names have been used in the literature [ table 1 ] . synonyms used for gorham 's disease idiopathic osteolysis was first described in 1838 by jackson as a case of disappearing humerus and led him title his work as a boneless arm. it was romer in 1924 who reported first case in jaws . it was gorham in 1954 and gorham and stout in 1955 who presented a case series . the condition was named after these physicians , lemuel whittington gorham and arthur purdy stout as gorham and stout syndrome . since the initial description of this disease , 60 years have elapsed ; but the etiology of gorham 's disease is still very speculative . there is no evidence of a malignant , neuropathic , or infectious component involved in the causation of this disorder . the pathologic process is the replacement of normal bone by an aggressively expanding nonneoplastic vascular tissue similar to a hemangioma or lymphangioma . it is likely that the blood flow through these vessels is slow , which produces local hypoxia and lowering of the ph , favoring the activity of various hydrolytic enzymes . strong activity of acid phosphatase and leucine aminopeptidase in mononuclear perivascular cells which are in contact with bone indicates that these cells are important in the process of osseous resorption . gorham and stout hypothesized that trauma may trigger the process by stimulating the production of vascular granulation tissue and that osteoclastosis is not necessary . , have suggested that bone resorption in patients with gorham disease is due to enhanced osteoclast activity and interleukin 6 plays a role in the increased resorption of bone . evidence that osteolysis is due to an increased number of stimulated osteoclasts was presented by moller et al . , cellular and humoral mechanisms of osteoclast formation and bone resorption was reported by hirayama et al . , which suggested that the increase in osteoclast is not due to an increase in the number of circulating osteoclast precursors , but rather is due to an increase in the sensitivity of these precursors to humoral factors , which promote osteoclast formation and bone resorption . it has also been suggested that thyroid c cells and calcitonin may play an important role in the pathogenesis of gorham 's disease . gorham 's disease is a rare condition of osteolysis without sex , race , or age predilection ; affecting bones in different regions . based on clinical , histological and radiological features ; diagnosis is difficult and requires exclusion of neoplastic , inflammatory , infectious and endocrinologic disease . disappearing bone disease can be severely disabling and about 16% of cases are fatal . it is usually monocentric , but locally aggressive with resorption of the affected bone extending into adjacent soft tissues . many investigators believe that massive osteolysis is an aggressive form of skeletal angiomatosis that is related to vascular proliferation and shows regional involvement , frequently involving the shoulder and hip areas and has been termed as hemangiomatosis of bone . massive osteolysis has been documented in patients upto 70 years of age , but most affected patients are children and young adults . the most typical presentation is that of osteolysis of a single bone or the bones connected by a shared joint , such as the shoulder . shoulder is one of the most commonly involved areas , along with the skull and pelvic girdle . lack of bone healing following fracture is the hallmark of the disease . in 30% of affected patients , maxillofacial involvement is noted , with the mandible being the most frequently affected jaw bone . sign and symptoms include mobile teeth , pain , malocclusion , deviation of mandible and clinically obvious facial deformity . obstructive sleep apnea syndrome has been noted secondary to posterior mandibular displacement after extensive osteolysis . involvement of temporomandibular joint ( tmj ) by gorham disease can be mistaken for tmj dysfunction . although the degree of osseous deformity in patients with massive osteolysis may become severe , serious complications are infrequent . paraplegia related to spinal cord involvement may occur in patients who have involvement of vertebrae . thoracic cage , pulmonary or pleural involvement can lead to compromise of respiratory function and death can ensue . heffeze et al . , described the criteria for diagnosis of massive osteolysis as : minimal or no osteoblastic response and absence of dystrophic calcification;positive biopsy for angiomatous tissue;absence of cellular atypia;evidence of local progressive osseous resorption;non - expansile , non - ulcerative lesion;absence of visceral involvement;osteolytic radiographic pattern;negative hereditary , metabolic , neoplastic , immunologic or infectious etiology . minimal or no osteoblastic response and absence of dystrophic calcification ; positive biopsy for angiomatous tissue ; absence of cellular atypia ; evidence of local progressive osseous resorption ; non - expansile , non - ulcerative lesion ; absence of visceral involvement ; osteolytic radiographic pattern ; negative hereditary , metabolic , neoplastic , immunologic or infectious etiology . anavi et al . , reviewed that the mean duration of symptoms before diagnosis was 6.4 years with the initial histopathological diagnosis inaccurate in 45% of cases , which highlights the difficulty faced by the clinician and the pathologists when attempting to diagnose the condition . the standard laboratory tests are usually within normal limits and do not help in diagnosis of massive osteolysis . radiographs , computed tomography ( ct ) , and magnetic resonance imaging ( mri ) have all been used . during the initial stage of the lesion , radiolucent foci appear in the intramedullary or subcortical regions , resembling findings seen in patchy osteoporosis . subsequently , slowly progressive atrophy , dissolution , fracture , fragmentation and disappearance of a portion of the bone occur with tapering or pointing of the remaining osseous tissue and atrophy of soft tissues . panoramic radiograph shows resorption and decreased vertical height of the mandibular body with the resorption extended towards the basal bone figure 1 . radiographic image shows radiolucency in 35 , 36 , 37 and38 region with their displacement and root resorption . the teeth show no bony support . right side of mandible appears normal ( courtesy : dong q , zhang y , sun c , guo j. gorham - stout syndrome affecting the left mandible : a case report.j exp therapeut med 2012:162 - 4 ) radioisotope bone scan may show increased vascularity on initial images and subsequently , an area of decreased uptake corresponding to the site of diminished or absent osseous tissue . the microscopic findings contrast sharply with the striking clinical and radiographic findings . in the early stages , tissue removed from radiolucent defects consists of a nonspecific vascular proliferation intermixed with fibrous connective tissue and a chronic inflammatory cell infiltrate composed of lymphocytes and plasma cells . osteoclastic reaction in adjacent bone fragments is usually not conspicuous . according to johnson and mcclure there are two stages : the first with vascular proliferation , followed by a second stage in which residual fibrous tissue replaces resorbed bone [ figure 2 ] . histopathological image shows vascular proliferation intermixed with fi brous connective tissue and a chronic infl ammatory cell infi ltrate with thinning of bony trabeculae ( h&e stain , 100 ) . the medical treatment for gorham 's disease includes radiation therapy , antiosteoclastic medications ( bisphosphonates ) , and alpha-2b interferon . surgical options include resection of the lesion and reconstruction using bone grafts and/or prostheses . in most cases , unfortunately , no single treatment modality has proven effective in arresting the disease . in patients who receive high - dose radiation therapy , the potential for secondary malignancy and growth restriction exists and the diagnosis of gorham 's disease should be suspected or made only after excluding other common underlying causes of osteolysis . aneurysmal bone cyst , extensive metastatic bone disease and osteosarcoma are some of the lesions that resemble vanishing bone disease and can be confirmed with a biopsy . when gorham 's disease involves the mandible , the role of the periodontologist is extremely important . gorham 's disease should be included among the pathologic entities mimicking periodontal disease on radiograph , such as inflammatory disease ( e.g. osteomyelitis ) , endocrine disease ( e.g. hyperparathyroidism ) , intraosseous malignancies or metastases , lymphoma , histiocytosis x , mainly eosinophilic granuloma , infective process ( e.g. tuberculosis and actinomycosis ) and odontogenic tumors [ table 2 ] . the diagnosis is based on anamnestic data ( nonhereditary ) , biochemical data ( absence of nephropathy ) , radiographical data ( progressive monocentric osteolysis without periosteal reaction ) and histological data ( intraosseous angiomatosis with either capillaries or lymph vessels , or both ; eventually fibrosis ) . it is therefore important for oral pathologists to be aware of its existence as a rare case of osteolysis in maxillofacial skeleton . we believe that disease is not as rare as it seems , but rather remains misdiagnosed .

gorham 's disease is a rare disorder of uncertain etiology characterized by spontaneous and progressive osteolysis of one or more skeletal bones . till date , less than 200 cases have been reported in the international literature with about 51 cases involving the maxillofacial site . the radiographic findings associated with gorham 's disease are particularly dramatic , as in some cases a complete resorption of the involved bone can occur , leading to the definition of phantom bone or disappearing bone disease . the purpose of this review is to make our community aware of this rare entity and to discuss the etiopathology , clinical presentation , radiographic findings , histopathology , differential diagnoses and treatment modalities for patients with vanishing bone disease .

success in exfoliating monolayer and few - layer graphene sheets from bulk graphite , combined with progress in their epitaxial growth , has opened up a rich new topic in two - dimensional electron systems ( 2des ) @xcite . graphene 2des are remarkable for several different reasons . the fact that they are truly two dimensional on an atomic length scale elevates 2des physics from the low - temperature world to the room - temperature world . furthermore , they are accurately described by very simple models over very wide energy ranges and yet have electronic properties that can be qualitatively altered simply by stacking them in different arrangements , and by adjusting external gate voltages or magnetic fields . lastly but not the least , it is relatively easy to access graphene samples and to purify them , which practically promotes the experimental examinations of fascinating theories on graphene 2des . the basic building block of all graphene 2des is the isolated monolayer , which is described by a massless dirac @xmath0 hamiltonian over a wide energy range @xcite . special for graphene , the dirac model is massless , with two weyl points @xcite of opposite chiralities located at valley @xmath1 and @xmath2 , i.e. , the two inequivalent brillouin zone corners . the massless dirac model has linear dispersions and chiral quasiparticles , and in the graphene case the chirality refers to the alignment between the direction of @xmath0 momentum and the direction of pseudospin associated with the a / b sublattice degree - of - freedom of graphene s honeycomb lattice . intriguingly , the two weyl points at valley @xmath1 and @xmath2 are protected by the translational symmetry , a chiral symmetry , and a berry phase @xmath3 . we will elaborate more on these two features below . when @xmath4 honeycomb graphene layers are stacked , electronic properties are strongly modified in a way that is controlled by the specific stacking arrangement @xcite . it turns out that among all the stacking possibilities , only the rhombohedral ( abc or chiral ) arrangement @xcite inherits and extends the most interesting features of monolayer graphene , as we now explain @xcite . ( i ) there are two low energy sublattice sites , as the other sublattice site energies are repelled from the fermi level by the interlayer hopping @xmath5 and thus irrelevant at low energies , as shown in fig . [ stacking ] . this suggests that a two - band model provides a useful tool to describe the long - wavelength physics . ( ii ) the low - energy sublattice sites are localized in the outermost layers , at @xmath6 and @xmath7 , and can be separated energetically by an electric field perpendicular to the film . ( iii ) hopping between low - energy sites via high - energy states is an @xmath4-step process which leads to @xmath8 dispersions in conduction and valence bands , and sublattice pseudospin chirality @xmath4 ( or berry phase @xmath9 ) . ( iv ) the low - energy bands are increasingly flat for larger @xmath4 , at least when weak remote hopping processes are neglected , and the opportunity for interesting interaction and disorder physics is therefore stronger . consequently , in the simplified chiral model , the density - of - states @xmath10 diverges as @xmath11 approaches zero for @xmath12 whereas it remains finite for @xmath13 and vanishes for @xmath14 . ( these properties also have some relevance to more general stacking arrangements since the low - energy hamiltonian of a multilayer with any type of stacking can always be chiral - decomposed @xcite to a direct sum of abc - stacked layers . monolayer and bilayer graphene can be viewed as abc - stacked few - layers with @xmath14 and @xmath13 , respectively . ) we refer the family of abc - stacked @xmath4-layer graphene collectively as the chiral 2des . it follows the properties ( i)-(iv ) that the electronic properties of @xmath4-layer chiral 2des can be well described by @xmath15 band hamiltonians @xcite @xmath16 \,.\end{aligned}\ ] ] we have used the notation @xmath17 and @xmath18 where @xmath19 labels @xmath1 and @xmath2 valleys . the pauli matrices @xmath20 act on a pseudospin degree - of - freedom , i.e. , the two low - energy sublattices @xmath6 and @xmath7 . we choose the positive and negative eigenstates of @xmath21 to denote @xmath7 ( bottom layer ) and @xmath6 ( top layer ) , respectively . the pauli matrices @xmath22 will be reserved to denote the electron spin . m / s is the fermi velocity in graphene , and @xmath24 ev is the nearest neighbor interlayer hopping energy . neutral chiral 2des with @xmath25 has been proved to be fertile ground for new many - body physics @xcite . because of the large density - of - states and the @xmath9 berry phases near low energy band - contact points , such 2des at zero external fields are susceptible to chiral symmetry breaking , leading to a family of gapped spontaneous quantum hall states distinguished by valley and spin dependent quantized hall conductivities @xcite . in these states , each spin - valley flavor spontaneously transfers charge between layers @xcite . particularly in high mobility suspended bilayers @xcite , reproducible experimental observations @xcite are in reasonable agreement with original theoretical predictions @xcite , both of which will be reviewed in this article . notably , the fermi surface consists of two band touching points at @xmath1 and @xmath2 for charge neutral chiral 2des , which are indeed protected . as implied by eq . ( [ h0 ] ) , the layer pseudospin rotates @xmath4 times faster than the momentum orientation angle . this amounts to acquiring a berry phase @xmath9 when a quasiparticle circles one of the band - contact points once @xcite . the berry phases are opposite for electron and hole bands , and for @xmath1 and @xmath2 valleys . the quantization of berry phase , instead of being accidental , is directly dictated by the following chiral ( sublattice ) symmetry @xcite @xmath26 this chiral symmetry requires that at any momentum @xmath27 a state with energy @xmath11 must have a partner state with energy @xmath28 . the gapless band - contact nature of the spectra of hamiltonians ( [ h0 ] ) is protected by the chiral symmetry , since any loop enclosing one band touching point has a nontrivial berry phase @xmath29 ( a topological winding number @xmath4 ) and is thus not contractible . one can always redefine the zero energy at each @xmath27 to respect the chiral symmetry if a @xmath30 term is introduced to eq . ( [ h0 ] ) . in this case , at each @xmath27 the eigenstates do not alter and the berry connection remains the same . the chiral symmetry is also robust to any perturbation proportional to @xmath31 . a notable example is the trigonal warping effect @xcite , in which the additional @xmath31 terms , instead of gapping a spectrum , only split a band - contact point with berry phase @xmath9 into weyl points with berry phase @xmath3 each and @xmath9 in total @xcite . however , the chiral symmetry is broken and the energy spectrum acquires a gap ( @xmath32 at @xmath33 ) in the presence of a @xmath34 term @xcite . in this case , at each @xmath27 the eigenstates becomes pseudospin polarized and the two monopoles at @xmath33 spread out near the two valley centers , producing substantial momentum - space berry curvatures . of course , even in the presence of the chiral symmetry , the band - contact points can be gapped out , if gauge symmetry or translational symmetry are broken . as two examples , a superconducting gap may open when a chiral 2des is in proximity to a bcs superconductor substrate or electrode @xcite ; the @xmath1 and @xmath2 valleys may couple to each other and become gapped in pair annihilation by kekul pattern of bond distortions @xcite . nevertheless , our focus will be the chiral symmetry breaking and spontaneous gap ( mass ) generation @xcite that is driven by electron - electron interactions @xcite . because of the large density - of - states and the @xmath9 berry phases near low - energy band touching points , chiral 2des with @xmath25 at zero external fields are strongly susceptible to broken symmetry states @xcite . it is of interesting to determine whether the layer pseudospin orientations in model ( [ h0 ] ) will be driven out - of - plane or acquire an in - plane distortion in the presence of electron - electron interactions @xcite . this amounts to asking for each spin - valley flavor whether the chiral symmetry or the rotational symmetry will be spontaneously broken . in this section we review perturbative renormalization group ( prg ) analysis @xcite , in which lattice effects are completely ignored and the long - range of the coulomb interaction is not treated explicitly . the continuum approach is strongly motivated by the low - density of strongly correlated electrons . the use of short - range interactions is crudely justified @xcite by appealing to screening considerations , and arguing that the momentum - independent interaction parameters represent an average over the relevant portion of momentum space . note that the lengthscale , related to the higher energy cutoff @xmath35 mev , is more than @xmath36 times of the graphene lattice constant @xmath37 . we therefore emphasize @xcite that unlike the hubbard model where the short - range interactions are the on - site repulsions , the short - range interactions approximation below correctly takes into account the long - range character of coulomb interactions implicitly . in our view models in which interactions are cut off at atomic length scales @xcite , although technically interesting , are unlikely to be relevant to few - layer graphene . interacting bilayer graphene behaves in many ways as if it is one dimensional electron system with linear dispersions , because it has fermi points instead of fermi lines and because its particle - hole energies have a quadratic dispersion which compensates for the difference between 1d and 2d phase spaces @xcite . prg analysis of bilayer graphene is inspiring when it is compared with the case for one - dimensional electron gas ( spinless luttinger liquid ) @xcite . the main merit of the prg is that it treats all virtual processes on an equal footing @xcite . the spontaneous symmetry breaking in bilayer graphene can be most easily understood by considering only one spin - valley flavor @xcite . in such a spinless and valleyless model , pauli exclusion principle allows only one antisymmetrized interaction parameter , i.e. , the interlayer interaction @xmath38 . a prg analysis determines how the bare interaction @xmath38 at the @xmath5 scale is renormalized to @xmath39 at energy @xmath40 by integrating out the high - energy fermion degrees of freedom . a standard calculation yields the following prg flow equation at the one - loop level @xmath41 where @xmath42 is the constant density - of - states per flavor in bilayer graphene . this flow equation implies a repulsive interaction instability toward a broken symmetry state @xcite . more insight into the likely nature of the broken symmetry state which occurs in bilayer graphene can be obtained by using the prg calculations to estimate the long - wavelength static limit of the layer pseudospin susceptibilities @xcite : @xmath43 with @xmath44 . the conservation of particle in the two layers at long wavelength implies @xmath45 . divergences in @xmath46 signal ordered states in which the charge density is transferred between layers for each flavor , breaking the chiral symmetry and producing an energy gap for charged excitations @xcite . divergences in @xmath47 or @xmath48 , on the other hand imply broken symmetry states in which the phase relationship between layers is altered and rotational symmetry within the layers is broken @xcite . the broken rotational symmetry state is usually referred to as the gapless nematic state . provided that the system has a single continuous phase transition , the ordered state character can in principle be determined by identifying the pseudospin susceptibility which diverges first as temperature is lowered . in the noninteracting case , the band state layer pseudospin structure yields susceptibilities @xcite @xmath49 these pseudospin susceptibilities capture the contribution of zero - momentum vertical interband quantum fluctuations involving states with energies measured from the @xmath1 and @xmath2 points between @xmath5 and @xmath50 . the factor of two difference between @xmath46 and @xmath47 demonstrates that the band state is more susceptible to a gap opening perturbation than to a nematic perturbation . this property can be understood in terms of the layer pseudospin orientations of the band states @xcite ; in particular a @xmath51 pseudospin effective field is perpendicular to the valence - band pseudospin for all momentum orientations , so that @xmath51 direction fields always yield a strong response . on the other hand @xmath52-@xmath53 plane pseudospin fields are not in general perpendicular to the valence - band pseudospin and consequently produce a weaker response averaged over momentum orientations . the larger response to a @xmath51 pseudospin effective field is related to the well - known property @xcite of bilayer graphene that a potential difference between the top and bottom layers lead to an energy gap at the @xmath1 and @xmath2 points . when the interactions flow to strong values , the susceptibilities are dominated by their interaction contributions . near the instability the renormalized interaction leads to @xmath54 suggesting that a gapped state breaking the chiral symmetry is most likely @xcite . recent experiments @xcite also appear to rule out the competing family of gapless nematic states @xcite . hereafter we will neglect the non physical gapless nematic state breaking the rotational symmetry . we point out that a more rigorous four - flavor model leads to results that are qualitatively similar , although the prg has a tendency to overestimate the instability toward the gapless nematic state @xcite . it is the layer pseudospin orientations of band states that frustrate the in - plane pseudospin distortion and favor the out - of - plane pseudospin alignment @xcite . similar spontaneously broken symmetry physics can also be generalized to thicker abc - stacked @xmath4-layer graphene @xcite . for larger @xmath4 , the low energy bands are increasingly flat and the pseudospin chirality ( berry phase ) is larger , at least when weak remote hopping processes are neglected , leading to larger opening for many - body interaction effects . in the simplified chiral model ( [ h0 ] ) , the density - of - states @xmath10 diverges as @xmath11 approaches zero for @xmath12 whereas it remains finite for @xmath13 and zero for @xmath14 . this difference corresponds to the fact that the short - range interactions at tree level are irrelevant for @xmath14 , marginal for @xmath13 , and relevant for @xmath12 . this indicates even stronger chiral symmetry breaking in @xmath12 films @xcite . in practice , however , the increased strength of trigonal warping would eventually dominate the decreased magnitude of interlayer exchange beyond a critical @xmath4 . in recent experiments interaction - driven spontaneous gaps @xmath55 mev and @xmath56 mev have been observed in suspended bilayers @xcite , trilayers @xcite , and tetralayers @xcite respectively , whereas there has been no evidence for a charge gap in monolayers @xcite . similar to the bilayer case , the competing ordered states in @xmath12 films are anticipated to be gapped states @xcite , which break the chiral symmetry . note that in these systems that have already been accessible in experiment , the many - body spontaneous gaps are larger than the single - particle trigonal warping energies . now we discuss the electronic properties of @xmath4-layer chiral 2des systems using the ordered state quasiparticle hamiltonians @xcite suggested by the above prg analysis @xmath57 where the mass term @xmath34 , whose sign is valley- and spin - dependent , breaks the chiral symmetry and produces an energy gap . we note that the berry curvatures are non - zero only when chiral symmetry is broken @xcite . indeed , the momentum - space monopoles , i.e. , the original band - contact points , become gapped and the berry curvature spreads out near the two valley centers . since @xmath58 the momentum dependence of @xmath59 can be neglected . the berry curvature @xcite of the @xmath4-layer chiral 2des is @xcite @xmath60 where the symbol @xmath61 denotes the conduction ( valence ) band , and the transverse and total pseudospin fields are @xmath62 and @xmath63 . the orbital magnetic moment carried by a bloch electron is @xmath64 for a two - band model with particle - hole symmetry @xcite . for the chiral 2des the orbital moment is @xcite @xmath65\mu_{b}\,,\end{aligned}\ ] ] where @xmath66 is the electron mass and @xmath67 is the bohr magneton @xmath68 . like the berry curvature the orbital magnetization changes sign when the valley label changes _ and _ when the sign of the mass term ( the sense of layer polarization ) changes , i.e. both are proportional to @xmath69 . the orbital magnetization is however independent of the band index @xmath70 . in the presence of an in - plane electric field , a quasi - electron acquires an anomalous transverse velocity proportional to the berry curvature , giving rise to an intrinsic hall conductivity . based on eq . ( [ eq : berry ] ) , the intrinsic hall conductivity contribution from a given valley and spin is given by @xcite @xmath71 where @xmath72 is the total pseudospin field at the fermi wavevector . provided that the fermi level lies in the mass gap , each spin and valley contributes @xmath73 to the hall conductivity , with the sign given by @xmath74 . as we will review in the next section , different broken chiral symmetry states can be classified by their charge , spin , and valley hall conductivities that are determined by the signs of @xmath59 for different valleys and spins @xcite . for this reason , the broken chiral symmetry states were often referred to as spontaneous quantum hall states . when spin is ignored only two different types of states can be distinguished : ones in which the @xmath1 and @xmath2 valleys are layer polarized in the opposite sense producing a quantum anomalous hall ( qah ) state with broken time - reversal symmetry ( @xmath75 ) and orbital magnetization , and ones in which the two valleys have the same sense of layer polarization producing a quantum valley hall ( qvh ) state with broken inversion symmetry ( @xmath76 ) and zero total hall conductivity @xcite . when spin is included , there are three additional states @xcite . the five distinct states in the spinful case can be obtained by each spin choosing to be a qvh state or a qah state . below we will explain how these states are distinguished by their charge , spin , and valley hall conductivities , by their orbital magnetizations , by their broken symmetries . these results are sketched in fig . [ 5states ] and summarized in table [ table : one ] . in fig . [ 5states](a ) , we consider the case in which each spin - valley is polarized in the same sense . the total hall conductivity is then zero for both spins , with the @xmath1 and @xmath2 valleys making hall conductivity and magnetization contributions of opposite sign . this state preserves time - reversal symmetry but breaks inversion symmetry . besides the layer polarization , the inversion symmetry breaking yields a valley hall effect , analogous to the quantum spin hall effect @xcite . the spontaneous mass term in this case can be modeled by @xmath34 which is spin - valley independent . compared to the other four states , the qvh state has more layer polarization and hence stronger hartree ( electrostatic ) energy cost @xcite . the qvh states can be favored experimentally by applying a perpendicular electric field , which breaks the inversion symmetry and produces the layer polarization . [ 5states](b ) describes the case in which the two valleys are polarized in the opposite sense , toward the top and bottom layers respectively . the spontaneous mass term can thus be modeled by @xmath77 which is spin independent but valley dependent . this implies hall conductivity and orbital moment ( or orbital magnetization ) contributions of the same sign for each spin and valley . this inversion symmetric state , breaks time - reversal symmetry and the valley ising ( @xmath78 ) symmetry , but its spin density is surprisingly everywhere zero . the total hall conductivity has the quantized value @xmath79 and we refer to this state as the qah state @xcite . in addition to its qah effect , this state has a substantial orbital magnetization @xcite . the qah state , without total layer polarization , is probably most simply identified experimentally by observing a @xmath80 quantum hall effect which persists to zero magnetic field . such a state can be favored experimentally by applying a perpendicular magnetic ( orbital ) field , which couples the orbital moments and hence lowers the energy @xcite . c | c c c c || c | c | c | c | c | c | c figure & @xmath81 & @xmath82 & @xmath83 & @xmath84 & @xmath85 & @xmath86 & @xmath87 & @xmath88 & insulator & mass operator & broken symmetries ' '' '' + ' '' '' [ 5states](a ) & t & t & t & t & @xmath89 & @xmath90 & @xmath89 & @xmath89 & qvh & @xmath34 & @xmath76 + [ 5states](b ) & t & t & b & b & @xmath89 & @xmath89 & @xmath90 & @xmath89 & qah & @xmath77 & @xmath75,@xmath78 + [ 5states](c ) & t & b & t & b & @xmath89 & @xmath89 & @xmath89 & @xmath90 & laf & @xmath91 & @xmath75,@xmath76,@xmath92 + [ 5states](d ) & t & b & b & t & @xmath90 & @xmath89 & @xmath89 & @xmath89 & qsh & @xmath93 & @xmath78,@xmath92 + [ 5states](e ) & t & t & t & b & @xmath4 & @xmath4 & @xmath4 & @xmath4 & all & @xmath94 & @xmath75,@xmath76,@xmath78,@xmath92 + [ table : one ] for the state depicted in fig . [ 5states](c ) , there is also no net charge transfer between the layers , as the two spins are layer polarized in the opposite sense . such a state can be viewed as the two spins having qvh effects of opposite sign and the two layers having spin polarizations of opposite sign . thus , its charge , spin , and valley hall conductivities are all zero , and only the spin - valley hall conductivity is nontrivial . the spontaneous mass term takes the form of @xmath91 , which is valley independent but spin dependent . evidently , this state breaks time - reversal symmetry , inversion symmetry , and the spin @xmath92 symmetry . in sharp contrast to the ordinary af state or spin - density - wave state that occurs in the lattice scale , the spontaneous state considered here , driven by the long - range coulomb interactions , only has a sizable interlayer spin density macroscopically . for instance , the spin density is negligible for each low - energy site . for these reasons , this state was dubbed as a laf state by the author originally @xcite . as we will discuss in a short while , the laf state is the ground state at zero external fields , favored by the intrinsic intervalley exchange interaction @xcite which is rather small . [ 5states](d ) depicts a state in which there is no layer polarization , and neither the top nor the bottom layer has spin or valley polarization . quite interestingly , if we consider only one layer , there are both spin hall and valley hall effects ; however , the orientations of the hall currents in the top and the bottom layers are the same ( opposite ) for the spin ( valley ) hall effects . while breaking the spin @xmath92 symmetry and the valley @xmath78 symmetry , this state does not break inversion and time - reversal symmetries , and instead has qah effects of opposite signs in the two spin subspaces . the spontaneous mass , may be viewed as an effective spin - orbit coupling ( soc ) , takes the form of @xmath95 , leading to a quantized spin hall conductivity . the spontaneous qsh effect is in several respects @xcite different from that discussed in the well known papers @xcite , which foreshadowed the identification of @xmath78 topological insulators . ( i ) the qsh effect here is driven by broken symmetries produced by electron - electron interactions , rather than by soc , which we neglect . the effective soc due to electron - electron interactions can be @xmath96 times larger than the intrinsic one . ( ii ) unlike the previous interaction - induced qsh phase , which appears only at finite interaction strengths @xcite , here the instability to the qsh phase is present even for weak interactions . the instability occurs only for @xmath25 systems rather than in the monolayer system . ( iii ) the spontaneous qsh phases are topologically characterized by the spin ( or mirror ) chern number with integer values , rather than by a @xmath78 label . of course , the @xmath4-odd layers are @xmath78 topological insulators . among the five possible distinct states , the most interesting is the one in which one spin - valley flavor polarizes in the opposite sense of the other three , as sketched in fig . [ 5states](e ) . this state has a qvh effect for the spin up flavor and a qah effect for the spin down flavor . this state can also be understood as a valley - filtered qah state @xcite . remarkably enough , charge , valley , and spin hall effects coexist in this state @xcite . for this reason , we dubbed such a state `` all '' state . the interaction induced mass term for the state sketched in fig . [ 5states](e ) may be modeled by @xmath97 . note that there are eight different `` all '' states , and their mass terms may be modeled by switching the signs of @xmath98 , @xmath99 , and/or @xmath21 in @xmath97 . the `` all '' state should be favored in the presence of an interlayer electric field and a finite magnetic field @xcite , because its energy is lowered by the orbital and spin coupling to the magnetic field and by the compensation of the hartree energy cost of its layer polarization by the electric field . the above five states are rather close in energy , e.g. , their energy differences are only a few percent of their condensation energies @xcite . when lattice effects are taken into account , _ intervalley exchange _ weakly favors states in which the sense of layer polarization is identical for both valleys of either spin @xcite . this effect , which is not accounted above , favors the laf state . more intriguingly , as we have discussed and will show below , distinct states or their adiabatic variations can be realized by tuning the external electric or / and magnetic fields . recently , suspended bilayer graphene devices can be fabricated to exhibit ultra - high mobilities @xmath100 @xmath101/(vs ) . this made possible a series of delicate measurements in quantum hall regime and in transport spectroscopy near charge neutrality @xcite . as we will review below , there have been strong experimental evidences for four of the five gapped states . ( note that the unobserved qsh state is similar to the @xmath102 state at large perpendicular magnetic field when the bilayer graphene is put on substrates . in this sense , one may argue the observation @xcite of qsh state , with a quantized spin chern number , although time - reversal symmetry is explicitly broken . ) the first experimental evidence @xcite of spontaneous quantum hall states was from the local inverse compressibility measurement in single gated suspended bilayer graphene near charge neutrality . as shown in fig . [ exp1](a ) and ( b ) , the @xmath102 and @xmath103 integer quantum hall states persist down to nearly zero magnetics fields . this unprecedented observation is suggestive of the existence of broken symmetry states with hall conductivities @xmath89 and @xmath104 . consistent with the earlier analysis that the qah states can be favored by a small perpendicular magnetic field that couples to the orbital moment . similar @xmath103 states have also been observed at nearly zero field by several other groups . [ exp1](c ) @xcite further shows transport measurements in dual gated suspended bilayer graphene . at zero magnetic field , the resistivity is larger than that of the non interacting case . more interestingly , as the interlayer electric field with either polarity increases , the resistivity decreases first and then increases with no drop . this phenomenon is consistent with the quantum phase transition between a qvh state and a gapped ground state without total layer polarization , although the gap nature is not conclusive here . more conclusive evidences for the gap nature and the ground state class have been observed based on reproducible @xcite two - terminal conductance measurements in dual gated bilayer graphene at charge neutrality @xcite . as shown in fig . [ exp2](a ) and ( b ) , the two - terminal conductance at zero magnetic field and zero electric field is nearly zero for a wide window of the source - drain bias . clearly , the conductance is much smaller than @xmath105 of the non interacting case . this strongly suggests a charge gap @xmath55 mev in bilayer graphene at zero field and zero density . at zero magnetic field in fig . [ exp2](c ) and ( d ) , as the interlayer electric field with either polarity increases from zero , the conductance increases quickly first and then drop gradually . this implies a quantum phase transition from a state without layer polarization to a qvh state that is favored in the presence of an interlayer potential difference . combining the evidences in fig . [ exp2](a)-(d ) , one can conclude that the ground state of bilayer graphene has zero charge hall conductivity , no protected edge states ( since the total conductance is almost zero ) , and no layer polarization . the asymmetry features at the positive and negative magnetic fields further indicate time - reversal symmetry breaking . all these experimental observations are consistent with the prediction that the ground state is likely a laf state . when the magnetic field is turned on , no matter it is in - plane or out - of - plane , the laf state becomes a canted af state @xcite . most recently , the `` all '' state ( see fig [ 5states](e ) and table [ table : one ] ) has been observed experimentally in the quantum hall regime in the presence of an interlayer electric field @xcite . in fig . [ exp4 ] , two @xmath106 states are observed in suspended bilayer graphene . phase i is only fully resolved at zero electric field and large magnetic fields , with a vanishing landau level gap at zero magnetic field . the fact that a large b is required to stabilize this phase has been anticipated in the quantum hall ferromagnetism theory of bilayer graphene @xcite . as phase i is only observed in the absence of electric field , it is evidently not layer polarized but a symmetric linear combination of the top and bottom layers , or the @xmath1 and @xmath2 valleys equivalently , and thus a valley - kekul state @xcite . remarkably in fig . [ exp4](a ) , in contrast to phase i , phase ii is observed at anomalously small magnetic fields and large electric field , with a landau level gap that extrapolates to a finite zero - magnetic - field intercept . its appearance at much smaller magnetic field than phase i is reminiscent of the `` all '' state at zero magnetic field . indeed phase ii is only metastable at zero external fields , most likely because it loses the ordering competition to the laf state at zero electric field and to the qvh state at finite electric fields . as observed in fig . [ exp4 ] @xcite and predicted earlier @xcite , however , phase ii can be preferred in the presence of both finite electric and finite magnetic fields , since states with different total hall conductivity are most stable at different carrier densities ; moreover , the energy of this phase is lowered by the orbital and spin coupling to the magnetic field and by the compensation of the hartree energy cost of its layer polarization by the electric field . we emphasize that this state is partially polarized in spin , valley , and layer , as shown in fig [ 5states](e ) and table [ table : one ] . when broken chiral symmetry physics occurs within each spin and valley of a chiral 2des , as suggested by the prg and susceptibility analysis , the spontaneous gap @xmath32 at zero carrier density can be obtained by solving the self - consistent mean - field gap equation @xcite @xmath107 @xmath108 is the effective interaction strength between electrons near the @xmath1 or @xmath2 valleys , and @xmath109 is a sample area . for the monolayer case with @xmath14 , the instability occurs for @xmath110 , where @xmath111 is the dirac - model density - of - states at the ultraviolet energy cutoff scale @xmath112 . thus , the symmetry breaking would only occur for large interaction strengths . we can conclude from this observation that the presence or absence of a broken symmetry state in monolayer graphene depends on atomic length scale physics beyond that captured by the chiral model [ h0 ] with @xmath14 . it has been established experimentally that the gaps , if present , can not be larger than @xmath113 mev in monolayer graphene @xcite . in sharp contrast to the @xmath14 case , the gap equation ( [ eqn : ngap ] ) always has a solution for any @xmath25 case , no matter how small @xmath108 is . this is consistent with the weak repulsive interaction instability that is concluded by the prg and susceptibilities analysis @xcite . we will focus on the bilayer case below . in suspended ultra - clean bilayer graphene at zero carrier density , where @xmath59 is small compared to @xmath5 , the solution of the gap equation is given accurately by @xcite @xmath114 the spontaneous gap @xmath115 mev observed in experiment at zero magnetic field corresponds to a dimensionless interaction strength @xmath116 , close to the value expected to be appropriate for screened coulomb interactions @xcite . when the bilayer graphene carrier density is nonzero , it is possible to show that the temperature @xmath117 mass is reduced to @xcite @xmath118 because of pauli blocking effects in the gap equation . mean - field theory therefore predicts that the broken symmetry state disappears once fermi energy becomes larger than @xmath119 mev , which corresponds to a carrier density larger than @xmath120 as compared in fig . [ exp3 ] , both the size of the gap at zero carrier density and the critical carrier density which destroys the gap are therefore roughly consistent with simple mean - field - theory estimates @xcite . the smallness of the density fluctuation that destroys the gapped state is consistent with its appearance only in suspended samples . the measured @xmath121 in fig . [ exp3](a ) ( as well as in fig . [ exp1](c ) ) at zero charge density and @xmath122 at zero temperature are in good agreement with the mean - field theory results in fig . [ exp3](c ) . the critical temperature at finite carrier density can be further determined by solving @xcite @xmath123 where @xmath124 is the fermi function at critical temperature @xmath121 . the solution for @xmath121 as a function of chemical potential and carrier density is plotted in fig . [ exp3](d ) . in conclusion , the mean - field - theory estimates and the experimental observations in bilayer graphene are in reasonable agreement with each other . the spontaneous chiral symmetry breaking in chiral 2des has provided a new paradigm for many - body physics , i.e. , the spontaneous quantum hall effects near zero magnetic field @xcite . below we will briefly discuss a few predictions and phenomena that are relevant to the physics reviewed in this article . the physical significance of spontaneous charge , valley , and spin anomalous hall effects also exhibits in their edge state spectra @xcite . evidently , the qah ( qsh ) states should have protected chiral ( helical ) edge states corresponding to their bulk topological invariants . similarly , the `` all '' states should also have protected chiral edge states , though the number is reduced by half . analogous to the helical edge states of qsh states , the qvh as well as the laf state have counterpropagating edge states at different valleys . importantly , the qvh edge states are not strictly topological and can be gapped out by a sufficiently strong , large - momentum scattering which couples the two valleys , even if the underlying symmetries are still preserved @xcite . it is therefore crucial that the valley index remains a good quantum number , for which short - range disorder , interlayer stacking , and electric fields must be smooth on the lattice scale . under this condition , backscattering is prohibited and the qvh edge states become protected and thus attractive . graphene edges often have sufficiently strong atomic scale defects that liberate intervalley scattering , and the edge states are thus destroyed . however , one can create a smooth domain wall that separates two different qvh states and observe robust edge states along the domain wall , since the smoothness of domain wall would prohibit intervalley scattering . for example , qvh - like edge states were predicted @xcite to exist along a domain wall that separates an ab and a ba stacked domains in bilayer graphene under an uniform interlayer electric field . recently , such qvh domain wall modes have been observed @xcite in a transport measurement . bilayer graphene is susceptible to a family of unusual broken chiral symmetry states that are rather close in energy . thus , domain walls , in which the sense of layer polarization of at least one flavor is reversed , are expected to be present in disordered bilayer graphene samples . a recent calculation @xcite shows that the metal - insulator transition temperature in bilayer graphene is reduced from mean - field estimates by thermal excitation of domain walls . the same calculation also demonstrates that the domain walls have interesting microscopic structure related to the topological character of the ordered states @xcite . it turns out there are @xmath125 distinct types of domain walls in the spinful case and @xmath126 in the spinless case , each of which has topological domain wall modes @xcite . these unusual domain wall modes are anticipated to exhibit novel luttinger liquid behaviors @xcite . while the three gapped states without layer polarization respond similarly to an interlayer electric field , which can induce first order transitions at which the total layer polarization jumps , they have distinct responses to zeeman coupling to their spin @xcite . when an in - plane magnetic field is included , the qah state quasiparticles simply spin - split , leaving the ground state unchanged but the charge gap reduced to @xmath127 . for a @xmath128 mev spontaneous gap at the zero field , a field of @xmath129 t drives the gap to zero . for the laf state , the in - plane magnetic field induces a noncollinear spin state in which the components of the spin - density perpendicular to the field are opposite in opposite layers , while those along the field direction grow smoothly with field strength and are identical . most importantly , the gap does not change as the zeeman field increases . as indicated by the mean - field mass terms above , a qsh state contains two copies of laf states with opposite signs for different valleys . in a recent experiment @xcite , the spontaneous gaps of bilayer graphene have been found robust to the zeeman fields , consistent with that earlier confirmation that the ground state is the laf state . however , this experiment only employed in - plane magnetic fields up to @xmath126 t , which is not sufficiently large enough to influence the observed ground states with gaps @xmath55 mev . a future experiment with a larger in - plane magnetic field could provide more conclusive evidences . the qah state and the qvh state are found to have interesting and distinct optical absorption of circularly polarized lights with a frequency close to the spontaneous gap . both valleys of the qah state only absorb lights with one helicity , whereas different valleys of the qvh state absorb lights with the opposite helicities @xcite . one can further analyze the optical absorption for other three broken symmetry states , since they can be viewed as the two spin flavors choosing to be different qvh and/or qah states . since the two spin flavors break time - reversal symmetry in the same sense , the qah state is the only one that can be distinguished by kerr optical spectroscopy @xcite . on one hand , each spontaneous quantum hall state at zero magnetic field is adiabatically connected to a quantum hall ferromagnet with the same charge hall conductivity @xcite . that said , there is a smooth evolution between the zero - field and high - field broken symmetry states in suspended chiral @xmath4-layer 2des with @xmath25 . on the other hand , even for chiral 2des put on substrates , where the chiral symmetry does not occur at zero magnetic field , the quantum hall ferromagnetism @xcite still occur at sufficiently high magnetic fields . moreover , an interlayer electric field can also drive quantum phase transitions between different quantum hall ferromagnets . what is unprecedented is the fact that integer quantum hall effects can occur in ab bilayers and abc trilayers way below @xmath113 t. what is more exotic would be the fractional quantum hall effects near zero magnetic field , which is still elusive . [ [ kondo - insulators - flat - band - insulators - and - van - der - waals - heterostructures ] ] kondo insulators , flat - band insulators , and van der waals heterostructures ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ finally , we briefly comment on three closely related phenomena . topological kondo insulators @xcite have been discovered in @xmath130 recently . the underlying mechanism is rather similar to the spontaneous qsh states of chiral 2des with @xmath25 . near the fermi energy the interaction induces an energy gap between the two already inverted bands , a nearly localized - flat @xmath131-band and a @xmath132-derived dispersive conduction band , leading to a transition from a kondo lattice metal to a small - gap topological kondo insulator . in a similar sense , the flat - band chern insulators driven by interactions are similar to the spontaneous qah states of chiral 2des with @xmath25 . an intriguing task is to identify _ realistic _ systems that host topological phases with fractionalized excitations @xcite , beyond the celebrated fractional quantum hall states . recently , two dimensional van der waals heterostructures constitute a new class of artificial materials formed by stacking atomically thin planar crystals . it is likely that exotic broken symmetry physics may occur when one layer is a chiral 2des and the other layers are materials with small dielectric constants . i would like to thank my main collaborators on this topic , a. h. macdonald and c. n. lau . i am also indebted to inspiring discussions with many other collaborators on few - layer graphene : w. bao , g. a. fiete , j. jung , c. l. kane , x. li , e. j. mele , h. min , q. niu , h. pan , m. polini , z. qiao , d. tilahun , j. velasco jr . , b. j. wieder , s. a. yang , j. zhu , and k. zou . this work was made possible by support from ut dallas research enhancement funds . a weyl point is two - fold degeneracy near which the effective hamiltonian can be written in the form a two - component weyl hamiltonian with either left or right chirality . in contrast , a dirac point is a four - fold degeneracy near which the effective hamiltonian can be written in the form of massless four - component dirac hamiltonian . a dirac point can be viewed as two weyl points with opposite chirality sit on top of each other . therefore , a @xmath1 or @xmath2 point in a graphene system is better called as a spin - degenerate weyl point , since the two spin species have exactly the same chirality . this was originally named as a layer - inversion symmetry for a single flavor , because the breaking of this symmetry yields charge transfer between the top and bottom layers for the considered flavor . yet , when all the four flavors are taken into account , the spatial inversion symmetry may or may not be broken , as shown in table [ table : one ] . besides the proposal by haldane @xcite and the possible broken symmetry states in chiral graphene @xcite , there are practical single - particle proposals that utilize extrinsic spin - orbital couplings and zeeman fields : z. qiao , s. a. yang , w. feng , w .- k . tse , j. ding , y. yao , j. wang , and q. niu , phys . rev . b * 82 * , 161414(r ) ( 2010 ) ; z. qiao , w. ren , h. chen , l. bellaiche , z. zhang , a. h. macdonald , and q. niu , phys . rev . lett . * 112 * , 116404 ( 2014 ) .

bilayer graphene and its thicker cousins with rhombohedral stacking have attracted considerable attention because of their susceptibility to a variety of broken chiral symmetry states . due to large density - of - states and quantized berry phases near their gapless band touching points , each spin - valley flavor spontaneously transfers charge between layers to yield opening of energy gaps in quasiparticle spectra and spreading of momentum - space berry curvatures . in this article we review the development of theories that predicted such chiral symmetry breaking and classified the possible topological many - body ground states , and the observations in recent experiments that are in reasonable agreement with these theories . = 1

once thought of as distinct ten - dimensional consistent perturbative theories , the five superstring theories are now understood as five different asymptotic expansions of a unifying eleven - dimensional m - theory in different corners @xmath2 of its moduli space , with _ string dualities _ providing the transition functions between these patches@xcite . due to the asymptotic nature of string perturbation theory , this still only covers a zero - measure set of the moduli space , while analytic continuation to finite @xmath3 can be achieved for quantities that are protected from quantum corrections , such as the bps spectrum and bps - saturated amplitudes . one - loop exact amplitudes on one patch translate into non - perturbative amplitudes in the dual one , and world - sheet instantons turn into semi - classical configurations of euclidean branes wrapped on non - trivial cycles of the target space . on the other hand , non - perturbative _ symmetries _ identify different points in the moduli space and hold for any amplitude . the prototypical example is the @xmath4 s - duality symmetry of ten - dimensional type iib theory , which was used to obtain the exact four - graviton @xmath5 amplitude as the weight @xmath6 @xmath4 eisenstein series @xcite : @xmath7 where @xmath8 is the einstein - frame inverse tension of a @xmath9 string , and @xmath10 the complex modulus in the upper half plane . this result follows from supersymmetry constraints and s - duality invariance @xcite . the weak coupling expansion reproduces the tree - level and one - loop contributions , implies perturbative non - renormalization beyond one - loop , and exhibits a sum of d - instanton effects . more generally , exact amplitudes should be given by ( non - holomorphic ) automorphic forms of the symmetry group , selected on the basis of the leading perturbative behaviour and supersymmetric constraints @xcite . from a study of this and other exact results , one may hope to infer the rules of instanton calculus in string theory@xcite . the purpose of this talk is to extend these considerations to the lower - dimensional case of m - theory compactified on a torus @xmath11 , where the symmetry gets enlarged to the u - duality group @xmath1 @xcite , and correspondingly more states come into play . we first review some basic facts about m - theory and its relation to type iia string theory , then discuss the continuous hidden symmetry @xcite of toroidally compactified 11d supergravity . only a discrete subgroup of this symmetry may remain as a quantum symmetry of m - theory , and we show how this u - duality follows from t - duality and 11d diffeomorphism invariance . we first focus on a set of weyl generators of these groups , and derive how the bps spectrum falls into representations thereof @xcite . borel generators are then included to obtain duality invariant mass formulae . finally , we use the connection between m - theory in discrete light - cone quantization and matrix gauge theories @xcite to uncover the spectrum of the latter theories , and discuss the realization of u - duality in these non - gravitational theories . this talk is a shortened version of ref . @xcite , to which the reader is referred for a more extensive discussion and list of references . m - theory was originally introduced @xcite as the strong coupling limit of type iia string theory . it reduces to 11d supergravity at low energies , and is conjectured to exhibit eleven - dimensional n=1 super poincar invariance . in particular , m - theory compactified on a circle @xmath12 of radius @xmath13 gives type iia string theory with @xmath14 where @xmath15 denotes the 11d planck length , and @xmath3 and @xmath16 the string coupling and length . indeed , one observes that at strong coupling @xmath17 the eleventh direction decompactifies . the massless spectrum of type iia string theory gets unified in the 11d setting as @xmath18 in terms of the m - theory graviton and antisymmetric three - form and the nsns fields @xmath19 and rr gauge potentials @xmath20 of type iia string theory ( the lower index denotes the number of antisymmetric indices ) ; so do the half - bps states , charged under these fields : @xmath21 here the first ( resp . second ) entry in each parentheses corresponds to longitudinal ( resp . transverse ) reduction with respect to the eleventh direction . this identification can be most easily seen from the mass or tension of the m - theory bps states , @xmath22 , @xmath23 , @xmath24 , @xmath25 for the kaluza - klein momentum state , m2 and m5 brane , and kk6-brane ( or taub - nut monopole ) , using the relations in ( [ matching ] ) . as a side remark , the kk6-brane may also be reduced along a non - compact direction of the taub - nut space , giving rise to a state with tension proportional to @xmath26 and a logarithmically divergent geometry at infinity ( first reference in @xcite ) . as we shall see , u - duality predicts many more such states with exotic tensions @xmath27 for compactification to @xmath28 dimensions @xcite . upon compactification on a torus @xmath29 , 11d sugra exhibits a group of continuous global symmetry @xmath30 , as well as a ( composite ) gauge invariance under its r - symmetry maximal compact subgroup @xmath31 , as listed in table 1 @xcite . the symmetry can be seen among the scalar fields , which take value in the symmetric space @xmath32 . the local @xmath31-invariance can be gauge - fixed thanks to the iwasawa decomposition @xmath33 into maximal compact @xmath31 , abelian @xmath34 and nilpotent @xmath35 subgroups . a natural gauge is obtained by taking @xmath36 , so that the moduli can be represented as a vielbein : @xmath37 or equivalently as a @xmath31-invariant matrix @xmath38 . in this representation , the abelian factor @xmath34 is parametrized by the radii @xmath39 of the internal torus , while the nilpotent factor @xmath35 incorporates the expectation values of the off - diagonal components of the metric and of the gauge potentials @xmath40 on the torus , as well as their poincar - dual @xmath41 and @xmath42 . the symmetry group @xmath43 acts on the right on the coset @xmath32 , and induces a compensating moduli - dependent @xmath31-rotation to preserve the gauge @xmath36 . the massless spectrum also includes a number of @xmath44-forms , given for @xmath45 in the last two columns of table 1 , where dualization into forms of lower degree has been carried out . they transform linearly under @xmath30 and induce charges for particles ( @xmath46 ) and strings ( @xmath47 ) respectively . those are linearly related to the central charges in the @xmath48 supersymmetry algebra by @xmath49 , so that the invariant quadratic form @xmath50 is precisely the invariant mass for half - bps states ( quarter - bps states receive further corrections ) . [ cols=">,>,<,<,<,<,<",options="header " , ] table 2 : particle multiplet , * 56 * of of @xmath51 and yang - mills interpretation . next , we wish to include the borel generators , corresponding to the right action of nilpotent matrices @xmath35 in the iwasawa decomposition ( [ iwa ] ) , in order to derive duality invariant mass formulae . in the case of t - duality , the borel generators include dehn twists from the mapping class group @xmath52 , acting on the homology lattice as @xmath53 , as well as the spectral flow of the b - field : @xmath54 using the @xmath55 boosts , a kk state with momentum 1 can be related to a state with any integer momentum @xmath56 along the circles of @xmath11 with mass @xmath57 . more generally , using ( [ tbor ] ) , the vector representation of the weyl group of t - duality becomes a lattice of kk and winding charges @xmath58 with mass @xmath59 subject to the half - bps condition @xmath60 . for quarter - bps states the mass formula receives an extra contribution proportional to @xmath61 . similarly , the d - particle states ( completely wrapped d - branes ) with masses @xmath62,@xmath63 , @xmath64 turn into a lattice of integer d0,d2,d4-charges @xmath65 transforming as spinor of @xmath0 . a careful analysis of the borel generators then gives the half - bps mass @xmath66\ ] ] where the @xmath67 are the dressed charges @xmath68 , with an extra contribution when the half - bps conditions , @xmath69 } + m~m^{ijkl } = 0 $ ] for @xmath70 , are not fulfilled . these bps mass formulae can also be obtained by analyzing the born - infeld action @xcite . in the case of the u - duality group , the borel generators include the usual dehn twists @xmath71 in @xmath52 as well as the @xmath72 shifts in @xmath73 , which can be conjugated into @xmath74 . when @xmath75 we also need to include shifts of the dual gauge fields @xmath76 . the u - duality invariant mass formula on tori with arbitrary gauge backgrounds can then again be obtained by considering the non - commuting @xmath40 , @xmath42 and @xmath41 flows . in @xmath77 , we obtain the result @xmath78 where the dressed charges are given by @xmath79 it turns out that the half - bps condition on the particle multiplet transforms as the string multiplet constructed out of the particle charges @xcite , which also follows on dimensional grounds : @xmath80 when these composite charges do not vanish , the state is at most quarter - bps , in which case its mass formula reads @xmath81 ^ 2 } $ ] with @xmath82 the half - bps tension formula for the string multiplet and @xmath83 the quadratic charges in ( [ cons ] ) . finally , we wish to use the information on u - duality and invariant mass formulae obtained above to obtain a better understanding of the degrees of freedom and symmetries of matrix gauge theory . according to this prescription @xcite the dlcq of m - theory on a lightlike circle @xmath12 ( radius @xmath84 ) times @xmath11 in the sector with @xmath85 is described by a supersymmetric @xmath86 gauge theory in @xmath87 dimensions on the maximal t - dual torus @xmath88 . in this description the kk state of the particle multiplet bound to @xmath35 d0-branes becomes ( after maximal t - duality ) a string wound on @xmath35 d@xmath89-branes with ym energy @xmath90 describing a half - bps state carrying electric flux . on the other hand , a wrapped membrane of the string multiplet bound to @xmath35 d0-branes becomes a kk state bound to @xmath35 d@xmath89-branes with energy @xmath91 describing a massless excitation . more generally , the u - duality invariant gauge theory masses can be computed as @xmath92 as an example , the last column of table 2 gives the corresponding gauge theory masses corresponding to the particle multiplet of @xmath51 . the first state is the state carrying electric flux mentioned above , while the second state carries magnetic flux , and corresponds in general to a d@xmath89-d@xmath93 bound state . in the case of the string multiplet , the details of which we omit here , the first states are the kk excitations , and the second is a ym instanton in 3 + 1 dimensions lifted to @xmath94 dimensions , corresponding to d@xmath89-d@xmath95 bound states . starting on @xmath96 , we see the occurrence of states with energy @xmath97 whose interpretation is problematic in pure yang - mills terms . we can make a more precise comparison of the u - duality invariant masses with the proposed quantum descriptions for @xmath98 . in the first case the d3-brane description is valid so that we have n=4 supersymmetric gauge theory in 3 + 1 dimensions . the u - duality symmetry @xmath99 corresponds to the mapping class group of the three - torus together with the s - duality symmetry of the gauge theory @xcite . in particular , the m - theory or type iib modular parameter @xmath100 is equated to @xmath101 , so that the m - theory gauge potential @xmath102 translates as a @xmath103 angle in the gauge theory . for @xmath70 the quantum theory is the ( 2,0 ) worldvolume theory on the m5-brane , where the extra dimension ( d4 @xmath104 m5 ) is generated by identifying @xmath105 . the @xmath106 u - duality symmetry is now naturally interpreted as the symmetry of m5 on the five - torus , and indeed from the invariant masses we can infer directly that @xmath107 appears as the kk gauge field on @xmath108 . finally , for @xmath109 the quantum theory is the non - critical string theory living on the ns5-brane ( obtained by type iib s - duality from the d5-brane ) with string length @xmath110 . the @xmath111 u - duality symmetry is now interpreted as the t - duality symmetry of the string theory , and from the invariant masses we infer that @xmath112 is the @xmath113-field of string theory on ns5-brane . for @xmath114 gravity does no longer decouple anymore . these conclusions can also be reached from the born - infeld action in the scaling limit @xcite . finally , we mention that the string and particle multiplet of @xmath1 , together with the momentum @xmath35 and some additional charges , make a string multiplet representation of @xmath115 , as should be the case if the dlcq proposal is correct @xcite . n. a. obers , b. pioline , and e. rabinovici _ nucl . * b525 * ( 1998 ) 163 , http://xxx.lanl.gov/abs/hep-th/9712084 [ hep - th/9712084 ] ; n. a. obers and b. pioline http://xxx.lanl.gov/abs/hep-th/9809039 [ hep - th/9809039 ] , to appear in phys . rept . n. berkovits http://xxx.lanl.gov/abs/hep-th/9709116 [ hep - 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th/9611164 ] ; o. j. ganor , s. ramgoolam , and w. taylor iv _ nucl . * b492 * ( 1997 ) 191 , http://xxx.lanl.gov/abs/hep-th/9611202 [ hep - th/9611202 ] .

based on our work @xcite , we discuss how u - duality arises as an exact symmetry of m - theory from t - duality and 11d diffeomorphism invariance . a set of weyl generators are shown to realize the weyl group of @xmath0 and @xmath1 , while borel generators extend these finite groups into the full t- and u - duality groups . we discuss how the bps states fall into various representations , and obtain duality invariant mass formulae , relevant for the computation of exact string amplitudes . the realization of u - duality symmetry in matrix gauge theory is also considered .

the @xmath0 antiferromagnetic ( af ) heisenberg model on a square lattice has attracted a lot of attention due to its close relation to the disappearance of the af order in high - t@xmath4 superconducting material @xcite and its possibility of realizing the so called spin liquid state @xcite . the spin liquids , defined as lacking long range order and supporting strong quantum fluctuation , have all the key properties of the insulating state `` nearby '' to a superconducting phase . hence a simple example of spin liquids , the resonating valence bond ( rvb ) state was proposed to describe high - t@xmath4 superconductivity @xcite . spin liquids have become the focus of research in modern condensed matter physics since the discovery of different kinds of spin liquids in theory @xcite . although the existence and stability of spin liquids in realistic models and real material are still in question @xcite . the nature of the ground state of the @xmath0 af heisenberg model in the intermediate coupling region has been debated @xcite for decades due to the highly frustrated nature of this model and is still a open question . recently , several numerical works revisited this model using novel concept , such as the topological entanglement entropy ( tee ) @xcite , and new numerical tools , such as the projected entangled pair states ( pepss ) @xcite . amazingly many of them have reached a consistent and the lowest ground state energy ever @xcite , however their resulting ground states behave diversely . a density matrix renormalization group ( dmrg ) study on long cylinders suggested a gaped @xmath5 spin liquids from the evidences of non - vanishing singlet and triplet gaps in the paramagnetic phase and a nonzero tee @xcite . the gutzwiller - projected bcs wavefunction study indicated a gapless spin liquid state supported by the existence of gapless triplet excitations at momenta @xmath6 and @xmath7 @xcite . most recently , the dmrg study with @xmath8 symmetry imposed on the states on long cylinders found a diverging dimer correlation length , and claimed a plaquette valence bond solid ( vbs ) state as the ground state @xcite . these controversial results pose the question about the numerical convergence and the system size dependence @xcite . in this paper , we propose a novel wavefunction and use the variational monte carlo ( vmc ) method to tackle this system . as one knows , the key to a meaningful variational method is to have a good trial wavefunction . here , we take a resonating valence bond state approach . the reasons for such a choice are the following , first of all , rvb states can describe a variety of phases including the spin liquids , the af long range ordered states and the valence bond solids @xcite ; second of all , recent development in pepss showed that a family of one parameter pepss with bond dimension @xmath9 , which described the rvb state beyond the nearest neighbor pairing , can greatly lower the variational energy of this model compared to that of the short range rvb state @xcite . we can imagine that with more build - in correlations and hence more variational parameters , the rvb states should approach the true ground state very well . the simplest rvb ansatz on a bipartite lattice is the valence bond amplitude product ( ap ) state , where the probability of having a valence bond of separation @xmath10 is independent of each other and is denoted as @xmath11 @xcite . consequently the bond amplitudes @xmath11 become the variational parameters for the valence bond ap states . simulations based on this variational ansatz has been done @xcite : it was found that the amplitude @xmath12 tends to be negative for @xmath13 in order to minimize the energy within this variational subspace . the place where @xmath12 changes sign signals the break down of the marshall s sign rule @xcite and is very close to the proposed critical point where the af long range order disappears . it is interesting to ask the question that does the onset of the negative amplitude in the valence bond ap state indicate a phase transition to new states ? in this paper , we will give our answer to this question from the correlated valence bond point of view . prior to our investigation , lin et al . introduced the so called correlated amplitude product ( cap ) state , where an extra weight factor has been given to a pair of valence bonds @xcite in order to build the bond - bond correlations into the wavefunction , however they have not yet applied the caps to the @xmath0 af heienberg model . the goal of this paper is to simulate the ground state of the @xmath0 af heisenberg model on square lattice using the correlated valence bond states , whose definition will be clear in sec [ wf ] . the rest of this paper is arranged as following : in sec . [ wf ] , we define the correlated valence bond states , which have some similarity but are essentially different from the caps @xcite . we introduce the variational monte carlo method and the optimization strategy for this wavefunction in sec . [ methods ] . upon optimization of the correlated valence bond states by minimizing the ground state energies , we arrive at the optimal states . in sec . [ results ] , we present the variational ground state energy and the ground state correlations for the optimized states . in sec . [ discussion ] , we discuss the advantages and limitation of this ansatz and conclude for the nature of the intermediate phase of the @xmath0 af heisenberg model on square lattice . the hamiltonian of the @xmath0 af heisenberg model on a square lattice is given by @xmath14 where the first summation runs over the nn pair @xmath15 and the second summation runs over the next nn ( nnn ) pair @xmath16 . an equal weight superposition of the short range rvb state has been applied as a trial wavefunction to the ground state of hamiltonian eq . ( [ afheisenberg ] ) @xcite , but the variational energy is not good and it is nowhere close to the true ground state at any coupling ratio @xmath17 . one step forward was made by introducing a positive amplitude to an arbitrary ranged bipartite valence bond in the frame work of the valence bond ap states @xcite ; the reported best thermodynamic energy at @xmath18 is @xmath19 per site , which is still much higher than the dmrg studies @xcite and has left a lot of room for improvement in the trial wavefunction . here we speculate that the bond - bond correlations may play a crucial role than the individual long range bonds @xcite . therefore , we define a class of ansatze called the correlated valence bond states by a set of statistical rules : 1 . considering without the presence of the correlated valence bond pairs , the ansatz is reduced to a short - bond amplitude product state : the bond amplitude @xmath20 and otherwise 0 . 2 . if two short individual bonds are sitting next to a common edge of the lattice , they are allowed to quantum fluctuate to any other valence bond tilings on these four sites , and _ vice versa _ , as illustrated in fig . each valence bond tiling of these four sites is associated with a amplitude marked as either 1 , @xmath21 or @xmath22 , where @xmath23 ( @xmath24 ) are the variational parameters . the two short bonds on the left hand side of the reversible - arrow in fig . [ cap ] are two individual bonds ( uncorrelated ) , which can be randomly rearranged with all other uncorrelated short bonds into any allowed short bond product state . however the two correlated bonds together with the lattice edge ( in blue dash line ) on the right hand side of the reversible - arrow form a single object such that the two bonds there in can not be treated independently . the correlated - bond - pair can only be flipped back to the two short bonds exactly shown on the left hand side of the reversible - arrow . the above three rules together form a statistical mechanic ensemble . before discussing the variational monte carlo algorithm , several comments are along the line . we choose such a statistical ensemble as the trial wavefunction in order to address bond - bond correlations . the amplitudes of the correlated - bond - pairs give extra factors to the wavefunction coefficients , and this ansatz goes beyond the ap state . the correlated - bond - pair amplitudes serve as the variational parameters of the trial wavefunction . we can easily translate this ansatz to a peps wavefunction that describes qualitatively the same statistical ensemble . we impose the translational and rotational symmetries to the wavefunction to reduce the number of variational parameters . this restriction is perfectly valid as long as we work with finite size systems . there are four distinct arrangements of two short bonds that are connected by a common lattice edge , as illuminated in fig . [ cap ] , therefore eight different correlated - bond - pairs whose amplitudes are denoted by @xmath25 and @xmath26 . hereafter , we use the word `` correlated - bond - pair '' and its amplitude interchangeably . given these clarifications , we can write the trial wavefunction as following @xmath27 is a compact pack of individual short bonds and correlated - bond - pairs on a lattice which produce a valence bond tiling configuration @xmath28 , @xmath29 ( @xmath30 ) is the number of @xmath21 ( @xmath22 ) in a compact pack @xmath31 . note that different packing @xmath31 can generate the same valence bond tiling configuration @xmath28 . . the arrows marked for @xmath28 ( in black lines ) align with the sign convention , whereas for @xmath32 ( in gray lines ) anti - align with the sign convention . @xmath33 , where @xmath34 is the number of arrows that violate the direction of the flow and @xmath35 is the number of loops in the transition graph . in this section , we first briefly describe the variational valence bond monte carlo method , followed by the optimization method used to determine the optimal variational parameters . given a variational wavefunction @xmath36 , the expectation value of any operator @xmath37 is written as @xmath38 with the importance sampling weight defined as @xmath39 and the operator matrix element defined as @xmath40 here @xmath41 is the overlap matrix element . if both the coefficients @xmath42 and the overlap matrix elements @xmath43 are positive definite , we could use the standard valence bond mc method @xcite . however our valence bond configuration @xmath28 allows valence bonds of the same sublattice pairing , therefore the overlap matrix elements can be negative ; in addition , the correlated - bond - pair amplitudes can take negative values , which means the coefficients @xmath42 can be negative too . thus our wavefunction encounters a negative sign problem . we can treat it in a standard way by rewriting eq . ( [ exp ] ) as @xmath44 where @xmath45 denotes the sign of the weight eq . ( [ wt ] ) . we sample using the absolute value @xmath46 ( abbreviated as @xmath47 ) as the importance weight . the operator expectation value can be obtained by taking the ratio of @xmath48 and @xmath49 . we now explain how to calculate the overlap matrix element @xmath43 and how to count the sign in @xmath45 . we fix the sign convention for any valence bond in @xmath28 : for the ab sublattice pairing , the direction of the valence bond is always pointing from the a sublattice to the b sublattice ; whereas for the same sublattice pairing , we refer to the signs drawn in fig . [ sign](a ) as the convention . given @xmath28 and @xmath32 , the overlap matrix element for a transition graph is @xmath50 , where @xmath35 is the number of loops in the transition graph and @xmath34 is the number of singlets that violate the direction of flow that is arbitrarily chosen for each loop in the transition graph . an example of the transition graph is shown in fig . [ sign](b ) . here @xmath51 is a normalization constant , since the maximum number of loops in a transition graph is @xmath52 . the total number of minus sign factors in the coefficient @xmath42 depends on the sign convention and the signs of the variational parameters @xmath23 . putting all signs together we have @xmath53 . next , we explain how to calculate the operator matrix element @xmath54 . since the singlet product states @xmath55 appear on both the numerator and the denominator , we can choose any singlet sign convention we want ( those sign factors will cancel if otherwise choose a difference sign convention ) . for any transition graph , we choose one such that every loop has @xmath56 structure , _ i.e. _ we choose the sign to be always pointing from @xmath57 to @xmath58 . here we use @xmath59 to differentiate the @xmath60 sublattices of the original lattice bipartition , and @xmath57 and @xmath58 only have a relative meaning within each loop . therefore all operator expectation values can be evaluated using the same formulas as in the ref . @xcite with the replacement of @xmath61 ( @xmath62 ) by @xmath57 ( @xmath58 ) . with coupling strength @xmath1 $ ] . parmeters not shown here are optimized close to 0 . ] the mc sampling of wavefunction eq . ( [ crvb ] ) takes two types of update . the first type of update is the local update . we begin by randomly selecting a link from the lattice , one of the following cases will happen : 1 . if the link is not occupied by any singlets and it sits beside two individual short bonds , propose to flip randomly to one of the correlated - bond - pairs or stay unchanged with the corresponding probability ; 2 . if the link belongs to a correlated - bond - pair and is exactly sitting on the reference edge in blue dashed lines in fig . [ cap ] , propose to flip to the two individual short bonds or stay unchanged with the corresponding probability ; 3 . for any other cases , abandon such a choice and iterate . if a local update is proposed , we accept or reject this local update with probability @xmath63 $ ] , where @xmath64 is the number of loop in the trial transition graph . the second type of update is the loop update . we randomly construct an allowed loop of alternating individual short bonds and vacant lattice links , then we shift all individual short bonds on that loop by one lattice space . this rearrangement can always be proposed with probability 1 , since all individual short bond have equal amplitudes , and it will keep all the correlated - bond - pairs untouched . the loop update is accepted or rejected with probability @xmath63 $ ] defined above . we use variational mc to calculate the derivative of the energy with respect to a variational parameter @xmath65 ( @xmath66 ) as @xmath67 and update them according to @xcite @xmath68 where @xmath69 is the iteration index , @xmath70 is a random number @xmath71 , and @xmath72 until the energy converges . the function form @xmath73 is chosen heuristically @xcite . the optimization results and correlation functions will be presented in the next section . ( green circle ) , @xmath74 ( green dots ) and @xmath75 ( blue triangles ) lattices , here the reference ground state energies for the @xmath75 lattice are taken from the dmrg results in ref . red square is a comparison to the projected fermionic bcs wavefunction for a @xmath74 lattice without lanczos projection step @xcite . ] we present the well optimized variational parameters for the wavefunction eq . ( [ crvb ] ) for system sizes @xmath2 at @xmath76 $ ] in fig . [ para ] . we find strong size dependence for the optimized variational parameters @xmath77 . however , parameters @xmath78 have less size dependence . other parameters that are not shown in fig . [ para ] are optimized close to zero . the absolute energy error per site @xmath79 for sizes @xmath80 compared with the exact diagonalization ( ed ) results @xcite and for size @xmath3 compared with the dmrg results @xcite are presented in fig . the absolute errors are small , _ e.g. _ , @xmath81 and @xmath82 . for comparison , we draw the gutzwiller - projected bcs wavefunction results without lanczos projection @xcite in the same frame : at @xmath83 , our absolute energy error is lower by about @xmath84 . we take the optimized parameters from size @xmath3 to calculate the order parameters and the correlation functions for system sizes @xmath85 until the average signs are no longer manageable , because optimizing variational parameters for @xmath85 becomes not feasible . we assume that the correlation functions at larger sizes will not be too sensitive to the variational parameters as long as they are within a reasonable range from the optimal values . in a log - log plot . power law functions @xmath86 , @xmath87 have been fitted to the points for @xmath88 . ] let us first define a set of order parameters . the sublattice magnetization is written as @xmath89 where @xmath90 , @xmath91 is the spin correlation function , and it is defined as @xmath92 the dimer order parameter is defined as @xmath93 where @xmath94 and @xmath95 , @xmath96 . the sublattice magnetization and the dimer order parameter are presented in log - log plots in fig . [ ordpara ] . the sublattice magnetization at couplings @xmath97 scale as @xmath98 , which is expected for the exponentially decaying spin correlation function eq . ( [ ssc ] ) . the dimer order parameter follows a power law decay with system size as @xmath99 where @xmath100 . therefore , we find a critical phase that has gapless singlet excitations and gaped triplet excitations within the range of @xmath1 $ ] . we next make some connections to the results given by previous work . a large optimal parameter @xmath101 is consistent with the results of an enhanced spin - spin correlation along the @xmath102 and @xmath103 axes shown in ref . a negative optimal parameter @xmath104 is consistent with the result of having negative @xmath12 in the simulation using an ap product state @xcite . our variational term @xmath105 generates configuration of parallel diagonal bond pair . the parallel diagonal bond pairs together with the short bonds , if contribute with equal weights to the resonating wavefunction on a square lattice , will give a @xmath5 spin liquid state @xcite . our optimized wavefunction , which contains both the parallel diagonal bonds and the short bonds , does not behave like a @xmath5 spin liquid , although it deviates from the special point of equal weights superposition defined in ref . we need to do further investigation to answer why it fails to be a @xmath5 spin liquid . the optimal parameter @xmath106 at system size @xmath3 grows rapidly as a function of @xmath107 , whose effect is to increase the dimer - dimer correlation . however given this optimized parameter strength , the effect of @xmath106 will not induce a quantum phase transition from a critical phase to the vbs phase as predicted in ref @xcite , because the latter phase requires a very large value in @xmath106 @xcite . let us turn to the question that we asked earlier : does a negative amplitude @xmath108 in an ap state indicate a phase transition ? from our example , the answer seems to be no . the critical phase presented in our work is simply a result of muting all the long range bonds in the ap state , as one increase the weights of @xmath104 and @xmath105 from 0 , there are no signs of a phase transition from the critical phase to either @xmath5 or vbs states . therefore we conclude that the negative amplitude @xmath108 along in an ap state could not trigger a phase transition . using the correlated valence bond state , we minimized the ground state energy of the @xmath0 antiferromagnetic ( af ) heisenberg model on a square lattice for a coupling ratio @xmath1 $ ] by turning a few correlated - bond - pair amplitudes . the energies are consistent with the exact diagonalization ( ed ) results on the @xmath109 and @xmath74 tori @xcite and the density matrix renormalization group ( dmrg ) results on the @xmath75 torus @xcite . we applied the optimal variational parameters from the @xmath75 system to the larger tori and studied their correlation functions using the valence bond monte carlo ( mc ) sampling method . we found that within the optimized phase , the neel order parameter scales as the inverse of the volume , and the dimer order parameter describing the columnar or plaquette valence bond solid ( vbs ) phases follows a power law decay with the system size @xmath110 approximately as @xmath111 . these correlation functions indicate a critical phase with gapless singlet excitations and gaped triplet excitations in the entire range of @xmath1 $ ] . due to the negative sign problem , we can not optimize even larger systems or further increase the number of variational parameters , such as turn on the individual long range bonds . our simulation provide insights of how and when the critical phase can turn into a vbs or a @xmath5 spin liquid . however with the current results , we can not conclude which one is the true ground state with the intermediate coupling strength . _ we thank j. richter for providing us the ed results . we would like to thank o. motrunich , f. verstraete , k. beach , a. sandvik , z .- c . gu , s .- s . gong , w .- j . hu for useful discussion . the author especially thanks o. motrunich for reading and giving comments on the manuscript . this work was supported by the institute for quantum information and matter , an nsf physics frontiers center with support of the gordon and betty moore foundation through grant gbmf1250 .

we propose a class of variational wavefunctions , namely the correlated valence bond states , for the frustrated hamiltonians in the paramagnetic phase . this class of wavefunctions admits negative amplitude and the same sublattice pairing when a bipartite lattice is considered , thus suffers from the negative sign problem . however if applied to small systems , the sign problem is manageable using the standard variational monte carlo method . we optimize the wavefunctions for the @xmath0 antiferromagnetic heisenberg model on a square lattice in the coupling region @xmath1 $ ] for system sizes @xmath2 . to calculate the correlation functions and the order parameters for larger systems , we make the extensive monte carlo samplings using the variational parameters optimized at system size @xmath3 . we find that the paramagnetic phase is a gapless spin liquid in the entire range of @xmath1 $ ] with a gapless singlet excitation and a gaped triplet excitation .

mental well - being is a core component of optimal health , and is a status that individuals can manage stress from daily living and make positive achievements pursuing public interest and contribution to the community . maintaining individual 's mental health is important to improve personal life values , to reduce medical cost and other social expenses to deal with mental disorders , and to enhance national competitiveness . mental disorders , which are the same as psychiatric disorders , are clusters of syndromes which disturb an individual 's cognition , emotion regulation or behavior . common mental disorders include bipolar disorders ( manic disorder , depression , and manic - depression ) , dementia , schizophrenia , and panic disorder . several factors affecting the development of mental disorders include genetic factors , stress , diet , physical inactivity , drugs , and other environmental factors . among these factors , dietary factors may aggravate or ameliorate symptoms and the progression of the disorders although those are not major etiologies . nutritional factors having beneficial effect on mental health are polyunsaturated fatty acids ( pufas ) , especially omega-3 fas , phospholipids , cholesterol , niacin , folate , vitamin b6 , vitamin b12 , and vitamin d . conversely , saturated fat and simple sugar can be hazardous for brain health , increasing the risk for mental illnesses as well as other metabolic disorders including diabetes and cardiovascular diseases ( cvd ) . the effects of nutritional factors on mental health have been investigated for a long time ; however , strong evidence has not reported as enough to suggest specific nutritional strategy as a preventive means except omega-3 fas . previous intervention studies often reported contrasting results , and meta - analysis on those reports showed weak or no association between specific nutrients and indices of mental function . limitations in conducting nutrition - mental health study are as follows : 1 ) it has difficulties in subject recruit , collection of precise and reliable data from subjects on memory - based questionnaires , identification of the cause - effect relationship , and acquirement of compliance on intervention , 2 ) due to its heterogeneity , responses to intervention are complex and various , and 3 ) the study requires involvement of highly trained experts . in this review , we will introduce known nutritional factors affecting mental health , and discuss recent issues of the nutritional impact on cognitive function and healthy brain aging . nutritional factors relating to mental health have a common aspect in that those factors are associated with the risk of cvd . folate , vitamin b6 and b12 are parts of homocysteine metabolism , and deficiencies of these nutrients result in increased blood levels of homocysteine , which aggravate mental health . niacin is an effective modulator to increase high - density lipoprotein cholesterol and to improve lipidomic profiles , and vitamin d is associated with the risks of cvd and metabolic syndrome . conversely , excess intake of saturated fat and sugar , which are risk factors for cvd , is detrimental to brain function . in addition , recent studies add a promising evidence that specific dietary patterns including mediterranean diet can be applied as effective strategies to prevent mental disorders . omega-3 fas ' action on brain is mainly as a structural and functional component of membrane phospholipids in brain and retina . alpha - linolenic acid , a plant - based omega-3 fa , is found in flaxseed oil and soybean oil , and main dietary source of eicosapentaenoic acid ( epa ) and docosahexaenoic acid ( dha ) is fish oil . anti - inflammatory activities of omega-3 fas are often related to the suppression of excess extents of pro - inflammatory actions of omega-6 fas . among several mental disorders , prevalence of dementia is evidently increasing as the portion of aged population is growing . in subjects with dementia at stage 1a ( age - associated memory impairment ) and 1b ( mild cognitive impairment ) , low blood levels of omega-3 fas were observed . as dementia progresses to stage 2 ( early dementia ) and stage 3 ( dementia with behavioral symptoms ) , mild and moderate protein - energy malnutrition ( pem ) often develops , which requires oral nutritional supplements with protein and energy supplementation rather than omega-3 fas intervention . in case of severe dementia ( stage 4 ) , enteral nutrition or parenteral nutrition omega-3 fas ( 1.0 - 3.4 g ) intervention improved symptoms of alzheimer 's disease ( ad ) , depression and schizophrenia as shown in table 1 . mechanisms underlying beneficial effects of omega-3 fas ' on symptoms of mental disorders are regulations of integrity and fluidity of membrane , neurite growth , neurotransmitters , endothelium , neuronal survival , neurodegeneration , transcription , and inflammation . although further investigations are needed to identify the ideal dose of omega-3 fas and the ratio of epa and dha , in general , 1 g daily intake of epa and dha is recommended to maintain brain health . ad , alzheimer 's disease ; bdi , beck depression inventory ; csf , cerebrospinal fluid ; epds , edinburgh postnatal depression scale ; panss , positive and negative syndrome scale . phospholipid is a principal component to maintain integrity and functionality of neuronal membrane , and is recently suggested as a blood biomarker for mental health . altered plasma phospholipids were observed in patients with mild cognitive impairment ( mci ) and ad . metabolome analyses enabled to screen phospholipid profiles and to identify altered levels in response to specific conditions in a comprehensive way . ether phospholipids , phosphatidylcholines , sphingomyelins and sterols were low in ad patients , and three metabolites [ 2,4-dihydroxybutanoic acid , unidentified carboxylic acid , and phosphatidylcholine { pc ( 16:0/16:0 ) } ] were identified as signature markers for the possible progression of mci to ad . mci , mild cognitive impairment ; pc , phosphatidylcholine ; pc aa , diacyl form ; pc ae , acyl - alkyl form . cholesterol also constitutes neuronal membrane to be responsible for fluidity , and acts as a signaling modulator for gene transcription , which is involved in nutrientsmetabolism and inflammation . in a large korean cancer prevention study cohort ( n = 1,329,525 ) , risk of depression was related to low levels of serum cholesterol concentration , suggesting the possible needs of cholesterol - raising regimen in subjects with depression . however , a dietary intervention in increasing blood cholesterol has not been tried because the cholesterol - raising regimen such as high intakes of saturated fat , trans - fat , cholesterol , and total calories can cause increased the risk of other metabolic diseases ( e.g. obesity , diabetes , and cvd ) . vitamin b is involved in energy metabolism as forms of cofactors , nicotinamide adenine dinucleotide ( nad ) and flavin adenine dinucleotide ( fad ) . in a nad - fad - dependent and independent ways , the b vitamins , especially niacin , folate , vitamin b6 , and vitamin b12 affect mental health . famous hypothesis for mental disorders is ' homocysteine hypothesis ' that excess homocysteine causes the development of psychiatric symptoms . particularly , folate , vitamin b6 , and vitamin b12 are involved in homocysteine metabolism , and low levels of the b vitamins and high levels of homocysteine were observed in subjects with mci , dementia , and depression . suggested mechanisms underlying homocysteine action on brain function are impairments in cerebral vasculature and function of neurotransmitters , and increases in neurotoxicity and oxidative stress . niacin 's action on brain function is less studied compared with other vitamin b nutrients . a case - study reported that a subject with pellagra , a disease from niacin deficiency , showed psychiatric disorders , mainly behavioral deterioration and dementia , which were recovered by niacin intervention . recent studies on dietary intervention of niacin , especially nicotinamide riboside ( nr ) , suggested that nr exerts neuroprotective effects , and restores cognitive decline by the regulation of beta - secretase 1 degradation and expressions of mitochondrial metabolism - related genes ( aconitase , citrate synthase , glucose phosphate isomerase 1 , phosphoglycerate kinase , and pyruvate dehydrogenase kinase ) relating to the action of proliferator - activated receptor- coactivator 1 . so far , vitamin b nutrients intervention relating to brain function showed equivocal results regarding their efficacy on cognitive function . the brain is vulnerable to oxidative stress because it has lipid - rich area especially in neuronal membrane and is metabolically active . tight balance between oxidative stress and antioxidant system is required to maintain the structural integrity and optimal functions of brain . vitamins a , c , and e are major non - enzymatic antioxidants in foods , and there are emerging evidences that these antioxidant vitamins are protective against cognitive decline and mental disorders including anxiety disorders , attention - deficit / hyperactivity disorder , autism , bipolar disorder , depression , schizophrenia , and substance abuse . perinatal retinol deficiency shown as low levels of serum retinol concentrations is significantly associated with the increased risk ( more than threefold ) of schizophrenia and other schizophrenia spectrum disorders in the prenatal determinants of schizophrenia study . subjects with high tertile of vitamins c and e intakes have lower risk of ad than subjects with lower intake tertiles of these antioxidant vitamins in the rotterdam study . especially , amyloid - beta deposition in brain relating to increased oxidative stress is one of the major causes of ad , and low levels of vitamins c and e in blood and/or cerebrospinal fluid were observed in ad patients . vitamin e intervention reduces amyloid - beta deposition , reactive oxygen species as well as nitric oxide synthesis , and prevents against cognitive impairment and the progression to ad . recently , a new approach to identify underlying mechanisms of neurodegenerative disorders and to investigate the intervention efficacy to improve the symptoms of mental disorders has applied . application of redox proteomics approach enables to identity disease stage - specific modifications in oxidative stress - related molecules and to demonstrate a cluster of changes in protein oxidative modification by the specific nutritional intervention . in general , existing intervention studies show beneficial effects of antioxidants on improving general symptoms of mental disorders , and the optimal combinations and the recommended duration of antioxidant vitamin intake need to be investigated . because many factors affecting mental health are overlapped as those for cvd , dietary saturated fat and western - style diet may impair cognitive function , and subjects with high bmi have low scores of a 37-item version of the mini - mental state examination . high levels of blood sugar due to excess sugar intake or uncontrolled blood sugar are main manifestations of diabetes . recent findings consistently reported the positive association between diabetes and dementia , and diabetes induces ad in animal models . also , higher blood glucose and hba1c concentrations were associated with reduced memory capacity and structural changes in hippocampus in cohort of healthy , older , nondiabetic individuals without dementia . intervention studies should focus on the development of practical dietary guidelines for each mental disorder and the identification of effective ways to compromise the negative effects of these saturated fat and simple sugars on mental disorders . identifying the optimal dietary patterns such as mediterranean diet is one of promising ways to find the effective dietary guidelines . omega-3 fas ' action on brain is mainly as a structural and functional component of membrane phospholipids in brain and retina . alpha - linolenic acid , a plant - based omega-3 fa , is found in flaxseed oil and soybean oil , and main dietary source of eicosapentaenoic acid ( epa ) and docosahexaenoic acid ( dha ) is fish oil . anti - inflammatory activities of omega-3 fas are often related to the suppression of excess extents of pro - inflammatory actions of omega-6 fas . among several mental disorders , prevalence of dementia is evidently increasing as the portion of aged population is growing . in subjects with dementia at stage 1a ( age - associated memory impairment ) and 1b ( mild cognitive impairment ) , low blood levels of omega-3 fas were observed . as dementia progresses to stage 2 ( early dementia ) and stage 3 ( dementia with behavioral symptoms ) , mild and moderate protein - energy malnutrition ( pem ) often develops , which requires oral nutritional supplements with protein and energy supplementation rather than omega-3 fas intervention . in case of severe dementia ( stage 4 ) , enteral nutrition or parenteral nutrition omega-3 fas ( 1.0 - 3.4 g ) intervention improved symptoms of alzheimer 's disease ( ad ) , depression and schizophrenia as shown in table 1 . mechanisms underlying beneficial effects of omega-3 fas ' on symptoms of mental disorders are regulations of integrity and fluidity of membrane , neurite growth , neurotransmitters , endothelium , neuronal survival , neurodegeneration , transcription , and inflammation . although further investigations are needed to identify the ideal dose of omega-3 fas and the ratio of epa and dha , in general , 1 g daily intake of epa and dha is recommended to maintain brain health . ad , alzheimer 's disease ; bdi , beck depression inventory ; csf , cerebrospinal fluid ; epds , edinburgh postnatal depression scale ; panss , positive and negative syndrome scale . phospholipid is a principal component to maintain integrity and functionality of neuronal membrane , and is recently suggested as a blood biomarker for mental health . altered plasma phospholipids were observed in patients with mild cognitive impairment ( mci ) and ad . metabolome analyses enabled to screen phospholipid profiles and to identify altered levels in response to specific conditions in a comprehensive way . ether phospholipids , phosphatidylcholines , sphingomyelins and sterols were low in ad patients , and three metabolites [ 2,4-dihydroxybutanoic acid , unidentified carboxylic acid , and phosphatidylcholine { pc ( 16:0/16:0 ) } ] were identified as signature markers for the possible progression of mci to ad . mci , mild cognitive impairment ; pc , phosphatidylcholine ; pc aa , diacyl form ; pc ae , acyl - alkyl form . cholesterol also constitutes neuronal membrane to be responsible for fluidity , and acts as a signaling modulator for gene transcription , which is involved in nutrientsmetabolism and inflammation . in a large korean cancer prevention study cohort ( n = 1,329,525 ) , risk of depression was related to low levels of serum cholesterol concentration , suggesting the possible needs of cholesterol - raising regimen in subjects with depression . however , a dietary intervention in increasing blood cholesterol has not been tried because the cholesterol - raising regimen such as high intakes of saturated fat , trans - fat , cholesterol , and total calories can cause increased the risk of other metabolic diseases ( e.g. obesity , diabetes , and cvd ) . vitamin b is involved in energy metabolism as forms of cofactors , nicotinamide adenine dinucleotide ( nad ) and flavin adenine dinucleotide ( fad ) . in a nad - fad - dependent and independent ways , the b vitamins , especially niacin , folate , vitamin b6 , and vitamin b12 affect mental health . famous hypothesis for mental disorders is ' homocysteine hypothesis ' that excess homocysteine causes the development of psychiatric symptoms . particularly , folate , vitamin b6 , and vitamin b12 are involved in homocysteine metabolism , and low levels of the b vitamins and high levels of homocysteine were observed in subjects with mci , dementia , and depression . suggested mechanisms underlying homocysteine action on brain function are impairments in cerebral vasculature and function of neurotransmitters , and increases in neurotoxicity and oxidative stress . niacin 's action on brain function is less studied compared with other vitamin b nutrients . a case - study reported that a subject with pellagra , a disease from niacin deficiency , showed psychiatric disorders , mainly behavioral deterioration and dementia , which were recovered by niacin intervention . recent studies on dietary intervention of niacin , especially nicotinamide riboside ( nr ) , suggested that nr exerts neuroprotective effects , and restores cognitive decline by the regulation of beta - secretase 1 degradation and expressions of mitochondrial metabolism - related genes ( aconitase , citrate synthase , glucose phosphate isomerase 1 , phosphoglycerate kinase , and pyruvate dehydrogenase kinase ) relating to the action of proliferator - activated receptor- coactivator 1 . so far , vitamin b nutrients intervention relating to brain function showed equivocal results regarding their efficacy on cognitive function . the brain is vulnerable to oxidative stress because it has lipid - rich area especially in neuronal membrane and is metabolically active . tight balance between oxidative stress and antioxidant system is required to maintain the structural integrity and optimal functions of brain . vitamins a , c , and e are major non - enzymatic antioxidants in foods , and there are emerging evidences that these antioxidant vitamins are protective against cognitive decline and mental disorders including anxiety disorders , attention - deficit / hyperactivity disorder , autism , bipolar disorder , depression , schizophrenia , and substance abuse . perinatal retinol deficiency shown as low levels of serum retinol concentrations is significantly associated with the increased risk ( more than threefold ) of schizophrenia and other schizophrenia spectrum disorders in the prenatal determinants of schizophrenia study . subjects with high tertile of vitamins c and e intakes have lower risk of ad than subjects with lower intake tertiles of these antioxidant vitamins in the rotterdam study . especially , amyloid - beta deposition in brain relating to increased oxidative stress is one of the major causes of ad , and low levels of vitamins c and e in blood and/or cerebrospinal fluid were observed in ad patients . vitamin e intervention reduces amyloid - beta deposition , reactive oxygen species as well as nitric oxide synthesis , and prevents against cognitive impairment and the progression to ad . recently , a new approach to identify underlying mechanisms of neurodegenerative disorders and to investigate the intervention efficacy to improve the symptoms of mental disorders has applied . application of redox proteomics approach enables to identity disease stage - specific modifications in oxidative stress - related molecules and to demonstrate a cluster of changes in protein oxidative modification by the specific nutritional intervention . in general , existing intervention studies show beneficial effects of antioxidants on improving general symptoms of mental disorders , and the optimal combinations and the recommended duration of antioxidant vitamin intake need to be investigated . because many factors affecting mental health are overlapped as those for cvd , dietary saturated fat and western - style diet may impair cognitive function , and subjects with high bmi have low scores of a 37-item version of the mini - mental state examination . high levels of blood sugar due to excess sugar intake or uncontrolled blood sugar are main manifestations of diabetes . recent findings consistently reported the positive association between diabetes and dementia , and diabetes induces ad in animal models . also , higher blood glucose and hba1c concentrations were associated with reduced memory capacity and structural changes in hippocampus in cohort of healthy , older , nondiabetic individuals without dementia . intervention studies should focus on the development of practical dietary guidelines for each mental disorder and the identification of effective ways to compromise the negative effects of these saturated fat and simple sugars on mental disorders . identifying the optimal dietary patterns such as mediterranean diet is one of promising ways to find the effective dietary guidelines . as the world is aging rapidly , attention on aging - related mental disorders has increased . increased r & d planning and investment relating to these illnesses aim to reduce medical cost burden and to improve mental health as well as quality of life . based on current evidence , especially , eating balanced meals on a regular basis and consuming nutrients for mental health including omega-3 fas , antioxidants , niacin , folate , vitamin b6 , and vitamin b12 at recommended dietary intake levels are suggested . development of dietary guideline that is specific to each type and stage of mental disorder , and the identification of nutritional biomarkers on cognitive functions are suggested to study in the future . because mental disorders are heterogeneous in symptoms and etiologies , well - designed diet intervention study on large cohorts

dietary intake and nutritional status of individuals are important factors affecting mental health and the development of psychiatric disorders . majority of scientific evidence relating to mental health focuses on depression , cognitive function , and dementia , and limited evidence is available about other psychiatric disorders including schizophrenia . as life span of human being is increasing , the more the prevalence of mental disorders is , the more attention rises . lists of suggested nutritional components that may be beneficial for mental health are omega-3 fatty acids , phospholipids , cholesterol , niacin , folate , vitamin b6 , and vitamin b12 . saturated fat and simple sugar are considered detrimental to cognitive function . evidence on the effect of cholesterol is conflicting ; however , in general , blood cholesterol levels are negatively associated with the risk of depression . collectively , the aims of this review are to introduce known nutritional factors for mental health , and to discuss recent issues of the nutritional impact on cognitive function and healthy brain aging .

SECTION 1. AMENDMENTS RELATING TO STATUTORY LICENSE FOR SATELLITE CARRIERS. Section 119 of title 17, United States Code, is amended as follows: (1) Subsection (a)(2)(C) is amended-- (A) in clause (i)-- (i) in the heading, by inserting ``commercial'' after ``single''; (ii) by inserting ``commercial'' after ``a single''; and (iii) by striking ``(47 CFR 76.51)'' and inserting ``(section 76.51 of title 47, Code of Federal Regulations)''; (B) in clause (ii), by striking ``47 of the Code'' and inserting ``47, Code''; (C) in clause (iii), by striking ``if the satellite carrier'' and inserting ``if a satellite carrier or cable system''; and (D) in clause (iv)(II), by inserting ``U.S. Television Household Estimates by'' after ``according to''. (2) Subsection (a)(2)(B)(i) is amended in the last sentence by striking ``under paragraph (3)'' and inserting ``authorized under paragraph (3)''. (3) Subsection (a)(3) is amended-- (A) in subparagraph (A), by striking ``Commission, to be'' and all that follows through the end and inserting ``Commission to be significantly viewed, as defined in section 76.5 of title 47, Code of Federal Regulations, as in effect on April 15, 1976.''; and (B) in subparagraph (C)(i) in the last sentence, by inserting ``otherwise'' after ``specifically stated''. (4) Subsection (a)(4)(E) is amended to read as follows: ``(E) Other provisions not affected.--Subparagraphs (A), (B), and (C) shall not affect the applicability of the statutory license to secondary transmissions authorized under paragraphs (3) and (12).''. (5) Subsection (a)(4)(F) is amended-- (A) in the first sentence, by striking ``(C) or (D)'' and inserting ``(A) or (B)''; and (B) in the last sentence, by inserting ``otherwise'' after ``specifically stated''. (6) Subsection (a)(14) is amended in the last sentence, by inserting ``otherwise'' after ``specifically stated''. (7) Subsection (c)(1) is amended-- (A) in subparagraph (B)-- (i) by inserting ``notice'' after ``shall cause''; (ii) by inserting ``and distributors'' after ``paid by satellite carriers''; and (iii) by striking ``analog transmission'' and inserting ``analog transmissions''; (B) in subparagraph (C) in the second sentence-- (i) by striking ``distributors and copyright'' and inserting ``distributors, and copyright''; and (ii) by striking ``royalty fee'' and inserting ``royalty fees''; (C) in subparagraph (D)-- (i) in clause (i), by striking ``that a parties thereto'' and inserting ``that are parties thereto''; and (ii) in clause (ii)(I), by striking ``subparagraph (E)'' and inserting ``subparagraph (F)''; and (D) in subparagraph (F)-- (i) in clause (i)-- (I) by striking ``royalty fee'' and all that follows through ``distributors'' and inserting ``royalty fees to be paid by satellite carriers and distributors for the secondary transmission of the primary analog transmissions of network stations and superstations under subsection (b)(1)(B)''; and (II) in the last sentence, by striking ``arbitrary'' and inserting ``arbitration''; (ii) in clause (ii), by striking ``fair market value of secondary transmissions'' and inserting ``fair market value of such secondary transmissions''; (iii) in clause (iii)-- (I) in subclause (I), by striking ``2004;'' and inserting ``2004,''; and (II) by striking all that follows subclause (I) and inserting the following: ``(II) is made by the Librarian under section 802(f) as in effect on the day before such date of enactment, shall be effective as of January 1, 2005.''; and (iv) in clause (iv)-- (I) by striking ``(iii)'' and inserting ``clause (iii)''; and (II) by striking ``distributors and copyright owners,'' and inserting ``distributors, and copyright owners''. (8) Subsection (c)(2) is amended-- (A) in subparagraph (A), by striking ``section 298.3(b)(1)'' and inserting ``section 258.3(b)(1)''; and (B) in subparagraph (C), by striking ``accordance with to'' and inserting ``accordance with''. (9) Subsection (a)(15)(A) is amended by striking the comma after ``television station''. (10) Subsection (a)(16)(B) is amended by inserting a comma after ``Alaska if''. (11) Subsection (d)(12) is amended by striking ``low power television as defined'' and inserting ``low power television station as defined''.

Makes technical corrections to satellite distant signal compulsory copyright license provisions (copyright law regarding secondary transmissions of superstations and network stations for private home viewing).

SECTION 1. SHORT TITLE. This Act may be cited as the ``Preserving Patient Access to Physicians Act of 2002''. SEC. 2. REFORM OF THE MEDICARE PHYSICIAN PAYMENT UPDATE SYSTEM THROUGH ELIMINATION OF THE SUSTAINABLE GROWTH RATE (SGR) PAYMENT UPDATE SYSTEM. (a) In General.--Section 1848(d) of the Social Security Act (42 U.S.C. 1395w-4(d)) is amended by adding at the end the following new paragraphs: ``(5) Update for 2003.--The update to the single conversion factor established in paragraph (1)(C) for 2003 is 2.5 percent. ``(6) Update for years beginning with 2004.-- ``(A) In general.--Unless otherwise provided by law, subject to the budget-neutrality factor determined by the Secretary under subsection (c)(2)(B)(ii), the update to the single conversion factor established in paragraph (1)(C) for a year beginning with 2004 is equal to the product of-- ``(i) 1 plus the Secretary's estimate of the percentage change in the value of the input price index (as provided under subparagraph (B)(ii)) for the year (divided by 100); and ``(ii) 1 minus the Secretary's estimate of the productivity adjustment factor under subparagraph (C) for the year. ``(B) Input price index.-- ``(i) Establishment.--Taking into account the mix of goods and services included in computing the medicare economic index (referred to in the fourth sentence of section 1842(b)(3)), the Secretary shall establish an index that reflects the weighted-average input prices for physicians' services for a year. Such index shall only account for input prices and not changes in costs that may result from other factors (such as productivity). ``(ii) Annual estimate of change in index.--The Secretary shall estimate, before the beginning of each year (beginning with 2004) the change in the value of the input price index under clause (i) from the previous year to the year involved. ``(C) Productivity adjustment factor.--The Secretary shall estimate, and cause to be published in the Federal Register not later than November 1 before the beginning of each year (beginning with 2004), a productivity adjustment factor that reflects the Secretary's estimate of growth in multifactor productivity in the national economy, taking into account growth in productivity attributable to both labor and nonlabor factors. Such adjustment may be based on a multi-year moving average of productivity (based on data published by the Bureau of Labor Statistics).''. (b) Conforming Amendments.--Section 1848 of the such Act (42 U.S.C. 1395w-4) is amended-- (1) in subsection (d)(1)(A), by striking ``subparagraph (B))'' and all that follows and inserting the following: ``subparagraph (B))-- ``(i) for years before 2001, adjusted by the update (established under paragraph (3)) for the year involved; ``(ii) for 2001 and 2002, multiplied by the update (established under paragraph (4)) for the year involved; ``(iii) for 2003, multiplied by the update (established under paragraph (5)) for that year; and ``(iv) for 2004 and each subsequent year, multiplied by the update (established under paragraph (6)) for the year involved.''; (2) by striking clause (i) of subsection (d)(1)(E) and inserting the following: ``(i) cause to have published in the Federal Register not later than November 1-- ``(I) of 2000 and each subsequent year, the conversion factor which will apply to physicians' services for the succeeding year; ``(II) of 2000 and 2001, the update determined under paragraph (4) for such succeeding year and the allowed expenditures under such paragraph for the succeeding year; ``(III) of 2002, the update determined under paragraph (5) for 2003; and ``(IV) of 2003 and each subsequent year, the update determined under paragraph (6) for the succeeding year; and''; (3) in subsection (d)(1)(E)(ii), by inserting ``(for years before 2003)'' after ``the sustainable growth rate''; (4) in subsection (d)(4)-- (A) in the heading, by striking ``years beginning with 2001'' and inserting ``2001 and 2002''; (B) in subparagraph (A), in the matter preceding clause (i), by striking ``for a year beginning with 2001'' and inserting ``for 2001 and 2002''; (C) in subparagraph (C)(iii), by striking ``Years beginning with 2000.--The allowed expenditures for a year (beginning with 2000)'' and inserting ``2000 and 2001.--The allowed expenditures for each of years 2000 and 2001''; (D) in subparagraph (E), by striking ``beginning with 2001'' and ``for a year beginning with 2001'' and inserting ``2001 and 2002'' and ``for 2001 and 2002'', respectively; and (E) in subparagraph (F), by striking ``subparagraph (A)'' and all that follows and inserting ``subparagraph (A), for each of 2001 and 2002, of -0.2 percent.''; and (5) in subsection (f)-- (A) in paragraph (1)(B), by striking ``November 1 of each succeeding year'' and inserting ``November 1, 2001,''; (B) in paragraph (2), by inserting ``and ending with 2002'' after ``beginning with 2000''; (C) in paragraph (3), by striking ``for a year beginning with 2001'' and inserting ``for 2001 and 2002''; (D) by striking subparagraph (C) of paragraph (3); and (E) in paragraph (4)(C)(ii), by inserting ``and ending with 2002'' after ``beginning with 2000''. (c) MedPAC Report on Payment for Physicians' Services.--Not later than 1 year after the date of the enactment of this Act, the Medicare Payment Advisory Commission shall submit to Congress a report on the effect of refinements to the practice expense component of payments for physicians' services, after the transition to full resource-based payment system in 2002, under section 1848 of the Social Security Act (42 U.S.C. 1395w-4) that examines the following matters by physician specialty: (1) The effect of such refinements on payment for physicians' services. (2) The interaction of the practice expense component with other components of and adjustments to payment for physicians' services under such section. (3) The appropriateness of the amount of compensation by reason of such refinements on physicians. (4) The effect of such refinements on access to care by medicare beneficiaries to physicians' services. (5) The effect of such refinements on physician participation under the medicare program.

Preserving Patient Access to Physicians Act of 2002 - Amends title XVIII (Medicare) of the Social Security Act, with respect to the Medicare physician payment update system, to: (1) specify the update to the single conversion factor for 2003; (2) prescribe an update for years beginning with 2004; (3) direct the Secretary of Health and Human Services to establish an index that reflects the weighted-average input prices for physicians' services for a year; and (4) require the Secretary to estimate annually a productivity adjustment factor reflecting estimated growth in multifactor productivity attributable to both labor and nonlabor factors. (Thus eliminates the sustainable growth rate (SGR) payment update system).

relationships between information theory and statistical physics have been widely recognized in the last few decades , from a wide spectrum of aspects . these include conceptual aspects , of parallelisms and analogies between theoretical principles in the two disciplines , as well as technical aspects , of mapping between mathematical formalisms in both fields and borrowing analysis techniques from one field to the other . one example of such a mapping , is between the paradigm of random codes for channel coding and certain models of magnetic materials , most notably , ising models and spin glass models ( see , e.g. , @xcite,@xcite,@xcite,@xcite , and many references therein ) . today , it is quite widely believed that research in the intersection between information theory and statistical physics may have the potential of fertilizing both disciplines . this paper is more related to the former aspect mentioned above , namely , the relationships between the two areas in the conceptual level . however , it has also ingredients from the second aspect . in particular , let us consider two questions in the two fields , which at first glance , may seem completely unrelated , but will nevertheless turn out later to be very related . these are special cases of more general questions that we study later in this paper . the first is a simple question in statistical mechanics , and it is about a certain extension of a model described in ( * ? ? ? * , problem 13 ) : consider a one dimensional chain of @xmath0 connected elements ( e.g. , monomers or whatever basic units that form a polymer chain ) , arranged along a straight line ( see fig . [ chain ] ) , and residing in thermal equilibrium at fixed temperature @xmath1 . the are two types of elements , which will be referred to as type ` 0 ' and type ` 1 ' . the number of elements of each type @xmath2 ( with @xmath2 being either ` 0 ' or ` 1 ' ) is given by @xmath3 , where @xmath4 ( and so , @xmath5 ) . each element of each type may be in one of two different states , labeled by @xmath6 , where @xmath6 also takes on the values ` 0 ' and ` 1 ' . the length and the internal energy of an element of type @xmath2 at state @xmath6 are given by @xmath7 and @xmath8 ( independently of @xmath2 ) , respectively . a contracting force @xmath9 is applied to one edge of the chain while the other edge is fixed . what is the minimum amount of mechanical work @xmath10 that must be carried out by this force , along an isothermal process at temperature @xmath1 , in order to shrink the chain from its original length @xmath11 ( when no force was applied ) into a shorter length , @xmath12 , where @xmath13 is a given constant ? the second question is in information theory . in particular , it is the classical problem of lossy source coding , and some of the notation here will deliberately be chosen to be the same as before : an information source emits a string of @xmath0 independent symbols , @xmath14 , where each @xmath15 may either be ` 0 ' or ` 1 ' , with probabilities @xmath16 and @xmath17 , respectively . a lossy source encoder maps the source string , @xmath18 , into a shorter ( compressed ) representation of average length @xmath19 , where @xmath20 is the coding rate ( compression ratio ) , and the compatible decoder maps this compressed representation into a reproduction string , @xmath21 , where each @xmath22 is again , either ` 0 ' or ` 1 ' . the fidelity of the reproduction is measured in terms of a certain distortion ( or distance ) function , @xmath23 , which should be as small as possible , so that @xmath24 would be as ` close ' as possible to @xmath25 . is required to be strictly identical to @xmath24 , in which case @xmath26 . however , in some applications , one might be willing to trade off between compression and fidelity , i.e. , slightly increase the distortion at the benefit of reducing the compression ratio @xmath20 . ] in the limit of large @xmath0 , what is the minimum coding rate @xmath27 for which there exists an encoder and decoder such that the average distortion , @xmath28 , would not exceed @xmath12 ? it turns out , as we shall see in the sequel , that the two questions have intimately related answers . in particular , the minimum amount of work @xmath10 , in the first question , is related to @xmath29 ( a.k.a . the _ rate distortion function _ ) , of the second question , according to @xmath30 provided that the hamiltonian , @xmath8 , in the former problem , is given by @xmath31 where @xmath32 is boltzmann s constant , and @xmath33 is the relative frequency ( or the empirical probability ) of the symbol @xmath34 in the reproduction sequence @xmath24 , pertaining to an optimum lossy encoder decoder with average per symbol distortion @xmath35 ( for large @xmath0 ) . moreover , the minimum amount of work @xmath10 , which is simply the free energy difference between the final equilibrium state and the initial state of the chain , is achieved by a reversible process , where the compressing force @xmath36 grows very slowly from zero , at the beginning of the process , up to a final level of @xmath37 where @xmath38 is the derivative of @xmath29 ( see fig . [ rd ] ) . thus , physical compression is strongly related to data compression , and the fundamental physical limit on the minimum required work is intimately connected to the fundamental information theoretic limit of the minimum required coding rate . this link between the the physical model and the lossy source coding problem is obtained from a large deviations perspective . the exact details will be seen later on , but in a nutshell , the idea is this : on the one hand , it is possible to represent @xmath29 as the large deviations rate function of a certain rare event , but on the other hand , this large deviations rate function , involves the use of the legendre transform , which is a pivotal concept in thermodynamics and statistical mechanics . moreover , since this legendre transform is applied to the ( logarithm of the ) moment generating function ( of the distortion variable ) , which in turn , has the form a partition function , this paves the way to the above described analogy . the legendre transform is associated with the optimization across a certain parameter , which can be interpreted as either inverse temperature ( as was done , for example , in @xcite,@xcite,@xcite,@xcite ) or as a ( generalized ) force , as proposed here . the interpretation of this parameter as force is somewhat more solid , for reasons that will become apparent later . one application of this analogy , between the two models , is a parametric representation of the rate distortion function @xmath29 as an integral of the minimum mean square error ( mmse ) in a certain bayesian estimation problem , which is obtained in analogy to a certain variant of the fluctuation dissipation theorem . this representation opens the door for derivation of upper and lower bounds on the rate distortion function via bounds on the mmse , as was demonstrated in a companion paper @xcite . another possible application is demonstrated in the present paper : when the setup is extended to allow information sources with memory ( non i.i.d . processes ) , then the analogous physical model consists of interactions between the various particles . when these interactions are sufficiently strong ( and with high enough dimension ) , then the system exhibits phase transitions . in the information theoretic domain , these phase transitions mean irregularities and threshold effects in the behavior of the relevant information theoretic function , in this case , the rate distortion function . thus , analysis tools and physical insights are ` imported ' from statistical mechanics to information theory . a particular model example for this is worked out in section 4 . the outline of the paper is as follows . in section 2 , we provide some relevant background in information theory , which may safely be skipped by readers that possess this background . in section 3 , we establish the analogy between lossy source coding and the above described physical model , and discuss it in detail . in section 4 , we demonstrate the analysis for a system with memory , as explained in the previous paragraph . finally , in section 5 we summarize and conclude . one of the most elementary roles of information theory is to provide fundamental performance limits pertaining to certain tasks of information processing , such as data compression , error correction coding , encryption , data hiding , prediction , and detection / estimation of signals and/or parameters from noisy observations , just to name a few ( see e.g. , @xcite ) . in this paper , our focus is on the first item mentioned data compression , a.k.a . _ source coding _ , where the mission is to convert a piece of information ( say , a long file ) , henceforth referred to as the _ source data _ , into a shorter ( normally , binary ) representation , which enables either perfect recovery of the original information , as in the case of _ lossless compression _ , or non perfect recovery , where the level of reconstruction errors ( or distortion ) should remain within pre - specified limits , which is the case of _ lossy data compression_. lossless compression is possible whenever the statistical characterization of the source data inherently exhibits some level of _ redundancy _ that can be exploited by the compression scheme , for example , a binary file , where the relative frequency of 1 s is much larger than that of the 0 s , or when there is a strong statistical dependence between consecutive bits . these types of redundancy exist , more often than not , in real life situations . if some level of errors and distortion are allowed , as in the lossy case , then compression can be made even more aggressive . the choice between lossless and lossy data compression depends on the application and the type of data to be compressed . for example , when it comes to sensitive information , like bank account information , or a piece of important text , then one may not tolerate any reconstruction errors at all . on the other hand , images and audio / video files , may suffer some degree of harmless reconstruction errors ( which may be unnoticeable to the human eye or ear , if designed cleverly ) and thus allow stronger compression , which would be very welcome , since images and video files are typically enormously large . the _ compression ratio _ , or the _ coding rate _ , denoted @xmath20 , is defined as the ( average ) ratio between the length of the compressed file ( in bits ) and the length of the original file . the basic role of information theory , in the context of lossless / lossy source coding , is to characterize the fundamental limits of compression : for a given statistical characterization of the source data , normally modeled by a certain random process , what is the minimum achievable compression ratio @xmath20 as a function of the allowed average distortion , denoted @xmath35 , which is defined with respect to some distortion function that measures the degree of proximity between the source data and the recovered data . the characterization of this minimum achievable @xmath20 for a given @xmath35 , denoted as a function @xmath29 , is called the _ rate distortion function _ of the source with respect to the prescribed distortion function . for the lossless case , of course , @xmath39 . another important question is how , in principle , one may achieve ( or at least approach ) this fundamental limit of optimum performance , @xmath29 ? in this context , there is a big gap between lossy compression and lossless compression . while for the lossless case , there are many practical algorithms ( most notably , adaptive huffman codes , lempel ziv codes , arithmetic codes , and more ) , in the lossy case , there is unfortunately , no constructive practical scheme whose performance comes close to @xmath29 . the simplest non trivial model of an information source is that of an i.i.d.process , a.k.a . a _ discrete memoryless source _ ( dms ) , where the source symbols , @xmath14 , take on values in a common finite set ( alphabet ) @xmath40 , they are statistically independent , and they are all drawn from the same probability mass function , denoted by @xmath41 . the source string @xmath42 is compressed into a binary representation depends on @xmath25 , the code should be designed such that the running bit - stream ( formed by concatenating compressed strings corresponding to successive @xmath0blocks from the source ) could be uniquely parsed in the correct manner and then decoded . to this end , the lengths @xmath43 must be collectively large enough so as to satisfy the kraft inequality . the details can be found , for example , in @xcite . ] of length @xmath44 ( which may or may not depend on @xmath25 ) , whose average is @xmath45 , and the compression ratio is @xmath46 . in the decoding ( or decompression ) process , the compressed representation is mapped into a reproduction string @xmath47 , where each @xmath22 , @xmath48 , takes on values in the _ reproduction alphabet _ @xmath49 ( which is typically either equal to @xmath40 or to a subset of @xmath40 , but this is not necessary ) . the fidelity of the reconstruction string @xmath24 relative to the original source string @xmath6 is measured by a certain distortion function @xmath50 , where the function @xmath51 is defined additively as @xmath52 , @xmath53 being a function from @xmath54 to the non negative reals . the average distortion per symbol is @xmath55 . as said , @xmath29 is defined ( in general ) as the infimum of all rates @xmath20 for which there exist a sufficiently large @xmath0 and an encoder decoder pair for @xmath0blocks , such that the average distortion per symbol would not exceed @xmath35 . in the case of a dms @xmath56 , an elementary coding theorem of information theory asserts that @xmath29 admits the following formula @xmath57 where @xmath2 is a random variable that represents a single source symbol ( i.e. , it is governed by @xmath56 ) , @xmath58 is the mutual information between @xmath2 and @xmath6 , i.e. , @xmath59 @xmath60 being the marginal distribution of @xmath6 , which is associated with a given conditional distribution @xmath61 , and the minimum is over all these conditional probability distributions for which @xmath62 for @xmath39 , @xmath6 must be equal to @xmath2 with probability one ( unless @xmath63 also for some @xmath64 ) , and then @xmath65 the shannon entropy of @xmath2 , as expected . as mentioned earlier , there are concrete compression algorithms that come close to @xmath66 for large @xmath0 . for @xmath67 , however , the proof of achievability of @xmath29 is non constructive . the idea for proving the existence of a sequence of codes ( indexed by @xmath0 ) whose performance approach @xmath29 as @xmath68 , is based on the notion of _ random coding _ : if we can define , for each @xmath0 , an ensemble of codes of ( fixed ) rate @xmath20 , for which the average per symbol distortion ( across both the randomness of @xmath6 and the randomness of the code ) is asymptotically less than or equal to @xmath35 , then there must exist at least one sequence of codes in that ensemble , with this property . the idea of random coding is useful because if the ensemble of codes is chosen wisely , the average ensemble performance is surprisingly easy to derive ( in contrast to the performance of a specific code ) and proven to meet @xmath29 in the limit of large @xmath0 . for a given @xmath0 , consider the following ensemble of codes : let @xmath69 denote the conditional probability matrix that achieves @xmath29 and let @xmath70 denote the corresponding marginal distribution of @xmath6 . consider now a random selection of @xmath71 reproduction strings , @xmath72 , each of length @xmath0 , where each @xmath73 , @xmath74 , is drawn independently ( of all other reproduction strings ) , according to @xmath75 this randomly chosen code is generated only once and then revealed to the decoder . upon observing an incoming source string @xmath25 , the encoder seeks the first reproduction string @xmath76 that achieves @xmath77 , and then transmits its index @xmath78 using @xmath79 bits , or equivalently , @xmath80 _ nats_. has the obvious interpretation of the number of bits needed to specify a number between @xmath81 and @xmath82 , the natural base logarithm is often mathematically more convenient to work with . the quantity @xmath83 can also be thought of as the description length , but in different units , called nats , rather than bits , where the conversion is according to @xmath81 nat @xmath84 bits . ] if no such codeword exists , which is referred to as the event of _ encoding failure _ , the encoder sends an arbitrary sequence of @xmath19 nats , say , the all zero sequence . the decoder receives the index @xmath78 and simply outputs the corresponding reproduction string @xmath76 . obviously , the per symbol distortion would be less than @xmath35 whenever the encoder does not fail , and so , the main point of the proof is to show that the probability of failure ( across the randomness of @xmath25 and the ensemble of codes ) is vanishingly small for large @xmath0 , provided that @xmath20 is slightly larger than ( but can be arbitrarily close to ) @xmath29 , i.e. , @xmath85 for an arbitrarily small @xmath86 . the idea is that for any source string that is _ typical _ to @xmath56 ( i.e. , the empirical relative frequency of each symbol in @xmath25 is close to its probability ) , one can show ( see , e.g. , @xcite ) that the probability that a single , randomly selected reproduction string @xmath24 would satisfy @xmath87 , decays exponentially as @xmath88 $ ] . thus , the above described random selection of the entire codebook together with the encoding operation , are equivalent to conducting @xmath82 independent trials in the quest for having at least one @xmath78 for which @xmath77 , @xmath74 . if @xmath89}$ ] , the number of trials is much larger ( by a factor of @xmath90 ) than the reciprocal of the probability of a single ` success ' , @xmath88 $ ] , and so , the probability of obtaining at least one such success ( which is case where the encoder succeeds ) tends to unity as @xmath68 . we took the liberty of assuming that source string is typical to @xmath56 because the probability of seeing a non typical string is vanishingly small . from the foregoing discussion , we see that @xmath29 has the additional interpretation of the exponential rate of the probability of the event @xmath87 , where @xmath25 is a given string typical to @xmath56 and @xmath24 is randomly drawn i.i.d . under @xmath70 . consider the following chain of equalities and inequalities for bounding the probability of this event from above . letting @xmath91 be a parameter taking an arbitrary non positive value , we have : @xmath92\right\}\right>\nonumber\\ & = & e^{-nsd}\left<\prod_{i=1}^n e^{sd(x_i,{\hat{x}}_i)}\right>\nonumber\\ & = & e^{-nsd}\prod_{i=1}^n\left < e^{sd(x_i,{\hat{x}}_i)}\right>\nonumber\\ & = & e^{-nsd}\prod_{x\in{{\cal x}}}\prod_{i:~x_i = x}\left < e^{sd(x,{\hat{x}}_i)}\right>\nonumber\\ & = & e^{-nsd}\prod_{x\in{{\cal x}}}\left[\left < e^{sd(x,{\hat{x}})}\right>\right]^{np(x)}\nonumber\\ & = & e^{-ni(d , s)}\end{aligned}\ ] ] where @xmath93 is defined as @xmath94\right\}.\ ] ] the tightest upper bound is obtained by minimizing it over the range @xmath95 , which is equivalent to maximizing @xmath93 in that range . i.e. , the tightest upper bound of this form is @xmath96 , where @xmath97 ( the chernoff bound ) . while this is merely an upper bound , the methods of large deviations theory ( see , e.g. , @xcite ) can readily be used to establish the fact that the bound @xmath96 is tight in the exponential sense , namely , it is the correct asymptotic exponential decay rate of @xmath98 . accordingly , @xmath99 is called the _ large deviations rate function _ of this event . combining this with the foregoing discussion , it follows that @xmath100 , which means that an alternative expression of @xmath29 is given by @xmath101.\ ] ] interestingly , the same expression was obtained in ( * ? ? ? * corollary 4.2.3 ) using completely different considerations ( see also @xcite ) . in this paper , however , we will also concern ourselves , more generally , with the rate distortion function , @xmath102 , pertaining to a given reproduction distribution @xmath103 , which may not necessarily be the optimum one , @xmath70 . this function is defined similarly as in eq . ( [ rdc ] ) , but with the additional constraint that the marginal distribution that represents the reproduction would agree with the given @xmath103 , i.e. , @xmath104 . by using the same large deviations arguments as above , but for an arbitrary random coding distribution @xmath103 , one readily observes that @xmath102 is of the same form as in eq . ( [ ldrdo ] ) , except that @xmath70 is replaced by the given @xmath103 ( see also @xcite ) . this expression will now be used as a bridge to the realm of equilibrium statistical mechanics . consider the parametric representation of the rate distortion function @xmath102 , with respect to a given reproduction distribution @xmath103 : @xmath105.\ ] ] the expression in the inner brackets , @xmath106 can be thought of as the partition function of a single particle of `` type '' @xmath2 , which is defined as follows . assuming a certain fixed temperature @xmath107 , consider the hamiltonian @xmath108 imagine now that this particle may be in various states , indexed by @xmath109 . when a particle of type @xmath2 lies in state @xmath6 its internal energy is @xmath8 , as defined above , and its length is @xmath7 . next assume that instead of working with the parameter @xmath91 , we rescale and redefine the free parameter as @xmath36 , where @xmath110 . then , @xmath36 has the physical meaning of a force that is conjugate to the length . this force is stretching for @xmath111 and contracting for @xmath9 . with a slight abuse of notation , the gibbs partition function ( * ? ? ? * section 4.8 ) pertaining to a single particle of type @xmath2 is then given by @xmath112\right\},\ ] ] and accordingly , @xmath113 is the gibbs free energy per particle of type @xmath2 . thus , @xmath114 is the average per particle gibbs free energy ( or the gibbs free energy density ) pertaining to a system with a total of @xmath0 non interacting particles , from @xmath115 different types , where the number of particles of type @xmath2 is @xmath116 , @xmath117 . the helmholtz free energy per particle is then given by the legendre transform @xmath118.\ ] ] however , for @xmath119 ( which is the interesting range , where @xmath120 ) , the maximizing @xmath36 is always non positive , and so , @xmath121.\ ] ] invoking now eq . ( [ ldrd ] ) , we readily identify that @xmath122 which supports the analogy between the lossy data compression problem and the behavior of the statistical mechanical model of the kind described in the third paragraph of the introduction : according to this model , the physical system under discussion is a long chain with a total of @xmath0 elements , which is composed of @xmath115 different types of shorter chains ( indexed by @xmath2 ) , where the number of elements in the short chain of type @xmath2 is @xmath116 , and where each element of each chain can be in various states , indexed by @xmath6 . in each state @xmath6 , the internal energy and the length of each element are @xmath123 and @xmath7 , as described above . the total length of the chain , when no force is applied , is therefore @xmath124 . upon applying a contracting force @xmath9 , states of shorter length become more probable , and the chain shrinks to the length of @xmath12 , where @xmath35 is related to @xmath36 according to the legendre relation is concave and @xmath125 is convex , the inverse legendre transform holds as well , and so , there is one to one correspondence between @xmath36 and @xmath35 . ] ( [ legendre ] ) between @xmath125 and @xmath126 , which is given by @xmath127 where @xmath128 and @xmath129 are , respectively , the derivatives of @xmath125 and @xmath102 relative to @xmath35 . the inverse relation is , of course , @xmath130 where @xmath131 is the derivative of @xmath126 . since @xmath102 is proportional to the free energy , where the system is held in equilibrium at length @xmath12 , it also means the minimum amount of work required in order to shrink the system from length @xmath11 to length @xmath12 , and this minimum is obtained by a reversible process of slow increase in @xmath36 , starting from zero and ending at the final value given by eq . ( [ fl ] ) . + _ discussion _ + this analogy between the lossy source coding problem and the statistical mechanical model of a chain , may suggest that physical insights may shed light on lossy source coding and vice versa . we learn , for example , that the contribution of each source symbol @xmath2 to the distortion , @xmath132 , is analogous to the length contributed by the chain of type @xmath2 when the contracting force @xmath36 is applied . we have also learned that the local slope of @xmath102 is proportional to a force , which must increase as the chain is contracted more and more aggressively , and near @xmath39 , it normally tends to infinity , as @xmath133 in most cases . this slope parameter also plays a pivotal role in theory and practice of lossy source coding : on the theoretical side , it gives rise to a variety of parametric representations of the rate distortion function @xcite,@xcite , some of which support the derivation of important , non trivial bounds . on the more practical side , often data compression schemes are designed by optimizing an objective function with the structure of @xmath134 thus @xmath36 plays the role of a lagrange multiplier . this lagrange multiplier is now understood to act like a physical force , which can be ` tuned ' to the desired trade off between rate and distortion . as yet another example , the convexity of the rate distortion function can be understood from a physical point of view , as the helmholtz free energy is also convex , a fact which has a physical explanation ( related to the fluctuation dissipation theorem ) , in addition to the mathematical one . at this point , two technical comments are in order : 1 . we emphasized the fact that the reproduction distribution @xmath103 is fixed . for a given target value of @xmath35 , one may , of course , have the freedom to select the optimum distribution @xmath70 that minimizes @xmath102 , which would yield the rate distortion function , @xmath29 , and so , in principle , all the foregoing discussion applies to @xmath29 as well . some caution , however , must be exercised here , because in general , the optimum @xmath103 may depend on @xmath35 ( or equivalently , on @xmath91 or @xmath36 ) , which means , that in the analogous physical model , the internal energy @xmath8 depends on the force @xmath36 ( in addition to the linear dependence of the term @xmath135 ) . this kind of dependence does not support the above described analogy in a natural manner . this is the reason that we have defined the rate distortion problem for a fixed @xmath103 , as it avoids this problem . thus , even if we pick the optimum @xmath70 for a given target distortion level @xmath35 , then this @xmath70 must be kept unaltered throughout the entire process of increasing @xmath36 from zero to its final value , given by ( [ fl ] ) , although @xmath70 may be sub optimum for all intermediate distortion values that are met along the way from @xmath136 to @xmath35 . an alternative interpretation of the parameter @xmath91 , in the partition function @xmath137 , could be the ( negative ) inverse temperature , as was suggested in @xcite ( see also @xcite ) . in this case , @xmath7 would be the internal energy of an element of type @xmath2 at state @xmath6 and @xmath33 , which does not include a power of @xmath91 , could be understood as being proportional to the degeneracy ( in some coarse graining process ) . in this case , the distortion would have the meaning of internal energy , and since no mechanical work is involved , this would also be the heat absorbed in the system , whereas @xmath102 would be related to the entropy of the system . the legendre transform , in this case , is the one pertaining to the passage between the microcanonical ensemble and the canonical one . the advantage of the interpretation of @xmath91 ( or @xmath36 ) as force , as proposed here , is that it lends itself naturally to a more general case , where there is more than one fidelity criterion . for example , suppose there are two fidelity criteria , with distortion functions @xmath138 and @xmath139 . here , there would be two conjugate forces , @xmath36 and @xmath140 , respectively ( for example , a mechanical force and a magnetic force ) , and the physical analogy carries over . on the other hand , this would not work naturally with the temperature interpretation approach since there is only one temperature parameter in physics . we end this section by providing a representation of @xmath102 and @xmath35 in an integral form , which follows as a simple consequence of its representation as the legendre transform of @xmath141 , as in eq . ( [ ldrd ] ) . since the maximization problem in ( [ ldrd ] ) is a convex problem ( @xmath141 is convex in @xmath91 ) , the minimizing @xmath91 for a given @xmath35 is obtained by taking the derivative of the r.h.s . , which leads to @xmath142 this equation yields the distortion level @xmath35 for a given value of the minimizing @xmath91 in eq . ( [ ldrd ] ) . let us then denote @xmath143 which means that @xmath144 taking the derivative of ( [ ds ] ) , we readily obtain @xmath145\nonumber\\ & = & \sum_{x\in{{\cal x}}}p(x ) \left[\frac{\sum_{{\hat{x}}\in\hat{{{\cal x}}}}q({\hat{x}})d^2(x,{\hat{x}})e^{sd(x,{\hat{x } } ) } } { \sum_{{\hat{x}}\in\hat{{{\cal x}}}}q({\hat{x}})e^{sd(x,{\hat{x}})}}-\right.\nonumber\\ & & \left.\left(\frac{\sum_{{\hat{x}}\in\hat{{{\cal x}}}}q({\hat{x}})d(x,{\hat{x}})e^{sd(x,{\hat{x } } ) } } { \sum_{{\hat{x}}\in\hat{{{\cal x}}}}q({\hat{x}})e^{sd(x,{\hat{x}})}}\right)^2\right]\nonumber\\ & = & \sum_{x\in{{\cal x}}}p(x)\cdot\mbox{var}_s\{d(x,{\hat{x}})|x\}\nonumber\\ & \equiv&\mbox{mmse}_s\{d(x,{\hat{x}})|x\},\end{aligned}\ ] ] where @xmath146 is the variance of @xmath7 w.r.t.the conditional probability distribution @xmath147 the last line of eq . ( [ derds ] ) means that the expectation of @xmath146 w.r.t . @xmath56 is exactly the mmse of estimating @xmath7 based on the ` observation ' @xmath2 using the conditional mean of @xmath7 given @xmath2 as an estimator . differentiating both sides of eq . ( [ rds ] ) , we get @xmath148 or , equivalently , @xmath149 and @xmath150 in @xcite , this representation was studied extensively and was found quite useful . in particular , simple bounds on the mmse were shown to yield non trivial bounds on the rate distortion function in some cases where an exact closed form expression is unavailable . the physical analogue of this representation is the fluctuation dissipation theorem , where the conditional variance , or equivalently the mmse , plays the role of the fluctuation , which describes the sensitivity , or the linear response , of the length of the system to a small perturbation in the contracting force . if @xmath91 is interpreted as the negative inverse temperature , as was mentioned before , then the mmse is related to the specific heat of the system . the theoretical framework established in the previous section extends , in principle , to information sources with memory ( non i.i.d . sources ) , with a natural correspondence to a physical system of interacting particles . while the rate distortion function for a general source with memory is unknown , the maximum rate achievable by random coding can still be derived in many cases of interest . unlike the case of the memoryless source , where the best random coding distribution is memoryless as well , when the source exhibits memory , there is no apparent reason to believe that good random coding distributions should remain memoryless either , but it is not known what the form of the optimum random coding distribution is . for example , there is no theorem that asserts that the optimum random coding distribution for a markov source is markov too . one can , however examine various forms of the random coding distributions and compare them . intuitively , the stronger is the memory of the source , the stronger should be the memory of the random coding distribution . in this section , we demonstrate one family of random coding distributions , with a very strong memory , which is inspired by the curie weiss model of spin arrays , that possesses long range interactions . consider the random coding distribution @xmath151 where @xmath152 , @xmath153 and @xmath154 are parameters , and @xmath155 is the appropriate normalization constant . using the identity , @xmath156 we can represent @xmath103 as a mixture of i.i.d . distributions as follows : @xmath157 where @xmath158 is the memoryless source @xmath159^n}\ ] ] and the weighting function @xmath160 is given by @xmath161\right]\right\}.\ ] ] next , we repeat the earlier derivation for each @xmath158 individually : @xmath162 where @xmath163 is a short hand notation for @xmath164 , which is well defined from the previous section since @xmath158 is an i.i.d . distribution . at this point , two observations are in order : first , we observe that a separate large deviations analysis for each i.i.d . component @xmath158 is better than applying a similar analysis directly to @xmath103 itself , without the decomposition , since it allows a different optimum choice of @xmath91 for each @xmath165 , rather than one optimization of @xmath91 that compromises all values of @xmath165 . moreover , since the upper bound is exponentially tight for each @xmath158 , then the corresponding mixture of bounds is also exponentially tight . the second observation is that since @xmath158 is i.i.d . , @xmath166 depends on the source @xmath56 only via the marginal distribution of a single symbol @xmath167 , which is assumed here to be independent of @xmath78 . a saddle point analysis gives rise to the following expression for @xmath102 , the random coding rate distortion function pertaining to @xmath103 , which is the large deviations rate function : @xmath168+r_{\theta}(d)\right\ } + \phi(b , j)\ ] ] where @xmath169 we next have a closer look at @xmath166 , assuming @xmath170 , and using the hamming distortion function , i.e. , @xmath171 since @xmath172 we readily obtain @xmath173\nonumber\\ & & + \ln\cosh(b+\theta).\end{aligned}\ ] ] on substituting this expression back into the expression of @xmath102 , we obtain the formula @xmath174\right\}\right ) + \phi(b , j),\end{aligned}\ ] ] which requires merely optimization over two parameters . in fact , the maximization over @xmath91 , for a given @xmath165 , can be carried out in closed form , as it boils down to the solution of a quadratic equation . specifically , for a symmetric source ( @xmath175 ) , the optimum value of @xmath91 is given by @xmath176-\ln[2(1-d)],\ ] ] where @xmath177 the details of the derivation of this expression are omitted as they are straightforward . as the curie weiss model is well known to exhibit phase transitions ( see , e.g. , @xcite,@xcite ) , it is expected that @xmath102 , under this model , would consist of phase transitions as well . at the very least , the last term @xmath178 is definitely subjected to phase transitions in @xmath153 ( the magnetic field ) and @xmath154 ( the coupling parameter ) . the first term , that contains the minimization over @xmath165 , is somewhat more tricky to analyze in closed form . in essence , considering @xmath179 as a function of @xmath165 , substituting it back into the expression of @xmath102 , and finally , differentiating w.r.t . @xmath165 and equating to zero ( in order to minimize ) , then it turns out that the ( internal ) derivative of @xmath180 w.r.t . @xmath165 is multiplied by a vanishing expression ( by the very definition of @xmath181 as a solution to the aforementioned quadratic equation ) . the final result of this manipulation is that the minimizing @xmath165 should be a solution to the equation @xmath182 this is a certain ( rather complicated ) variant of the well known magnetization equation in the mean field model , @xmath183 , which is well known to exhibit a first order phase transition in @xmath153 whenever @xmath184 . it is therefore reasonable to expect that the former equation in @xmath165 , which is more general , will also have phase transitions , at least in some cases . in this paper , we have drawn a conceptually simple analogy between lossy compression of memoryless sources and statistical mechanics of a system of non interacting particles . beyond the belief that this analogy may be interesting on its own right , we have demonstrated its usefulness in several levels . in particular , in the last section , we have observed that the analogy between the information theoretic model and the physical model is not merely on the pure conceptual level , but moreover , analysis tools from statistical mechanics can be harnessed for deriving information theoretic functions . moreover , physical insights concerning phase transitions , in systems with strong interactions , can be ` imported ' for the understanding possible irregularities in these functions , in this case , non smooth dependence on @xmath153 and @xmath154 .

we draw a certain analogy between the classical information theoretic problem of lossy data compression ( source coding ) of memoryless information sources and the statistical mechanical behavior of a certain model of a chain of connected particles ( e.g. , a polymer ) that is subjected to a contracting force . the free energy difference pertaining to such a contraction turns out to be proportional to the rate distortion function in the analogous data compression model , and the contracting force is proportional to the derivative this function . beyond the fact that this analogy may be interesting on its own right , it may provide a physical perspective on the behavior of optimum schemes for lossy data compression ( and perhaps also , an information theoretic perspective on certain physical system models ) . moreover , it triggers the derivation of lossy compression performance for systems with memory , using analysis tools and insights from statistical mechanics .

two - decades of ecological research has demonstrated that alcohol - related violence is not simply an individual - level problem but rather must be understood within the community context , and that alcohol availability and the opportunity that this creates for drinking are an integral part of this problem . both cross - sectional and longitudinal studies have been used to assess the ecological relationship of various outlet density measures and place / population characteristics with violent crime across small geographic scales , including census block groups , census tracts , neighborhoods [ 4 , 5 ] , and zip codes [ 6 , 7 ] . although the specific relationship has varied by study setting , general findings show that neighborhoods with higher availability of alcohol are more likely to have higher rates of violent crime . there has also been some debate within the field of alcohol epidemiology as to whether alcohol outlet type , specifically on - sale versus off - sale premises , has differential effects on rates of violence . a recent study by toomey and colleagues found that the association with violence was stronger and more consistent in the case of on - sale than off - sale outlets although they noted that half of the previous studies that assessed on - sale outlets separately found no effect on violence . moreover , there are ecological theories about drinking environments that focus on the role of on - sale outlets in attracting specific types of people into specific geographic locations and the types of interactions that occur within these microenvironments [ 8 , 9 ] . because there are still inconsistent findings of the effects of on - sale alcohol outlets on violent crime , this study was conducted to examine the nature of the relationship , with appropriate spatial methods , between on - sale alcohol availability , neighborhood population characteristics , and violent crime in a unique study setting . specifically , the present study takes advantage of two features that distinguish it from previous research , and both of which arise from the nature of the study site , lubbock , texas . first , since alcohol was almost exclusively sold for on - premise consumption in lubbock until september of 2009 , this study site allows us to examine the effects of such premises on violence uncontaminated by the effect of off - sale premises . second , lubbock is geographically isolated from other large population centers and is surrounded by sparsely populated counties in which alcohol is not readily available . thus , one might reasonably consider the sale and consumption of alcohol in lubbock to be a closed system in which the alcohol - related problems that occur are likely to be a function of the alcohol sold within the city . in addition , since spatial data are often characterized by two fundamental properties , spatial dependence and nonstationarity , statistical methods that are appropriate in spatial analyses were also employed to examine the nature of the spatial relationship between violent crime , neighborhood sociocultural characteristics , and on - sale alcohol environment . specifically , geographically weighted regression ( gwr ) , combined with global regression models , was utilized in exploring local associations while taking into consideration spatial dependence and nonstationarity of the spatial data and identifying important covariates in the spatial associations between neighborhood population / place characteristics and violence . as noted above , the city of lubbock provides a fairly unique setting to investigate the relationship between on - sale alcohol availability and violence , because of its geographically isolated location and ( prior to august , 2009 ) its retail alcohol market being comprised almost exclusively of on - premise outlets ( only a handful of off - sale outlets existed in an area south of the city known as the strip ) . the estimated population of the city for 2009 was 226,000 , making it the 11th largest city in the state of texas . the city is also home to texas technical university which had a student population of 30,049 in the fall semester of 2009 . the closest population center to the north of lubbock is amarillo , which is 124 miles away and about a two - hour journey by car . the nearest cities after this ( oklahoma city , fort worth , albuquerque , and las cruces ) are each 300 to 400 miles away . in addition , the eight counties that surround lubbock have low population density and three are totally dry none of the remaining five is totally wet : about half of the precincts in four of these countries are dry , and the one county that has no dry precincts allows only off - premise sales of beer and wine . as part of a larger study designed to examine the effects of the introduction of off - sale licenses in the city on september 23 , 2009 , the present analysis focuses on the association between on - sale alcohol outlet density and violent crime prior to the introduction of off - sale outlets , hence the discontinuation of the dataset in august , 2009 . first , data pertaining to reports of violent crime ( murder , rape , robbery , and aggravated assault ) during the time period january , 2005 and august , 2009 were obtained directly from the city of lubbock police department . the dataset contained the date , time , and street address for each violent crime incident . there were a total of 7327 violent crimes for the 56-month time period , of which 49 ( 0.7% ) were murders , 374 ( 5.1% ) rapes , 1422 ( 19.4% ) robberies , and 5482 ( 74.8% ) assaults . close to 99% of these violent crimes were geocoded by street address using centrus desktop . these data were then aggregated to the census block group level and the violent crime rate was calculated as crimes per 1,000 persons . second , a list of all alcohol outlets active during the same 56-month time period in the city of lubbock was obtained from the texas alcoholic beverage commission ( abc ) online database , which includes the name , geographic location , and type of permit or license of the outlet . there were a total of 197 on - sale licenses over the study time period , and outlet density per 1000 residents was used as a measure of alcohol availability . all outlets were geocoded and aggregated to the census block group level in the analysis . third , neighborhood population and sociostructural variables were extracted from the 20062010 american community survey 5-year estimate . consistent with previous ecological studies of alcohol availability and violence [ 3 , 4 ] , 12 neighborhood sociostructural variables were used as potential covariates in the analysis . these 12 neighborhood sociostructural variables fell into three major categories : ( 1 ) concentrated disadvantage : % families below poverty , % households receiving public assistance , % unemployed over age 16 , % female - headed households with children , % black , and % hispanic ; ( 2 ) residential instability : % of residents over age 1 who have lived in the same house 1 year ago , % homes that are owner occupied , % vacant housing units ; ( 3 ) sociodemographic measures of the resident population : adult to child ratio , population density , and % population that is male and aged 1524 . multivariate regression analysis was first conducted to examine the relationship between alcohol outlet densities , neighborhood sociostructural characteristics , and violent crime rate . specifically , a stepwise ordinary least square ( ols ) procedure was run to identify significant explanatory variables , with a 0.01 significance level for entry and a 0.05 level for removal . the candidate covariates in the study were the 12 factors pertaining to neighborhood characteristics described previously . before performing the regression analysis , percent the dependent variable ( violent crime per 1,000 population ) was also log transformed , and a small constant was added to transform zero values . plots of leverage values were used to identify outlying extreme values , and the variance inflation factors ( vif ) were obtained for each of the explanatory variables to assess multicollinearity . residual plots and partial regression plots were also checked for nonrandom pattern and model specification to ensure the inclusion of all the important explanatory variables in the final model . regressions were also run with mean replacement for a small number of missing neighborhood variables , but results essentially remained unchanged and therefore are not reported . to explore spatial association in the relationships between alcohol outlet densities , neighborhood sociostructural characteristics and the violent crime rate across the study area , the geographically weighted regression ( gwr ) method was also employed . the gwr produces a separate parameter estimate of regression coefficients , goodness - of - fit , and significance assessment for each observation . to minimize potential problems associated with multiple testing and multicollinearity among predictor variables , those statistically valid and significant predictors identified using ols procedures were used in gwr model . for gwr modeling , we used adaptive kernels based on bisquare weighting function due to the irregular shape of the study area . this method is often preferred in identifying the optimal number of nearest neighbors , considering the density and size of samples . to identify the optimal size of kernels , we used the akaike information criteria ( aic ) optimization method which identifies the bandwidth that minimizes the aic score and that accounts for the local variation in the size of the data set [ 12 , 14 ] . estimates of spatial autocorrelation ( moran 's i ) were also obtained to ensure that residuals were not spatially correlated . monte - carlo significance tests were conducted to assess statistical significance of nonstationarity for alcohol availability and each of the covariates . descriptive summary statistics ( mean and standard deviations ) for six neighborhood variables included in the model ( percent hispanic , percent black , percent families below poverty , percent owner occupied , percent residential stability , and population density ) , on - sale outlet density , and violent crime rates are shown in table 1 . summary statistics for each individual crime type ( assault , robbery , rape , and murder ) are also included in the table . table 2 presents the summary of regression parameters ( coefficients , standard errors , t values , and 95% confidence intervals ) and diagnostics ( adjusted r - squared and aic ) for the ols model of violent crime that was constructed with six neighborhood variables and on - sale alcohol outlet density . these predictors explained about 63% of the variance in violent crime ( adjusted r - squared = 0.628 ) and were all statistically significant at p values of < 0.01 . the table shows that a 1% increase in on - sale outlet density was associated with a 0.25% increase in violent crime . variance inflation factors ( vif ) included in the table indicate that multicollinearity among explanatory variables was removed in the model . the local gwr model was also constructed with the above neighborhood variables and on - sale alcohol outlet density ( table 3 and figure 1 ) . the map clearly shows spatial patterns of violent crime rates after taking into account local variations of the neighbourhood sociostructural characteristics and including alcohol availability . specifically , a higher rate of violent crime was identified in the north - east of the city where combined outlet density and neighborhood characteristics have a relatively strong influence . further , the parameters of each explanatory variable produced by the local gwr model ( 5-number summary values ) differ across the study area with varying degrees of magnitude and sign of the statistical association ( table 3 ) . we also identified block groups with positive and negative values of the t - statistic at the 95% level of significance , using standard values of 1.96 . alcohol outlet density along with several covariates , including percent black and percent hispanic , indicated positively significant relationships in a majority of block groups ( about 60% ) , while percent owner occupied and population density showed negatively significant relationships in most block groups within the city ( close to 90% of the block groups ) . additionally , spatial nonstationarity of predictor variables was further assessed by the p values obtained from the monte - carlo tests . two predictor variables ( percent black and percent hispanic ) exhibited statistically significant nonstationarity , while the rest of the variables , including alcohol outlet density , were not statistically significant . we further conducted sensitivity analyses in assessing statistical significance of spatial nonstationarity of predictor variables ; results from the monte - carlo tests with all 12 sociostructural neighbourhood variables remained unchanged , indicating that errors due to model misspecification unlikely . finally , regression coefficients and diagnostic values were used to compare the performance between the two models . as indicated previously , the best ols model explained slightly less than two - thirds of the variability in violence within the study area , while the gwr improved the model with an additional 7% in explained variance ( mean adjusted r - squared value of 0.704 ) . the aic score for the gwr model ( 361.97 ) was much smaller than the aic from the global ols model ( 388.46 ) , which suggests that the local gwr model provided a better fit to the data , and thus significant improvement over the global model . the spatial distribution of local r - squared values produced by the gwr analysis is also presented in figure 2 . spatial variations in these local r - squared statistics demonstrate how the combined effects of neighborhood population and place characteristics ( including outlet density ) on violent crime vary across block groups within the city . this map also identifies geographic areas where the gwr produces an improvement in overall model fit with respect to the global model . more than 50% of census block groups showed an improvement over the r - squared of 0.63 from the global ols model , especially in a majority of block groups east of the city . this study investigated whether violent crime is spatially and/or locally associated with neighborhood sociostructural characteristics , including the availability of alcohol through on - sale premises , in the city of lubbock , texas . using the ols procedure we identified several neighborhood sociostructural variables , including on - sale alcohol outlet density , that showed a statistically significant association with violent crime in the city , and which explained 63% of the variance in this outcome . an additional 7% was explained by the local gwr model , which explained more than two - thirds of the variability in violence within the study area . we also observed spatially varying population and neighborhood variables associated with violent crime within the study area , often not captured by the global model . the findings provide evidence of the ecological association between on - sale alcohol outlets and violence overall and show that violence is spatially and locally associated with neighborhood and on - sale alcohol environment . the findings concerning alcohol outlet density and violence add to a growing body of research that has examined the association between these two variables [ 1 , 5 ] . as noted above , while a positive association between on - sale alcohol outlets and violence has been reported in a number of studies , overall the previous research in this area has produced mixed results with many studies reporting no association . the current study may provide more credible evidence on the inconsistent associations reported previously as it allows assessment of the influence of on - sales outlets on violence in the almost total absence of off - sale outlets . we found that such outlets explained an additional 3% of the variance in violent crime in the ols model . a number of mechanisms have been proposed as explanations of this relationship . at the most basic level , alcohol consumption will increase as availability increases and this , in turn , will lead to a rise in both excessive drinking and alcohol - related harms . beyond availability , it has also been proposed that on - sale outlets can have a deleterious effect on local communities . for example , livingston and colleagues argue that on - sale alcohol outlets can have an amenity effect which operates primarily in terms of the types of individuals that they attract into a neighborhood and the interactions that occur between them following the consumption of alcohol . along similar lines , gruenewald 's niche theory posits that alcohol outlets market their products to specific segments of the drinking population and that different types of drinkers are attracted to different types of drinking environments some of which are more conducive to the generation of violence than others . first , the question as to whether neighborhood characteristics and outlet density are causally linked to the increased violence remains to be answered . similarly , interpretations of our findings should consider limitations inherent due to the study design and measures used in the study ; these include the use of population - based measures of violence and outlet density and potential aggregation problems of outlet density due to the cross - sectional study design . study designs that take advantages of longitudinal changes in neighborhood characteristics and violence and that employ improved measures of violence ( that consider population movement ) and outlet density ( that consider alcohol sales and duration of outlet operations ) may help address this question . second , we can not rule out the possibility that there may be other unmeasured neighborhood population and/or place characteristics that may be associated with violence . other aspects of neighborhood social and built environments that may be directly or indirectly related to violence need to be further investigated , such as social capital , drug availability and other neighborhood institutions [ 1820 ] . these too may require the use of methods other than those employed in our study . third , the results reported pertain to one isolated city in north - west texas and may not be generalizable beyond this setting . lastly , while gwr certainly provides the capability to explore and interpret the significance and sign of spatial and local associations , often undetected by conventional global models , it is not without limitations [ 2224 ] . however , we additionally conducted sensitivity analyses to make sure that important predictor variables were not omitted in assessing statistical significance of spatial nonstationarity and to ensure that potential problems due to multiple testing and multicollinearity were not present by using statistically valid and significant predictors in the model .

objectives . despite the increasing evidence of the associations between alcohol availability and violence , there are still inconsistent findings on the effects of on- and off - sale alcohol outlets on violent crime . the aim of this study was to examine spatial associations between on - sale alcohol availability , neighborhood characteristics , and violent crime in a geographically isolated city in texas . methods . geographically weighted regression ( gwr ) and global regression models were employed to analyze the nature of the spatial relationship between violent crime , neighborhood sociocultural characteristics , and on - sale alcohol environment . results . we found strong effects of neighborhood characteristics combined with on - sale alcohol availability on violence outcomes . several neighborhood variables combined with alcohol availability explained about 63% of the variability in violence . an additional 7% was explained by the gwr model , while spatially nonstationary associations between violence and some predictor variables were observed . conclusions . this study provided more credible evidence of the influence of on - sale alcohol outlets on violence in a unique setting . these findings have important policy implications in addressing the question of public health consequences of alcohol - related violence in local contexts .

bladder outlet obstruction ( boo ) caused by benign prostatic hyperplasia ( bph ) is the most common cause of male lower urinary tract symptoms ( luts ) . among patients with bph , some require surgery owing to the failure of medical treatment or complications such as acute urinary retention , hematuria , and urinary stones . however , about 25% to 35% of patients report dissatisfaction with the results after transurethral resection of the prostate ( tur - p ) , despite the resolution of the boo induced by bph [ 3 - 5 ] . according to one study , there may be other causes of luts , such as a functional impairment of the bladder ; moreover , men with bph may have concomitant bladder dysfunction such as detrusor underactivity ( du ) . there have been some studies about the effect of surgery such as tur - p in men with bph and du ; however , it remains controversial whether elimination of boo improves luts or not . therefore , it was done in selected patients whose luts was suspected to be induced by problems other than bph . however , men with bph may have other concomitant abnormalities that influence bladder function . generally , most men with bph are older adults ; therefore , they also have comorbidities , like diabetes , that influence bladder function . also , bladder function in older adults can be altered by aging itself . as a result , luts in these men can be induced by mixed etiologies rather than bph alone . therefore , if we get information about bladder function as well as the degree of boo through preoperative urodynamic study , it would be a great help in selecting good candidates for surgery as well as in predicting postoperative outcomes . recently , there have been many reports about the effect of laser surgery for bph . this procedure shows similar effects and patient satisfaction with conventional tur - p and , in addition , may have several advantages compared with tur - p . retrograde ejaculation and urethral stricture are reported to be lower than with tur - p . particularly , the 120 w high - performance system ( hps ) laser has been regarded as an effective and safe procedure among the various types of laser surgery for bph [ 7 - 10 ] . therefore , we evaluated the short- and long - term outcomes according to the degree of detrusor contractility by preoperative urodynamic study in patients with bph after 120 w hps laser surgery . the subjects were patients who were diagnosed as having bph , who underwent 120 w greenlight hps laser photoselective vaporization of the prostate ( pvp ) from march 2009 , and who were available for follow - up for up to 12 months after surgery . history taking , physical examination , prostate - specific antigen ( psa ) measurement , transrectal ultrasonography , the international prostate symptom score ( ipss ) questionnaire , and urodynamic study were performed in all patients . patients with a history of neurogenic bladder , prostate cancer , or urethral stricture were excluded . pressure - flow study ( pfs ) was performed on the patients , and the degree of boo and the contractility of the detrusor muscle were assessed by use of the schfer nomogram . according to the results of the pfs , the patients were divided into two groups : the group with boo only ( boo group ) and the group with boo with du ( boo+du group ) . we defined du as patients whose contractility was lower than weak by the schfer nomogram . indications for operation were persistent symptoms even after the administration of alpha - blockers or the combination of alpha - blockers and 5 alpha reductase inhibitors for longer than 3 months and cases in which medications were avoided because of the side effects . general or spinal anesthesia was used , and the surgery was performed by a single surgeon . a continuous irrigation system 22 fr resectoscope with a 30 degree lens and a 75 degree laser fiber all prostate tissue causing obstruction was removed until a fine surgical cavity was formed , as in turp . an 18 fr urethral catheter was placed after the operation and was removed the next day , taking into consideration the degree of hematuria . operation time , the energy used during the operation , the catheter indwelling period , and the hospitalization period were analyzed . the outcomes and effectiveness of surgery at 1 month and 12 months after surgery were compared with preoperative values by assessing the ipss , maximal flow rate ( qmax ) , and postvoid residual urine volume ( pvr ) . postoperative qmax , pvr , and ipss with quality of life ( qol ) score were obtained at 1 and 12 months after surgery . postoperative qmax , pvr , ipss , and qol score were compared with preoperative values by using the t - test ; p - values of less than 0.05 were defined as significant . postoperative qmax , pvr , and ipss with quality of life ( qol ) score were obtained at 1 and 12 months after surgery . postoperative qmax , pvr , ipss , and qol score were compared with preoperative values by using the t - test ; p - values of less than 0.05 were defined as significant . the patient group with only boo included 239 cases ( 64.4% ) , and the patient group with boo+du included 132 patients ( 35.6% ) . patient distribution of du was analyzed according to the schfer nomogram as weak+ , weak- , and very weak . the number of patients in the weak+ group was 92 , that in the weak- group was 32 , and that in the very weak group was 8 ( fig . the patients ' preoperative clinical characteristics , such as age , prostate volume , psa level , and ipss , were compared , and there were no significant differences between the two groups . in addition , there were no statistically significant differences in the qmax or pvr between these two groups ( table 1 ) . there were no significant differences in operation time , lasing time , total laser energy , or postoperative urinary catheter indwelling time between these two groups ( table 2 ) . one month after the operation , the total ipss of the boo group was significantly improved from 20.359.15 points to 9.927.16 points . the voiding symptom score was significantly improved from 12.175.01 points to 6.646.16 points , and the storage symptom score was improved from 8.274.55 points to 4.313.06 points at 1 month after the operation . the total ipss of the boo+du group was significantly improved from 20.428.78 to 10.638.47 , and the voiding symptom score was significantly improved from 12.055.15 to 7.225.60 . the storage symptom score was significantly improved from 9.263.51 to 5.173.76 at 1 month after the operation ( p<0.05 ) . one month after the operation , the qol score in the boo group was significantly improved from 4.281.15 to 2.001.13 , and in the boo+du group , the qol score was significantly improved from 4.260.99 to 2.771.41 ( p<0.05 ) . in the boo group , compared with preoperative data , the postoperative 1 month qmax was improved from 10.15.7 ml / s to 15.39.05 ml / s and pvr was improved from 102.35100.51 ml to 23.0821.61 ml . in the boo+du group , postoperative 1 month qmax was improved from 8.715.15ml / s to 13.357.80 ml / s , and pvr was improved from 117.33101.51 ml to 30.0140.34 ml . at 12 months after the operation , in the boo group , total ipss , voiding symptom score , storage symptom score , qol score , qmax , and pvr showed significant improvement compared with preoperative data ( p<0.05 ) . in the boo+du group at 12 months after the operation , total ipss , voiding symptom score , storage symptom score , qol score , qmax , and pvr showed significant improvement compared with preoperative data ( p<0.05 ) . there were no significant differences between the boo and boo+du groups at the same time interval period after the operation ( postoperative 1 and 12 months ( tables 3 , 4 ) . there were no severe postoperative complications that required re - hospitalization or re - do operation for gross hematuria , retrograde ejaculation , urethral stricture , or urinary tract infection . acute urinary retention was observed in a total of 27 patients ( 7% ) : 14 cases in the boo group and 13 cases in the boo+du group . in all cases , only temporary urinary catheterization for 2 weeks was needed . after the catheter was removed , the patients were all able to void well . a total of 48 cases ( 13% ) of mild dysuria were observed : 21 cases in the boo group and 27 cases in the boo+du group . in all cases , the symptoms were managed by follow - up or conservative care such as temporary analgesic medications . in the patients with boo associated with impaired detrusor contractility , it is still controversial whether eliminating boo improves luts . but , according to our results , patients with boo and du showed improvements in preoperative luts and were satisfied about their postoperative results after relief of boo by the 120 w hps laser . bph is the major cause of male luts , and the symptoms in many patients with bph are related to boo induced by enlargement of the prostate . however , boo may not develop in all patients with bph , and luts in some patients with bph are associated with not only boo but also bladder function . some investigators reported that boo is observed in about 50% to 70% of males with bph ; moreover , 37% to 47% of patients with bph also have bladder dysfunction such as impaired detrusor contractility as well as boo . impaired detrusor contractility can be induced by boo itself , because alteration of bladder function can appear as a secondary change following boo . in addition , hormonal changes , aging , concomitant disease , and neurologic disorders can affect bladder function and lead to impairment of detrusor contractility . most patients with bph are of old age , and aging is one of the factors that affect bladder function . moreover , the incidence of a lower testosterone level and diseases such as diabetes or stroke increase in males with old age . luts in several patients with bph may be related to both boo and functional impairment of the bladder . similar to previous reports , we also observed that 35.6% of bph patients who needed surgical treatment showed boo and du in this study . therefore , assessment of detrusor function as well as boo in men with luts induced by bph is important for selecting a treatment strategy and , in addition , may help to predict which patients need additional medications after relieving boo . abrams et al reported that the success rate of the operation was approximately 72% when urologists select surgical candidates according to qmax only . however , the success rate of surgery rose to 88% when the candidates for surgery were selected by the results of urodynamic evaluation including pfs . this higher success rate after surgery suggested that it is possible to diagnose the patients who have true boo . in such a manner , thus , urodynamic study could be of great help in the selection of patients before surgery and in the prediction of postsurgical prognosis . because of deterioration of bladder emptying , du leads to a decreased flow rate and higher pvr . therefore , it was thought that men with boo and du would have greater pvr and a higher ipss as well as lower flow rates compared with those without du . however , in this study , only a small difference was observed in qmax and pvr between the boo only and boo+du groups preoperatively , and the difference was not significant . we supposed that this result was related with voiding by abdominal straining in the patients in the boo+du group , because an elevation in abdominal pressure was noted in most of the patients in the boo+du group during pfs . in addition , the severity of du might be mild compared with that in other previous studies . du is one of the important factors that influences the prognosis of bph treatment and is found in approximately 20% to 25% of males with luts . thomas et al reported in a study conducted on patients with du that deterioration of detrusor muscle contractility is the major cause of persistent symptoms after surgery . thus , du has been considered to be a risk factor that predicts poor prognosis even after surgery in patients with bph . there were reports that luts can be improved by eliminating boo through transurethral surgery or photoselective vaporization of the prostate in patients with bph without postoperative alterations of detrusor contractility . in addition , monoski et al reported that even in bph patients with impaired detrusor contractility and a preoperative history of urinary retention , eliminating boo by ktp laser improves both subjective and objective parameters . park et al reported that there were significant improvements in qmax , voiding urine volume , pvr , ipss , and qol scores at 6 months after pvp treatment . in our study , similarly , in the boo with du group , 1 month after 120 w hps laser operation , ipss scores , qol , qmax , and pvr were improved and the improvements were maintained for 12 months . during the follow - up period , in the boo with du group , cholinergic medication was able to be reduced to less than preoperative doses or stopped altogether after the operation in almost all patients . in this study , most of the men with boo induced by bph benefited from 120 w hps laser with an improvement in both subjective and objective voiding parameters regardless of the presence of du . additionally , further evaluation is necessary about the effect of concomitant du on outcomes after bph surgery because bladder function can deteriorate as patients grow older . as a result , more long - term follow - up is needed to evaluate the changes in luts in patients with boo and du . our results suggest that relieving boo may improve the luts and qol in bph patients with boo and du as well as in patients without du . therefore , surgery to relieve boo in patients with bph seems to be an appropriate treatment modality regardless of the existence of du .

purposemost men with benign prostatic hyperplasia ( bph ) have bothersome lower urinary tract symptoms ( luts ) . this study aimed to investigate the safety and efficacy of high - performance system ( hps ) laser photoselective vaporization of the prostate ( pvp ) for the treatment of bph in men with detrusor underactivity ( du).materials and methodsfrom march 2009 , 371 patients with bph were divided into 2 groups according to the findings of preoperative urodynamic study : 239 ( 64.4% ) patients with bladder outlet obstruction ( boo ) and 132 ( 35.6% ) patients with bladder outlet obstruction with detrusor underactivity ( boo+du ) . 120 w hps laser pvp was performed to resolve the boo . the perioperative data and postoperative results at 1 month and 12 months , including the international prostate symptom score ( ipss ) , maximum urinary flow ( qmax ) , and postvoid residual urine ( pvr ) values , were evaluated.resultscompared with the preoperative parameters , significant improvements in ipss , qmax , and pvr were observed in each group at 1 and 12 months after the operation . in addition , ipss , qmax , and pvr were not significantly different between the boo and boo+du groups at 1 and 12 months after the operation.conclusionssurgery to relieve boo in the patients with bph seems to be an appropriate treatment modality regardless of the existence of du .

glaucoma is a multifactorial disease associated with optic nerve damage , visual field defects , and often elevated intraocular pressure . nevertheless , there are several aspects of intraocular pressure that have been researched to clarify its role in the pathology of glaucoma . central cornea thickness , bioelasticity , and intraocular pulse amplitude are points of special interest.1 dynamic contour tonometry is a device capable of measuring intraocular pressure with less central cornea influence and ocular pulse amplitude.2 the main purpose of this study is to determine if there can be any differences in dynamic contour tonometry and ocular pulse amplitude in asymmetric glaucoma patients with the same applanation intraocular pressure . this was a prospective , observational study of 30 glaucoma patients and 11 controls between june 2007 and february 2008 . inclusion criteria were : the same intraocular pressure on applanation tonometry in both eyes ; a difference of 6 db in mean deviation of visual field ; a difference 0.2 in cup - to - disc ratio ; and a dynamic contour tonometry measurement quality score reading of 1 or 2 in glaucoma patients . dynamic contour tonometry intraocular pressure , ocular pulse amplitude , corneal thickness , applanation tonometry , and fundus examination was undertaken in both groups . statistical analyses were performed using the kolmogorov - smirnov and shapiro - wilk tests and pearson s linear correlation . results with p the study was conducted in accordance with the clinical research regulations prevailing in brazil ( resolution 196/96 ) and with the ethical standards stated in the 1964 declaration of helsinki regarding ethical principles for medical research involving human subjects . mean applanation intraocular pressure was 14.28 mmhg for the right eye and 14.10 mmhg for the left eye ( p > 0.05 ) . corneal thickness was 519.10 m for the right eye and 511.07 m for the left eye ( p > 0.05 ) . mean dynamic contour tonometry intraocular pressure was 17.28 mmhg for the right eye and 17.25 mmhg for the left eye ( p > 0.05 ) . mean ocular pulse amplitude was 2.80 mmhg for the right eye and 2.92 mmhg for the left eye ( p > 0.05 , table 1 ) . in glaucoma patients , mean applanation intraocular pressure was 15.70 mmhg for the worst eye and 14.93 mmhg for the best eye ( p = 0.078 , table 2 , figure 1 ) . mean dynamic contour tonometry intraocular pressure was 20.63 mmhg for the worst eye and 18.19 mmhg for the best eye . this difference was statistically significant ( p < 0.05 , table 3 , figure 2 ) . mean ocular pulse amplitude was 2.76 mmhg for the worst eye and 2.68 mmhg for the best eye ( p = 0.501 , table 4 , figure 3 ) . corneal thickness was 516.60 m for the worst eye and 507.07 m for the best eye ( p > 0.05 , table 5 , figure 4 ) . some studies report that thinner corneas are more likely to be associated with glaucoma probably because of underestimation of intraocular pressure measurement by applanation tonometry . the ocular hypertension treatment study showed that decreased corneal thickness is associated with a higher risk of development of glaucoma in patients with ocular hypertension.3 studies regarding elasticity and other properties of the cornea are still unclear . weizer et al showed that increased ocular pulse amplitude seems to correlate with less severe glaucoma and with increased central corneal thickness.4 punjabi et al published a study comparing intraocular pressure and ocular pulse amplitude in different types of glaucoma using dynamic contour tonometry and concluded that ocular pulse amplitude was higher in patients with ocular hypertension.5 romppainen et al found that subjects with ocular hypertension showed significantly higher ocular pulse amplitude values ( 3.6 1.3 mmhg ) than healthy eyes ( 3.1 1.4 mmhg ) and eyes with low - tension glaucoma ( 2.9 1.4 mmhg ) . after trabeculectomy , the values were significantly lower ( 2.4 1.3 mmhg ) than in healthy eyes.6 stalmans et al studied the ocular pulse amplitude in normal tension and primary open - angle glaucoma and concluded that ocular pulse amplitude was reduced in patients with primary open - angle glaucoma and normal tension compared with healthy controls . ocular pulse amplitude is influenced by intraocular pressure , but not by corneal thickness.7 sullivan - mee et al in a very similar study of patients with asymmetric glaucoma demonstrated that dynamic contour tonometry intraocular pressure was significantly higher in eyes with a higher agis score than in eyes with a lower agis score ( 16.3 versus 15.5 mmhg , p = 0.004 ) , but applanation intraocular pressure was not significantly different in the same eyes ( 14.5 mmhg versus 14.4 mmhg , p = 0.56 ) . these findings suggest that dynamic contour tonometry intraocular pressure is more related to the extension of damage of glaucoma than is applanation intraocular pressure . the most likely explanation for these results is that applanation intraocular pressure systematically underestimates intraocular pressure compared with dynamic contour tonometry intraocular pressure.8 in our study , ocular pulse amplitude was similar in both asymmetric eyes and in controls . however , dynamic contour tonometry intraocular pressure was significantly different between the worst and best eye in glaucoma patients . we found a 2.44 mmhg higher dynamic contour tonometry intraocular pressure in the worst eye than in the best eye , despite the same applanation intraocular pressure . perhaps these results can be explained in light of the underestimation of applanation tonometry intraocular pressure compared with dynamic contour tonometry intraocular pressure . further , some as yet unknown corneal factors could be responsible for this difference between worst and best eyes with glaucoma . this difference could represent a new risk factor for glaucoma prognosis , onset , or progression . no differences in ocular pulse amplitude were found between the groups or between the worst and the best eye . in spite of the lack of difference in ocular pulse amplitude , dynamic contour tonometry intraocular pressure was 2.44 mmhg higher in the worst eye than in the best eye in glaucoma patients , even with the same applanation intraocular pressure . further studies are needed to confirm if this difference is related to glaucoma progression and/or a worse prognosis , and whether dynamic contour tonometry intraocular pressure should be considered as a new risk factor .

backgroundthe purpose of this study was to determine any difference in dynamic contour tonometry and ocular pulse amplitude in asymmetric glaucoma patients with the same applanation intraocular pressure.methodsthis is a prospective , observational study of 30 glaucoma patients and 11 controls from june 2007 to february 2008 . most of the glaucoma patients were on prostaglandin analog treatment.resultsmean applanation intraocular pressure in the control group was 14.28 mmhg for the right eye and 14.10 mmhg for the left eye ( p > 0.05 ) . corneal thickness was 519.10 m for the right eye and 511.07 m for the left eye ( p > 0.05 ) . mean dynamic contour tonometry intraocular pressure was 17.28 mmhg for the right eye and 17.25 mmhg for the left eye ( p > 0.05 ) . mean ocular pulse amplitude was 2.80 mmhg for the right eye and 2.92 mmhg for the left eye ( p > 0.05).conclusionno differences in ocular pulse amplitude were found between the two groups and between the worst and the best eye . in spite of there being no difference in ocular pulse amplitude , dynamic contour tonometry intraocular pressure was 2.44 mmhg higher in the worst eye than in the best eye in the glaucoma patients , even with the same applanation intraocular pressure . further studies are needed to confirm if this difference is related to glaucoma progression or a worst prognosis and whether it can be considered to be a new risk factor .

these aldehydes include aliphatic and aromatic aldehydes from the environment , food , and those generated during cell metabolism . when aldh2 was overexpressed , the deleterious effects of acetaldehyde in the heart were diminished . a single point mutation in aldh2 greatly reduces aldh2 activity in east asians , which leads to accumulation of acetaldehyde and ultimately facial flushing and other harmful effects . moreover , this mutation is reportedly associated with diabetic complications and coronary diseases in east asians . it is suggested that the toxicity of reactive aldehydes plays main role in the pathogenesis . we focus on the secondary products of oxidative stress , that is , reactive aldehydes . toxic reactive aldehydes such as 4-hydroxy-2-nonenal ( 4hne ) are produced by lipid peroxidation during oxidative stress in the mitochondria . 4hne is especially toxic as it forms adducts with proteins and leads to cellular dysfunction [ 714 ] . in another recent report , we have shown that pharmacological inhibition of aldh2 per se induces mitochondrial dysfunction and cell death . to provide an extension of our previous results , we planned to investigate the effect of aldh2 inhibition using disulfiram ( dsf ) , an aldh2 inhibitor , on high glucose stress in h9c2 cardiomyocyte cell lines . h9c2 cell lines { atcc clr-1446 , routinely used as cardiomyocytes [ 1618 ] } , were cultured and grown in dmem medium . after 1 hr of starving , h9c2 cells were treated with dsf ( santa cruz chemicals , santa cruz , ca ) , an inhibitor of aldh2 or dmso for 2 hours , and then subjected to high glucose stress for 24 hours . the high glucose stress was induced by replacing the culture medium with 33 mm of d - glucose ( hg ) . we maintained the glucose concentration in the cell culture medium throughout the study period by measuring the glucose level using a glucometer . to nullify the osmotic stress caused by high concentration of solute in the culture medium is not the cause for the observed cellular stress , the culture medium of another set of cells was replaced with the same 33 mm d - mannitol ( ctrl ) . we chose 2 doses for dsf , that is , 10 m and 2 m after performing a dose - response curve using dsf in inhibiting aldh2 activity as shown in supplementary figure 1 ( see supplementary material available online at http://dx.doi.org/10.1155/2016/1390861 ) . we used 2 m for the mitochondrial studies as mitochondrial oxygen consumption rate ( ocr ) was decreased below detection level with 10 m dsf treatment . intracellular ros can oxidize the nonfluorescent 29,79-dichlorofluorescein diacetate ( dcfh - da ) to generate fluorescent 29,79-dichlorofluorescein ( dcf ) . fluorescence intensity of dcf can be measured using a fluorimeter . therefore to measure intracellular ros in h9c2 cells , we used the dcf kit and followed the manufacturer 's instructions ( abcam inc . briefly , cells were washed twice with pbs after the study protocol , and then the ros detection solution was added . the fluorescence intensity of dcf was measured using a fluorimeter at 504 nm excitation and 524 nm emission wavelengths . aldh2 activity was measured by following the procedure described elsewhere [ 19 , 20 ] . in brief , enzymatic activity of aldh2 from cell lysate was determined spectrophotometrically by using the reductive reaction of nad+ to nadh at 340 nm . all assays were carried out at 25c in 0.1 m sodium pyrophosphate buffer , ph = 9.5 with 2.4 mm nad+ as a cofactor and 10 mm acetaldehyde as the substrate . 4hne protein adducts were evaluated by western immunoblot as described earlier [ 21 , 22 ] . in brief , protein samples from cell lysates were separated using sds - page and the proteins were then transferred to immobilon - p membranes ( millipore , billerica , ma ) . anti-4hne - cys / his / lys rabbit antibody ( millipore ) and anti--actin mouse monoclonal antibody ( scbt , santa cruz , ca ) at a concentration of 1 : 1000 ( 4c overnight ) were used . the bound antibody was visualized with horseradish peroxidase- ( hrp- ) coupled secondary antibody and chemiluminescence detection reagents . the ratios of levels of 4hne protein adducts and -actin , the loading control , were calculated and plotted as graphs . cells grown at 6070% confluence were starved for 1 hr using dmem media without serum . the plates were then divided into the following treatment groups ( n = 6 plates each ) . at the end of the protocol , cells were washed with tbs buffer and trypsinized . trypan blue was added at a concentration of 1 : 1 and subsequently an automated cell counter ( bio - rad ) was used to determine % of live cells remaining . mitosox reagent was used to measure mitochondrial ros as explained in the manufacturer 's instructions . 1.02.0 ml of 5 m mitosox reagent working solution was used to cover h9c2 cells and incubated for 10 minutes at 37c , protected from light . after washing cells with warm buffer , we processed the cells for imaging using florescent microscope with absorption at 510 nm and emission 580 nm . we also quantified the fluorescence using synergy h1 multi - mode reader ( biotek inc . ) . 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolyl - carbocyanine iodide ( jc-1 ; sigma - aldrich ) was used to determine changes in mitochondrial transmembrane potential ( m ) . jc-1 ( 10 l ; 200 m ; final concentration 2 m ) was added to h9c2 cells on coverslips , incubated for 45 min in the dark , and washed twice with pbs . jc-1 fluorescence was measured from a single excitation wavelength ( 490 nm ) with dual emission ( shift from green at 530 nm to red at 590 nm ) using a fluorimeter . loss of mitochondrial m is presented as the relative ratio of green to red fluorescence . h9c2 cells were seeded at 30,000 cells / well onto bioscience v7 culture plates in growth medium containing 15% fbs ( fetal bovine serum ) on the first day . the next day , medium was replaced , and cells were grown in the culture growth medium . within 24 hrs of seeding , a confluent monolayer of h9c2 cells was formed and then cells were used as described below . xf24 analyzer ( seahorse biosciences ) was used to measure ocr to be monitored in real time function in h9c2 cardiomyocytes as mentioned in our earlier report . for all measurements , the culture medium was changed to serum - free media for 1 hr prior to assay . at the end of the treatment , cells were washed with buffer and cell mito stress test ( cmst ) media for cell bioenergetics measurements were added into each well . oligomycin , an atp synthase inhibitor ( to check the atp mediated respiration ) ; fccp , a known uncoupler and proton translocating ionophore ( to determine maximal respiration and the mitochondrial reserve capacity ) ; and antimycin a , an inhibitor of the mitochondrial electron transport chain ( to check ocr from nonmitochondrial respiration related ) prepared in cmst were injected sequentially through ports in the seahorse flux pak cartridges and then mitochondrial ocr was recorded . dsf pretreatment significantly increased ros levels in cultured h9c2 cardiomyocytes subjected to high glucose stress compared to dsf - untreated cells presented with equimolar concentrations of glucose or mannitol . surprisingly , dsf pretreatment significantly increased ros levels in the mannitol group compared to the dsf - untreated group . however , dsf pretreatment enhanced the ros increase significantly higher in h9c2 cells with high glucose stress compared to cells in the control ( mannitol ) group ( figure 1 ) . dsf pretreatment significantly reduced aldh2 activity in cultured h9c2 cardiomyocytes subjected to high glucose stress compared to dsf - untreated cells presented with equimolar concentrations of glucose or mannitol . furthermore , this dsf pretreatment significantly reduced aldh2 activity in h9c2 cells with high glucose stress compared to cells in the control ( mannitol ) group ( figure 2 ) . dsf pretreatment for 2 hours significantly augmented 4hne adducts formation in cells subjected to high glucose stress compared to dsf - untreated cells presented with equimolar concentrations of glucose or mannitol in their culture medium . moreover , among the dsf - pretreated cells , increase in 4hne adduct formation was found at a significantly higher amount in the hg group compared to the ctrl group ( figure 3 ) . pretreatment with dsf significantly increased cell death in the high glucose group compared to the untreated high glucose group . surprisingly , dsf pretreatment significantly increased cell death in the mannitol group compared to cells in the dsf - untreated group . among the dsf treated groups , cell death was significantly increased in the hg group compared to the mannitol group ( figure 4 ) . pretreatment with dsf reduced mitochondrial membrane potential in the hg group compared to the dsf - untreated hg and ctrl groups . furthermore , dsf enhanced the reduction in mitochondrial membrane potential in cultured h9c2 cardiomyocytes subjected to high glucose stress compared to cells presented with equimolar mannitol in their culture medium ( figure 5 ) . hg increased mitochondrial ros in cultured h9c2 cardiomyocytes which was further enhanced in both ctrl and hg groups with dsf pretreatment ( supplementary figure 2 ) . basal and fccp - induced maximal ocr were decreased in hg group compared to ctrl group . pretreatment with dsf enhanced maximal ocr reduction significantly in hg group but not in ctrl group ( figure 6 ) . in this study , we report that the pharmacological inhibition of aldh2 potentiates high glucose induced deleterious effects in cultured h9c2 cardiomyocyte cell lines . in a recent study , we reported that aldh2 inhibition by 75 m dsf per se attenuated mitochondrial respiration and induced cell death in cultured h9c2 cardiomyocyte cell lines without any stress . while dsf inhibited recombinant mitochondrial aldh2 enzyme with an ic50 value of 36.4 m , we found that dsf 75 m actually attenuated 50% of aldh2 activity in h9c2 cells without any stress . , we plan to pretreat cells with dsf in high glucose stress . in order to do this , we performed a pilot study to determine the dsf dose as explained in the method section . we first inhibited aldh2 activity in h9c2 cells using dsf and then subjected them to high glucose stress . to induce high glucose stress in vitro the cell culture medium was replaced with 33 mm d - glucose or 33 mm d - mannitol as per previous reports . as we explained in our previous report , h9c2 cardiomyocyte cell lines are suitable alternatives for primary cardiomyocytes to be used in hyperglycemic studies . in fact , it was shown that isolated cardiomyocytes and h9c2 cells respond similarly under high glucose stress . we and others reported that hyperglycemia decreases myocardial aldh2 activity in rodents [ 19 , 26 , 27 ] . the possible mechanism that we propose for this reduction is that hyperglycemia increases ros generation which attenuates aldh2 activity and thereby increases 4hne adduct formation , which ultimately leads to cellular dysfunction and then death . increased ros in type 1 and type 2 diabetes is implicated in the development of diabetic cardiomyopathy [ 28 , 29 ] . this result suggests that aldh2 inhibition by dsf itself can induce ros generation independent of high glucose stress . dsf treatment further enhanced the increase in ros levels in high glucose stress compared to control . it appears dsf pretreatment made the cells more susceptible to high glucose mediated aldh2 impairment . next , we found a significant increase in 4hne protein adducts only in dsf - pretreated cells with high glucose stress . this increase was not present in the control group or the dsf - untreated hg group . though we observed increased ros levels and reduced aldh2 activity in the control group with dsf treatment , we did not observe an increase in the level of 4hne protein adducts . however we suppose the 20% aldh2 activity remaining may be sufficient to metabolize 4hne in the control group . perhaps , this could have caused the observed reduction in the level of 4hne protein adducts . the mitochondrial membrane potential was reduced in the dsf treated hg group compared to the dsf - untreated hg group and dsf treated control group . it unequivocally suggests that dsf increases the susceptibility in cells subjected to high glucose stress to a drop in mitochondrial membrane potential despite the difference in glucose levels . progressive decrease in mitochondrial transmembrane potential is associated with apoptotic cell death . in our study , there was a decrease in the mitochondrial potential under the hyperglycemic condition , suggesting that hyperglycemia could act as an apoptosis - inducing stimulus . next , we found mitochondrial ocr at basal and fccp - induced maximal response were reduced in hg stress . aldh2 inhibition per se attenuated ocr and further this reduction in ocr is linked with cell death . but dsf pretreatment increased the cell death to more than 90% in the high glucose group . this data again implicates the role of aldh2 inhibition in maintaining cell viability and potentiating high glucose mediated cell death . this was also seen in our earlier study as aldh2 inhibition by dsf and aldh2 sirna contributed to cell death by decreasing mitochondrial function in h9c2 cells during 24 hours . decrease in aldh2 activity by dsf without causing 4hne adducts formation itself was noted to cause significant reduction in mitochondrial reserve capacity and subsequently cell death in h9c2 cells . similarly we observed an increase in cell death in control cells perhaps due to the reduction in mitochondrial respiratory defects demonstrated previously . strikingly , the aldh2 inhibition by dsf led to a significant increase in 4hne adducts as well as a decrease in mitochondrial membrane potential in cells under high glucose stress . earlier reports have shown that hyperglycemia reduced the activity and levels of myocardial aldh2 [ 27 , 32 ] . overexpression of aldh2 conferred cardioprotection by attenuating 4hne toxicity in stz - injected hyperglycemic mice . taken altogether , we suggest aldh2 activity plays an important role in the process of hyperglycemia - induced cardiac damage . similarly we speculate that the hyperglycemic stress in aldh22 carriers with diabetes or noncarriers with other comorbidities with low aldh2 activity may be vulnerable to cardiac tissue damage . our previous observation points out that long - term diabetes in patients reduces aldh2 activity and increases 4hne adduct formation in diabetic hearts . it also implies that chronic hyperglycemia can lead to an inevitable decrease in aldh2 activity and cause an exacerbation of hyperglycemia - induced cardiac damage . we conclude this report by stating that the inhibition of aldh2 activity potentiates high glucose stress - induced deleterious effects in cardiac cells . our study implicates individuals with compromised aldh2 activity may have higher propensity to develop diabetic cardiac complications or increase the severity of the damage .

aldehyde dehydrogenase ( aldh ) gene superfamily consists of 19 isozymes . they are present in various organs and involved in metabolizing aldehydes that are biologically generated . for instance , aldh2 , a cardiac mitochondrial aldh isozyme , is known to detoxify 4-hydroxy-2-nonenal , a reactive aldehyde produced upon lipid peroxidation in diabetic conditions . we hypothesized that inhibition of aldh leads to the accumulation of unmetabolized 4hne and consequently exacerbates injury in cells subjected to high glucose stress . h9c2 cardiomyocyte cell lines were pretreated with 10 m disulfiram ( dsf ) , an inhibitor of aldh2 or vehicle ( dmso ) for 2 hours , and then subjected to high glucose stress { 33 mm d - glucose ( hg ) or 33 mm d - mannitol as an osmotic control ( ctrl ) } for 24 hrs . the decrease in aldh2 activity with dsf pretreatment was higher in hg group when compared to ctrl group . increased 4hne adduct formation with dsf pretreatment was higher in hg group compared to ctrl group . pretreatment with dsf leads to potentiated hg - induced cell death in cultured h9c2 cardiomyocytes by lowering mitochondrial membrane potential . our results indicate that aldh2 activity is important in preventing high glucose induced cellular dysfunction .

As we now move into the official Political Aftermath period of the Boston bombing -- the period that will determine the long-term legislative fallout of the atrocity -- the dynamics of privilege will undoubtedly influence the nation's collective reaction to the attacks. That's because privilege tends to determine: 1) which groups are -- and are not -- collectively denigrated or targeted for the unlawful actions of individuals; and 2) how big and politically game-changing the overall reaction ends up being. This has been most obvious in the context of recent mass shootings. In those awful episodes, a religious or ethnic minority group lacking such privilege would likely be collectively slandered and/or targeted with surveillance or profiling (or worse) if some of its individuals comprised most of the mass shooters. However, white male privilege means white men are not collectively denigrated/targeted for those shootings -- even though most come at the hands of white dudes. Likewise, in the context of terrorist attacks, such privilege means white non-Islamic terrorists are typically portrayed not as representative of whole groups or ideologies, but as "lone wolf" threats to be dealt with as isolated law enforcement matters. Meanwhile, non-white or developing-world terrorism suspects are often reflexively portrayed as representative of larger conspiracies, ideologies and religions that must be dealt with as systemic threats -- the kind potentially requiring everything from law enforcement action to military operations to civil liberties legislation to foreign policy shifts. "White privilege is knowing that even if the bomber turns out to be white, no one will call for your group to be profiled as terrorists as a result, subjected to special screening or threatened with deportation," writes author Tim Wise. "White privilege is knowing that if this bomber turns out to be white, the United States government will not bomb whatever corn field or mountain town or stale suburb from which said bomber came, just to ensure that others like him or her don’t get any ideas. And if he turns out to be a member of the Irish Republican Army we won’t bomb Dublin. And if he’s an Italian-American Catholic we won’t bomb the Vatican." Because of these undeniable and pervasive double standards, the specific identity of the Boston Marathon bomber (or bombers) is not some minor detail -- it will almost certainly dictate what kind of governmental, political and societal response we see in the coming weeks. That means regardless of your particular party affiliation, if you care about everything from stopping war to reducing the defense budget to protecting civil liberties to passing immigration reform, you should hope the bomber was a white domestic terrorist. Why? Because only in that case will privilege work to prevent the Boston attack from potentially undermining progress on those other issues. ||||| Interesting enough. But Sears also included a long exegesis of what it meant that Tamerlan Tsarnaev had the name of the bloody 15th century central Asian-Muslim warlord Tamerlane, which he said was akin "to naming an American child 'Stalin-Mao-Hitler." Which seemed to indicate he considered the Tsarnaevs more Asian, or maybe "Cock-Asian," than good old-fashioned American white. We still know comparatively little about the Tsarnaev brothers, but they seem to have more in common with other American mass murderers than with al-Qaida terrorists of any race and ethnicity. No less an expert than former CIA Deputy Director Philip Mudd said on Fox News Sunday that they have more in common with the Columbine killers than with hardened al-Qaida terrorists. Likewise, Columbine expert Dave Cullen compares the “dyad” of apparent mastermind Tamerlan and follower-younger brother Dzhokhar to the Columbine pair of disturbed plot architect Eric Harris and follower Dylan Klebold.

– Conservatives jumped all over a Salon columnist who wrote a piece last week headlined, "Let's Hope the Boston Marathon Bomber Is a White American"—and when the suspects were revealed, conservatives gloated that they were not, in fact, white Americans. But the Tsarnaev brothers "are quite literally Caucasian, as in from the Caucuses," writes Joan Walsh on Salon. Plus, the US Census Bureau considers Americans of Chechen or Russian descent to be white, and one of the brothers was a naturalized American citizen. So why don't right-wingers consider them to be white? Walsh considers a few possibilities: America has a history of "sorting white from non-white." Many European immigrants "became" white as time went on, society became more accepting, and decidedly "non-white" people started arriving. "Embracing racism and xenophobia, sadly, could be a shortcut to white status for previously non-white European immigrants." Of course, it could boil down to the simple fact that the Tsarnaevs are Muslim, immigrants, or simply that "they’re 'bad,' and whiteness must be surrendered when white people are bad," Walsh writes. But, Walsh points out, the brothers actually have more in common with other mass murderers than they do with al-Qaeda terrorists. By insisting they're not white, conservatives are simply proving the original Salon columnist's point: White American murderers basically escape scapegoating and racial profiling, but with the Tsarnaevs being viewed as non-white, you can expect "a destructive new wave of ... anti-Muslim agitation [and] generalized xenophobia." Click for Walsh's full column.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Biofuels Energy Independence Act of 2001''. SEC. 2. FINDINGS. The Congress finds as follows: (1) The over reliance of the United States on imported petroleum creates a major strategic vulnerability for the Nation, with nearly half of the energy supply of the United States dependent on foreign sources. (2) From the economically damaging Arab oil embargoes of 1973-74 and 1979 to the current recession precipitated by rising oil prices which began in 1999, the economic stability of the United States has too often been shaken by economic forces outside its borders. (3) This Act would shift America's dependence away from foreign petroleum as an energy source toward alternative, renewable, domestic agricultural sources. Its aim is to convert the current petroleum trade deficit to a trade balance by replacing foreign sources of supply with steady increases of biobased fuels through domestic production. (4) Currently the United States annually consumes about 164,000,000,000 gallons of vehicle fuels and 5,600,00,000 gallons of heating oil. In 2000, 52.9 percent of these fuels were imported, yielding a $109,000,000,000 trade deficit with the rest of the world. Since 1983, the United States importation of petroleum and its derivatives has nearly tripled, rising from 1,215,225,000 barrels in 1983 to 3,319,816,000 barrels in 2000. (5) Further Strategic Petroleum Reserve policy should encourage domestic production to the greatest extent possible. Currently the Strategic Petroleum Reserve holds 545,000,000 barrels (out of a potential 700,000,000 barrels), sufficient to cushion the United States from wild price swings for a period of 53 days. None of the fuel in this Reserve is biobased. In fact, 92.2 percent of the Strategic Petroleum Reserve has been purchased from foreign sources: 41.9 percent from Mexico, 24 percent from the United Kingdom, and over 20 percent from OPEC nations. (6) Strategic Petroleum Reserve policy also should encourage the development of alternatives to the Nation's reliance on petroleum such as biomass fuels. (7) As a first step in diversification, the Strategic Petroleum Reserve should exchange 2,100,000 barrels from our current reserves for 32,000,000 gallons of ethanol and biodiesel, which would comprise less than 2 percent of the United States market, but yield a doubling of ethanol products. (8) The benefits of biofuels are as follows: (A) Energy security.-- (i) Biofuels hold potential to address our dependence on foreign energy sources immediately. With agricultural surpluses, commodity prices have reached record lows; concurrently world petroleum prices have reached record highs and are expected to continue rising as global petroleum reserves are drawn down over the next 25 years. It also is clear that economic conditions are favorable to utilize domestic surpluses of biobased oils to enhance the Nation's energy security. (ii) In the short term, biofuels can supply at least one-fifth of current United States fuel demand using existing technologies and capabilities. Additional plant research, newer processing and distribution technologies, and placing additional acres under cultivation can yield even greater results. (iii) Biofuels can be used with existing petroleum infrastructure and conventional equipment. (B) Economic security.-- (i) Continued dependence upon imported sources of oil means our Nation is strategically vulnerable to disruptions in our oil supply. (ii) Renewable biofuels domestically produced directly replace imported oil. (iii) Increased use of renewable biofuels would result in significant economic benefits to rural and urban areas and also reduce the trade deficit. (iv) According to the Department of Agriculture, a sustained annual market of 100,000,000 gallons of biodiesel alone would result in $170,000,000 in increased income to farmers. (v) Farmer-owned biofuels production has already resulted in improved income for farmers, as evidenced by the experience with State-supported rural development efforts in Minnesota where prices to corn producers have been increased by $1.00 per bushel. (C) Environmental security.-- (i) The use of grain-based ethanol reduces greenhouse gas emissions from 35 to 46 percent compared with conventional gasoline. Biomass ethanol provides an even greater reduction. (ii) The American Lung Association of Metropolitan Chicago credits ethanol-blended reformulated gasoline with reducing smog- forming emissions by 25 percent since 1990. (iii) Ethanol reduces tailpipe carbon monoxide emissions by as much as 30 percent. (iv) Ethanol reduces exhaust volatile organic compounds emissions by 12 percent. (v) Ethanol reduces toxic emissions by 30 percent. (vi) Ethanol reduces particulate emissions, especially fine-particulates that pose a health threat to children, senior citizens, and those with respiratory ailments. (vii) Biodiesel contains no sulfur of aromatics associated with air pollution. (viii) The use of biodiesel provides a 78.5 percent reduction in CO&lt;INF&gt;2&lt;/INF&gt; emissions compared to petroleum diesel and when burned in a conventional engine provides a substantial reduction of unburned hydrocarbons, carbon monoxide, and particulate matter. TITLE I--BIOFUELS FEEDSTOCKS ENERGY RESERVE PROGRAM SEC. 101. ESTABLISHMENT. The Secretary of Agriculture (in this title referred to as the ``Secretary'') may establish and administer a reserve of agricultural commodities (known as the ``Biofuels Feedstocks Energy Reserve'') for the purpose of-- (1) providing feedstocks to support and further the production of energy from biofuels; and (2) supporting the biofuels energy industry when production is at risk of declining due to reduced feedstocks or significant commodity price increases. SEC. 102. PURCHASES. (a) In General.--The Secretary may purchase agricultural commodities at commercial rates, subject to subsection (b), in order to establish, maintain, or enhance the Biofuels Feedstocks Energy Reserve when-- (1)(A) the commodities are in abundant supply; and (B) there is need for adequate carryover stocks to ensure a reliable supply of the commodities to meet the purposes of the reserve; or (2) it is otherwise necessary to fulfill the needs and purposes of the biofuels energy reserve program. (b) Limitation.--The agricultural commodities purchased for the Biofuels Feedstocks Energy Reserve shall be-- (1) of the type and quantity necessary to provide not less than 1-year's utilization for renewable energy purposes; and (2) in such additional quantities to provide incentives for research and development of new renewable fuels and bio-energy initiatives. SEC. 103. RELEASE OF STOCKS. Whenever the market price of a commodity held in the Biofuels Feedstocks Energy Reserve exceeds 100 percent of the economic cost of producing the commodity (as determined by the Economic Research Service using the best available information, and based on a 3-year moving average), the Secretary shall release stocks of the commodity from the reserve at cost of acquisition, in amounts determined appropriate by the Secretary. SEC. 104. STORAGE PAYMENTS. (a) In General.--The Secretary shall provide for the storage of agricultural commodities purchased for the Biofuels Feedstocks Energy Reserve by making payments to producers for the storage of the commodities. The payments shall-- (1) be in such amounts, under such conditions, and at such times as the Secretary determines appropriate to encourage producers to participate in the program; and (2) reflect local, commercial storage rates, subject to appropriate conditions concerning quality management and other factors. (b) Announcement of Program.-- (1) Time of announcement.--The Secretary shall announce the terms and conditions of the storage payments for a crop of a commodity by-- (A) in the case of wheat, December 15 of the year in which the crop of wheat was harvested; (B) in the case of feed grains, March 15 of the year following the year in which the crop of corn was harvested; and (C) in the case of other commodities, such dates as may be determined by the Secretary. (2) Content of announcement.--In the announcement, the Secretary shall specify the maximum quantity of a commodity to be stored in the Biofuels Feedstocks Energy Reserve that the Secretary determines appropriate to promote the orderly marketing of the commodity, and to ensure an adequate supply for the production of biofuels. (c) Reconcentration.--The Secretary may, with the concurrence of the owner of a commodity stored under this program, reconcentrate the commodity stored in commercial warehouses at such points as the Secretary considers to be in the public interest, taking into account such factors as transportation and normal marketing patterns. The Secretary shall permit rotation of stocks and facilitate maintenance of quality under regulations that assure that the holding producer or warehouseman shall, at all times, have available for delivery at the designated place of storage both the quantity and quality of the commodity covered by the producer's or warehouseman's commitment. (d) Management.--Whenever a commodity is stored under this section, the Secretary may buy and sell at an equivalent price, allowing for the customary location and grade differentials, substantially equivalent quantities of the commodity in different locations or warehouses to the extent needed to properly handle, rotate, distribute, and locate the commodity that the Commodity Credit Corporation owns or controls. The purchases to offset sales shall be made within 2 market days following the sales. The Secretary shall make a daily list available showing the price, location, and quantity of the transactions. (e) Review.--In announcing the terms and conditions under which storage payments will be made under this section, the Secretary shall review standards concerning the quality of a commodity to be stored in the Biofuels Feedstocks Energy Reserve, and such standards should encourage only quality commodities, as determined by the Secretary. The Secretary shall review inspection, maintenance, and stock rotation requirements and take the necessary steps to maintain the quality of the commodities stored in the reserve. SEC. 105. USE OF COMMODITY CREDIT CORPORATION. The Secretary shall use the Commodity Credit Corporation, to the extent feasible, to carry out this title. To the maximum extent practicable consistent with the effective and efficient administration of this title, the Secretary shall utilize the usual and customary channels, facilities, and arrangements of trade and commerce. SEC. 106. REGULATIONS. Not later than 60 days after November 28, 2001, the Secretary shall issue such regulations as are necessary to carry out this title. TITLE II--BIOFUELS FINANCIAL ASSISTANCE SEC. 201. LOANS AND LOAN GUARANTEES. (a) In General.--The Secretary of Agriculture (in this section referred to as the ``Secretary'') may make and guarantee loans for the production, distribution, development, and storage of biofuels. (b) Eligibility.-- (1) In general.--Except as provided in paragraph (2), an applicant for a loan or loan guarantee under this section shall be eligible to receive such a loan or loan guarantee if-- (A) the applicant is a farmer, member of an association of farmers, member of a farm cooperative, municipal entity, nonprofit corporation, State, or Territory; and (B) the applicant is unable to obtain sufficient credit elsewhere to finance the actual needs of the applicant at reasonable rates and terms, taking into consideration prevailing private and cooperative rates and terms in the community in or near which the applicant resides for loans for similar purposes and periods of time. (2) Loan guarantee eligibility precludes loan eligibility.--An applicant who is eligible for a loan guarantee under this section shall not be eligible for a loan under this section. (c) Loan Terms.-- (1) Interest rate.--Interest shall be payable on a loan under this section at the rate at which interest is payable on obligations issued by United States for a similar period of time. (2) Repayment period.--A loan under this section shall be repayable in not less than 5 years and not more than 20 years. (d) Revolving Fund.-- (1) Establishment.--The Secretary shall establish a revolving fund for the making of loans under this section. (2) Deposits.--The Secretary shall deposit into the revolving fund all amounts received on account of loans made under this section. (3) Payments.--The Secretary shall make loans under this section, and make payments pursuant to loan guarantees provided under this section, from amounts in the revolving fund. (e) Regulations.--The Secretary may prescribe such regulations as may be necessary to carry out this section. (f) Limitations on Authorization of Appropriations.--For the cost (as defined in section 502(5) of the Federal Credit Reform Act of 1990) of loans and loan guarantees under this section, there are authorized to be appropriated to the revolving fund established under subsection (d) of this section such sums as may be necessary for fiscal years 2002 through 2009.

Biofuels Energy Independence Act of 2001 - Authorizes the Secretary of Agriculture to administer a Biofuels Feedstocks Energy Reserve to: (1) provide feedstocks in furtherance of biofuel-based energy production; and (2) support the biofuels energy industry when production is at risk due to reductions in feedstocks or commodity prices. Sets forth related provisions respecting commercial commodity purchases, release of commodity stocks, and storage payments.Authorizes the Secretary to make and guarantee loans for biofuel production, distribution, development, and storage. Sets forth loan eligibility provisions. Directs the Secretary to establish a related revolving fund.

the study of the thermodynamic behaviour of a single model molecule in solution has be re - invigorated of late with a variety of new experimental techniques able to tease out more refined features and also with an escalating interest in biopolymers . it is therefore perhaps surprising to find that alternative simple models of a single polymer display different phase structures : for some models there exist only two thermodynamic phases , a high - temperature swollen coil and a disordered liquid - like globule , whereas for other models there is a third , compact phase with crystalline order . in this letter we present a unified description of these models , based on the study of a particular model that provides the missing link . this model incorporates attractive interactions between segments of the polymer and bending stiffness . computer simulations allow us to conclude that all the two - dimensional models in the literature are one or two parameter slices of a larger model in which only three phases exists . we therefore _ conjecture _ that in any model of an isolated non - oriented polymer restricted to a substrate ( so being effectively two - dimensional ) , with homogeneous short - ranged attractive interactions between parts of the polymer , regardless of whether these parts are single monomers or groups of monomers ( so that an effective stiffness is introduced ) , only the three phases mentioned above will occur in the larger parameter space . the phase transition between the swollen coil and the globule is described by the traditional @xmath0-point , while the transition between the swollen coil and the crystal is first order . finally the most interesting transition between the globule and the crystal is second order ( in two dimensions ) . the canonical description of the thermodynamic states of a isolated polymer has a reference high temperature disordered state known as the ` swollen coil ' or ` extended state ' which is described by the @xmath1 of the magnetic o(@xmath2 ) model and correspondingly by the @xmath3 of the @xmath4 o(@xmath2 ) field theory @xcite . the lattice model of self - avoiding walks is a good model of this situation where in both two and three dimensions the fractal dimension of the polymer @xmath5 is less than the dimension of space and also less than the fractal dimension of simple random walks ( which is 2 ) . the values of @xmath6 , where @xmath7 is the exponent describing the scaling of the radius of gyration of the polymer with its length , are @xmath8 in two dimensions @xcite and @xmath9 in three dimensions , have been well studied @xcite . it is expected that if the temperature is lowered then the polymer will undergo a collapse at one particular temperature , called the @xmath0-temperature . at temperatures lower than the @xmath0-temperature the fractal dimension of the polymer attains that of space , that is @xmath10 . the standard description of the collapse transition is a tricritical point related to the @xmath3 limit of the @xmath4@xmath11 o(@xmath2 ) field theory @xcite . thermodynamically this implies that there is a second - order phase transition on lowering the temperature : the specific heat exponent @xmath12 is conjectured to be @xmath13 in two dimensions @xcite and @xmath14 in three dimensions with a logarithmic divergence of the specific heat . in two dimensions the fractal dimension of the polymer is expected to be @xmath15 @xcite . the low temperature state has been likened to a liquid drop ; it is compact but disordered @xcite . the corresponding lattice model which displays this collapse @xmath0-transition is the _ interacting self - avoiding walk _ model ( isaw ) @xcite where an attractive potential is associated with pairs of sites of the walk adjacent on the lattice though not consecutive along the walk . however , more recently two other simple models of a single polymer have been studied . these have been introduced in the context of biopolymers where hydrogen bonding plays an important role @xcite , and the interacting residua lie on partially straight segments of the chain . the first one , the _ interacting hydrogen - bond _ model ( ihb ) @xcite , modifies the isaw model such that a pair of sites on the self - avoiding walk acquires a hydrogen - like bond potential if the sites are ( non - consecutive ) nearest neighbours , as in the isaw model , and each site lies on a straight section of the walk . this model displays , in contrast to isaw , a single collapse transition which is _ first order _ in both two and three dimensions . here the low temperature state is an anisotropic ordered compact phase that is described as a polymer crystal . the second model introduced to account for hydrogen bonding is the _ attracting segments _ model ( as ) @xcite ( also known as ` interacting bonds ' ) . it is a lattice model based upon self - avoiding walks where an attractive potential is assigned to _ bonds _ of the walk that lie adjacent and parallel on the lattice ( though not consecutive along the walk ) , see figure [ fig_ssas - model ] . this model has been less extensively studied on regular lattices it has been studied on the square lattice @xcite though _ two _ phase transitions have been identified , one of which is identified as the @xmath0-point . crucially , there is a different modification of the isaw model that displays two phase transitions for a range of parameters , namely the _ semi - flexible _ isaw model @xcite . here two energies are included : the nearest - neighbour site interaction of the isaw model and also a stiffness energy associated with consecutive parallel bonds of the walk ( equivalently , a bending energy for bends in the walk ) . this has been studied on the cubic lattice by bastolla and grassberger @xcite . they showed that when there is a strong energetic preference for straight segments , this model undergoes a single first - order transition from the excluded - volume high - temperature state to a crystalline state . on the other hand , if there is only a weak preference for straight segments , the polymer undergoes two phase transitions . on lowering the temperature the polymers undergoes a @xmath0-point transition to the liquid globule followed at a lower temperature by a first - order transition to the frozen crystalline phase . recent work @xcite on the semi - flexible isaw model on the square lattice displays a similar phase diagram though the transition between the globule and the frozen state has been seen to be second order . it would seem reasonable to conjecture that the phases and phase transitions seen in the semi - flexible isaw model are essentially those seen in both the ihb model and the as model . on the other hand the addition of stiffness to the ihb model has been seen to change little of the behaviour of that model @xcite . importantly , the ihb model was recently extended @xcite to a hybrid model ( ihb - inh ) that includes both the hydrogen - like bond interactions and non - hydrogen like bond interactions , with separate energy parameters . when the non - hydrogen bonding energy is set to zero the ihb model is recovered . if both energies are set to be the same value then the isaw _ without stiffness _ is recovered . they found for large values of the ratio of the interaction strength of hydrogen - bonds to non - hydrogen bonds , that a polymer will undergo a single first - order phase transition from a swollen coil at high temperatures to a folded crystalline state at low temperatures . on the other hand , for any ratio of these interaction energies less than or equal to one there is a single @xmath0-like transition from a swollen coil to a liquid droplet - like globular phase . for intermediate ratios two transitions can occur , so that the polymer first undergoes a @xmath0-like transition on lowering the temperature , followed by a second transition to the crystalline state . in three dimensions it was found that this second transition is first order , while in two dimensions they found that it is probably second order with a divergent specific heat . in other words , by adding an energy to both the hydrogen - like and non - hydrogen like interactions a phase diagram similar to the one for the semi - flexible isaw is found . we note that the ihb model has been generalised on the cubic lattice in such a way that two different crystalline phases were observed @xcite . here we bring together the pieces of this puzzle by studying the as model in the presence of stiffness on the square lattice . we concentrate our study in two dimensions where only one type of crystalline phase has been observed . our semi - flexible attracting segments model ( semi - flexible as model ) is a simple self - avoiding walk on square lattice , with self - interactions as in the as model @xcite and a stiffness ( or equivalently bend energy ) added . specifically , the energy of a single chain ( walk ) consists of two contributions ( see figure [ fig_ssas - model ] ) : the energy @xmath16 for each attracting segment pair , being a pair of occupied bonds of the lattice that are adjacent and parallel on the lattice and not consecutive along the walk ; and an energy @xmath17 for each stiffness segment pair , being a pair of bonds consecutive along the walk that are parallel . a walk configuration @xmath18 of length @xmath19 has total energy @xmath20 where @xmath21 denote the number of attracting segment pairs and @xmath22 denotes the number of stiffness segment pairs . the partition function is defined then as @xmath23 where @xmath24 and @xmath25 for temperature @xmath26 and boltzmann constant @xmath27 . @xmath28 is the density of states , which we have estimated by means of monte carlo simulations . on the square lattice we performed simulations using the flatperm algorithm @xcite , estimating the density of states up lengths for @xmath29 over the two parameters @xmath21 and @xmath22 . we have also estimated the end - to - end distance as a measure of the size of the polymer : this enables us to estimate the fractal dimension of the polymer via estimation of the exponent @xmath7 . the density of states allows us to calculate the internal energy and the specific heat , or equivalently , the mean values and the fluctuations of @xmath21 and @xmath22 , respectively . this allows to locate phase transitions through the possible divergences in the specific heat . to detect orientational order , we estimated the _ anisotropy parameter _ @xcite . in two dimensions , denoting the number of bonds parallel to the @xmath30- , and @xmath31-axes by @xmath32 and @xmath33 , respectively , we define @xmath34 to be the anisotropy parameter . in a system without orientational order , this quantity tends to zero as the system size increases . a non - zero limiting value less than one of this quantity indicates weak orientational order with @xmath35 , while a limiting value of one indicates strong orientational order , where @xmath36 . figure [ fig_mod_asss ] shows the peak positions of the fluctuations in @xmath21 and @xmath22 at length 128 from simulations on the square lattice . it is clear from shorter lengths that some of these peaks are asymptotically diverging . we therefore have a finite - size approximation to a phase diagram in this figure . to characterise the possible phases in each region we have considered the scaling of the end - to - end distance . for small @xmath39 we find that the exponent @xmath7 is close to @xmath40 : specifically we find @xmath41 for @xmath42 . on the other side of the first curve separating small @xmath39 from larger @xmath39 we find that @xmath7 is close to @xmath43 no matter how large @xmath39 becomes : at points @xmath44 being @xmath45 , @xmath46 and @xmath47 we find @xmath48 . hence the two phases to the right of the leftmost curve are dense . to clarify the two low temperature phases we have measured the anisotropy parameter . we find that the anisotropy parameter is tending to zero for values of @xmath39 smaller that the right boundary and tending towards one for values of @xmath39 larger that the right boundary . that is , it tends to zero in the swollen and globular phases and one in the crystal phase . in figure [ fig_bs1.5_ro ] we show the anisotropy parameter at fixed @xmath49 and at fixed @xmath50 plotted for three different polymer lengths . there are stronger corrections to scaling in the globule to crystal transition evident . for @xmath49 ( left ) and @xmath50 ( right ) for polymer lengths @xmath51 , @xmath52 and @xmath53 . for @xmath49 it is converging to 0 for small @xmath39 and to 1 for large @xmath39 , changing over roughly at @xmath54 . for @xmath50 it is converging to 0 for small @xmath55 and to 1 for large @xmath55 , changing over roughly at @xmath56.,title="fig : " ] for @xmath49 ( left ) and @xmath50 ( right ) for polymer lengths @xmath51 , @xmath52 and @xmath53 . for @xmath49 it is converging to 0 for small @xmath39 and to 1 for large @xmath39 , changing over roughly at @xmath54 . for @xmath50 it is converging to 0 for small @xmath55 and to 1 for large @xmath55 , changing over roughly at @xmath56.,title="fig : " ] we therefore surmise that for high temperatures the polymer is in the swollen phase , while at intermediate temperatures the polymer may be in a globular state , and for low enough temperatures always enters the anisotropic crystalline state . one can compare the finite size phase diagram that we have to that of the semi - flexible isaw model @xcite , see figure [ fig_mod_isss ] . apart from a shift of boundaries , so that for @xmath57 there is only one phase transition , the two diagrams are remarkably similar . to test the similarity of these diagrams further we have explored the phase transition between the phases . it has been found that the swollen - to - crystal transition in the semi - flexible isaw model @xcite is first - order in two ( and three ) dimensions . we find the same here for our semi - flexible as model in two dimensions : the scaling of fluctuations of @xmath21 have a classic first - order behaviour with a linear divergence in polymer length and a transition width scaling as the inverse length . the globule - to - crystal transition has been found to be second order in two dimensions . to consider the globule - to - crystal transition on the square lattice in our model more closely , we have also simulated longer length polymers up to @xmath58 for constant @xmath56 . using these simulations we find results similar to those found for the semi - flexible isaw model . the swollen - globule transition is expected to be in the universality class of the @xmath0-point and its specific heat signature is weak ( @xmath59 ) . this is difficult to see at the lengths considered here though the transition is clearly weakening with length . finally , it is instructive to consider the phase diagram of the extended interacting hydrogen - bonding model @xcite . while the different type of parameters make comparisons indirect , we note that the same phases occur and same phase transitions as the two semi - flexible models discussed in two dimensions . this supports the idea that regardless of how stiffness is introduced in the interacting polymer model , these three phases will occur in an appropriate parameter space . to make this conclusion more concrete one can realise that by enlarging the parameter space of concern in the manner considered in @xcite the isaw model , the ihb and the as models are all specialisations of a more general model . now we have seen that with the addition of a further stiffness parameter the general phase structure of the more general model should still only contain the three phases and phases transition discussed above . in this article we have developed a more complete and consistent understanding of the phase structure of a single polymer in solution , and restricted to a substrate so that it is effectively two - dimensional , than had previously been available . for the three - dimensional model we expect a weaker result where more than one crystalline phase may exist . ( our preliminary studies of the as model on the cubic lattice show that only one phase transition occurs which makes it less relevant to the discussion here : the observations may be understood as the weaker effect of as model effective stiffness there . ) it should be in this context that experimental results of polymer collapse be analysed .

recently it has been shown that a two - dimensional model of self - attracting polymers based on attracting segments displays two phase transitions , a @xmath0-like collapse between swollen polymers and a globular state and another between the globular state and a polymer crystal . on the other hand , the canonical model based on attracting monomers on lattice sites displays only one : the standard tricritical @xmath0 collapse transition . here we show that by considering both models with the addition of stiffness the two models display the _ same _ generic phase diagram . in fact we claim that any two - dimensional model of a self - attracting single polymer in solution based upon a fully volume - excluded backbone with isotropic short range attraction should show this same phase structure . we point to the model of hydrogen bonded polymers to demonstrate this observation . in three dimensions we note that more than one crystalline phase may occur .

SECTION 1. SHORT TITLE. This Act may be cited as the ``Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''. SEC. 2. REAUTHORIZATION OF URANIUM ENRICHMENT DECONTAMINATION AND DECOMMISSIONING FUND. (a) Amounts in Fund.--Section 1802 of the Atomic Energy Act of 1954 (42 U.S.C. 2297g-1) is amended-- (1) in subsection (a)-- (A) by striking ``$518,233,333'' and inserting ``$790,000,000''; and (B) by striking ``the Energy Policy Act of 1992'' and inserting ``the Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''; (2) in subsection (c), by inserting after ``adjusted for inflation'' the following: ``beginning 1 year after the date of enactment of the Energy Policy Act of 1992''; (3) in subsection (d), by striking ``15 years after the date of the enactment of this title'' and inserting ``12 years after the date of enactment of the Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''; and (4) in subsection (e)-- (A) in paragraph (1), by striking ``15 years after the date of the enactment of this title'' and inserting ``12 years after the date of enactment of the Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''; and (B) in paragraph (2), by striking ``under such subsection'' and inserting ``during the 12-year period beginning on the date of enactment of the Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''. (b) Reports.--Section 1805 of the Atomic Energy Act of 1954 (42 U.S.C. 2297g-4) is amended-- (1) in the first sentence, by striking ``the date of the enactment of this title'' and inserting ``the date of enactment of the Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''; and (2) in the second sentence, by striking ``5th report submitted under this section'' and inserting ``third report submitted after the date of enactment of the Uranium Enrichment Decontamination and Decommissioning Fund Reauthorization Act of 2009''. SEC. 3. AUTHORIZATION AND DETERMINATION OF BENEFITS FOR AFFECTED PARTICIPANTS. (a) Authorization for Payment to Affected Participants.--To the extent provided in advance in appropriations Acts, the Secretary of Energy (referred to in this Act as the ``Secretary'')-- (1) shall establish a program under which the Secretary shall pay any affected participant described in subsection (b) a one-time lump sum payment in an amount to be determined by the Secretary under subsection (c); and (2) may contract for the procurement of information necessary to enable the Secretary to effectively carry out the provisions of this section. (b) Affected Participant.--For the purposes of this section, an affected participant is a person described under section 3110(a)(6)(B) of the USEC Privatization Act (42 U.S.C. 2297h-8(a)(6)(B)). (c) Determination of Payment for Affected Participants.-- (1) In general.--The Secretary shall pay an affected participant, pursuant to an application timely filed by such participant, a one-time lump sum payment equal to an amount which bears the same ratio to the total recoverable amount described in paragraph (2) as the actuarial present value of the accrued benefits of the affected participant under the pension plan from which a transfer of plan assets and liabilities required under section 3110(a)(2) of the USEC Privatization Act (42 U.S.C. 2297h-8(a)(2)) was made (as of immediately before the transfer) bears to the actuarial present value of the accrued benefits of all affected participants under the pension plan from which the transfer under such section was made (as of immediately before the transfer). (2) Total recoverable amount.--For purposes of this subsection, the total recoverable amount is an amount equal to the excess of-- (A) the present value of benefits that would have been accrued or accruable by all affected participants under the pension plan from which the transfer under section 3110(a)(2) of the USEC Privatization Act was made if such transfer had not occurred and if benefit increases had occurred, in connection with the transferred liabilities, under such plan equivalent to benefit increases that have occurred under such plan in connection with the other liabilities under such plan, over (B) the present value of benefits accrued or accruable by all such affected participants under the pension plan to which the transfer under section 3110(a)(2) of the USEC Privatization Act (42 U.S.C. 2297h-8(a)(2)) was made. (3) Considerations.--In determining a payment under this section, the Secretary shall consider, with respect to the pension plan from which the transfer under section 3110(a)(2) of the USEC Privatization Act (42 U.S.C. 2297h-8(a)(2)) was made and the pension plan to which such transfer was made, benefits accrued as of the date of enactment of this Act and accruable through attainment of normal retirement age, assuming continued service under the plan until attainment of such age and the same rate of basic pay subject to increases reflective of reasonably anticipated increases in the cost of living. (4) Successor plans.--For the purposes of paragraphs (2) and (3), any reference to the pension plan from which the transfer under section 3110(a)(2) of the USEC Privatization Act (42 U.S.C. 2297h-8(a)(2)) was made shall include a reference to any successor to such plan (other than the pension plan to which the transfer required by such section was made) if such successor plan received assets in excess of the actuarial present value of accrued benefits under such plan upon succession. (d) Pro Rata Reduction of Payment.--The Secretary shall provide for pro rata reductions in payment amounts determined by the Secretary under subsection (c) to affected participants described in subsection (b) to the extent necessary to adjust for amounts provided in appropriation Acts for purposes of the program under subsection (a). (e) Determination of Findings of Fact.--The Secretary may make findings of facts and decisions as to the rights of any affected participant applying for a payment under this section. (f) Rulemaking.--Not later than 60 days after the date of enactment of this Act, the Secretary shall issue regulations to carry out this section. Such regulations shall provide a requirement for applicants for payments under this section to consent to the release of any information requested by the Secretary. (g) Public Notice.--To the extent practicable, the Secretary shall provide notice to individuals who may be eligible to receive a payment under this section. (h) Application for Payment.--To be eligible for a payment under this section, an affected participant shall prepare and submit to the Secretary an application-- (1) not later than 240 days after the date of enactment of this Act; (2) in such manner; and (3) containing such information as the Secretary requires. (i) Timely Payments.--To the extent practicable, the Secretary shall determine and make a payment to an affected participant not later than 180 days after such participant's submission of an application for payment under subsection (h). (j) Election To Treat Payment as Rollover Contribution to IRA.-- (1) In general.--Any affected participant who receives a payment under this section may, at any time during the 1-year period beginning on the day after the date on which such payment was received, make one or more contributions in an aggregate amount not to exceed the amount of such payment to an individual retirement plan (as defined by section 7701(a)(37) of the Internal Revenue Code of 1986). (2) Treatment of contributions to iras.--For purposes of the Internal Revenue Code of 1986, if a contribution is made to an individual retirement plan pursuant to paragraph (1), then-- (A) except as provided in paragraph (3), such contribution shall not be included in gross income, and (B) to the extent of the amount of such contribution, such contribution shall be treated-- (i) as a distribution described in section 408(d)(3) of such Code, and (ii) as having been transferred to the individual retirement account in a direct trustee to trustee transfer within 60 days of the distribution. (3) Special rule for roth iras.--If a contribution is made under paragraph (1) to a Roth IRA, such contribution shall be includible in gross income and, unless the taxpayer elects not to have this clause apply, such contribution shall be so included ratably over the 2-taxable-year period beginning with the first taxable year in which such contribution is made. (k) Hearing and Judicial Review.-- (1) Hearing.-- (A) In general.--Upon request by any affected participant applying for a payment under this section, who makes a showing in writing that such participant's rights may have been prejudiced by any decision the Secretary has rendered, the Secretary shall give such participant reasonable notice and opportunity for a hearing with respect to such decision, and, if a hearing is held, shall, on the basis of evidence adduced at the hearing, affirm, modify, or reverse the Secretary's findings of fact and such decision. (B) Request for hearing.--Any request for a hearing under this subsection must be filed within 60 days after notice of a decision by the Secretary is received by the affected participant making such a request. (C) Secretary.--The Secretary is further authorized, on the Secretary's own motion, to hold such hearings and to conduct such investigations and other proceedings as the Secretary may deem necessary or proper for the administration of this section. (2) Judicial review.-- (A) In general.--Any affected participant, after any final decision of the Secretary made after a hearing to which such participant was a party, irrespective of the amount in controversy, may obtain a review of such decision by a civil action commenced within 60 days after the mailing to such participant of notice of such decision or within such further time as the Secretary may allow. (B) Jurisdiction and venue.--An action under this section shall be brought in the district court of the United States for the judicial district in which the affected participant plaintiff resides, or where such plaintiff has a principal place of business, or, if such plaintiff does not reside or have a principal place of business within any such judicial district, in the United States District Court for the District of Columbia. (C) Judicial determination.--The court shall have power to enter, upon the pleadings and transcript of the record, a judgment affirming, modifying, or reversing the decision of the Secretary, with or without remanding the cause for a rehearing. (D) Final judgment.--The judgment of the court shall be final, except that it shall be subject to review in the same manner as a judgment in other civil actions. (E) Change in secretary.--Any action instituted in accordance with this section shall survive notwithstanding any change in the person occupying the office of Secretary or any vacancy in such office. (l) Secretary's Responsibility; No Third Party Liability.-- (1) Secretary's responsibility.--The Secretary shall be responsible for all payments and costs under this section, for reporting payments to affected participants and the Internal Revenue Service on Form number 1099R (or such other form as required by the Internal Revenue Service) for income tax purposes, and for answering questions relating to the implementation of this section for affected participants and applicants for payment. In no event shall the current or former employer of an affected participant or applicant be responsible for providing communication, making payments, reporting payments, answering questions, or providing calculations. (2) No third party liability.--Nothing in this section shall be deemed to impose any liability or cost, or authorize any claim against the operator of the Department of Energy's uranium enrichment facility in Paducah, Kentucky, or against any person or entity other than the Secretary. (m) Authorization of Appropriations.--There are authorized to be appropriated to the Secretary such amounts as necessary to carry out this section. SEC. 4. RE-ENRICHMENT PLAN. (a) Plan.--Not later than 180 days after the date of enactment of this Act, the Secretary shall develop, complete, and publish in the Federal Register, a plan to re-enrich and sell certain cylinders of uranium tailings. (b) Contents.--The plan under subsection (a) shall provide for the following: (1) Re-enrichment requirement.-- (A) Requirement.--The Secretary shall seek to enter into a contract with the operator of the Department of Energy's uranium enrichment facility in Paducah, Kentucky, for the re-enrichment of cylinders of uranium tailings, with an assay of such value as the Secretary finds economically suitable, located at Government- owned uranium enrichment sites in Paducah, Kentucky, and Portsmouth, Ohio. (B) Amount.--A contract under subparagraph (A) shall provide for re-enrichment at the Paducah facility of 50 percent of the materials in the cylinders described in subparagraph (A). (C) Schedule.--A contract under subparagraph (A) shall provide for re-enrichment to begin not later than 90 days after the date of the publication in the Federal Register of the plan under this section, subject to plant capacity and availability. (D) Suspension or cancellation.--The Secretary may suspend or cancel a contract under subparagraph (A) for re-enrichment, in accordance with the Federal Acquisition Regulation, if the Secretary determines-- (i) the operator of the Paducah facility has not fulfilled obligations regarding such re-enrichment under the contract; or (ii) economic considerations are not conducive to carry out the contract at that time. (2) Sale of product of re-enrichment.--The Secretary shall sell or contract for the sale of the product of re-enrichment carried out pursuant to paragraph (1). (3) Sale of remaining uranium tailings.-- (A) In general.--The Secretary shall sell 50 percent of the materials in the cylinders described in subparagraph (A) of paragraph (1) to qualified buyers. (B) Qualified buyer.--For purposes of this paragraph, the term ``qualified buyer'' means any entity licensed, under the Atomic Energy Act of 1954 (42 U.S.C. 2011 et seq.), to possess materials in the cylinders described in subparagraph (A) of paragraph (1). (C) Preference.--In selling the materials in the cylinders described in subparagraph (A) of paragraph (1), the Secretary shall give preference to qualified buyers committed (as determined by the Secretary) to re-enrichment of such materials in the United States. (D) Additional contract for material not sold.--The Secretary shall seek to enter into a contract with the operator of the Department of Energy's uranium enrichment facility in Paducah, Kentucky, for the re- enrichment of any materials in the cylinders described in subparagraph (A) of paragraph (1) not sold pursuant to subparagraph (A) of this paragraph. (4) Unable to contract.--If the Secretary does not enter into a contract under subparagraph (A) of paragraph (1) within 270 days after the date of enactment of this Act, the Secretary may do either or both of the following: (A) Defer negotiation of such a contract until not later than the last day of calendar year 2014. (B) Sell the amount of the materials in the cylinders described in subparagraph (B) of paragraph (1) under terms consistent with the plan under this section.

Uranium Enrichment Decontamination and Decomissioning Fund Reauthorization Act of 2009 - Amends the Atomic Energy Act of 1954 to reauthorize, and increase the maximum mandatory amounts in, the Uranium Enrichment Decontamination and Decommissioning Fund. Directs the Secretary of Energy to establish a program to pay any affected participant under the USEC Privatization Act a one-time sum payment of benefits in an amount to be determined by the Secretary. Limits affected participants to persons who: (1) retired from active employment at one of the gaseous diffusion plants on or before the United States Enrichment Corporation (USEC) privatization date as vested participants in a pension; and (2) are employed by the USEC's operating contractor on or before the privatization date and are vested participants in a pension plan. Directs the Secretary to develop, complete, and publish in the Federal Register a plan to re-enrich and sell certain cylinders of uranium tailings.

SECTION 1. SHORT TITLE. This Act may be cited as the ``Healthcare Innovation Zone Program Act of 2009''. SEC. 2. HEALTHCARE INNOVATION ZONE DEMONSTRATION PROGRAM. (a) Establishment.--Not later than 6 months after the date of enactment of this Act, the Secretary of Health and Human Services shall establish a Healthcare Innovation Zone pilot program to increase healthcare provider integration and align healthcare provider incentives to improve health and to reduce healthcare costs. (b) Features of Program.--The HIZ pilot program established under subsection (a) shall consist of the following: (1) An HIZ planning grant program, as described in section 3. (2) An HIZ demonstration project, as described in section 4. (c) Definitions.--In this Act: (1) Grant program.--The term ``grant program'' means the HIZ planning grant program as described in section 3. (2) HIZ.--The term ``HIZ'' means a Healthcare Innovation Zone, consisting of an integrated healthcare delivery network that works with local employers, community leaders, and private and governmental payors in a geographic region, that-- (A) provides a full spectrum of care, including inpatient, outpatient, post-acute, and preventive care, to individuals including Medicare beneficiaries; (B) has an academic medical center that provides tertiary and quaternary care, has existing capabilities to conduct health services research, and provides clinical training for health professionals; and (C) is able to accept alternative payment structures beyond fee-for-service and per diem amounts. (3) Secretary.--The term ``Secretary'' means the Secretary of Health and Human Services. SEC. 3. HIZ PLANNING GRANT PROGRAM. (a) Establishment.--The Secretary shall make grants to eligible entities for the purposes of researching and preparing an HIZ model plan, in accordance with subsection (f). (b) Conditions.--A grant recipient under this section must apply for the HIZ demonstration project described in section 4. If a grant recipient under this section is not selected to participate in such project, then such recipient must return any unused grant funds to the Secretary. (c) Eligibility.--The following persons are eligible entities for purposes of this section: (1) A healthcare institution or provider licensed and accredited in the United States. (2) An academic medical center. (3) A large multispecialty group practice. (4) Any other clinical organization. (5) Any other organization that is able to establish, through a memorandum of understanding or by other means to be defined by the Secretary, an intent to collaborate with a person listed in paragraphs (1) through (4). (d) Application.--An application for a grant under this section shall include the following: (1) A demonstration that the grant applicant is located in a geographic region that has the necessary breadth of healthcare providers to support the HIZ. (2) The support and endorsement of the HIZ concept by the following persons: (A) At least one leader of a clinical entity that provides the full spectrum of care. (B) At least one private payer. (3) A demonstration that the grant applicant has the resources and expertise to implement the features listed in subsection (f). (4) A proposed budget setting forth the costs to be incurred in creating the model HIZ plan. (e) Criteria for Awarding Grants.--The Secretary shall give preference to a grant application that demonstrates a likelihood that the HIZ model plan will meet the requirements of subsection (f). (f) HIZ Model Plan Requirements.--A recipient of a grant under this section must submit to the Secretary, within 6 months of receiving such grant, an HIZ model plan describing the HIZ to be implemented in the demonstration project under section 4. Such HIZ model plan must contain the following: (1) A description of innovative models of care that improve quality and decrease costs. (2) A provider network that will provide the full spectrum of care. (3) A target population and mechanisms to enroll such population, supported by evidence that such population is willing to participate in an HIZ demonstration. (4) A mechanism to provide for knowledge and information- sharing across the HIZ participants. (5) A description of how the HIZ would incorporate the training of the next generation of physicians, nurses, and allied health professionals in a new model of cost-effective quality healthcare. (6) A description of the governance of the HIZ, and how it would affect the administration of the model and management of the organizational and cultural changes necessary for a successful HIZ. (7) A description of non-financial barriers to innovation that must be addressed for the creation of a successful HIZ, including physician self-referral laws, anti-trust considerations, State laws, and accreditation or certification requirements. (8) A process for data reporting, annual site visits, and developing community health impact assessments. (9) A set of indicators to help track performance and success of the HIZ model plan, including measures to address cost containment, access to care, and quality improvement, and how the HIZ model plan would facilitate achievement of these improvements. (10) A description of mechanisms to achieve involvement by the community and external experts as ongoing monitors of the success of the HIZ model plan. (11) Payment methodology options that address both funding mechanisms to the HIZ as well as how the HIZ would distribute funds to the HIZ participants. (g) Number and Amount of Planning Grants.--The Secretary shall award at least 10 but not more than 25 grants under this section in an amount of at least $250,000 and not more than $1,000,000 per grant. (h) Funding.--Amounts made available under the heading ``Agency for Healthcare Research and Quality--Healthcare Research and Quality'' in title VIII of division I of the American Recovery and Reinvestment Act of 2009 (Public Law 111-5) may be used by the Secretary to make grants under this section. SEC. 4. HEALTHCARE INNOVATION ZONE DEMONSTRATION PROJECT. (a) Establishment.--The Secretary shall establish an HIZ demonstration project in order to test the effectiveness of HIZs in increasing healthcare provider integration, improving healthcare services, and reducing healthcare costs. Such demonstration project shall not be subject to current requirements regarding shared savings under demonstration projects. The Secretary shall select demonstration project participants from the persons that have received grants under section 3. (b) Duration.--The demonstration project shall operate for a period of at least 3 years, and shall be subject to renewal at the Secretary's discretion. (c) Application.--An eligible entity shall submit an application for participation in the HIZ demonstration project to the Secretary at such time and manner, and containing such information as the Secretary may require. (d) Eligibility.--To be eligible to participate in the demonstration project established under this section, a person must-- (1) have submitted an HIZ model plan in accordance with section 3(f) that is approved by the Secretary; (2) agree to submit the necessary data so that Secretary can assess the costs, quality of care, and access to care for the population participating in the HIZ demonstration project; (3) demonstrate a culture of innovation and commitment to preventive and public health; (4) possess structural elements to provide the full range of care necessary for a successful HIZ; (5) provide clinical training for healthcare professionals in a medical environment that emphasizes coordinated, integrated, high-quality care delivered at a controlled cost; (6) have the ability to allocate resources within the members of the HIZ; (7) have a broad research infrastructure that supports data gathering, analytics, and synthesis of unrelated population elements, including quality-related data elements; (8) have significant investment in health information technology that extends across the system to include healthcare providers, physicians, and other clinicians; (9) possess advance innovations including, but not limited to, creation of medical homes, pay for performance, and other cost-effective delivery platforms; (10) demonstrate long-term economic sustainability; (11) demonstrate strong hospital and physician leadership and the willingness to undergo a full portfolio assessment and reengineering of core patient care and administrative processes; (12) possess robust financial infrastructure and administrative support to assure the HIZ's success; and (13) demonstrate arrangements that maintain oversight and accreditation standards. (e) HIZ Requirements.--An HIZ established under this section shall-- (1) provide healthcare services to individuals who voluntarily enroll to receive such services for multi-year periods from the HIZ; and (2) provide comprehensive healthcare services, as described in subsection (f). (f) Comprehensive Healthcare Services.--The comprehensive healthcare services referred to in subsection (e)(2) shall consist of hospital care, physician services, post-acute care, preventive care, education, tertiary and quaternary care, and palliative care, and shall include the following: (1) For a primary care practice, contractual agreements with practices that deliver both primary and preventive care. (2) For a teaching hospital or other hospital, arrangements with teaching and nonteaching hospitals and arrangements with community hospitals. (3) For a network of outpatient facilities, arrangements with outpatient facilities, including Federally Qualified Health Centers and community health providers. (4) For a network of post-acute care providers, arrangements with post-acute care providers for rehabilitation services, home health services, hospice services, skilled nursing services, and such other post-acute care services as the Secretary determines to be appropriate. (5) For a network of community services, arrangements for the provision of ambulance services and community outreach service. (6) Arrangements for the provision such additional services as the Secretary may require. (g) Payment.--The Secretary may determine the payments that are required to be made for receipt of healthcare services provided under a model plan implemented with a grant under this section. The Secretary shall determine those amounts based on the methodology options submitted through the grant program established under section 3. (h) Assumption of Financial Risk for Costs Above HIZ Payment Amounts.--An HIZ established under this section shall assume the full financial risk for the costs of healthcare services delivered to an individual receiving services from the HIZ that are in excess of any payments made to the HIZ and must have sufficient reserves to accommodate any such additional costs. (i) Waiver of Rights to Payment Under Private or Public Programs.-- An HIZ established with amounts provided under this section shall waive any right to additional reimbursement under any Federal healthcare entitlement program, including under titles XVIII and XIX of the Social Security Act (42 U.S.C. 1395 et seq.; 42 U.S.C. 1396 et seq.), and under any group health plan or from any health insurance issuer offering group or individual health insurance coverage for healthcare services furnished to an individual receiving healthcare services from the HIZ and for which payment is made under this subsection for such services. (j) Scoring Cost Savings.--The Secretary shall collaborate with the Government Accountability Office in scoring the healthcare costs and savings associated with implementing HIZs on a nationwide basis. (k) Waiver.--Any requirements under titles XI and XVIII of the Social Security Act (42 U.S.C. 1301 et seq.; 42 U.S.C. 1395 et seq.), or under any other provision of law that would preclude the establishment or operation of an HIZ under this section, shall not apply with respect to such establishment or operation. (l) Reports.-- (1) HIZ report.--An entity that establishes an HIZ under this section shall submit to the Secretary a report that describes and evaluates the activities of the HIZ. (2) Secretary report.--The Secretary shall submit to Congress an evaluation of the current status of the demonstration program within 6 months after the end of the first year of the demonstration program, and every 6 months thereafter until the end of the demonstration program.

Healthcare Innovation Zone Program Act of 2009 - Directs the Secretary of Health and Human Services (HHS) to establish a Healthcare Innovation Zone (HIZ) pilot program, consisting of an HIZ planning grant program and an HIZ demonstration project, to increase health care provider integration and align health care provider incentives to improve health and reduce health care costs. Defines an "HIZ" as an integrated health care delivery network that works with local employers, community leaders, and private and governmental payors in a geographic region and that: (1) provides a full spectrum of care, including inpatient, outpatient, post-acute, and preventive care, to individuals, including Medicare beneficiaries; (2) has an academic medical center that provides tertiary and quaternary care, has existing capabilities to conduct health services research, and provides clinical training for health professionals; and (3) is able to accept alternative payment structures beyond fee-for-service and per diem amounts. Directs the Secretary to award between 10 and 25 grants of $250,000 to $1 million each to eligible entities for purposes of researching and preparing an HIZ model plan. Lists required contents of a plan, including: (1) a description of innovative models of care that improve quality and decrease costs; (2) a provider network that will provide the full spectrum of care; and (3) a target population and mechanisms to enroll such population. Directs the Secretary to: (1) establish an HIZ demonstration project to test the effectiveness of HIZs in increasing health care provider integration, improving health care services, and reducing health care costs; and (2) select project participants from HIV model plan grant recipients. Requires the project to operate for at least three years, subject to renewal at the Secretary's discretion. Requires an HIZ established under this Act to provide comprehensive health care services to individuals who voluntarily enroll to receive such services for multi-year periods from the HIZ.

SECTION 1. SHORT TITLE. This Act may be cited as the ``National Endowment for the Arts Termination Act of 1997''. SEC. 2. TERMINATION OF THE NATIONAL ENDOWMENT FOR THE ARTS AND THE NATIONAL COUNCIL ON THE ARTS. Sections 5, 5A, and 6 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 954, 954A, and 955) are repealed. SEC. 3. CONFORMING AMENDMENTS. (a) Declaration of Purpose.--Section 2 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 951) is amended-- (1) in paragraphs (1) and (6) by striking ``arts and the''; (2) in paragraphs (2) and (5) by striking ``and the arts''; (3) in paragraph (4) by striking ``the arts and''; (4) in paragraph (5) by striking-- (A) by striking ``and the arts''; and (B) by striking ``arts and''; (5) in paragraph (7)-- (A) by striking ``practice of art and the''; (B) by striking ``artist or''; and (C) by striking ``creative''; (6) in paragraph (9) by striking ``arts and''; (7) by striking paragraph (11); and (8) in paragraph (12)-- (A) by striking ``the Arts and''; and (B) by redesignating such paragraph as paragraph (11). (b) Definitions.--Section 3 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 952) is amended-- (1) by striking subsections (b), (c), and (f); and (2) in subsection (d) by striking ``, including programs'' and all that follows through ``understanding of the arts,''; (A) in paragraph (1)-- (i) by striking ``the National Council on the Arts or''; and (ii) by striking ``, as the case may be,''; (B) in paragraph (2)-- (i) by striking ``sections 5(l) and'' and inserting ``section''; (ii) in subparagraph (A) by striking ``artistic or''; and (iii) in subparagraph (B)-- (I) by striking ``the National Council on the Arts and''; and (II) by striking ``, as the case may be,''; and (C) by striking ``(d) The'' and inserting ``(b) The''; and (3) by redesignating subsections (e) and (g) as subsections (c) and (d), respectively. (c) Establishment of National Foundation on the Arts and Humanities.--Section 4(a) of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 953(a)) is amended-- (1) in subsection (a)-- (A) by striking ``the Arts and'' each place it appears; and (B) by striking ``a National Endowment for the Arts,''; (2) in subsection (b) by striking ``and the arts''; and (3) in the heading of such section by striking ``the arts and''. (d) Federal Council on the Arts and the Humanities.--Section 9 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 958) is amended-- (1) in subsection (a) by striking ``the Arts and''; (2) in subsection (b) by striking ``the Chairperson of the National Endowment for the Arts,''; (3) in subsection (c)-- (A) in paragraph (1) by striking ``the Chairperson of the National Endowment for the Arts and''; (B) in paragraph (3)-- (i) by striking ``the National Endowment for the Arts,''; and (ii) by striking ``Humanities,'' and inserting ``Humanities''; (C) in paragraph (6) by striking ``arts and''; and (D) in paragraph (7) by striking ``the arts and''. (e) Administrative Functions.--Section 10 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 959) is amended-- (1) in subsection (a)-- (A) in the matter preceding paragraph (1)-- (i) by striking ``in them''; (ii) by striking ``the Chairperson of the National Endowment for the Arts and''; and (iii) by striking ``, in carrying out their respective functions,''; (B) by striking ``of an Endowment'' each place it appears; (C) in paragraph (2)-- (i) by striking ``of that Endowment'' the first place it appears and inserting ``the National Endowment for the Humanities''; (ii) by striking ``sections 6(f) and'' and inserting ``section''; and (iii) by striking ``sections 5(c) and'' and inserting ``section''; and (D) in paragraph (3) by striking ``define their duties, and supervise and direct their activities'' and inserting ``define the activities of the employees, and supervise and direct the activities of the employees''; (2) in subsection (b)-- (A) by striking paragraphs (1), (2), and (3); and (B) in paragraph (4)-- (i) by striking ``one of its Endowments and received by the Chairperson of an Endowment'' and inserting ``the National Endowment for the Humanities and received by the Chairperson of that Endowment''; and (ii) by striking ``(4)''; (3) by striking subsection (c); (4) in subsection (d)-- (A) by striking ``Chairperson of the National Endowment for the Arts and the''; and (B) by striking ``each'' the first place it appears; (5) in subsection (e)-- (A) by striking ``National Council on the Arts and the''; and (B) by striking ``, respectively, may each'' and inserting ``may''; and (6) in subsection (f)-- (A) in paragraph (1)-- (i) by striking ``Chairperson of the National Endowment for the Arts and the''; and (ii) by striking ``their respective Endowments under sections 5(c) and'' and inserting ``the Endowment under section''; (B) in paragraph (2)(A)-- (i) by striking ``either of the Endowments'' and inserting ``the National Endowment for the Humanities''; and (ii) by striking ``involved''; and (C) in paragraph (3)-- (i) by striking ``that provided such financial assistance'' each place it appears; and (ii) in subparagraph (C) by striking ``the National Endowment for the Arts or''. SEC. 4. AUTHORIZATION OF APPROPRIATIONS. Section 11 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 960) is amended-- (1) in subsection (a)(1)-- (A) by striking subparagraph (A); and (B) in subparagraph (B) by striking ``(B)''; (2) in subsection (a)(2)-- (A) by striking subparagraph (A); and (B) in subparagraph (B)-- (i) by striking ``(B)''; and (ii) by redesignating clauses (i) and (ii) as subparagraphs (A) and (B), respectively; (3) in subsection (a)(3)-- (A) by striking subparagraph (A); (B) in subparagraph (B)-- (i) by striking ``(B)''; and (ii) by redesignating clauses (i) and (ii) as subparagraphs (A) and (B), respectively; and (C) by striking subparagraph (C); (4) in subsection (a)(4)-- (A) by striking ``Chairperson of the National Endowment for the Arts and the''; (B) by striking ``, as the case may be,''; and (C) by striking ``section 5(e), section 5(l)(2), section 7(f),'' and inserting ``section 7(f)''; (5) in subsection (c)-- (A) by striking paragraph (1); and (B) in paragraph (2) by striking ``(2)''; (6) in subsection (d)-- (A) by striking paragraph (1); and (B) in paragraph (2) by striking ``(2)''; and (7) by striking subsection (f). SEC. 5. SHORT TITLE. Section 1 of the National Foundation on the Arts and the Humanities Act of 1965 (20 U.S.C. 951 note) is amended by striking ``the Arts and''. SEC. 6. TRANSITION PROVISIONS. The Director of the Office of Management and Budget shall provide for the termination of the affairs of the National Endowment for the Arts and the National Council on the Arts, including the appropriate transfer or other disposition of personnel, assets, liabilities, grants, contracts, property, records, and unexpended balances of appropriations, authorizations, allocations, and other funds held, used, arising from, available to, or to be made available in connection with implementing the authorities terminated by the amendments made by this Act. SEC. 7. EFFECTIVE DATES. (a) General Effective Date.--Except as provided in subsection (b), this Act shall take effect on the date of enactment of this Act. (b) Effective Date of Amendments.--Sections 2, 3, 4, and 5 shall take effect on the first day of the first fiscal year beginning after the date of enactment of this Act.

National Endowment for the Arts Termination Act of 1997 - Amends the National Foundation on the Arts and the Humanities Act of 1965 to abolish the National Endowment for the Arts (NEA) and the National Council on the Arts (NCA). Renames such Act the National Foundation on the Humanities Act of 1965. Requires the Director of the Office of Management and Budget to provide for the termination of the affairs of the NEA and the NCA.

diabetes was recently recognized to induce microvascular complications affecting the renal , visual , and peripheral nervous systems . the clinical manifestation of diabetes mellitus is characterized by vascular and neuropathic complications . in the inner ear , angiopathy may occur both directly - by interfering with cochlear blood supply and reducing nutrient transportation - and indirectly - by reducing blood flow due to narrowed vasculature - causing secondary degeneration of the eighth cranial nerve . although many studies have reported an association between diabetes and hearing loss , these reports have had some limitations ; the use of data from animal studies , few subjects , or a cross - sectional study design . most studies have reported only an abstractive correlation between common hearing loss and the incidence of diabetes . thus , there is a need for further research with experimental conditions that control for other variables beyond diabetes , such as noise - induced hearing loss . accordingly , we conducted our present study to evaluate the impact of diabetes on the occurrence of and recovery from noise - induced hearing loss . we compared the sensitivity and the recovery for noise - induced hearing loss between normal and diabetic mice . we used 5-week - old male mice with a normal preyer 's reflex and normal hearing threshold ; c57blks / j - m wild type ( + /+ ) mice were used as the control group ( 11 mice ) while c57blks / j - db / db mice were used as the diabetic group ( 13 mice ) . the mice were allowed to adapt to the laboratory environment for 1 week before the experiment . the animals were housed in silent cages at a temperature of 241 temperature and maintained in environmentally controlled rooms with a 12-h light / dark cycle , with food and water available ad libitum . zolazepam / tiletamine ( zoletil ; virbac , carros , france ) 25 mg / kg and xylazine ( rompun ; bayer , seoul , korea ) 10 mg / kg were administered intraperitoneally for anesthesia , and half of the above amounts were additionially added if necessary . all animal experiments were performed with the approval of the animal care committee of the university of ulsan college of medicine . mice were divided into a control group ( 8 mice ) and a diabetic group ( 9 mice ) . the hearing levels of each mouse , none of whom was exposed to white noise were evaluated weekly for 7 weeks . the remaining animals were divided into two groups , a control group ( 3 mice ) and a diabetic group ( 4 mice ) . both control and diabetic groups were exposed to broad band white noise of 110 db spl ( sound pressure level ) in a soundproof booth for 3 hours . white noise ( 0.3 - 10 khz ) was generated by a personal computer and amplifier ( r-399 ; interm , seoul , korea ) and delivered through a speaker ( 290 - 8l ; altec lansing , oklahoma city , ok , usa ) in a noise booth . the amplifier with the speaker on top was placed in the left corner of the noise booth , and the horn was attached at a 45-degree angle . the hearing levels of each mouse were analyzed before and immediately after noise exposure and at following periods ; 1 , 3 , 5 , and 7 days , and 2 , 3 , and 4 weeks after exposure . for the measurement of hearing levels , we analyzed the auditory brainstem response ( abr ) and distortion product otoacoustic emission ( dpoae ) results with an auditory evoked potential workstation ( tucker - davis technologies , alachua , fl , usa ) . the frequencies measured were 4 , 8 , 16 , and 32 khz , and we gained the waveform by repeatedly decreasing the stimulation tone by 10 db from a strength of 90 db spl . we judged a waveform with an amplitude greater than 0.2 v that appeared to be similar to the response to the previous stimulation tone to be a significant waveform . we generated f1 and f2 primary stimulation tones ( f2/f1=1.2 ) using a dual channel synthesizer . for the measurement of frequency - specific responses , we set the f2 stimulation tone to 4 , 8 , 11.3 , 16 , 22.6 , and 32 khz . the threshold was determined when the dpoae response exceeded the noise level on the measured graph at each frequency . the hearing thresholds of the control and diabetic groups were compared using the mann - whitney u test . to evaluate the effects of diabetic on recovery from noise - induced hearing loss , we calculated the rate of hearing level recovery each week . the recovery rate for each week was obtained as follows : recovery rate=(recovered hearing threshold / deteriorated hearing threshold)100% where the recovered hearing threshold is the difference in the hearing threshold immediately after noise exposure and at each week and the deteriorated hearing threshold is the difference in the hearing threshold before and immediately after noise exposure . the hearing recovery rates of the two groups were statistically validated with the mann - whitney u test . all statistical analyses were performed using spss version 21.0 ( ibm , armonk , ny , usa ) . we used 5-week - old male mice with a normal preyer 's reflex and normal hearing threshold ; c57blks / j - m wild type ( + /+ ) mice were used as the control group ( 11 mice ) while c57blks / j - db / db mice were used as the diabetic group ( 13 mice ) . the mice were allowed to adapt to the laboratory environment for 1 week before the experiment . the animals were housed in silent cages at a temperature of 241 temperature and maintained in environmentally controlled rooms with a 12-h light / dark cycle , with food and water available ad libitum . zolazepam / tiletamine ( zoletil ; virbac , carros , france ) 25 mg / kg and xylazine ( rompun ; bayer , seoul , korea ) 10 mg / kg were administered intraperitoneally for anesthesia , and half of the above amounts were additionially added if necessary . all animal experiments were performed with the approval of the animal care committee of the university of ulsan college of medicine . mice were divided into a control group ( 8 mice ) and a diabetic group ( 9 mice ) . the hearing levels of each mouse , none of whom was exposed to white noise were evaluated weekly for 7 weeks . the remaining animals were divided into two groups , a control group ( 3 mice ) and a diabetic group ( 4 mice ) . both control and diabetic groups were exposed to broad band white noise of 110 db spl ( sound pressure level ) in a soundproof booth for 3 hours . white noise ( 0.3 - 10 khz ) was generated by a personal computer and amplifier ( r-399 ; interm , seoul , korea ) and delivered through a speaker ( 290 - 8l ; altec lansing , oklahoma city , ok , usa ) in a noise booth . the amplifier with the speaker on top was placed in the left corner of the noise booth , and the horn was attached at a 45-degree angle . the hearing levels of each mouse were analyzed before and immediately after noise exposure and at following periods ; 1 , 3 , 5 , and 7 days , and 2 , 3 , and 4 weeks after exposure . mice were divided into a control group ( 8 mice ) and a diabetic group ( 9 mice ) . the hearing levels of each mouse , none of whom was exposed to white noise were evaluated weekly for 7 weeks . the remaining animals were divided into two groups , a control group ( 3 mice ) and a diabetic group ( 4 mice ) . both control and diabetic groups were exposed to broad band white noise of 110 db spl ( sound pressure level ) in a soundproof booth for 3 hours . white noise ( 0.3 - 10 khz ) was generated by a personal computer and amplifier ( r-399 ; interm , seoul , korea ) and delivered through a speaker ( 290 - 8l ; altec lansing , oklahoma city , ok , usa ) in a noise booth . the amplifier with the speaker on top was placed in the left corner of the noise booth , and the horn was attached at a 45-degree angle . the hearing levels of each mouse were analyzed before and immediately after noise exposure and at following periods ; 1 , 3 , 5 , and 7 days , and 2 , 3 , and 4 weeks after exposure . for the measurement of hearing levels , we analyzed the auditory brainstem response ( abr ) and distortion product otoacoustic emission ( dpoae ) results with an auditory evoked potential workstation ( tucker - davis technologies , alachua , fl , usa ) . the frequencies measured were 4 , 8 , 16 , and 32 khz , and we gained the waveform by repeatedly decreasing the stimulation tone by 10 db from a strength of 90 db spl . we judged a waveform with an amplitude greater than 0.2 v that appeared to be similar to the response to the previous stimulation tone to be a significant waveform . we generated f1 and f2 primary stimulation tones ( f2/f1=1.2 ) using a dual channel synthesizer . for the measurement of frequency - specific responses , we set the f2 stimulation tone to 4 , 8 , 11.3 , 16 , 22.6 , and 32 khz . the threshold was determined when the dpoae response exceeded the noise level on the measured graph at each frequency . the hearing thresholds of the control and diabetic groups were compared using the mann - whitney u test . to evaluate the effects of diabetic on recovery from noise - induced hearing loss , we calculated the rate of hearing level recovery each week . the recovery rate for each week was obtained as follows : recovery rate=(recovered hearing threshold / deteriorated hearing threshold)100% where the recovered hearing threshold is the difference in the hearing threshold immediately after noise exposure and at each week and the deteriorated hearing threshold is the difference in the hearing threshold before and immediately after noise exposure . the hearing recovery rates of the two groups were statistically validated with the mann - whitney u test . all statistical analyses were performed using spss version 21.0 ( ibm , armonk , ny , usa ) . the hearing levels of the control group were better than those of diabetic group from 1 to 7 weeks at all abr frequencies ( 4 , 8 , 16 , and 32 khz ) . the average abr thresholds at 1 week at 4 , 8 , 16 , and 32 khz were 445 db spl , 338 db spl , 545 db spl , and 579 db spl , respectively , in the diabetic mice and 364 db spl , 268 db spl , 364 db spl , and 345 db spl , respectively , in the control group . the abr thresholds of the diabetic group were significantly poorer than those of the control group at all frequencies at 1 , 2 , and 3 weeks , and the dpoae thresholds of the diabetic group were significantly worse than those of the control group at 8 , 11.3 , and 16 khz at 4 and 5 weeks ( table 1fig . 1 ) . both the diabetic and control groups showed an increase in the hearing threshold immediately after noise exposure , which began to slowly recover at all frequencies . although it did not recover to the resting hearing level in either group , the diabetic group showed a higher abr threshold at all abr frequencies ( 4 , 8 , 16 , and 32 khz ) at 4 weeks after noise exposure , and a higher dpoae threshold at 8 khz at 1 week and 2 , 3 , and 4 weeks , compared with the control group ( table 2fig . 2 ) . in order to compensate for the different resting hearing levels before the noise exposure in the two groups , the recovery rates of elevated hearing thresholds after noise exposure were analyzed each week . there were no statistically significant differences in the rate of hearing recovery between the two groups ( table 3 ) . the hearing levels of the control group were better than those of diabetic group from 1 to 7 weeks at all abr frequencies ( 4 , 8 , 16 , and 32 khz ) . the average abr thresholds at 1 week at 4 , 8 , 16 , and 32 khz were 445 db spl , 338 db spl , 545 db spl , and 579 db spl , respectively , in the diabetic mice and 364 db spl , 268 db spl , 364 db spl , and 345 db spl , respectively , in the control group . the abr thresholds of the diabetic group were significantly poorer than those of the control group at all frequencies at 1 , 2 , and 3 weeks , and the dpoae thresholds of the diabetic group were significantly worse than those of the control group at 8 , 11.3 , and 16 khz at 4 and 5 weeks ( table 1fig . 1 ) . both the diabetic and control groups showed an increase in the hearing threshold immediately after noise exposure , which began to slowly recover at all frequencies . although it did not recover to the resting hearing level in either group , the diabetic group showed a higher abr threshold at all abr frequencies ( 4 , 8 , 16 , and 32 khz ) at 4 weeks after noise exposure , and a higher dpoae threshold at 8 khz at 1 week and 2 , 3 , and 4 weeks , compared with the control group ( table 2fig . 2 ) . in order to compensate for the different resting hearing levels before the noise exposure in the two groups , the recovery rates of elevated hearing thresholds after noise exposure were analyzed each week . there were no statistically significant differences in the rate of hearing recovery between the two groups ( table 3 ) . kakarlapudi , et al . reported that sensorineural hearing loss was more common in diabetic patients and that the severity of the hearing loss appeared to correlate with disease progression . a previous animal study reported that diabetic rats had impaired recovery from noise - induced temporary hearing loss . , however , found that diabetes mellitus alone did not cause significant capillary changes in the cochlea of a genetic diabetic rats models ; the changes were observed only in combination with noise exposure or obesity . these reports suggested that this pathogenesis includes cochlear microangiopathy , hyperglycemia of the cerebrospinal fluid or perilymph , auditory neuropathy , diabetic encephalopathy , thickened vessels of the stria vascularis , atrophy of the stria vascularis and loss of outer hair cells . in our present study in the mouse , the resting hearing levels were significantly worse in the diabetic group than in the normal group . after noise exposure , the hearing thresholds were increased in both the control and diabetic groups , but the changes of the hearing thresholds after exposure were not significantly different between the groups . in contrast to previous studies using diabetic rat model , the recovery rates of deteriorated hearing thresholds after noise exposure were similar in our diabetic and control mice , suggesting that diabetes had no significant effect on hearing recovery from noise - induced hearing loss . in clinical studies , ishii , et al . have reported that patients with diabetes are more prone to the development of severe noise - induced hearing loss and agrawal , et al . also observed significant interactions between firearm noise exposure and hearing loss in diabetic patients at 3 khz . previous studies that reported adverse effects of diabetes on noise - induced hearing loss suggested that disrupted microcirculation in diabetic cochlea may cause loss of spiral ganglion cells and irreversible hearing impairment . first , in our present study with mice , noise - induced hearing impairment was not recovered to the resting hearing level in either the diabetic or control groups . it must be noted that because of the residual hearing impairment at 4 weeks after noise exposure , delayed or limited recovery of diabetic mice may have been missed . we suggested this is the reason why our study showed recovery from noise - induced hearing loss was not affected by diabetes contrary to the previous studies . therefore , further long - term follow ups of the hearing levels in diabetic mice are needed . seconds , histopathological studies are needed to assess physiological and morphological alterations in the cochleae over time in mice with or without diabetes . the hearing level with aging is significantly impaired earlier in diabetic compared with normal mice . after noise exposure , however , the hearing recovery was similar between these groups of mice up to the 4-week follow - up .

background and objectivesmany studies have reported an association between diabetes and hearing loss . however , these reports were mainly abstractive correlations between common hearing loss and the incidence of diabetes . therefore , we evaluated the impact of diabetes on the occurrence of and recovery from noise - induced hearing loss.materials and methodswe used 5-week - old c57blks / j - m wild type ( + /+ ) and c57blks / j - db / db male mice as the control and diabetic groups , respectively . in one set of experiments , the hearing levels of control and diabetic mice were measured weekly for 7 weeks . in a second set of experiments , control and diabetic mice were exposed to broadband white noise of 110 db spl for 3 hours ; hearing levels were analyzed before and immediately after exposure , 1 , 3 , and 5 days , and 1 , 2 , 3 , and 4 weeks after the noise exposure.resultsthe hearing levels of the control group were better than those of the diabetic group at each weekly revision for 7 weeks at all auditory brainstem response frequencies ( 4 , 8 , 16 , and 32 khz ) . after noise exposure , both groups of mice showed an immediate increase in the hearing level threshold at all frequencies . subsequent threshold recovery was seen in both groups with no difference in the hearing level recovery rates between the two groups.conclusionshearing level with aging becomes significantly impaired earlier in diabetic mice but hearing recovery after noise exposure is similar between diabetic and control mice .

the study of insulating topological states of matter has emerged as an intensely active field of research . for non - interacting systems there is a variety of topological states which have been identified and subsequently classified based on their elementary symmetries @xcite . the most prominent example of this kind are the integer quantum hall insulator states @xcite . many other symmetry protected topological insulator states , such as for instance quantum spin hall systems or three dimensional @xmath0 topological insulators have been identified theoretically @xcite and also experimentally realized @xcite . the _ entanglement spectrum _ ( es ) @xcite has attracted substantial attention as a theoretical tool to characterize and identify topological states . given a partition of the system into parts 1 and 2 , the entanglement spectrum is ( the negative logarithm of ) the spectrum of the reduced density matrix of part 1 , which is obtained by tracing out the degrees of freedom of part 2 from the density matrix corresponding to the system ground state . ref . @xcite introduced the notion that the es for a topological state contains a representation of the physical edge modes . even though the system may not possess an edge ( e.g. , due to periodic boundary conditions ) , the cut separating the partitions serves as a virtual edge for the es . this notion is important and relevant both for interacting topological states like fractional quantum hall states and spin liquids @xcite and for non - interacting topological states @xcite . the entanglement spectrum can be regarded as the spectrum of a ` hamiltonian ' that has support on part 1 . this entanglement hamiltonian can be thought of as possessing some of the properties of the physical hamiltonian of the system , albeit with a boundary due to the restriction to part 1 . when the system ground state is topological , the entanglement hamiltonian is argued to also be a hamiltonian with topological properties , and since part 1 has a boundary , the es can be expected to display an edge mode . the general properties of the entanglement hamiltonian , and the physical content of the es , are not completely understood and remain a topic of active research . in this work , we examine the entanglement spectrum of a two - dimensional chern insulator on a cylinder geometry , i.e. , on a system having periodic boundary conditions in one spatial direction but not in the other , similar to ref . @xcite . in such a system , there are _ physical _ chiral edge modes , in addition to the virtual edge modes present in the es . we consider cuts parallel to the edges . by varying the distance to the edge , this setup allows us to study the interplay of the physical edge modes and the partitioning . in particular , when the smaller partition is small enough , the entanglement hamiltonian should encode the physics of a single ( virtual ) chiral edge mode . this is a rather unusual opportunity , because chiral edge modes generally occur in pairs . we demonstrate that , when the cut is near enough to the edge so that the edge modes spatially cross the cut , the es generically becomes gapped . this is analogous to topological matter on a thin strip , when the physical edge modes on opposite edges have the opportunity to hybridize and produce a gap in the spectrum . we use a chern insulator model for which the localization of the boundary modes can be parametrically tuned , in particular , they can be made to localize sharply at the physical edge . at such special points , we find that the es remains gapless , containing a single chiral channel , even when the cut is such that the partition contains only a single row at the edge . partitioning the system , such that the smaller subsystem contains only a single row , yields an effectively one - dimensional system . since the es has a chiral channel , the entanglement hamiltonian must correspond to a 1d chiral hamiltonian , accomplished by complex long - ranged hopping . in this article , we study the properties of such entanglement hamiltonians and argue that their ground states carry a so - called ` persistent current ' @xcite . we also study the effect of two different schemes of ` flux insertion ' through the cylinder on the entanglement spectrum . [ [ outline ] ] outline + + + + + + + + + in section [ sec : mandm ] , we introduce the tunable model hamiltonian we consider , and provide the definitions we use for the entanglement spectrum and the entanglement hamiltonian . we use a ` single - particle ' version of the es , as is conventional in the literature on non - interacting topological insulators . in the same spirit , we also introduce a single - particle version of the entanglement hamiltonian , which is a tight - binding hopping hamiltonian . in section [ sec : es ] , we present the es of a a cylindrical chern insulator as a function of the distance of the cut towards an edge , see fig . [ fig : cylinder ] . we characterize the gap in the es and relate it to the size of the partition ( distance between physical edge and entanglement cut ) and the localization length of the edge mode . in section [ sec : entham ] , we extract and present the most prominent features of the entanglement hamiltonian in the extreme case where the smaller partition contains just one row . section [ sec : flux ] introduces the two schemes of flux insertion on the cylinder , discusses their properties and shows their relation to previous flux insertion and spectral flow studies on the torus @xcite . in contrast to the torus we find that no spectral flow is admitted on finite size systems . however , in the thermodynamic limit , spectral flow can occur for certain fine - tuned entanglement hamiltonians . . , scaledwidth=48.0% ] underlying our study in this paper is the so - called two - orbital chern insulator @xcite . the hopping hamiltonian is given by @xmath1 where @xmath2 are the standard pauli matrices acting in the orbital space ( the wave function @xmath3 is a spinor whose entries refer to the two orbitals involved ) and @xmath4 is a tuning parameter for the model ( we assume henceforth a lattice constant @xmath5 ) . the model has trivial and non - trivial insulating phases : for @xmath6 we have a band insulator with chern number @xmath7 , for @xmath8 we have a band insulator with chern number @xmath9 while for @xmath10 and @xmath11 we have a trivial band insulator with chern number zero . at @xmath12 the bulk spectrum is gapless and the system exhibits semimetallic behavior . the phase diagram is shown in fig . [ fig : pd ] schematically showing the bulk gap as a function of @xmath4 and the respective chern numbers @xmath13 . in the regime @xmath14 ( except for @xmath15 where the bulk itself is gapless ) we have chiral edge channels on the opposing edges of the cylinder . this is shown in fig . [ fig : spectrumob ] which shows the spectrum of a system on a cylindrical geometry ( compare fig . [ fig : cylinder ] ) with mass parameter @xmath16 and @xmath17 in the chern insulating phase . . the phases are characterized by their respective chern numbers @xmath18 . non - zero values of @xmath18 signal topological phases with gapless chiral edge modes.,scaledwidth=45.0% ] and b ) @xmath17 . the x - axis denotes the momentum along the cylinder circumference . the occurrence of the edge modes in the bulk gap is visible for both cases . for the special point @xmath16 the edge modes are sharply localized due to the flat dispersion of the bulk bands . the other case , @xmath17 , can be regarded as a representative generic situation . , scaledwidth=50.0% ] localization length @xmath19 of boundary states versus @xmath4 . the localization length @xmath20 is obtained by fitting @xmath21 to the single - particle eigenstate just below the chemical potential , @xmath22 . , scaledwidth=45.0% ] the decay of the boundary modes into the bulk depends on the parameter @xmath4 . when defining the corresponding localization length @xmath19 , we consider only the single - particle eigenstate directly below the chemical potential , as it turns out to be the boundary mode that is most relevant for the properties of the es . as a measure for the localization length we use the square of the wavefunction and determine the distance @xmath19 when it has decayed to half its original value . [ fig : loclength_vs_m ] shows the behavior of @xmath19 as a function of the mass parameter @xmath4 . we note that @xmath19 decreases upon approaching @xmath23 ( at @xmath23 the boundary mode is _ exactly _ localized on the outermost row ) , and diverges upon approaching the gapless points of the spectrum , i.e. , as one approaches @xmath24 ( towards the trivial phases ) or @xmath15 , where the chern number is changed . for a system of free fermions , the entanglement spectrum of a subsystem can be obtained from the hermitian correlation matrix @xcite @xmath25 where @xmath26 are fermionic operators , and the site / orbital labels @xmath27 are restricted to be within the subsystem . here @xmath28 is the reduced density matrix of the subsystem . for non - interacting fermionic systems , all higher order correlation functions can be expressed in terms of the one - particle correlation matrix . following common practice @xcite , we show the spectra @xmath29 of the correlation matrix @xmath18 and even refer to it as the entanglement spectrum . this is a ` single - particle ' version of the entanglement spectrum that is studied in interacting systems . the reduced density matrix is related to the entanglement hamiltonian @xmath30 via @xmath31 where @xmath32 is a normalization constant . for free fermions , the entanglement hamiltonian also takes a quadratic form @xmath33 it can be shown @xcite that the eigenvalues @xmath34 of the correlation matrix @xmath18 and the eigenvalue @xmath35 of the entanglement hamiltonian @xmath30 are in one - to - one correspondence via @xmath36 the correlation matrix , if thought of as an operator , is also of quadratic form : @xmath37 with @xmath38 obtained through a unitary transformation that diagonalizes the correlation matrix . one then finds @xmath39 so that @xmath40 . clearly , the operator @xmath41 can be interpreted as a hopping hamiltonian with properties that are qualitatively similar to the entanglement hamiltonian . we start with a short reminder of the entanglement spectrum for a cut on a torus geometry . on the torus there are two boundaries ( cuts ) between the two subsystems . one immediate consequence of this is the existence of two boundary modes ( one chiral mode living at each boundary ) . two typical entanglement spectra for a cut on the torus for @xmath16 and @xmath17 are shown in fig . [ fig : estorus ] . note that there are many degenerate modes at energies 0 and 1 , while the gap - crossing chiral modes are non - degenerate except at the crossing point at energy 1/2 . this crossing point is protected by inversion symmetry as long as the system is cut into two partitions of equal size @xcite . when reducing one of the two partitions while keeping the total system size fixed , the two virtual edge modes generically hybridize and open a gap , except at the special points @xmath23 , where the chiral edge modes persist even when one of the partitions becomes arbitrarily small . entanglement spectrum of a chern insulator with a ) @xmath16 and b ) @xmath17 on a torus geometry . the occurrence of two boundary modes is due to the existence of two boundaries . , scaledwidth=49.0% ] we start with stating the main expectations for the entanglement spectrum of the system in fig . [ fig : cylinder ] with open boundary conditions . here , we focus solely on the properties in the topological phase : \(i ) instead of observing two edge modes connecting the upper and lower bands as in the torus geometry , compare fig . [ fig : estorus ] , we expect one edge mode if the cut is performed far away from the physical boundary since then we only probe the bulk of the system@xcite . \(ii ) upon the cut approaching the physical edge the entanglement spectrum should detect that the system with open boundaries is not a topological insulator but instead a trivial insulator and consequently a gap should open in the entanglement spectrum , as expected for a trivial insulator . \(iii ) the opening of the gap in the entanglement spectrum should be sensitive to the localization length of the boundary mode . in order to support the first two points we have studied the entanglement spectrum upon varying the mass parameter @xmath4 as well as the distance towards the physical boundary . the generic behavior , exemplified by choosing the mass parameter @xmath42 is shown in the top row of fig . [ fig : mdep ] . we observe that there seems to be one gapless mode connecting the lower and upper bands when the cut is far away from the physical edge , i.e. , when the number of rows @xmath43 in the smaller partition is significantly larger than 1 . significantly , a gap opens in the entanglement spectrum upon approaching the physical edge . the qualitative behavior is different for the special point @xmath23 where the edge mode is spatially maximally restricted . this is shown in the second row of fig . [ fig : mdep ] . the aforementioned gap in the entanglement spectrum does not open , even for @xmath44 , i.e. , even if the cut is performed in the row adjacent to the system edge where the physical edge state is hosted . this happens since for this special value of the mass parameter the edge state is not localized _ exponentially _ at the physical edge , but instead _ exactly _ , which can be traced back to the flat dispersion of the lower edge of the bulk spectrum , shown in fig . [ fig : spectrumob ] . we note that the hamiltonian corresponding to the entanglement spectrum seemingly supports a single chiral channel realized in a one dimensional model . since chiral modes are generally thought to occur in pairs in physical hamiltonians , this is somewhat peculiar . we will investigate this aspect further in sec . [ sec : eham ] . the foregoing discussion showed the sensitivity of the gap in the entanglement spectrum to the spatial extent of the physical edge state and the relative position of the cut . we will now demonstrate this more quantitatively . the localization length @xmath19 can be tuned by varying the mass parameter @xmath4 , as discussed previously ( figure [ fig : loclength_vs_m ] ) . figure [ fig : gap_versus_loclength ] shows the entanglement gap as a function of @xmath19 , for partitions containing one , two , four , and six rows . in the dependence of the entanglement gap on the boundary localization length , we observe ` activated ' behavior , roughly when @xmath19 reaches one - eighth of the number of rows in the partition . in other words , the entanglement gap is almost zero when the partition contains almost all the weight of the boundary mode , but becomes significant when a significant amount of the weight is outside the partition . the ` activation ' part of these curves are reasonably well described by a function of the form @xmath45 $ ] , with the exponent @xmath46 . the length scale of activation defined in this way , @xmath47 , is found to be approximately one - sixth of the number of rows in the partition . gap as function of localization length @xmath19 . each point is obtained by calculating @xmath19 and the entanglement spectrum for a different @xmath4 value.,scaledwidth=40.0% ] let us now discuss some general properties of the correlation matrix as defined in . we consider the case where the system is cut after a single site and is effectively one - dimensional . the reduced correlation matrix is a hermitian matrix and thus can be used to define a one - dimensional hopping hamiltonian @xmath48 . in the following this hamiltonian will be denoted as the entanglement hamiltonian . this is a minor abuse of notation as the entanglement hamiltonian @xmath49 is defined by instead . however , regarding the correlation matrix @xmath48 as the entanglement hamiltonian is consistent with the common practice @xcite of focusing on @xmath29 , which are the eigenvalues of @xmath48 , instead of on the entanglement spectrum itself . note that we can always reconstruct the full many - body entanglement spectrum from the eigenvalues of @xmath48 , implying that all the information about the system is already captured in the correlation matrix . as the system is translationally invariant , we can denote the hopping amplitudes of @xmath48 by @xmath50 , where @xmath51 and @xmath52 denote the orbital degree of freedom and @xmath53 is the distance between the sites ( in units of the lattice constant ) . absolute value of the hopping amplitudes in the entanglement hamiltonian as a function of distance @xmath53 . the solid line in the inset is a fit @xmath54 for mass @xmath16.,scaledwidth=48.0% ] we find that , everywhere in the topological regime , the entanglement hamiltonian is long - ranged , even though the original hamiltonian contains only nearest - neighbor hopping . for large systems the magnitudes of the hopping coefficients fall off as the inverse of the distance between the two sites . the absolute values of the hopping amplitudes for large distances are well described by @xmath55 . when the system is in the trivial regime , however , the corresponding entanglement hamiltonian is always short - ranged . this behavior is not unexpected , as the ground state in the trivial phase can always be adiabatically connected to the atomic insulator , which by definition has a short - range entanglement hamiltonian ( see also ref . @xcite ) . . the solid line is a fit @xmath56 for mass @xmath16 . [ fig : phase ] , scaledwidth=48.0% ] let us also note the remarkable fact that the phases @xmath57 of the long - range hopping amplitudes are highly correlated for large values of @xmath53 and independent of the orbital indices . more specifically , away from the phase transition points @xmath57 can be very well approximated by a linear function of @xmath53 : @xmath58 an example of this behavior is seen in fig . [ fig : phase ] , where @xmath57 is plotted for @xmath16 and system size @xmath59 . there is some deviation at small distances from the exact linearity . an interesting property of this hamiltonian is that it shows the phenomenon of a so - called persistent current @xcite . a simple way to see this is from the spectrum itself , shown in fig . [ fig : mdep ] ( second row , leftmost panel ) . the current can be determined as a summation of all the velocities @xmath60 for occupied states . irrespective of the chemical potential we will only sum positive group velocities meaning there will always be a finite net current , leading to the persistent current . we have seen in sec . [ sec : escylinder ] that for @xmath16 the enanglement spectrum is not gapped even if the cut is performed in the row adjacent to the physical edge mode . consequently , the spectrum looks as if it was a one dimensional chiral hamiltonian . this seems contradictory to the fermion doubling theorem for systems with chiral and translational symmetry @xcite , but the way out is via long - range hoppings ( @xmath61 ) which effectively mimics a higher dimensional system . let us now discuss what happens when magnetic flux is threaded through the cylinder . this can be done in several , inequivalent ways . following ref . the flux can be inserted in the original hamiltonian . in this scenario , the hamiltonian is invariant under @xmath62 flux insertion , but the correlation matrix ( and hence the entanglement hamiltonian ) are not , because the ground state evolves into an excited state . under flux insertion the spectrum of the correlation matrix changes such that effectively one state is transported from @xmath63 to @xmath64 ( or vice versa depending on the direction of the flux ) , but all other states transform into each other . despite this change in the correlation matrix ( and hence the entanglement spectrum ) the authors of ref . concluded that the entanglement spectrum shows spectral flow . however , when considering the correlation matrix as a hopping hamiltonian , we can also insert flux in this effective hamiltonian . this is not equivalent to the scheme explained above , because in this case , the spectrum has to be invariant under @xmath65 flux insertion . in particular , we are interested how the flux insertion affects the spectrum at the fine - tuned points @xmath23 , where the entanglement spectrum appears gapless with a single chiral channel . the appearance of a single chiral channel is worrisome as it suggests that a level can be transported upon flux insertion from the lower to the upper band , while the reverse process is not possible . this implies that the system can not go back to itself upon adiabatic insertion of flux @xmath62 if the upper and the lower band are indeed connected . consequently , the existence of a chiral channel must be deceiving . this can be seen most clearly when the mass parameter @xmath66 . when the cut approaches the edge , i.e. the entanglement hamiltonian becomes more and more one - dimensional , a gap opens in the entanglement spectrum . in this case , adiabatic flux insertion is expected to act separately on the upper and lower band and there is no spectral flow in the entanglement spectrum . at the special points the situation is more intriguing since there is no gap in the entanglement spectrum and a more thorough analysis of the effects of flux insertion is needed in order to determine whether or not adiabatic level transport between the bands is possible . a consistent way to introduce flux in expression and is by changing the boundary conditions from periodic to @xmath67 . the correlation matrix is written as a sum over the hopping range @xmath53 : @xmath68 and the boundary condition is consequently applied every time @xmath69 . the factor @xmath70 in the second line is needed to avoid double - counting . in this setup , the entanglement spectrum never shows spectral flow for finite size systems . when the hamiltonian is not tuned to @xmath23 , there is a gap in the spectrum and the eigenstates of the lower and upper band transform into each other separately , as expected . in the fine - tuned case , the situation is more complicated . however , for any finite system sizes , there is a finite - size gap preventing the transport of a level from the lower to the upper band . in the thermodynamic limit , the entanglement spectrum becomes discontinuous due to the long - range hopping and the special phase relations shown in figs . [ fig : amplitude ] and [ fig : phase ] . in this case , the chiral mode transports a state from the lower to the upper band , but at the same time another state is transported from the upper to the lower band via the band discontinuity . as a result , the entanglement spectrum shows spectral flow in the thermodynamic limit at the special points @xmath23 . as a final comment we should note , that inserting flux in the correlation matrix and the entanglement hamiltonian is not equivalent in this setup . in particular , the eigenvalues are no longer connected by eq . , when the flux is non - zero . in this work we have investigated the entanglement spectrum of chern insulators in a half - open geometry as a function of the distance of the entanglement cut to the physical edge of the system . in contrast to the by - now standard entanglement studies which create and study _ virtual _ edge modes at the entanglement cut , this unusual setup is designed to study effects of the _ physical _ edge mode at the physical boundary on the entanglement spectrum and the entanglement hamiltonian . in the extreme case where one of the partitions contains only a single row , the virtual and physical edges are the same . this is reminiscent of entanglement spectra studies of ( non - topological ) ladder systems with the cut between the two ladder legs @xcite . we presented consequences of the interplay between the spatial extent of the edge mode and the cut position , exploiting the tunability of the model hamiltonian to also examine special points where the physical edge mode is sharply localized . strictly speaking , in such a geometry the system is either a trivial insulator , if the edge modes are exponentially localized , or a metal if the edge modes are localized exactly . in the first case we observe an opening of the gap in the entanglement spectrum upon approaching the physical edge , while in the second case we find a seemingly single chiral channel . in the former case we found that no level transport across the gap is permitted accounting for the fact that the system with open boundaries is topologically trivial . in the latter , level transport is prohibited for any finite size system . in the thermodynamic limit , level transport between the upper and lower band is allowed at the expense of the spectrum becoming discontinuous . we also analyzed the one dimensional entanglement hamiltonian , obtained by placing the cut directly at the edge , in more detail . the resulting hamiltonian , living on a closed chain , has remarkable properties , such as long - range hopping amplitudes with highly correlated complex phase factors . in addition , the ground state of this hamiltonian hosts a persistent current . while the details depend on the value of the mass parameter , the generic properties remain the same throughout the topological phase . this persistent current in the entanglement hamiltonian ground state is a reflection the virtual chiral edge mode of the subsystem . for generic mass parameters , the effective one - dimensional system is gapped . the corresponding spectrum is that of an insulator if the chemical potential is in this gap , although the notion of chemical potential for an entanglement hamiltonian is somewhat ambiguous . the question remains if these properties are a peculiarity of the particular model we chose or if they may be more general . in order to investigate this , we studied the properties of another simple topological insulator model on the checkerboard lattice , first introduced in ref . @xcite . even though the details are different , we find that the main features remain the same . in particular , we find that the gapless , seemingly chiral channels can again persist even when cutting the system directly at the physical edge . the resulting one - dimensional entanglement hamiltonian is long - range . the dependence of the phases of the complex hopping amplitudes on hopping distance is more complicated than the present case , but the overall trend is similar . this system also seems to support a persistent current . given this supporting information from a second topological insulator model , we believe that the features we have presented in this work are generic to chern insulators . an intriguing conjecture is that analogous features might also be generic to _ interacting _ topological states . it is also interesting to ask how these results for 2d topological systems are generalized and modified for different classes of 3d topological insulators . the authors acknowledge useful discussions with e. ardonne , e. bergholtz and f. pollmann . this work was supported by the `` deutsche forschungsgemeinschaft '' within unit sfb tr12 ( m. hermanns ) and the emmy - noether program fr 2627/3 - 1 ( lf ) . this work is also part of the d - 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we study the entanglement spectrum of a chern insulator on a cylinder geometry , with the cut separating the two partitions taken parallel to the cylinder edge , at varying distances from the edge . in contrast to similar studies on a torus , there is only one cut , and hence only one virtual edge mode in the entanglement spectrum . the entanglement spectrum has a gap when the cut is close enough to the physical edge of the cylinder such that the edge mode spatially extends over the cut . this effect is suppressed for parameter choices where the edge mode is sharply localized at the edge . in the extreme case of a perfectly localized edge mode , the entanglement spectrum is gapless even if the smaller partition consists of a single edge row . for the single - row cut , we construct the corresponding entanglement hamiltonian , which is a one - dimensional tight - binding hamiltonian with complex long - range hopping and interesting properties . we also study and explain the effect of two different schemes of flux insertion through a ring described by such an entanglement hamiltonian .

the cosmic microwave background ( cmb ) , interpreted as relic radiation from an early hot dense phase of the universe , is generally acknowledged as one of our primary probes of conditions in the early universe(hu and dodelson 2002 and references therein ) . mapping the temperature anisotropies of the cmb has been the subject of intensive effort over the past two decades , with the results of many studies published within the last 3 years : boomerang ( netterfield et al . 2001 ) , maxima(lee et al . 2001 ) , cbi ( mason et al 2002 ) , dasi(halverson et al . 2002 ) , archeops ( benoit et al . 2002 ) , and acbar(kuo et al . 2002 ) among others ( see bersanelli et al 2002 for a recent review ) . temperature anisotropy measurements have been used to calibrate the amplitude of the initial density perturbations and constrain the primordial spectral index ( gorski et al . 1996 ) , measure the overall density of the universe(de bernardis et al . 2001 , etc . ) , and recently to make detailed comparisons between competing scenarios for structure formation , leaving a rather narrow range of consistent adiabatic inflationary models . in combination with recent constraints from supernova snia and large scale structure ( lss ) data , cmb temperature anisotropy data strongly suggest models with a large fraction of the total energy density in a cosmological constant or other dark sector. cmb data are normally reduced to an estimate of the angular power spectrum of fluctuations for comparison to theoretical predictions . the salient features of the currently allowed adiabatic inflationary models are a series of acoustic peaks and troughs in the power spectrum from @xmath3 ( spherical harmonic multipole ) of about 200 and up.(bond & efstathiou 1987 ) the positions and amplitudes of these peaks pin down the details of the cosmological models . each of the aforementioned experiments was designed to target a particular region of @xmath3-space or portion of the angular power spectrum . sensitivity to high @xmath3 modes is limited by the angular resolution of the telescope . resolution in @xmath3-space is limited by the size of the region studied . amplitude uncertainties at all @xmath3 are limited by the detector noise and integration time . at low @xmath3 values in particular , sample variance can increase the amplitude uncertainty of a measurement , an effect which can only be reduced by increasing sky coverage . beast , in particular the observing campaign described in this paper , has been optimized to study the first of these peaks in detail . beast is a mixed q - band ( 38 - 45 ghz ) and ka - band ( 25 - 35 ghz ) focal plane that views the sky through a 2.2 m off - axis telescope followed by a modulating flat mirror . primarily funded by nasa , beast is largest aperture cmb telescope flown to date . the instrument is described in detail in childers et al . ( 2003 ) , while the optical design is described in figueiredo et al . beast is most similar to one of our previous balloon borne telescopes , hacme ( staren et al . 2000 ; tegmark et al . 2000 ) but with a much larger telescope and a focal plane array . after two balloon flights in 2000 , beast was reconfigured to take advantage of the uc white mountain research station ( wmrs ) site on barcroft mountain , ca ( altitude 3800 m ) . the data described here were taken with 6 elements of the array operational , 2 ka - band and 4 q - band detectors . 2 of the q - band detectors are installed on an ortho - mode transducer ( omt ) using a single horn split into vertical and horizontal polarizations . the other horns have single polarization receivers , oriented at various angles . the telescope was installed in an unused building , modified so the roof can be rolled off . beast is aligned at 74 degrees east of north , and can view nominal central elevation angles from 60 to greater than 90 degrees . the instrument was fully installed and operational at barcroft in july , 2001 , and took data nearly continuously until december 2001 . two more weeks of data were obtained in february 2002 and a longer campaign took place from august through october of 2002 . beast views the sky through a large ( 2.5 meter diameter ) spinning flat mirror , tilted 2.2 degrees from its rotation axis . as the flat spins this tilt moves the field of view of the telescope around a nearly elliptical path on the sky of diameter about 9 degrees . the 5 operational feeds thus follow the path shown in figure 1 for the normal telescope elevation angle of 90.4 degrees . two main strategies were employed in taking data . the first involved scanning the nominal ( central ) elevation of the telescope from 80 to 90 degrees and back continuously , the second method was to keep the elevation angle fixed near 90 degrees and allow earth rotation to provide the mapping scan . all of the data reported here are from the fixed elevation data set . this choice was made primarily for the simpler and more robust pointing solution obtained in fixed elevation mode , and the fact that there were no significant improvements in systematic tests gained from the elevation scans . the resulting map is an annulus around the north celestial pole ( ncp ) of width @xmath5 degrees , around declination 37 degrees . figure 2 shows the entire q - band map with the beam trajectories overlaid . the output of each radiometer is amplified , ac coupled with a highpass filter time constant of 15 seconds , and then integrated in an ideal or boxcar integrator with nearly 100% duty cycle . the integration time is set for @xmath6s and digitized to 16 bits . the angular position of the flat mirror ( rotating at 2 hz ) is measured simultaneously so the data can be synchronized with the instantaneous position of the relevant telescope beam . the first step of analysis involves rebinning the raw 1250 hz data stream into optical sectors , corresponding to 250 angular positions of the flat mirror . each optical sector therefore , identifies an angular position of the flat , which is related by the telescope geometry to a precise azimuth - elevation pointing for each of the 5 active detector elements . these pointing data are converted to celestial coordinates and then ultimately to healpix ( hierarchical equal area isolatitude pixelisation , gorski et al . ( 1998 ) ) pixel numbers . the resulting optical sector data stream has an effective sampling rate of approximately 450 hz . the raw data amount to approximately 3.7 gigabytes per day . the receivers are calibrated hourly by passing an ambient temperature microwave absorber between the feeds and the secondary mirror . the output of the acquisition system is then corrected for the effects of the ac coupling in addition to a small ( order 10% ) correction for compression of the detector outputs while viewing the ambient target . the difference between the load and the sky temperatures is then used to compute the calibration coefficients , measured in k / v . this hourly calibration constant is applied to the data during pipeline analysis . calibration and effective beamsize were confirmed independently using cygnus a as the celestial source . overall calibration uncertainty is @xmath710% . calibration and beamsize issues are covered more completely in childers et al . figure 3 shows a sample section of time ordered data for a typical channel . the top strip of small points is the raw data stream , including electrical and any radiometric offset . the large nearly sinusoidal component is due to the varying atmospheric contribution as the flat sends the beam through different elevations and therefore different optical depths . this variation is approximately 60 mk peak - to - peak for this q - band ( 38 - 45 ghz ) channel . we obtain a high signal to noise estimate of the nearly constant atmospheric contribution for each revolution by binning all the data for each hour by optical sector to produce a template signal for that hour . we then subtract this template from every revolution in that hour to remove the first order atmospheric contribution . note that systematic errors fixed in the telescope frame or phase locked to the flat revolution would be removed as well . examples of such effects are fixed sidelobe contamination and electrical noise synchronous with the flat motion . since our strategy keeps the telescope fixed , in principle any sidelobe illumination of the observatory or ground would be removed . there is no direct evidence for any contribution except atmosphere . the solid line plotted through the raw data points is the template for this hour , while the central strip of data points clustered near zero are the residuals from the template subtraction . the lower strip of data points show the result of highpass filtering the template - removed data set at 10 hz corresponding to about 6 degrees on the sky ( effectively giving us a low @xmath3-space cutoff ) . these data have been offset from zero for clarity . the combination of 1 hour template removal and steep 10 hz highpass filter is a reasonable compromise between between extending the low @xmath3 coverage and minmizing the increasing effects of 1/f instrument and atmospheric noise contributions . other filters have also been tried and will be reported on in the future . without the template removal , harmonics of the spin rate remain in the data and can show up as striping in the maps . hourly sections of data are our natural units since calibrations happen on the hour , breaking the continuity of the data stream . there appears to be no benefit to using longer sections for calculating the template : we have not yet investigated in detail the advantages of using shorter time periods for template subtraction . both hourly template removal and 10 hz highpass filter were used in the analysis described below . estimates for the noise amplitude spectral density for this hour are given in figure 4 , calibrated in @xmath8 . the large signal near 2 hz and its higher frequency harmonics are due to the atmospheric contribution discussed above . notice that due to fact that the beam trajectory is not circular , and passes beyond zenith , the resulting atmospheric signal is distorted from sinusoidal , producing significant harmonics of the spin frequency . also shown on the plot is the noise density after template removal and 10 hz highpass filtering . the plot demonstrates the beast detector noise has significant contributions from correlated , long memory ( or `` 1/f '' ) noise . the knee frequency of `` 1/f '' noise is defined as the frequency where the total noise power spectral density ( 1/f + white ) exceeds by a factor of two its white noise level . the latter determines our sensitivity per unit time for angular scales near the beam size . table 1 summarizes the receiver and atmospheric noise and signal performance for a typical accepted hour of data from this campaign . crrrr channel & frequency & white noise & @xmath9 knee & template p - p + & ( ghz ) & ( @xmath8 ) & ( hz ) & ( mk ) + 2 & 38 - 45 & 697 & 38 & 84 + 3 & 38 - 45 & 1324 & 40 & 149 + 4 & 38 - 45 & 770 & 60 & 102 + 6 & 25 - 35 & 1106 & 105 & 76 + 7 & 25 - 35 & 966 & 110 & 107 + 8 & 38 - 45 & 642 & 58 & 87 + the beast scan strategy produces a large area map ( 2470 square degrees ) with high resolution , and we require a precise pointing solution to associate every optical sector for every channel with a position in celestial coordinates . we know the geometry of the telescope , but not well enough to calculate the beam positions to sufficient accuracy for map reconstruction . deviation from ideality of the optics gives uncertanties on the `` a priori '' knowledge of the beam positions . beast was placed in an existing building that did not allow us to move the telescope appreciably in azimuth , and we are unable to target the moon , sun or any planets for pointing verification . we bootstrapped the pointing model by starting with the known geometry , then flying a small airplane equipped with gps over the system in a grid pattern . the spikes in the beast data due to the airplane thermal emission were then correlated with the measured relative position of the airplane to make a crude improvement to the pointing model . cygnus a as well as several other well known radio sources are included in our map , and we have been able to use these sources to further refine the pointing model , beamsize and calibration . figure 5 is a portion of the final map ( all q - band channels averaged ) showing cygnus a and the cygnus loop region . the reconstruction returns an effective resolution of 23 arcminutes fwhm in q - band . this is in contrast with the previously measured telescope resolution of 19 arcminutes . the smearing from the design resolution to the measured effective fwhm of 23 arcminutes is due to a combination of unmeasured pointing errors ( telescope flex , long term telescope sag ) , residual errors in the pointing reconstruction algorithm , smearing due to the finite healpix resolution of 6.9 arcminutes , and smearing from the inital flat rotation sectors ( about 6.7 arcminutes ) . the pointing model is converted to a lookup table of azimuth and elevation for each horn , sector and telescope elevation for use in the pipeline processing . the first data reduction step was to reformat the data into optical sectors , and incorporate relevant pointing information into a single file ( hereafter called level 0 fits file ) , which conforms to the fitsio standard . a single file was produced for each hour , including all channels , as well as telescope elevation , and other pointing information . in addition to rebinning to optical sectors we measured some statistics on these hourly sets to allow simple data culling later . in particular we measured the rms of each channel for the hour as well as the rms after highpass filtering the data at 10 hz . transients ( generally due to thermal emission from airplanes crossing the instruments field of view ) were removed and replaced with adjacent data . these points were flagged as unusable for later analysis stages . level 0 processing was:1 ) import 1 hour receiver and pointing data , 2 ) calculate statistics ( rms and highpass filtered rms ) , 3 ) rebin raw ( not highpass filtered ) data to optical sectors , 4 ) remove transients , flag bad or replaced points 5 ) store data to fits , save summary statistics in header . the next step was to cull the data for bad weather and out of specification performance ( ie when systems were off or under test or during calibrations ) . this was done by looking at the statistics of the highpass filtered data rms in the level 0 headers . generally all the channels showed the same sensitivity to bad weather , and there was a clear knee in the distribution of rms s for making the cut . we then moved to level 1 data files , which integrated the pointing data into map pixel indices . we chose to use the healpix ( gorski et al . 1998 ) set of standards and routines , partly for the inherent advantages of the pixelization scheme and partly for the extensive infrastructure of tools available from the healpix team for manipulating and visualizing the resulting maps . this standardization and set of tools has been invaluable in performing all of our subsequent analysis . every sample for each channel was then associated with an azimuth - elevation pointing via the lookup table mentioned above , then to a celestial coordinate pointing using the known observation time and location , thence to a healpix index using the healpix idl library routines . we chose to use nside=512 , with a resolution corresponding to 6.9 arcminute pixels as a reasonable oversampling of our beamsize . level 1 data files then included time , 6 columns of data , 1 column of goodness - of - data flag , and 6 columns of healpix indices . to produce a map , we 1 ) read in level 1 file , 2 ) calculate and subtract hourly atmospheric template from all channels , 3 ) highpass filter all channels at 10 hz , 4 ) bin into daily map ( ignoring flagged points , saving statistics ) , 5 ) iterate for all hours to complete daily map for all channels , 6 ) save daily map to disk , start next day this generates a map with statistics for each day for each channel . we then co - added ( averaged by pixel ) the daily channel maps into total data set channel maps , weighting by the average noise per pixel per day . the q - band channels were then co - added with appropriate noise weighting to create the total q - band data maps , as were the ka channels . in addition to these averaged maps , we made difference maps , where we binned 1/2 of the days into one map , the other 1/2 of the days into another . then we generated the difference of these two maps on a pixel by pixel basis , dividing by 2 to maintain the noise statistics of the average maps . these difference maps give us a measure of the noise in the maps vs the signal + noise in the average maps . some of these difference maps are displayed below . figures 6 and 7 display two representative sections of the beast q - band average map . each figure contains 3 panels . the top panel is the full nside=512 resolution map in gnomonic projection around @xmath10 = 38 degrees and @xmath4= 0 and 160 degrees . the second panel is this same map smoothed with a 0.5 degree fwhm gaussian . the third panel is the 0.5 degree fwhm smoothed difference map as a visual guide to the effective noise level in the smoothed average map . figure 8 shows the distribution of pixel values for the q - band map , compared with a gaussian distribution . the distributions with and without the galaxy and point source cuts are shown . one measure of the noise and signal in the map is to calculate the standard deviation of the map ( after removing foreground contaminated regions ) and compare with the standard deviation in the difference map , which should have the same noise characteristics , but no cmb signal . for q - band we find @xmath11 at 6.9 pixels for the sum map and @xmath12 for the difference map . smoothing to 30 arcminutes fwhm we get @xmath13 for the sum and @xmath14 for the difference , consistent with a signal rms contribution of @xmath15 k ( rayleigh - jeans units ) . converting to blackbody spectrum and correcting for 3% atmospheric attenuation we obtain @xmath16 ( quoted error dominted by calibration uncertainty ) . note that this includes the map smoothing , and the complex beast filter produced by our ac coupling , beam shape , highpass filter , and template removal , so is not our best estimate of sky signal , but only an indicator of a statistically significant sky signal . any sensitve cmb map of this size will cross regions of significant foreground contamination as is seen in our maps with the galactic crossings . other than a few regions the map appears to be remarkably clean . by comparison with foreground maps , we have been able to determine a very conservative cut in galactic latitude which removes diffuse foregrounds , while for point sources we have used a strict point source finding algorithm operating on the data maps . point sources were removed by excising a 1 degree diameter circle of pixels centered on each source . the most interesting feature of our foreground contamination is a large structure near @xmath4=60 degrees , @xmath10=36.5 degrees . the feature is 0.75 mk in the smoothed q - band map and 1.4 mk in ka - band , implying a power law spectral index of -1.9 , consistent with free - free emission . we see a large correlation with a feature in the combined iras / dirbe map ( finkbeiner et al . ) , but no correlation at all with the haslam map at 408 mhz . initially we thought this might be evidence for spinning dust grains , but a comparison with integrated h@xmath4 emission showed a very large correlation , consistent with free - free emission . this comparison was made possible by the availability of a map of integrated h@xmath4 emission produced by d. finkbeiner ( finkbeiner , 2003 ) using data from wham ( reynolds et al . 2002 ) , vtss ( dennison et al . 1998 ) , and shassa ( gaustad et al . the expected free - free emission is estimated by scaling from bennett et al . ( 1992 ) which predicts @xmath17 /rayleigh at 40 ghz . for our structure we measure @xmath18k / rayleigh . since the correlations with the h@xmath4 map were so much more evident than with haslam and iras that we used the h@xmath4 data to estimate our required galactic latitude cut : by cutting out data with @xmath19 less than @xmath20 we expect less than @xmath21k contamination from free - free emission . this is a very conservative cut and we expect to refine this further to increase the accepted sky fraction . our resulting foreground removal template is shown in figure 9 , shaded regions are used in the power spectrum analysis . we have produced extended ( @xmath22 square degree ) sky maps with good angular resolution and control of systematics . visual inspection of the smoothed maps shows unmistakable structure . quantitative results for the power spectrum of cmb fluctuations which is consistent with our data are presented in a companion paper ( odwyer et al . in addition to cosmic structures we have interesting correlations with known astrophysical foregrounds . further analysis will yield important information about the amplitude , spectra and possibly polarization of these foregrounds . as an aid in interpreting our maps , and as a guide to our @xmath3-space filter , we have made a single realization of a white power spectrum sky ( equal power on all scales ) , and then simulated the beast pipeline over that map . we created a full sky map with normally distributed noise in each pixel . this map was then smoothed with a gaussian of fwhm=23 arcminutes to simulate our effective beam . next we simulated the time ordered data expected from this map without additional noise by sampling with the beast pointing timestream . we ran the resulting timeline through the beast analysis pipeline , including template removal , filtering and binning . finally we cut using the same foreground template used in the actual data map . pseudocl power spectra ( that is power spectra calculated assuming full sky coverage but actually covering only a particular region ) were calculated for the full unsmoothed white input map , the smoothed white map , the smoothed and foreground cut white map , and the full beast simulated smoothed and foreground cut map . the results are shown in figure 10 . the two all sky power spectra have been scaled by the sky fraction ( 2.85% of full sky ) of the foreground cut template in order to put them onscale , and to demonstrate that the primary effect of limited sky coverage on our @xmath3-space filter is just amplitude . all of the smoothed maps display the high @xmath3 cutoff of our beam . below @xmath3 of about 150 , the input map power spectrum is virtually the same as the smoothed and cut sky power spectra , while the beast simulated map power spectrum displays the low @xmath3 cutoff of the combined template removal and 10 hz highpass filter . the loss of sensitivity from @xmath23 to @xmath24 is dominated by the highpass filter cutoff . note that this analysis neglects correlations among different @xmath3s . figure 11 gives an approximation to the @xmath3 space window function based on these calculation . power spectra from the data and cosmological parameter estimates will be presented in a companion paper ( odwyer et al . we have shown the utility of making large area sky maps with a simple scanning strategy and expect to add significantly more data in the near future . the data presented so far are the result of 27 days of `` good data '' . our experience so far is we can achieve `` good data '' more than 50% of the days at our observatory . the site has proven to be extremely good in our wavelength range and the atmosphere stable . a paper discussing the site is in preparation . one year of observations with the existing system only improved by new hemt s should yield 7 @xmath25k errors per 30 arcminute pixel on 10% of the sky . the beast optics are precise enough to observe to nearly 1 thz so a variety of sky surveys are possible . at 90 ghz the beam size would be about 8.5 arc minutes fwhm while at 150 ghz it is 5 arcminutes . it is a pleasure to thank k. gorski , d. maino , d. finkbeiner , s. myers , t. montroy and j. r. bond for useful discussions . m. lim and j. staren made significant contributions early in the development of beast . we wish to thank the white mountain rearch station , particularly d. trydahl , r. masters , and m. morrison , for heroic efforts in getting beast sited . wmrs director f. powell s enthusiastic support has been critical to our success . beast was built with help from numerous talented ucsb physics undergraduates , as well as the superb ucsb machine shop , and administrative staff . we wish to thank e.mattaini and e.santambrogio from iasf milano for there contributions . we also want to thank the national scientific balloon facility staff for their support on our two balloon campaigns leading up to the current ground based work . the develpment and operations of beast were supported by nasa office of space sciences , the national science foundation , university of california white mountain research station , and the california space institute ( calspace ) . production of the superb beast optics were made possible by personal and corporate support from k. kedward ( ucsb me ) , m. pryor ( coi ) , s. dummer ( surface optics ) , j. wafer and t. ives(thin film technology),trw , j. anthony ( union carbide ) and able engineering . we had support from nrao and m. pospieszalski , as well as trw in developing our hemt amplifiers . n.f . and a.p were partially supported by cnpq grant # 470531/2001 - 0 . jm is supported by fapesp grants 01/13235 - 9 and 02/04871 - 1 . tv and caw were partially supported by fapesp grant # 00/06770 - 2 . tv was partially supported by cnpq grants # 466184/00 - 0 and 302266/88 - 7-fa . caw was partially supported by cnpq grant # 300409/97 - 4 and fapesp grant # 96/06501 - 4 . the research described in this paper was performed in part at the jet propulsion laboratory , california institute of technology , under a contract with the national aeronautics and space administration . bennett c. l. et al . 1992 , , 396,l5 bond , j.r . & efstathiou , g. 1987 , mon . not . r. astron.soc . 226 , 655 benoit , a. et al . 2002 , a&al , in press , astro - ph/0210305 bersanelli , m. , maino , d. , mennella , d. , 2002 , la rivista del nuovo cimento , astro - ph/0209215 . childers , j. et al . 2003 , in preparation odwyer , i. et al . 2003 , in preparation reynolds , r.j . , haffner , l.m . , & madsen , g.j . 2002 in `` galxies : the thrird dimension '' , asp conf . series vol 282 , eds . m. rosado , l. binette , & l. arias , in press

we present the first sky maps from the beast ( background emission anisotropy scanning telescope ) experiment . beast consists of a 2.2 meter off axis gregorian telescope fed by a cryogenic millimeter wavelength focal plane currently consisting of 6 q band ( 40 ghz ) and 2 ka band ( 30 ghz ) scalar feed horns feeding cryogenic hemt amplifiers . data were collected from two balloon - borne flights in 2000 , followed by a lengthy ground observing campaign from the 3.8 km altitude university of california white mountain research station . this paper reports the initial results from the ground based observations . the instrument produced an annular map covering the sky from @xmath0 . the maps cover an area of 2470 square degrees with an effective resolution of 23 arcminutes fwhm at 40 ghz and 30 arcminutes at 30 ghz . the map rms ( smoothed to 30 arcminutes and excluding galactic foregrounds ) is @xmath1k at 40 ghz . comparison with the instrument noise gives a cosmic signal rms contribution of @xmath2k . an estimate of the actual cmb sky signal requires taking into account the @xmath3 space filter function of our experiment and analysis techniques , carried out in a companion paper ( odwyer et al . 2003 ) . in addition to the robust detection of cmb anisotropies , we find a strong correlation between small portions of our maps and features in recent h@xmath4 maps ( finkbeiner 2003 ) . in this work we describe the data set and analysis techniques leading to the maps , including data selection , filtering , pointing reconstruction , mapmaking algorithms and systematic effects . a detailed description of the experiment appears in childers et al . ( 2003 ) .

it is well accepted that galaxies are intimately linked to the gaseous cosmic web and that the evolution of galaxies is governed in large part by the dissipative response of baryonic gas due to the trade off of cooling and dynamical timescales as it accretes into dark matter halos ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) . in general , distinct modes of accretion are believed to operate and the mode is dependent primarily upon the dark matter halo mass ( e.g. , * ? ? ? * ; * ? ? ? * ) , with some dependence on environment ( e.g. , * ? ? ? * ) and on feedback ( e.g. , * ? ? ? `` hot - mode '' accretion is the mechanism in which inflowing gas is shock heated as it is compressed by the hot hydrostatic gas halo . this mode dominates around high mass galaxies , where the dynamical time is shorter than the cooling time . for the most part , the gas accretes into the halo , but not necessarily onto the galaxy itself . `` cold - mode '' accretion is the mechanism primarily around low mass galaxies , where the cooling time is shorter than the dynamical time so that hot hydrostatic halos do not form and cold gas accretes directly onto the galaxy . at lower redshifts , as densities decrease , the cooling time is generally longer than dynamical time and the rate of infalling material decreases so that cold mode accretion is a minor channel of accretion onto galaxies ( e.g. , * ? ? ? * ; * ? ? ? * ) , though it remains an important channel for the growth of galaxies at all redshifts ( e.g. , * ? ? ? a possible third mode is the case in which cold dense filaments can penetrate directly into a hot halo of a massive galaxy . if the conditions are favorable for short cooling times in the filament , then shock heating can be avoided and the filamentary gas can directly accrete onto the galaxy ( e.g. , * ? ? ? * ; * ? ? ? however , though cold streams can penetrate the hot atmospheres of massive halos at @xmath6 , this process significantly diminishes at lower redshift ( e.g. , * ? ? ? * ; * ? ? ? * ) , though there is plausible evidence of this process occuring in some @xmath7 galaxies @xcite . one observable signature of a filament may be a `` complex '' of absorption with a large velocity spread ( @xmath8 ) . alternatively , such absorbing complexes may trace the warm hot intergalactic medium ( whim ) , or the intracluster and/or intragroup medium . if an observed absorption complex arises from a filament , it is plausible that the filament may be accreting from the intergalactic medium into a galaxy halo or even directly onto a galaxy . thus , absorption complexes provide unique astrophysical laboratories for placing constraints on our understanding of the intergalactic medium , and the processes giving rise to extended galaxy halos in the context of dark matter overdensities . at high redshifts ( @xmath9 ) , kinematically extended absorbing complexes were studied by @xcite with keck / hires spectra . they deduced that these structures were filamentary in nature . at lower redshift ( @xmath10 ) @xcite , @xcite , @xcite , and @xcite studied three different complexes with high resolution ultraviolet spectra in which metal lines were detected . for these three complexes , several galaxies were found in the vicinity , suggesting moderate size groups . each of these studies favored a different scenario of explanation for the physical picture of the complex , including arising in `` nearside / backside '' shocked infall into the potential well of the galaxy group @xcite , intragroup gas or an unvirialized filamentary structure through the group @xcite , and tidally stripped material from one of the nearby galaxies @xcite . the spectrum of the quasar q1317 + 277 ( ton 153 , cso 0873 , j131956 + 272808 , @xmath11 , @xmath12 ) exhibits a dramatic @xmath8 complex observed in absorption at @xmath0 . several optical and ultraviolet spectra of the quasar are available and have been the focus of this complex and/or the lyman limit metal - line system at @xmath13 @xcite . besides being at intermediate redshift , what is unique to this complex is that it lies at 58 kpc projected from a single bright elliptical galaxy at @xmath14 @xcite . an analysis of the @xmath15 complex was presented in ( * ? ? ? * hereafter paper i ) based upon _ hst _ g160l / g190h fos spectra ( pid 2424 , pi : j. n. bahcall ) , an _ hst _ e230m / stis spectrum ( pid 8672 , pi : churchill ) , and a keck / hires spectrum of the quasar ( see * ? ? ? * ) . in the fos spectrum , the complex was found to comprise five components of optically thin absorbing gas , which span a velocity range of @xmath16 . no metal - lines were clearly detected in the fos , stis , and hires spectra . galaxies at the absorber redshifts were first reported by @xcite as part of the their absorption - selected galaxy survey . the quantified morphological and spectral properties of these galaxies were presented in paper i based upon an _ hst_/wfpc2 f702w image ( pid 5984 ; pi : steidel ) of the quasar field and keck / lris spectra of the galaxies . updated analysis of the galaxies is included in @xcite , @xcite , and @xcite . in summary , the galaxy at the redshift of the complex has @xmath17 and an impact parameter of @xmath2 kpc . it is classified as a late - type e / s0 galaxy . the galaxy at the redshift of the @xmath18 absorber , which is a rich metal - line lyman limit system , has @xmath19 , an impact parameter of @xmath20 , and is an inclined sab galaxy . in paper i , we deduced that the gas in the complex has column densities in the range @xmath21 , temperatures in the range @xmath22 , and upper limits on metallicity in the range @xmath23 . we further deduced the complex is consistent with a combination of photo and collisional ionized gas . based upon expectations of simulations ( e.g. * ? ? ? * ) , we favored a shock heated structure with chemical enrichment consistent with the high redshift intergalactic medium . our interpretation was that the complex is a shock heated filamentary structure that originated as a photoionized diffuse phase of gas at high redshift and is accreting in the vicinity of the @xmath17 elliptical galaxy . however , the fos data did not provide the information required to examine the detailed structure of the kinematic and ionization conditions . thus , we were unable to constrain the kinematic relationships between the putative shock heated gas , the photo and/or collisionally ionized gas , and the @xmath17 galaxy . such information is critical for examining the physics of gas accretion onto galaxies and for comparing with other observations and with cosmological simulations . for example , @xcite claim that clustered lines at @xmath24 are observed to have higher ionization conditions at the velocity extremes and suggest this layered structure is a signature of collapsing structures . while this may be a signature for intergalactic filaments , it is not clear that accretion of a filament into a galaxy potential will yield the same velocity - ionization structure . in theoretical treatment ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) and cosmological simulations ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) accretion onto massive galaxies is expected to shock heat upon entry into a hot coronal halo , and the resulting kinematic - ionization structure may reflect this very different process . in order to better study the q1317 + 277 complex at @xmath0 , we have obtained a high resolution @xmath25 _ hst_/cos spectrum of the quasar , with focus on the lyman series lines and absorption . we further improved our knowledge of the star formation history , age , and mass of the @xmath17 galaxy by obtaining multi - band imaging of the quasar field . our motivations include ( 1 ) a thorough examination of the kinematic , ionization , and chemical structure of the complex , ( 2 ) a direct comparison with the galaxy properties to help place the galaxy - absorber system in the context of galaxy evolution scenarios predicted by theories and cosmological simulations for an improved interpretation , and ( 3 ) examination whether there is a connection between the @xmath0 complex and the galaxy - absorber pair at @xmath26 , perhaps in the form of `` bridge '' of weak absorption between the galaxies . the paper is structured as follows : reduction and analysis of the imaging and spectroscopic data are presented in [ sec : data ] . our analysis of the galaxy images is presented in [ sec : imanal ] and our analysis of the absorption line data is presented in [ sec : specanal ] . in [ sec : models ] and [ sec : gasconditions ] , we present our ionization modeling and resulting constraints on the physical conditions of the absorbing gas . we discuss and interpret the data and our findings in [ sec : discuss ] . we provide brief a conclusion in [ sec : conclude ] . throughout this work , we assume the cosmological parameters @xmath27 , @xmath28 , @xmath29 , and @xmath30 ( based on * ? ? ? * ) . 0.1 in we have acquired new data on the @xmath13 and @xmath0 absorption and the two galaxies g1 and g2 . first , we obtained a cycle-17 @xmath31 cos spectrum ( pid 11667 ; pi : churchill ) of the quasar covering the transitions examined in the fos spectra . our goals include measuring higher detection sensitivities and detailed kinematics of the absorption lines . second , we obtained @xmath32 , @xmath33 , @xmath34 , and @xmath35 ground - based images of the quasar field . the multi - band images provide colors from which galaxy stellar populations , metallicities , and masses can be estimated . as part of a larger campaign for imaging absorption galaxies , we obtained @xmath32 , @xmath33 , @xmath34 band images of the quasar field using the seaver prototype imaging camera ( spicam ) on the apache point observatory s ( apo ) 3.5-m telescope . the detector is a @xmath36 ccd with 24 @xmath37 m pixels , giving an unbinned plate scale of 0.14 pixel@xmath38 and a field of view of @xmath39 . we binned the ccd @xmath40 during readout for a plate scale of 0.28 pixel@xmath38 . multiple @xmath32 , @xmath33 , and @xmath34 band images were obtained on the nights of 2006 march 24 - 25 , for which the seeing varied between 1.2 - 1.5 , and additional @xmath32 band images were obtained the night of 2007 march 15 for which the seeing was 0.7 . the total summed exposure times are 5190 , 4630 , and 4350 seconds for the @xmath32 , @xmath33 , and @xmath34 filters , respectively . each frame was reduced using standard idl and iraf scripts and tasks . flat fielding incorporated a combination of dome and sky flats . cosmic rays were removed in each individual frame . the astrometry was calibrated by position matching of usno a2.0 stars in the field . final images were obtained by coadding the individual calibrated frames . the photometric zero points were obtained using stars in sdss images . color terms are required because the filter plus detector throughput of the apo facility is not identical to that of the sdss facility . these color terms , which are of order 0.1 , were determined from spicam and sdss images of roughly 30 quasar fields from our more extensive database . the near - infrared band images were obtained on 1994 february 24 using the kitt peak mayall 4-m telescope through the @xmath35 filter ( 1.992.32 @xmath37 m ) with the irim nicmos iii @xmath41 array camera . these images were obtained as part of the campaign culminating in the work of @xcite . the field of view is @xmath42 with plate scale of @xmath43 pixel@xmath38 . the nicmos images were reduced using the contributed iraf package dimsum . updated photometric zero points were determined using stars from the 2mass point - source catalog @xcite . all photometric measurements were conducted using sextractor @xcite ; we adopted the automag results . the dust maps of @xcite were used to correct for galactic dust extinction . in figures [ fig : data]@xmath44-[fig : data]@xmath45 , we present @xmath46 sections of the ground - based images centered on the quasar q1317 + 277 . a @xmath47 section of the _ f702w image is presented as figure [ fig : data]@xmath48 . galaxies g1 and g2 labeled in all images . in the _ hst _ image , note the object to the north by north - east within 2.1 of the quasar . we have no estimate of the redshift of this object , which we label g3 . reduction and analysis of the f702w image was described in paper i , @xcite , and @xcite . expanded views of the two galaxies are presented in figures [ fig : data]@xmath49 and [ fig : data]@xmath50 . the keck / lris spectra of galaxies g1 and g2 ( originally described in paper i ) are presented in figures [ fig : data]@xmath51 and [ fig : data]@xmath52 . the g1 galaxy redshift was determined using gaussian centroiding to the absorption features and the redshift of g2 was determined using gaussian centroiding to the @xmath53 emission line . we obtained a cycle-17 @xmath31 cos spectrum ( pid 11667 ; pi : churchill ) of the quasar covering the transitions first examined in the fos spectra . two nuv / g185 m spectra were obtained 2010 may 26 and optimally co - added . the first was centered at 1921 for a 5420 sec exposure , and the second was centered at 1941 for a 4970 sec exposure . the overlap region was 22232037 on stripe c , which provided a total of 10,390 sec of integration on the the absorption complex . the fuv / g160 m spectrum was obtained 2010 june 26 centered at 1600 for an 12,580 sec exposure . the spectra were reduced following the procedures outlined by @xcite . we continuum fit the lower order shape of the spectrum using the iraf _ sfit _ task and refined the higher order continuum features using our own code fitter @xcite . for the @xmath13 and @xmath0 absorbers , the and absorption lines were captured in the nuv on segment a , the was not captured ( fell between segments ) , and the higher order lyman series lines were captured on segment b. a re - analysis - correction resulted in an overestimate of @xmath54 and @xmath55 in paper i. we also converted all magnitudes to the ab system . ] of the _ f702w image was undertaken , presented , and fully described by @xcite . we adopt the measured quantities from that work . the g1 quasar - galaxy impact parameter is @xmath56 kpc . the galaxy photometric properties are @xmath57 , @xmath58 , and @xmath59 ( ab ) . the @xmath60-band luminosity is @xmath61 , where we use @xmath62 from the fit with redshift reported by @xcite . from an analysis using gim2d @xcite , we measure a half - light radius of @xmath63 kpc , disk scale length of @xmath64 kpc , and bulge - to - total ratio of @xmath65 . the galaxy classifies as an e / s0 based upon its c - a morphology @xcite . the galaxy inclination is @xmath66 , and the angle between the quasar sight line and the major - axis of the projected ellipse of the galaxy is @xmath67 . for the properties of galaxy g2 , see @xcite and our companion paper @xcite . photometric analysis of the ground - based images yielded dust- , color- , and seeing - corrected ab apparent magnitudes for galaxy g1 of @xmath68 , @xmath69 @xmath70 and @xmath71 . a color composite image of the ground - based images can be viewed in our companion paper @xcite , from which it can be ascertained that galaxy g1 is clearly redder than galaxy g2 and that the other galaxies in field ( see figures [ fig : data]@xmath44-[fig : data]@xmath45 ) are likely at substantially different redshifts . for galaxy g3 , we measured an f702w apparent magnitude of @xmath72 . this value is based upon a dithered co - added image constructed by a. shapley , in which she removed the quasar via point spread function ( psf ) subtraction . the quoted uncertainty is statistical based upon the sky background ; due to the psf subtraction , the error could be substantially underestimated . assuming galaxy g3 is at the redshift of the absorption complex , i.e. , @xmath73 , and adopting the quoted apparent magnitude , we compute @xmath74 ( @xmath75 ) and @xmath76 ( sdss @xmath77-band ) . at this redshift , the impact parameter to g3 is @xmath78 kpc . in figure [ fig : color - color ] , we plot the @xmath79 colors versus @xmath80 colors for g1 and g2 . following @xcite , @xcite , and @xcite , we used stellar population models to determine stellar masses , @xmath81 , of galaxies g1 and g2 from the observed colors . we employed the stellar population models of @xcite assuming a @xcite initial mass function and an exponential star formation history with an @xmath48-folding time of 1 gyr . also shown in figure [ fig : color - color ] are the locust of observed colors as a function redshift for the @xcite stellar population models for the metallicities @xmath82 = -0.4 $ ] , @xmath83 , and @xmath84 . we find galaxy g1 is consistent with a @xmath85 gyr old , solar metallicity stellar population with a formation epoch of @xmath86 . the stellar population models also yield the galaxy @xmath87-band mass to light ratio , @xmath88 . from this ratio and the @xmath87-band magnitude , we estimate @xmath89 for galaxy g1 , where @xmath90 is the solar value . using the technique of halo abundance matching , the galaxy virial mass , @xmath91 , can be estimated from the stellar mass ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? abundance matching assumes a monotonic functional relation between @xmath91 and @xmath81 by assigning the number of halos with @xmath92 equal to the number of galaxies with @xmath93 . as such , it matches the halo mass and stellar mass functions globally with a roughly 0.25 dex uncertainty in @xmath94 at fixed @xmath81 , primarily due to the systematics in estimates of @xmath81 @xcite . we employed the parameterized functions presented by @xcite . lccc @xmath95 & @xmath96 & @xmath97 & @xmath98 + @xmath99 & @xmath100 & @xmath101 & @xmath102 + @xmath103 , k & @xmath104 & @xmath105 & @xmath106 + @xmath107 , & 550 & 280 & 150 + @xmath108 , kpc & 750 & 380 & 180 + @xmath109 & @xmath110 & @xmath98 & @xmath111 + @xmath112 & @xmath113 & @xmath114 & @xmath115 + @xmath116 & 0.05 & 0.09 & 0.34 for galaxy g1 , we obtained @xmath117 m@xmath118 , where the lower value is given by the @xcite and @xcite fits and the higher value is from the @xcite fit m@xmath118 . for less massive halos , the stellar mass function is not tightly constrained . for higher mass halos , particularly massive ellipticals , there is substantial scatter between the published abundance matching predictions / relations . thus , for a single case , abundance matching is not highly robust for mapping @xmath91 from @xmath81 when @xmath119 m@xmath118 . * private communication ) ] . we adopted the @xcite and @xcite values @xmath120 m@xmath118 . under the assumption that galaxy g3 resides at @xmath0 , we use the @xmath121cdm bolshoi simulation database of @xcite to estimate a virial mass of @xmath122 m@xmath118 using abundance matching . this mass is the average of 18,500 galaxies in the absolute magnitude bin @xmath123 with average @xmath124 . the abundance matching in this database is constrained by the observed luminosity - circular velocity relation , the baryonic tully - fisher relation , and the circular velocity function , allowing all types of galaxies to be included . using the parameterized abundance matching function for @xmath125 of @xcite , we estimate that g3 has a stellar mass of @xmath126 m@xmath118 . the average gas mass , @xmath127 , of a galaxy with stellar mass @xmath81 can be estimated using the parameterized relation of @xcite based upon the baryonic tully - fisher relation study of @xcite , the stellar , gas , and dynamical mass relation of @xcite , and galaxy gas fraction stellar mass study of @xcite . we obtain @xmath128 m@xmath118 for galaxy g1-@xmath81 correlation for disk galaxies , and is therefore not directly applicable to elliptical galaxies . however , as shown in fig . 2 of @xcite , for @xmath129 m@xmath118 , the gas - poor disk galaxy gas fractions reasonably match those of the red galaxy sample of @xcite . thus , we can crudely apply the relation to @xmath130 m@xmath118 elliptical galaxies ( * ? ? ? * private communication ) . ] and estimate @xmath131 m@xmath118 for g3 . thus , we deduce averaged baryonic gas fractions , @xmath132 , of 5% for g1 and 34% for g3 . the virial radii , virial temperatures , and circular velocities for galaxies g1 and g3 were computed using the relations of @xcite for @xmath133 . for galaxy g1 , we obtained @xmath134 kpc , @xmath135 k , and @xmath136 and for galaxy g3 , we obtained @xmath137 kpc , @xmath138 k , and @xmath139 . in table [ tab : galprops ] , we summarize the deduced galaxy properties , which are representative averages for galaxies with their observed photometric properties . in the fos spectrum , a very broad absorption complex was observed ( first reported by * ? ? ? * ) . in paper i we fitted the with five gaussian components at redshifts @xmath140 , 0.67157 , 0.67355 , 0.67559 , and 0.67707 , respectively . the total rest - frame equivalent width was determined to be @xmath141 over a rest - frame velocity spread of 1420 . from the stis spectrum , the @xmath142 @xmath143 equivalent width limit was estimated to be @xmath144 at @xmath145 . in the fos spectrum , the @xmath142 @xmath146 equivalent width limit was estimated to be @xmath147 . for @xmath148 in the hires spectrum , we obtained @xmath149 m to @xmath142 . these values assumed unresolved absorption . for this work , we objectively locate absorption lines or place limits on their equivalent widths employing the optimized methods of @xcite and @xcite as modified using the methods for unresolved lines and pattern noise developed by @xcite . we adopt a @xmath150 detection threshold and quote @xmath142 limits . in figure [ fig : hifits ] , we present the , , , , and absorption observed in the cos spectrum as a function of rest - frame velocity relative to the @xmath17 galaxy . no absorption was detected for lyman series lines higher than . there is significant blending in the , , , and lines , which are identified in figure [ fig : hifits ] , when possible . the curves through the data are @xmath151 minimized voigt profile ( vp ) fits obtained using our code minfit @xcite . the ticks above the normalized continuum provide the vp component velocities . during the fitting , the cos instrumental line spread function ( isf ) was convolved with the vp model . the cos isf appropriate for the spectrograph settings and the observed wavelength of each transition was determined via interpolation of the on - line tabulated data ( cf . * ; * ? ? ? * ) . for the vp fitting , pixels compromised by blending were masked out of the least - squares fit vector . we present the results of our vp modeling in table [ tab : hiresult ] . we fitted a total of 21 components , or `` clouds '' ( minfit returns the minimum number of components based upon their statistical significance through a series of f - tests and confidence level checks ) . assuming thermal broadening , we converted the doppler @xmath152 parameter into the `` cloud '' temperature . lcrccc 1 & 0.668645 & @xmath153 & @xmath154 & @xmath155 & @xmath156 + 2 & 0.668861 & @xmath157 & @xmath158 & @xmath159 & @xmath160 + 3 & 0.669000 & @xmath161 & @xmath162 & @xmath163 & @xmath164 + 4 & 0.669112 & @xmath165 & @xmath166 & @xmath167 & @xmath168 + 5 & 0.669199 & @xmath169 & @xmath170 & @xmath171 & @xmath172 + 6 & 0.669290 & @xmath173 & @xmath174 & @xmath175 & @xmath176 + 7 & 0.671203 & @xmath177 & @xmath178 & @xmath179 & @xmath180 + 8 & 0.671244 & @xmath181 & @xmath182 & @xmath183 & @xmath184 + 9 & 0.671617 & @xmath185 & @xmath186 & @xmath187 & @xmath188 + 10 & 0.671739 & @xmath189 & @xmath190 & @xmath191 & @xmath192 + 11 & 0.672319 & @xmath193 & @xmath194 & @xmath195 & @xmath196 + 12 & 0.672994 & @xmath197 & @xmath198 & @xmath199 & @xmath200 + 13 & 0.673291 & @xmath201 & @xmath202 & @xmath203 & @xmath204 + 14 & 0.673562 & @xmath205 & @xmath206 & @xmath207 & @xmath208 + 15 & 0.673787 & @xmath209 & @xmath210 & @xmath211 & @xmath212 + 16 & 0.674297 & @xmath213 & @xmath214 & @xmath215 & @xmath216 + 17 & 0.674872 & @xmath217 & @xmath218 & @xmath219 & @xmath220 + 18 & 0.675272 & @xmath221 & @xmath222 & @xmath223 & @xmath224 + 19 & 0.675789 & @xmath225 & @xmath226 & @xmath227 & @xmath228 + 20 & 0.676366 & @xmath229 & @xmath230 & @xmath231 & @xmath232 + 21 & 0.676776 & @xmath233 & @xmath234 & @xmath235 & @xmath236 the strong absorption centered at @xmath237 ( @xmath238 ) is blended with at @xmath239 associated with the absorption identified by @xcite at @xmath240 in the fos spectrum , which we confirmed in the stis spectrum . prior to vp fitting the complex , we deblended the @xmath237 feature using vp modeling and employing both the cos and stis isfs . in figure [ fig : deblend]@xmath44 , we present the vp fits at @xmath241 . the flux decrement of the vp model was then subtracted from that of the @xmath237 absorption from the complex . the resulting deblended profile is illustrated in figure [ fig : deblend]@xmath152 . prior to and following the deblending process , we experienced difficulty obtaining a satisfactory simultaneous fit to the and absorption in the @xmath237 feature . though the deblending provided an improved vp model , we caution that the number of vp components and the resulting column densities and doppler @xmath152 parameters we adopted should be viewed with discretion ( see comments for table [ tab : hiresult ] ) . we examined the cos , stis , and hires quasar spectra for associated metal - line transitions , including the , , , and zero - volt resonance doublets , and transitions from , , , , etc . in figure [ fig : metals ] , we present the wavelength regions of the quasar spectra corresponding to detected metal lines @xmath242 ( cos ) , ( stis ) , and ( cos ) . we also show the absorption over the same velocity range . vp components # 7 through # 11 are shown , where the `` cloud '' number is given in column 1 of table [ tab : hiresult ] . only clouds # 7 , # 8 , and # 10 have detected metals . in paper i , we reported no detected metal absorption in ( stis ) and ( fos ) . however , we clearly detected absorption in the cos spectrum in the velocity range @xmath243 relative to @xmath17 . we also detected @xmath244 absorption at @xmath245 . we then re - examined the absorption , and formally detected @xmath246 aligned in velocity with the and absorption . the @xmath247 absorption , which we had interpreted as noise in paper i , is detected at the @xmath248 level . in figure [ fig : metals ] , the curves through the data are fitted vp components . for these fits , we modified minfit to hold the vp component redshifts ( velocities ) and doppler @xmath152 parameters constant , allowing only the column densities to be @xmath151 minimized , and fitted the metal lines using the velocities and doppler @xmath152 parameters from the vp fits to the lyman series lines . as with the fits described above , the cos isf @xcite and the stis isf @xcite appropriate for the spectrograph settings and the observed wavelength of each transition was determined via interpolation of the on - line tabulated data . when a vp component column density was objectively determined to be insignificant , minfit returned an upper limit . several tests for significance were conducted during the least - square fitting convergence ; in short , for a column density to be deemed significant , the fitted vp value and its uncertainty had to be inconsistent with the upper limit on the column density ( in that precise region of the spectrum and for that doppler @xmath152 parameter ) , and the integrated apparent optical depth @xcite had to be consistent with the vp component and inconsistent with the the upper limit on the column density . in table [ tab : metals ] , we list the metal - line absorption properties for all clouds . in minfit , the equivalent width limits are determined directly from the spectra using the methods of @xcite and @xcite , but modified for partially or fully resolved features ( see * ? ? ? * ) . for each transition , we use the doppler @xmath152 parameter from the vp fit to the series convolved with the appropriate isf to measure the upper limit on the equivalent width in each cloud . the uncertainty in the doppler @xmath152 width is used to determine the @xmath249 spread in this limit . the column density limits and the @xmath250 spread in these are determined from the curve of growth . we employed our own photo+collisional ionization code @xcite , which is very similar to the code linespec @xcite . the code treats photoionization , auger ionization , direct collisional ionization , excitation - autoionization , photo - recombination , high and low temperature dielectronic recombination , charge transfer ionization by h@xmath251 , and charge transfer recombination by h@xmath252 and he@xmath252 . metals up to zinc can be incorporated , and all ionization stages for each elemental species are modeled . the code is appropriate for optically thin gas in which no ionization structure is present . lcrrrrrrr 1 & 0.668645 & @xmath153 & @xmath253 & @xmath254 & @xmath255 & @xmath256 & @xmath257 & @xmath258 + 2 & 0.668861 & @xmath157 & @xmath259 & @xmath260 & @xmath261 & @xmath262 & @xmath263 & @xmath264 + 3 & 0.669000 & @xmath161 & @xmath265 & @xmath266 & @xmath267 & @xmath268 & @xmath269 & @xmath270 + 4 & 0.669112 & @xmath165 & @xmath271 & @xmath272 & @xmath273 & @xmath274 & @xmath275 & @xmath276 + 5 & 0.669199 & @xmath169 & @xmath277 & @xmath278 & @xmath279 & @xmath280 & @xmath281 & @xmath282 + 6 & 0.669290 & @xmath173 & @xmath283 & @xmath284 & @xmath285 & @xmath286 & @xmath287 & @xmath288 + 7 & 0.671203 & @xmath177 & @xmath289 & @xmath290 & @xmath291 & @xmath292 & @xmath293 & @xmath294 + 8 & 0.671244 & @xmath181 & @xmath295 & @xmath296 & @xmath297 & @xmath298 & @xmath299 & @xmath300 + 9 & 0.671617 & @xmath185 & @xmath301 & @xmath302 & @xmath303 & @xmath304 & @xmath305 & @xmath306 + 10 & 0.671739 & @xmath189 & @xmath307 & @xmath308 & @xmath309 & @xmath310 & @xmath311 & @xmath312 + 11 & 0.672319 & @xmath193 & @xmath313 & @xmath314 & @xmath315 & @xmath316 & @xmath317 & @xmath318 + 12 & 0.672994 & @xmath197 & @xmath319 & @xmath320 & @xmath321 & @xmath322 & @xmath323 & @xmath324 + 13 & 0.673291 & @xmath201 & @xmath325 & @xmath326 & @xmath327 & @xmath328 & @xmath329 & @xmath330 + 14 & 0.673562 & @xmath205 & @xmath331 & @xmath332 & @xmath333 & @xmath334 & @xmath335 & @xmath336 + 15 & 0.673787 & @xmath209 & @xmath337 & @xmath338 & @xmath339 & @xmath340 & @xmath341 & @xmath342 + 16 & 0.674297 & @xmath213 & @xmath343 & @xmath344 & @xmath345 & @xmath346 & @xmath347 & @xmath348 + 17 & 0.674872 & @xmath217 & @xmath349 & @xmath350 & @xmath351 & @xmath352 & @xmath353 & @xmath354 + 18 & 0.675272 & @xmath221 & @xmath355 & @xmath356 & @xmath357 & @xmath358 & @xmath359 & @xmath360 + 19 & 0.675789 & @xmath225 & @xmath361 & @xmath362 & @xmath363 & @xmath364 & @xmath365 & @xmath366 + 20 & 0.676366 & @xmath229 & @xmath367 & @xmath368 & @xmath369 & @xmath370 & @xmath371 & @xmath372 + 21 & 0.676776 & @xmath233 & @xmath373 & @xmath374 & @xmath357 & @xmath375 & @xmath376 & @xmath377 the input cloud parameters are the hydrogen number density , , equilibrium kinetic temperature , @xmath378 , and the mass fraction of metals , @xmath379 . solar abundance mass fractions are taken from table 1.4 of @xcite , based upon @xcite , though the code has the option of modifying the relative abundances . a @xcite ionizing spectrum is used for the ultraviolet background ( uvb ) . however , a stellar ionizing spectrum or a combined stellar plus uvb ionizing spectrum can be incorporated ( see * ? ? ? * for details ) . the code obtains an initial guess solution for the density of each ionic species based upon the assumption of adjacent ion stage ionization and recombination balance ( i.e. , neglecting auger and charge transfer processes ) . then , the rate matrix is solved using the code dqed.f , a hanson / krogh nonlinear least squares algorithm with linear constraints based on quadratic - tensor local model @xcite . the outputs of the ionization code are the electron density , and the ionization and recombination rate coefficients , ionization fractions and the number densities for all ionic species . since the galaxy g1 is 58 kpc from the location where the gas is probed in absorption , and the stellar population is clearly dominated by red stars , we assume a uvb - only ionizing spectrum . we also assume a solar abundance pattern and include metals up to iron ( however , we omitted lithium , beryllium , boron , fluorine , and the nobel gas elements for which many of the ionization and recombination rates are not well determined ) . for a given cloud model , the resulting column density of ionic species x is obtained by @xmath380 where @xmath381 is the column density from the vp fit to the data , is the input hydrogen density of the cloud model , and where @xmath382 is the ionization fraction of h@xmath383 and @xmath384 is the number density of ionic species x output by the code , respectively . note that the metallicity of the model is implied . in practice , @xmath384 in a given model scales directly in proportion to @xmath379 . thus , if the metallicity of the cloud model is @xmath385 , for which the resulting density of species x is @xmath386 , then @xmath387 . for a given , such scaling of the models is valid only if @xmath382 is independent of metallicity , which holds for @xmath388 . comparing eq . [ eq : colden ] to the measured values of @xmath389 from our vp fitting , we can constrain the metallicity and of each cloud . the range in these constrained quantities are based upon the @xmath249 uncertainties in the measured column densities . only three clouds have detected metal lines and therefore measured @xmath390 . these clouds are # 7 , # 8 , and # 10 . we examine these clouds in the following subsections . clouds # 7 and # 8 are located at @xmath391 with respect to the systemic velocity of g1 and are separated by @xmath392 , which is on the order of half a single resolution element . the profile is highly suggestive of a narrow plus a broad component combining to yield a deep core with a broad wing . the vp components reflect this profile shape , with cloud # 7 providing the profile core , @xmath393 and @xmath394 , and with cloud # 8 providing the broadened wings , @xmath395 and @xmath396 . the requirement for the broader cloud is significant at the 99% confidence level , even though some contribution to the blue portion of the broad wing is due to the extremely broad vp component ( cloud # 11 ) at @xmath397 . at @xmath391 , , and are formally detected in the spectra . however , from the vp fitting , both clouds # 7 and # 8 have associated and , whereas only cloud # 7 has associated . inspection of figure [ fig : metals ] shows that the absorption appears to be offset in velocity from the . however , the is measured in the stis spectrum , whereas the and are measured in the cos spectrum . thus , the measured velocity offset relies heavily on the accuracy of the wavelength zero points between the two independent spectra . assuming thermal broadening , the implied temperature of cloud # 7 is 8000 k , which is too cool to host strong and absorption . the implied temperature of cloud # 8 is @xmath398 k , which is consistent with the temperature at which absorption peaks for collisional ionization equilibrium . to analyze this absorption structure and constrain its hydrogen density and metallicity , we opted to assume a single phase of gas that is dominated by cloud # 8 ( however , in [ sec : hydroeq ] we also model these clouds as two distinct ionization phases ) . we added the and metal column densities from clouds # 7 and # 8 . for this exercise , we found that the column density limits for , , and did not contribute to constraining the gas properties . in figure [ fig : cloud78 ] , we illustrate our analysis of clouds # 7 + 8 . the ionization code was run for @xmath399 for @xmath400 k , and for @xmath401 and @xmath402 , which brackets the @xmath249 uncertainty in the temperature . in figure [ fig : cloud78]@xmath44 , we illustrate the model column densities for , , and for @xmath403 and metallicity @xmath404 . in figure [ fig : cloud78]@xmath152 , we show the metallicity constraints as a function of for each metal ion , where the range in the constraints are based on the uncertainty in the temperature and the uncertainty in the and metal ion column densities . the region of overlap indicates where the three ions provide consistent constraints on and @xmath405 . allowing for the uncertainties in the data , the gas is constrained to have @xmath406 and @xmath407 by all three metal ions . note that metallicity is contrained primarily by @xmath408 , whereas hydrogen density is constrained primarily by @xmath409 . cloud # 10 is located at @xmath410 with respect to the systemic velocity of g1 . it is optically thin in neutral hydrogen , with @xmath411 and an implied temperature of @xmath412 k. the only detected metal line absorption is from , with @xmath413 . a high abundant the o@xmath414 ion in a @xmath415 k cloud may be somewhat surprising . for @xmath416 and @xmath417 , analysis of the rate coefficients output by the ionization code show that the balance of o@xmath418 , o@xmath414 , and o@xmath419 is dominated by photoionization and recombination via charge exchange with h@xmath251 , which dominates over free electron recombination by 2 orders of magnitude for o@xmath414 . for cloud # 10 , the measured upper limit on is @xmath420 and on is @xmath421 . as with with our exercise for clouds # 7 + 8 , we found that the column density limits for , , and did not contribute to constraining the gas properties . in figure [ fig : cloud10 ] , we illustrate our analysis of cloud # 10 . the ionization code was run for @xmath422 for @xmath415 k. in figure [ fig : cloud10]@xmath44 , we show the column densities for , , and for @xmath423 and metallicity @xmath424 . the metallicity and hydrogen density constraints for cloud # 10 are shown in figure [ fig : cloud10]@xmath152 . if we account for the uncertainty in the implied temperature , we find that for @xmath425 k , the curves in figure [ fig : cloud10]@xmath152 are unchanged for @xmath426 , and are shifted upward in the diagram by no more than 0.7 dex ( higher @xmath379 at a given ) for @xmath427 . as temperature is decreased , the curves shift to the upper right in the diagram such that at @xmath428 k , a minimum metallicity in the allowed range @xmath429 occurs at @xmath430 instead of @xmath431 at @xmath432 . it seems less likely that absorption would be as strong as we detect in 12,000 degree gas . the remainder of the absorption complex is characterized by multiple components with gas temperatures in the range 20,00090,000 k , though a hot , nearly million degree component is also present ( cloud # 11 ) . for the clouds with no detected metals , the densities , ionization corrections , and therefore metallicities can not be constrained without additional assumptions . in [ sec : hydroeq ] , we assume hydrodynamic equilibrium and undertake an analysis of the clouds with only upper limits on the metal line column densities . below , we motivate the assumption of hydrodynamic equilibrium as a reasonable scenario . in general , ionization equilibrium is valid when the collisional ionization time scale , @xmath433 , and the photoionization time scale , @xmath434 , are shorter than the cooling time of the gas , @xmath435 . for a monatomic gas , the cooling time is the ratio of the energy per unit volume and the energy loss per unit volume per unit time , @xmath436 , where @xmath437 is the electron density , @xmath438 is the total density of all ions , and @xmath439 is the specific cooling function for metallicity @xmath379 . we obtain @xmath437 and @xmath438 from our ionization code as a function of and @xmath378 . our cloud models are optically thin , such that @xmath440 and @xmath441 at a given @xmath378 , we thus find that the behavior of the cooling time follows @xmath442 at fixed @xmath378 . we adopt the @xmath443 specific cooling function of @xcite for a gas in collisional ionization equilibrium ( also see * ? ? ? since our models include photoionization , we corrected for photoionization heating ( see * ? ? ? * ) , which reduces the magnitude of @xmath444 , and therefore increases the estimated cooling time . we found that photoionization heating from the uvb at @xmath445 is negligible for the density and temperatures ranges we explored . metals strongly contribute to the cooling rate , so the @xmath443 curve provides an upper limit on the estimated cooling time under the assumption of ionization equilibrium . however , the effect is negligible for @xmath446 and is a maximum difference of 0.4 dex at @xmath447 for @xmath448 ( see * ? ? ? * ) . for a given ion , the collisional time scale is well approximated as @xmath449 $ ] , whereas the photoionization time scale is @xmath450 , where @xmath451 and @xmath452 are the recombination and collisional ionization rate coefficients , and @xmath453 is the photoionization rate for the given ion , respectively . we obtain these quantities directly from our ionization code . since @xmath454 at a given @xmath378 , we have @xmath455 at fixed @xmath378 . thus , the ratio @xmath456 is effectively constant as a function of for fixed temperature . note that for lower temperatures , @xmath452 vanishes so that @xmath457 becomes equal to the recombination time scale , @xmath458 . lcrrrrrrrrrrrrrc 7 + 8 & 14.30 & 5.06 & @xmath459 & @xmath460 & @xmath461 & @xmath462 & 9.40 & 5.70 & 10.01 & 11.71 & 4.43 & 15.84 & 2.73 & 10.72 & ju + 7 + 8 & 14.30 & 5.06 & @xmath463 & @xmath464 & @xmath461 & @xmath462 & 8.40 & 4.70 & 9.51 & 9.78 & 2.51 & 11.05 & 2.23 & 10.22 & ju + 7 + 8 & 14.30 & 5.06 & @xmath465 & @xmath466 & @xmath461 & @xmath462 & 7.40 & 3.70 & 9.01 & 8.19 & 0.91 & 7.27 & 1.73 & 9.72 & ee + 10 & 13.70 & 4.31 & @xmath459 & @xmath467 & @xmath468 & -@xmath469 & 8.13 & 8.75 & 10.01 & 10.88 & 3.23 & 12.22 & 2.36 & 9.60 & ju + 10 & 13.70 & 4.31 & @xmath463 & @xmath470 & @xmath468 & -@xmath469 & 7.13 & 7.76 & 9.51 & 8.88 & 1.23 & 7.22 & 1.86 & 9.10 & ee + 10 & 13.70 & 4.31 & @xmath465 & @xmath471 & @xmath468 & -@xmath469 & 6.14 & 6.77 & 9.01 & 6.89 & @xmath472 & 2.25 & 1.36 & 8.60 & ee + 11 & 13.43 & 5.68 & @xmath459 & @xmath473 & @xmath474 & @xmath475 & 10.86 & 4.99 & 10.01 & 11.13 & 4.17 & 15.03 & 3.04 & 11.65 & ju + 11 & 13.43 & 5.68 & @xmath463 & @xmath476 & @xmath474 & @xmath475 & 9.86 & 3.99 & 9.51 & 9.39 & 2.43 & 10.81 & 2.54 & 11.15 & ee + 11 & 13.43 & 5.68 & @xmath465 & @xmath477 & @xmath474 & @xmath475 & 8.86 & 2.99 & 9.01 & 8.14 & 1.17 & 8.04 & 2.04 & 10.65 & ee + 15 & 13.68 & 4.95 & @xmath459 & @xmath478 & @xmath479 & @xmath480 & 9.06 & 5.92 & 10.01 & 11.05 & 3.72 & 13.69 & 2.68 & 10.56 & ju + 15 & 13.68 & 4.95 & @xmath463 & @xmath481 & @xmath479 & @xmath480 & 8.06 & 4.92 & 9.51 & 9.10 & 1.77 & 8.84 & 2.18 & 10.06 & ee + 15 & 13.68 & 4.95 & @xmath465 & @xmath482 & @xmath479 & @xmath480 & 7.06 & 3.93 & 9.01 & 7.40 & 0.07 & 4.73 & 1.68 & 9.56 & ee + 18 & 14.26 & 4.84 & @xmath459 & @xmath483 & @xmath484 & @xmath485 & 9.06 & 6.20 & 10.01 & 11.59 & 4.20 & 15.14 & 2.62 & 10.40 & ju + 18 & 14.26 & 4.84 & @xmath463 & @xmath486 & @xmath484 & @xmath485 & 8.06 & 5.20 & 9.51 & 9.62 & 2.23 & 10.23 & 2.12 & 9.90 & ju + 18 & 14.26 & 4.84 & @xmath465 & @xmath487 & @xmath484 & @xmath485 & 7.06 & 4.21 & 9.01 & 7.82 & 0.43 & 5.82 & 1.62 & 9.40 & ee + 20 & 13.10 & 4.41 & @xmath459 & @xmath488 & @xmath489 & -@xmath490 & 8.41 & 8.05 & 10.01 & 10.30 & 2.70 & 10.63 & 2.41 & 9.75 & ju + 20 & 13.10 & 4.41 & @xmath463 & @xmath491 & @xmath489 & -@xmath490 & 7.41 & 7.05 & 9.51 & 8.30 & 0.70 & 5.63 & 1.91 & 9.25 & ee + 20 & 13.10 & 4.41 & @xmath465 & @xmath492 & @xmath489 & -@xmath490 & 6.41 & 6.07 & 9.01 & 6.32 & @xmath493 & 0.69 & 1.41 & 8.75 & ee in what follows , we briefly explore selected clouds using representative densities for the purpose of illustration . in table [ tab : cldphys ] , we present a summary of cloud models for the values @xmath494 , @xmath495 , and @xmath496 , where ion specific quantities apply for hydrogen . the hydrogen photoionization rate from the uvb at @xmath445 is @xmath497 s@xmath38 , yielding @xmath498 yr . as we shall see , the photoionization time is significantly shorter than the cooling times for all models ; as such , only the longer collisional time scales constrain whether the clouds are in ionization equilibrium . for clouds # 7 + 8 , at @xmath400 k , @xmath499 and @xmath500 @xmath501 s@xmath38 , respectively . assuming @xmath502 , we obtain @xmath503 yr and @xmath504 yr . with @xmath505 , hydrogen is clearly in ionization equilibrium in clouds # 7 + 8 ; the short photoionization and collisional ionization time scales relative to the recombination time scale are indicative of the highly ionized condition ( @xmath506 ) . the condition @xmath507 indicates photoionization marginally dominates over collisional ionization . for cloud # 10 , at @xmath415 k , @xmath508 and @xmath509 @xmath501 s@xmath38 . this cloud is constrained to have @xmath510 ; assuming @xmath494 , we obtain @xmath511 yr and @xmath512 yr . for this assumed density , we find @xmath513 , suggesting that ionization equilibrium may be marginal in cloud # 10 for hydrogen ( the gas temperature evolves on a similar time scale that the balance can be achieved ) . as listed in table [ tab : cldphys ] , the thermal time scale is shorter than the ionization time scale for the presented range of . for cloud # 11 , the hot , @xmath514 k , cloud , we have @xmath515 and @xmath516 @xmath501 s@xmath38 . for @xmath517 and @xmath518 , we obtain @xmath519 yr , and @xmath520 yr , where the longer times correspond to the lower density . cloud # 11 has @xmath521 , indicating an ionization equilibrium condition . note that if @xmath522 , we have @xmath523 , indicating that hydrogen ionization ( @xmath524 ) is driven by both photo and collisional processes . if @xmath525 , then @xmath526 , which is dominated by photoionization ( @xmath527 ) ; the larger ratio due to the longer recombination time scale results in a higher ionization condition for this lower density . with regard to the remaining clouds in the complex with only limits on the metal line measurements , we selected clouds # 15 [ @xmath528 , # 18 [ @xmath529 , and # 20 [ @xmath530 as representative . of clouds with no detected metals , # 15 has the highest temperature and an intermediate @xmath381 as compared to all clouds in the complex . cloud # 20 has the lowest temperature and the smallest @xmath381 , and cloud # 18 has an intermediate temperature and the highest @xmath381 . the models , for hydrogen , are given in table [ tab : cldphys ] . note that @xmath531 for these representative clouds , indicating the validity of ionization equilibrium . for strict ionization equilibrium to hold , the ionization time scales must be smaller than the cooling time for all ions . the same arguments invoked for hydrogen above apply to the metals . consider the o@xmath414 ion ; the photoionization rate from the uvb at @xmath445 is @xmath533 s@xmath38 , which yields @xmath534 yr . for clouds # 7 + 8 , at @xmath400 k , @xmath535 and @xmath536 are @xmath537 and @xmath538 @xmath501 s@xmath38 , respectively . for @xmath539 , we obtain @xmath540 yr , where both scale in proportion to @xmath541 . we thus have @xmath542 independent of , indicating that the o@xmath414 ion is marginally in ionization equilibrium . similarly , we find @xmath543 for c@xmath532 . for cloud # 10 , at @xmath415 k , @xmath544 @xmath501 s@xmath38 and @xmath536 is negligible , indicating that collisional processes have vanishing importance in the ionization balance of o@xmath414 . for @xmath494 , we obtain @xmath545 yr . for all densities , we have @xmath546 . similarly , for c@xmath532 , we find @xmath547 . as with hydrogen , ionization equilibrium may be marginal for cloud # 10 for o@xmath414 and c@xmath532 . for cloud # 11 , at @xmath548 , we have @xmath549 and @xmath550 @xmath501 s@xmath38 for o@xmath414 . when @xmath517 , and @xmath518 , we obtain @xmath551 yr , where the longer times correspond to the lower density . we have @xmath552 for which o@xmath414 is predominantly in collisional equilibrium , i.e. , @xmath553 if @xmath554 , and roughly equally balanced by photo and collisional equilibrium , i.e. , @xmath555 for @xmath494 . for c@xmath532 , we obtain @xmath556 . cloud # 11 is clearly in ionization equilibrium . for clouds # 15 , # 18 , and # 20 , we find @xmath557 , @xmath558 , and @xmath559 , respectively for o@xmath414 . for c@xmath532 , we find @xmath560 , @xmath561 , and @xmath562 , respectively . for these clouds , o@xmath414 is marginally in ionization equilibrium , whereas c@xmath532 is marginally not in equilibrium . note that the cooling times are 13 orders of magnitude shorter than the hubble time , @xmath563 yr , except for cloud # 11 for @xmath564 ( recall that the cooling time scales inversely with for fixed @xmath378 ) . this would indicate that the cloud thermal conditions have evolved ; however it is not possible to estimate the thermal histories of the clouds beyond speculating that they were hotter ( and presumably less dense ) at @xmath565 . for @xmath566 and for @xmath567 , the cooling time increases toward higher temperatures , so we can infer that the thermal evolution of clouds in these temperature was slower at epochs prior to @xmath445 assuming the cloud densities have not strongly evolved . in view of the inferred thermal evolution of the absorbing clouds , it is interesting to examine their dynamical stability . this can be achieved by comparing the cloud dynamical and sound crossing time scales . additionally , it would be of interest to estimate the cloud sizes and masses . to within a dimensionless factor of order unity , the dynamical time ( see * ? ? ? * ) , or free - fall time , of a cloud with total mass density @xmath568 , is @xmath569 , where @xmath570 is the atomic weight of hydrogen , @xmath571 is the atomic mass unit , @xmath572 is the mass fraction of hydrogen . a low metallicity primordial abundance pattern has @xmath573 , which yields a 5% difference in @xmath574 . ] and @xmath575 is the fraction of the baryonic mass in gas . evaluating , we have @xmath576 yr . the sound crossing time is @xmath577 , where @xmath578 is the physical length scale of the cloud and the sound speed is @xmath579 , where @xmath580 is the gas pressure , @xmath581 for an ideal monatomic gas , and @xmath37 is the mean molecular weight . our ionization models indicate that the clouds are highly ionized , so we assume @xmath582 , appropriate for a fully ionized gas with @xmath583 . we thus obtain , @xmath584 yr , when @xmath578 is given in kpc . the `` absorption '' length scale of the cloud can be estimated as the line of sight path length required to give rise to the measured @xmath381 for the inferred from the ionization models , @xmath585 . assuming spherical geometry , the gas mass of the cloud is crudely estimated from @xmath586 m@xmath118 when @xmath578 is given in kpc . a spherical geometry with unity volume filling factor is likely a very poor model , and one which will significantly overestimate the cloud mass . if the absorber geometry is cylindrical of length @xmath578 and radius @xmath587 with aspect ratio @xmath588 , then @xmath589 if the line of sight probes parallel to @xmath578 . it is well established based on observational and theoretical grounds , that in general , forest clouds can not be pressure confined @xcite . @xcite convincingly argues that clouds which develop due to the gravitational influence of underlying dark matter density perturbations persist in a near hydrodynamic equilibrium state _ local to the region giving rise to the absorption_. effectively , this is equivalent to stating that the dynamical time is equal to the sound crossing time , @xmath590 , consequently implying that the characteristic length of the _ absorbing region _ will be on the order of the local jean s length , @xmath591 ( see * ? ? ? equating @xmath592 and @xmath593 , the jean s length is @xmath594 kpc , from which the jean s gas mass , usually applies to the total mass . if the gas fraction , @xmath595 , in these clouds is near the cosmic mean , then gas mass and total mass are related by @xmath596 . ] can be estimated , @xmath597 m@xmath118 . for @xmath598 the condition is @xmath599 ; the cloud is jean s unstable to further gravitational contraction and will adjust on the dynamical time scale via fragmentation or due to shock processes . conversely , for @xmath600 the condition is @xmath601 , and the cloud will adjust in the sound crossing time scale , either via evaporation or expansion @xcite . the criterion assumes that the cloud is isolated , spherical , homogeneous , and exhibits no bulk motions . the dynamical and sound crossing times , deduced cloud sizes and cloud gas masses are listed in table [ tab : cldphys ] for cloud # 7 + 8 , # 10 , # 11 , and the representative clouds # 15 , # 18 , and # 20 for @xmath602 , @xmath495 , and @xmath518 . as described above , cloud # 7 + 8 is well constrained to have @xmath603 , whereas cloud # 10 and the remaining clouds with only limits on the metal line column densities are not well constrained . for @xmath604 , @xmath495 , and @xmath518 , we obtain @xmath605 , @xmath606 , and @xmath607 yr , respectively . note that @xmath608 , whereas @xmath609 , and @xmath610 . the relative behavior of these times scales is such that a transition from @xmath611 to @xmath612 occurs as increases . this indicates that for larger , the clouds have a propensity to be in the regime of jean s instability , whereas as for smaller , the clouds become unstable to evaporation and expansion . the last column of table [ tab : cldphys ] notes whether a cloud model is inferred to be jean s unstable ( ju ) or unstable to expansion and/or evaporation ( ee ) . the behavior with suggests that between @xmath613 there is a density at which the clouds would classify as being in hydrodynamic equilibrium . this is also reflected in the behavior of the jean s lengths , @xmath591 , which would be equivalent to the absorption length scales , @xmath578 , when @xmath614 . note that the absorption scale lengths , @xmath578 , and the cloud gas masses , @xmath615 , become unphysically large as hydrogen density decreases . this would suggest that the clouds have @xmath616 , though we caution that the masses are probably overestimates due to the assumption of a spherical geometry . if more akin to cylindrical structures , viewed along the long axis , a factor of @xmath617 reduces the masses by two orders of magnitude . however , the absorption length scale along the line of sight is independent of geometry . in view of the arguments given by @xcite that clouds should be in the regime of hydrostatic equilibrium , and in view of the unphysically large cloud scale lengths we deduce in the regime of jean s instability , it is reasonable to explore the inferred cloud conditions under the assumption of hydrodynamic equilibrium . this assumption will yield an equilibrium value for , from which the ionization conditions and metallicities can be constrained . equating the dynamical time and the sound crossing time , and invoking the absorption scale length , @xmath618 , we derive the condition of hydrodynamic equilibrium , @xmath619 ^ 2 = g a_{\hbox{\tiny h } } \mu m^2_{\rm a } \ , [ n({\hi})]^2 \ , , \label{eq : hydroeq}\ ] ] where @xmath381 and @xmath378 are measured from the vp fit models to the profiles , and @xmath620 and are computed using ionization models of the clouds . since the hydrogen ionization fraction is a function of @xmath621 , eq . [ eq : hydroeq ] is a transcendental equation and must therefore be solved numerically for the equilibrium hydrogen density for a cloud with temperature @xmath378 . for each cloud , we interpolate a grid of ionization models with metallicity @xmath622 for @xmath623 in steps of @xmath624 and @xmath625 in steps of @xmath626 . we set @xmath378 equal to the measured cloud temperature ( based upon the doppler @xmath152 parameter from the vp fits ) , interpolate to obtain @xmath620 as a function at that @xmath378 , and iterate using brent s method to locate the @xmath621 that satisfies eq . [ eq : hydroeq ] to a tolerance @xmath627 . the method assumes that @xmath620 is independent of metallicity ( which we verified for @xmath628 ) . for this exercise , we treat clouds # 7 and # 8 separately ( i.e. , as a multiphase structure as opposed to a single - phase cloud as done in [ sec : clds78 ] ) . we also omit cloud # 9 , which has a very uncertain doppler @xmath152 parameter in that its temperature is consistent with @xmath629 k. once eq . [ eq : hydroeq ] is satisfied , the cloud absorption scale length , @xmath578 , can be computed , from which the cloud gas mass can be estimated . note that these quantities , while determined from the measured @xmath381 and @xmath378 as constrained by the ionization models , will be equivalent to the jean s length and jean s gas mass for the equilibrium @xmath621 . for each cloud , the uncertainty in the equilibrium @xmath630 and @xmath382 are obtained by accounting for the measured uncertainties in both @xmath381 and @xmath378 from the vp fits . the uncertainties in @xmath578 account for the uncertainties in @xmath381 , , and @xmath382 . the uncertainties in @xmath615 account for the uncertainties in @xmath574 ( due to @xmath621 ) and @xmath578 . once the equilibrium values are determined , the cloud metallicities and their uncertainties can be estimated from the equilibrium ionization cloud model . denoting this metallicity as @xmath379 ( in solar units ) , we have @xmath631 _ { \hbox{\tiny vp } } + \log \left [ \frac{z_{\rm m } f_{\hbox{\tiny hi}}\hbox { \hden}}{n_{\hbox{\tiny x } } } \right ] _ { \rm eq } \ , , \label{eq : metaleq}\ ] ] where @xmath381 is the measured neutral hydrogen column density obtained from the vp fit to the data , @xmath389 is the measured or upper limit on the column density species x from the vp modeling , and @xmath384 is the number density of species x from the ionization model for the equilibrium @xmath382 and and the model metallicity @xmath385 . that is , we scale the equilibrium ionization model with @xmath385 to obtain @xmath379 and an estimate of its uncertainty . in figure [ fig : equilib ] , we present the deduced cloud properties under the assumption of hydrodynamic and ionization equilibrium . solid data points satisfy the condition of hydrogen ionization equilibrium , whereas open data points do not . the measured @xmath381 and @xmath378 are shown in panels [ fig : equilib]@xmath44 and [ fig : equilib]@xmath152 , respectively . the equilibrium and @xmath382 are presented in panels [ fig : equilib]@xmath632 and [ fig : equilib]@xmath45 , respectively . note that , as suggested by the analysis presented in table [ tab : cldphys ] , the clouds have @xmath633 and @xmath634 . the metallicities are plotted in figure [ fig : equilib]@xmath48 . except for clouds # 7 , # 8 , and # 10 , the metallicities are upper limits . for the assumption of single ionization phase clouds , each metal line provides a unique limit . the most stringent limits are presented , with the data point color coded by the ion that provides this best limit ( red for o@xmath414 , green for c@xmath532 , and blue for c@xmath635 ) . in general , the upper limits are @xmath636 . the measured values for clouds # 7 , # 8 , and # 10 are @xmath637 , @xmath638 , and @xmath639 , respectively . the absorption scale length ( which is equal to the jean s length under the assumption of hydrodynamic equilibrium ) , is shown in figure [ fig : equilib]@xmath51 for each cloud . the typical scale length is few hundred kpc , except for clouds # 2 , # 3 , # 4 , and # 5 , which have the lowest temperatures and thus relatively high densities and low ionization conditions . recall , that the vp fits for clouds # 1 through # 6 should be viewed with caution . the gas masses , @xmath615 , of the clouds ( which equal the jean s gas masses under the assumption of hydrodynamic equilibrium ) are presented in figure [ fig : equilib]@xmath50 . assuming spherical clouds , the gas masses are on the order of @xmath640-@xmath641 m@xmath118 , except for cloud # 11 , which has @xmath642 m@xmath118 . these mass estimates should be viewed as upper limits by as much as one to two orders of magnitude . cloud # 11 is the highest temperature cloud with the highest ionization condition . the larger mass is a result of the large scale length and the fact that the hydrogen density is relatively high , @xmath643 . the cooling time , @xmath644 , is presented in panel [ fig : equilib]@xmath51 . note that under the assumption of hydrodynamic equilibrium , the clouds have thermal stability in the order of 12 orders of magnitude shorter than the hubble time . the collisional time , @xmath645 , is presented in panel [ fig : equilib]@xmath52 . except for clouds # 10 and # 14 , the clouds are in ionization equilibrium . however , clouds # 2 through # 6 also may not be in ionization equilibrium ; we again remind the reader that the vp fits to these latter clouds are to be viewed with caution . the dynamical time ( which is equal to the sound crossing time under the assumption of hydrodynamic equilibrium ) , is presented in figure [ fig : equilib]@xmath646 for each cloud . in all cases , @xmath647 and @xmath593 are a factor of a few less than the hubble time , which is indicated by the dashed line . the values obtained from this exercise are in remarkable agreement with those predicted from the simple scaling relations proposed by @xcite for the assumption of hydrodynamic equilibrium . for comparison between the individual models of clouds # 7 and # 8 and the combined cloud # 7 + 8 modeled in [ sec : clds78 ] , we indicate the results of the latter analysis as dashed boxes on figure [ fig : equilib ] . for cloud # 7 + 8 , the measured column densities were summed , from which the density and metallicity were simultaneously constrained assuming a single ionization phase ( see figure [ fig : cloud78 ] ) . that analysis resulted in a slightly larger than the assumption of hydrodynamic equilibrium in the individual clouds , through the metallicities are consistent between analysis methods . the difference in is likely due to the adding of the column densities . we also compare the individual cloud equilibrium and the combined cloud @xmath578 , @xmath615 , @xmath644 , and @xmath647 @xmath645 , shown as the dashed boxes on panels [ fig : equilib]@xmath49@xmath646 . note that cloud # 7 has @xmath648 , where @xmath649 yr , indicating that the hydrogen in this cooler cloud is photoionized . on the other hand , cloud # 8 has @xmath555 for both hydrogen and o@xmath414 , and thus has a substantial collisional ionization contribution . cloud # 11 is of particular interest . this component is the hottest and most highly ionized , @xmath650 , cloud in the complex , and is among the highest density , @xmath651 , of the clouds . we find @xmath652 for hydrogen , and @xmath653 for o@xmath414 ; thus hydrogen is equally photo and collisionally ionized , whereas o@xmath414 , though not detected , is predominantly collisionally ionized . it is plausible that this cloud ( # 11 ) is shock heated gas , as further suggested by the fact that the deduced cooling time ( @xmath654 gyr ) is substantially longer than the deduced dynamical time ( @xmath655 gyr ) . crudely adopting the dynamical time as a proxy for the compression time ( e.g. , * ? ? ? * ; * ? ? ? * ) , and considering the temperature and ionization conditions , we find that cloud # 11 is the only component in the complex that is suggestive of shocked gas . the analysis we have presented has employed many simplifying assumptions . the vp fitting method philosophy assumes that the gas structure comprises several spatially distinct isothermal clouds . in fact , it is very possible that the complex is a quasi - continuous nonuniform structure with temperature and density variations having a range of bulk motions ( and possibly at least one shock front , i.e. , cloud # 11 ) . it is also plausible that such bulk motions can align in line of sight velocities creating caustics that emulate distinct clouds so that some vp components actually model a heterogeneous physical condition . furthermore , the analysis invoking the dynamical time , sound crossing time , and jean s mass and length is predicated on a homogeneous cloud . a cloud in thermodynamic equilibrium can not simultaneously be homogeneous and isothermal , as we have assumed here . in support of the assumption of hydrodynamic equilibrium , we note that @xcite argues that a spherical cloud with an isothermal density profile , i.e. , @xmath656 , has a well defined characteristic that is on the order of the maximum density probed by the line of sight . for the gas mass estimates , we have assumed spherical clouds , which is probably a very poor assumption . as such , the estimated gas masses should be considered upper limits . finally , the ionization modeling assumes photoionization and collisional ionization equilibrium , which we have shown to be a valid condition for the majority , but not all of the clouds . in addition , the metallicity estimates are based upon the assumption of single phase ionization conditions . if some of the plausible concerns expressed above with regard to heterogeneous physical conditions aligned in line of sight velocity hold , then multi - phase structure could be present that would affect the metallicity estimates . overall , the assumption of ionization equilibrium in single phase gas is critical to all deduced quantities , especially the metallicities and the thermal equilibrium values presented in [ sec : hydroeq ] . with a velocity extent of 1600 , the absorption complex at @xmath0 in the quasar q1317 + 277 is a most intriguing gaseous structure . absorption with velocity spreads on the order of @xmath657 occur in approximately 10 - 15% of quasars @xcite . in almost all cases , extreme absorption of this nature is produced by material ejected from the quasar itself ( i.e. , broad absorption line quasars ) ; however , the properties of the @xmath0 complex studied here are not suggestive of absorption `` associated '' with or `` intrinsic '' to the quasar . for example , the exhibits no evidence of partial covering , which is an adopted signature of associated gas @xcite . furthermore , the kinematics of the metals absorption lines are kinematically similar to the velocity spreads observed in galaxy halos @xcite . thus , the complex is likely inervening absorption . early on , @xcite suggested that the environments of galaxy clusters may give rise to extensive , intervening broad absorption line complexes , but few potential candidates have been identified . in this section , we summarize and further examine the nature and environment of the @xmath0 complex toward q1317 + 277 , compare it to other similar complexes , and discuss the possible origin of the q1317 + 277 complex , such as hot - mode or cold - mode accretion , galactic winds , accreting filaments , intracluster gas , and/or the warm - hot phase of the intergalactic medium ( whim ) . the q1317 + 277 complex at @xmath0 is characterized by a velocity spread of 1600 and 21 components with @xmath658 , as determined by voigt profile fitting . under the assumption that the components ( clouds ) are near hydrodynamic equilibrium , the temperatures , hydrogen number densities , and hydrogen ionization fractions primarily range between @xmath659 k , @xmath660 , and @xmath661 . the deduced cloud sizes are on the order of 200 kpc , and the cloud baryonic gas masses range between @xmath662@xmath641 m@xmath118 . because the gas masses scale as @xmath663 , the large masses result from the low hydrogen number densities and the high ionization conditions of the clouds . the metallicities are measured only for clouds # 7 , # 8 , and # 10 and are @xmath664 , @xmath665 , and @xmath666 , respectively . upper limits on the remaining clouds are @xmath667 to @xmath636 . the limits on the cloud metallicities do not rule out enrichment at the level of the high redshift igm ( e.g. , * ? ? ? * ; * ? ? ? on the other hand , the low metallicities are 12 orders of magnitude below the @xmath668 metallicities measured in @xmath669 x - ray clusters @xcite . further insight is gained by examination of the kinematic - ionization substructure . near the velocity center of the complex , at @xmath670 with respect to the galaxy g1 , is a hot @xmath671 k , collisionally ionized component ( cloud # 11 ) , which is very likely shocked gas . the narrow velocity region just blueward of cloud # 11 comprises four clouds , within which the only metal lines are detected . the general overall absorption morphology of these four components ( clouds # 710 ) , is that of a double profile suggesting two absorbing structures contiguous in velocity space . cloud # 10 , separated by @xmath672 from cloud # 11 , has detected absorption , which is deduced to arise in cool @xmath67330 k photoionized gas . clouds # 7 and # 8 , which have detected , , and absorption , give rise to a single profile , which is best modeled with a narrow core ( cloud # 7 , cool photoionized gas with @xmath674 k ) and a broad component ( cloud # 8 , hot collisionally ionized gas with @xmath675 k ) . the velocity centroids are separated by less than half of a single cos spectral resolution element of @xmath676 . in addition , cloud # 9 appears to be a very narrow ( @xmath677 k ) blue wing of cloud # 10 offset by @xmath678 that overlaps with the red wing of cloud # 8 . these substructures may be suggestive of clouds moving through a hot , @xmath679 k , medium in which a conductive interfaces arises at the boundary between the cool , warm , and hot gas ( e.g. , * ? ? ? * ) . knowing the environment of the complex and relationship to galaxies would be instrumental for a broader interpretation . the proximate galaxy is g1 , which lies at @xmath2 kpc from the quasar line of sight and has a redshift very near the mean of the complex . the virial mass of galaxy g1 is estimated to be within a factor of two of the virial mass of m87 ( @xmath680 , * ? ? ? * ) , suggesting that galaxy g1 could be a central galaxy in a virgo - like cluster . however , we find no clearly compelling evidence that g1 resides in a galaxy cluster or in a group with an x - ray emitting intracluster medium . a search of the nasa extragalactic database ( ned ) and simbad database yielded no reported x - ray measurements of q1317 + 277 . within @xmath681 of q1317 + 277 , there are no sources in the rosat all - sky survey bright source catalog @xcite . of the five closest x - ray sources that are not identified either as a star or an agn / quasar ( which have known redshifts ) , one ( 1rxs j131954.5 + 253210 ) lies at @xmath682 from q1317 + 277 ( 50 mpc projected at @xmath0 ) . the bright @xmath683 galaxy identified within 29 of the x - rays would be 2 mpc projected from this source at @xmath0 . if the x - ray source is associated with this galaxy , it is likely that the galaxy and x - ray source reside at a redshift much lower than the complex . in the rosat hr1 band , a minimum of 0.04 cnts s@xmath38 is required for a source to be included in the rosat catalog . applying this upper limit , and invoking the relationship @xcite between the count rate and the total flux in the band ( accounting for the aperture correction ) , we estimate @xmath684 erg s@xmath38 . this is four orders of magnitude below the expected x - ray luminosity of @xmath685 erg s@xmath38 for a cluster with a central galaxy of virial mass of g1 , where we have employed the bolometric x - ray luminosity to virial mass scaling relation of @xcite and corrected for the x - ray band ( see * ? ? ? the virial temperature of galaxy g1 is estimated to be on the order of @xmath686 k , which yields a coronal temperature of @xmath687 kev . according to the compilation of @xcite , our upper limit on @xmath688 is not inconsistent with the observed x - ray luminosities of early - type galaxies with similar @xmath689 . we have successfully measured spectroscopic redshifts for only galaxies g1 and g2 . as such , we can not directly deduce the presence of a cluster at @xmath0 , nor estimate the velocity dispersion of the galaxies that may reside at this redshift . based upon the photometric properties examined in the imaging date , it is difficult to definitively rule out or favor the presence of a cluster at @xmath445 . however , the upper limits on the x - ray flux within 50 mpc projected from q1317 + 277 and the low metallicity of the complex , 1 - 2 dex below intracluster gas measurements @xcite , do not favor a large cluster nor a hot intracluster medium . such considerations leave open the possibility that the complex may be a phenomenon closely linked to a massive old elliptical galaxy that is not in an overdense environment . taken together at face value , the data and the results of our analysis suggest a low metallicity structure , possibly a filament or the remnants of a disrupted filament . there remains the question of the possible connection to the smaller galaxy g3 , which unfortunately does not have a measured or estimated redshift . given the dramatic velocity spread and kinematics of the complex toward q1317 + 277 , and given its proximity to galaxy g1 ( and possibly g3 ) , it is of interest to investigate how rare / common are such absorbing complexes , what their observed relationships are with respect to galaxies , and what interpretations have been adopted in view of the role of gas in the evolution of individual and group galaxies . such insights may help identify the q1317 + 277 complex in a broader context . one example is the @xmath690 absorber complex toward the `` tololo pair '' ( tol 103727 , @xmath691 , and tol 103827 , @xmath692 ) , which may be produced by intracluster gas @xcite . the doublets , later observed in two additional quasars in proximity on the sky , exhibit multiple discrete components with velocity widths ranging between 501000 and may extend some 18 mpc @xcite . another possible intracluster absorption complex , at @xmath693 toward the @xmath694 quasar pg 2302 + 029 @xcite , exhibits broad ( @xmath695 ) high ionization , , and doublets . in the fos spectrum ( velocity resolution @xmath696 ) , the absorption is segregated into multiple individual components each with @xmath697 distributed across the full velocity range of the metals . near the central velocity , narrow , , and are present in one component . no low ionization species are present . @xcite suggest three possible interpretations : ( 1 ) material ejected from the quasar at extreme ejection velocity , ( 2 ) material associated with galaxies or the intracluster medium of a cluster or supercluster of galaxies , and ( 3 ) remnant material from supernovae in a galaxy . unfortunately , their observations did not provide data capable of distinguishing between these scenarios . toward the @xmath698 quasar h1821 + 643 , @xcite reported an complex at @xmath699 comprising five components distributed over a velocity interval of @xmath700 in high resolution stis and _ fuse _ spectra . the @xmath701 column densities range from 12.713.8 . absorption from is present in a single broad wing of the central component , for which collisional ionization is favored with @xmath702 k and @xmath703}\leq -0.6 $ ] . seven galaxies in the velocity range of the absorption are present at impact parameters ranging from 1402400 kpc , with the 140 kpc galaxy aligned in redshift with the absorption . @xcite favor the scenario in which the complex is intragroup gas or an unvirialized filamentary structure . using ghrs , stis and _ fuse _ spectra of the @xmath704 bl lac object pks 2155304 , @xcite and @xcite analyzed an complex with 14 components centered at @xmath705 spread over a velocity interval of 2270 . they estimate the column densities have the range @xmath706 with @xmath707 and cloud depths less than 400 kpc . five emitting galaxies are found in the range @xmath708 with impact parameters 400790 kpc . the two strongest blends have detectable and possible absorption measured in a _ chandra _ spectrum . if the gas is the warm - hot ionized medium ( whim ) then the density is constrained to @xmath709 . @xcite favor a scenario in which the arises in `` nearside '' and `` backside '' shocked infall into the potential well of the galaxy group . in high resolution stis and _ fuse _ spectra of the @xmath710 quasar hs 0624 + 6907 , @xcite report a cluster of 13 lines at @xmath711 with a velocity spread of 1000 . the column densities range between @xmath712 . only in the central component , with total @xmath713 , are metal lines detected ( , , and , but no ) from which the gas is deduced to be photoionized with metallicity @xmath714 , very near to solar enrichment , with @xmath715 . the gas temperatures are deduced to be @xmath716 k. the estimated baryonic mass of this component is @xmath717 m@xmath118 with an absorption length scale of 35 kpc . they report 10 galaxies within 1351370 kpc in the range @xmath718 , but this group is not consistent with elliptical - rich groups . on account of the high metallicity and cool temperatures , @xcite favor the interpretation that this complex is tidally stripped material from one of the nearby galaxies . the complexes toward h1821 + 643 , pks 2155304 , and hs 0624 + 6907 have both similarities and differences with the complex toward q1317 + 277 . however , the q1317 + 277 complex bares little resemblance to the metal - rich complexes observed toward pg 2303 + 029 and toward the tol 103727 and tol 103827 pair . these latter two complexes may be examples of metal enriched intracluster gas . the broad component in the complex toward h1821 + 643 exhibits that is likely to be predominantly collisionally ionized with a relatively high metallicity . similarly , cloud # 8 in the q1317 + 277 complex appears to be a @xmath719 k , collisionally ionized absorber , but accompanied by and absorption . on the other hand , the hottest , broad component in the q1317 + 277 complex has no detected and has upper limits on metallicity indicating that it is metal poor in comparison . the h1821 + 643 absorber is at a substantially larger impact parameter to the nearest galaxy , which resides in a group that clearly has no massive elliptical galaxy , whereas the q1317 + 277 complex quite is very close in projected to the massive elliptical galaxy g1 . the column density for the low metallicity absorber in the complex absorption toward pks 2155304 is 12 orders of magnitude greater than the @xmath381 of the components in the q1317 + 277 complex . however , the clouds have similar @xmath621 . in both complexes , the resides to the wings of largest components . @xcite interpret this as a shock interface , and this interpretation may apply in the case of the q1317 + 277 complex . however , as with the h1821 + 643 absorber , the environment of the pks 2155304 complex resides within a moderate group of galaxies having no massive elliptical galaxy . of the three examples , the complex toward hs 0624 + 6907 has an absorption profile morphology most similar to that of the q1317 + 277 complex . the cool photoionized cloud with , , and absorption compares to the cool photoionized absorbing cloud # 10 in the q1317 + 277 complex , but cloud # 10 has no or absorption . though the clouds have similar @xmath621 , cloud # 10 has lower @xmath381 , higher ionization conditions , and a much lower metallicity as compared to the nearly solar metallicity cloud in the hs 0624 + 6907 complex . because of the low ionization deduced for the latter cloud , the mass is @xmath720 orders of magnitude smaller than the mass deduced for cloud # 10 . again , the galaxy environment of the hs 0624 + 6907 complex contains no massive elliptical galaxy . overall , two unique features to the q1317 + 277 complex are that it is at substantially higher redshift ( @xmath0 ) compared to the other reported complexes ( @xmath721 , @xmath722 and @xmath723 ) and that it is in close projected proximity to a region dominated by massive , metal - rich elliptical with an old stellar population . summarizing the gas properties of the q1317 + 277 complex , we find ( 1 ) a hot , photo and collisionally ionized component that is consistent with shocked gas , ( 2 ) a cool component with photoionized absorption , and ( 3 ) a cool component plausibly layered within a warm component that is both photo and collisionally ionized and exhibits , and absorption , ( 4 ) several additional warm components spread over 1600 in the rest - frame of @xmath0 , and ( 5 ) measurements of and limits on metal - enrichment between @xmath724 . if the rest - frame velocity spread of the complex is due to the local hubble flow , then the line - of - sight proper length of the structure would be @xmath725 , where @xmath1 and @xmath726 . at @xmath445 , we estimate @xmath727 mpc . based upon the ionization modeling , the deduced physical sizes of the the complex are not consistent with a single structure of this extent . if the velocities of the absorbers are due to hubble flow , then the complex must comprise absorbers that are spatially segregated ; there are five main absorption features apparent in the profile , which would imply an average separation of 3 mpc and that we have by chanced probed several isolated absorption systems . considering the similarities of the properties of the complexes toward h1821 + 643 , pks 2155304 , and hs 0624 + 6907 , and that they are clearly connected with galaxies on scales of 0.11 mpc , we do not favor the interpretation that the q1317 + 277 complex is multiple individual absorbers tracing a 15 mpc hubble flow . is it reasonable that the individual peaks in the column density are a result of having fragmented from a single structure ? if this structure were jean s unstable , i.e. , @xmath728 , then fragmentation and/or shock disruption into the observed components would be plausible . crudely modeling this hypothetical single structure as having the @xmath381 weighted mean temperature of the components , @xmath729 ( prior to fragmentation or shock disruption , where the latter could subsequently heat the shocked components ) , and assuming that the length of its long axis is the sum of the jean s lengths for each of the components , we find that @xmath730 independent of the assumed mean hydrogen density , @xmath731 , where @xmath732 and @xmath733 yr . the model is consistent with the plausibility that the multiple component structure of the absorption complex could very well have resulted from the fragmentation of a quasi - coherent single gaseous structure . our simple model yields a total jean s length of @xmath734 mpc and a total jean s mass of @xmath735 mpc , where the total mass is simply the sum of the jean s masses for the individual components . the implied aspect ratio @xmath736 for a cylindrical structure is @xmath737 . if @xmath738 , then the complex could be crudely envisioned as a @xmath739 m@xmath118 mass cylindrical filament 2 mpc long with a 200 kpc diameter . these values would scale as @xmath740 . summarizing the luminous environment of the complex , we find ( 1 ) a massive , red , high - metallicity , elliptical galaxy ( g1 ) with an old stellar population ( @xmath741 gyr ) residing at @xmath2 kpc and aligned in velocity _ between _ the shocked component and the metal - enriched components , near the profile velocity centroid , and ( 2 ) the upper limits on the x - ray luminosity consistent with the measured range for ellipticals with @xmath742 kev and well below expected values for clusters dominated by massive ellipticals . in addition to the x - ray data not supporting the idea that galaxy g1 resides in a large cluster , the metallicity of the absorbing gas is constrained to be 1 - 2 orders of magnitude below the average enrichment of clusters at @xmath743 @xcite . the observations of @xcite and @xcite indicate that old , massive , metal - rich late - type galaxies were present in the field as early as @xmath744@xmath745 . the stellar population models for galaxy g1 suggest a formation epoch at @xmath746 . it may be that galaxy g1 is not a dominant elliptical galaxy of a large group , but may be a galaxy in the field that formed at high redshift . in addition to the aforementioned supporting observations , a massive , red , metal - rich elliptical far from a cluster environment is theoretically plausible . the cosmological simulations of @xcite , which treat accretion and feedback processes , yield a substantial fraction of red , high mass galaxies independent of overdensity . @xcite demonstrate that massive early - type galaxies are built in two phases . the first is an initial growth via in situ star formation fed by cold accretion ( @xmath747 ) that is later quenched via virial shocking ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? the second phase is accretion of stellar material ( @xmath748@xmath749 ) , called `` dry minor mergers '' due to the fact that their gas is heated and stripped by shock heating in the hot virial halo of the massive galaxy ( e.g. , * ? ? ? * ; * ? ? ? these general results are also found by @xcite . with a mass of @xmath750 , galaxy g1 is well above the `` critical mass '' where the cooling time of the gas is much longer than the dynamical time , such that an accretion shock is established near the virial radius ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? the rate at which the cooling time increases with decreasing redshift [ @xmath751 is more rapid than the increase in the dynamical time with decreasing redshift , [ @xmath752 . thus , it is generally found in simulations that , at high redshifts , cold streams can often penetrate the hot halos and accrete onto the galaxies , whereas at intermediate to low redshifts , the longer cooling time results in the heating and shocking of the cold filaments , which then accrete into the halo but not onto the galaxy @xcite . galaxy g1 may have experienced the process in which it formed stars early during its initial accretion , perhaps even experiencing cold accretion from the filament that we are observing , and then at later times the accretion penetrated no further than into the halo , resulting in a high mass , metal - rich , early - type galaxy with quenched star formation . given such a scenario , the complex could be interpreted as a filamentary structure with igm chemical enrichment levels that is undergoing shock disruption near the viral radius of galaxy g1 . the hot cloud ( # 11 ) exhibits the signature of the shocked portion of the filament , and the multiphase absorbers ( clouds # 8 - 10 ) exhibit the signature of a conductive interface . galaxy g1 is probed by the quasar sight line impact parameter at @xmath753 . simulations indicate that `` cold '' filaments ( i.e. , those that have not been heated above @xmath754 ) penetrate no deeper than @xmath755 at intermediate redshifts @xcite , suggesting that the sight line is intercepting the filament in the outer part of the virialized halo . a cartoon model of this interpretation is illustrated in figure [ fig : cartoon ] . the cartoon is consistent with simulation results and is guided by inspection of figure 7 ( top panel , for a @xmath744 , @xmath756 m@xmath118 galaxy ) from @xcite and the `` cold only '' panel of figure 6 for a @xmath757 , @xmath758 m@xmath118 galaxy from @xcite . presumably , any components of the filament that have not yet been shocked will be shock heated and their cooling time will increase to be on the order of the hubble time ( as is deduced for cloud # 11 ) . those components that may reside within the shock radius will likely not survive past @xmath759 and be assimilated into the hot halo . this would imply that , ultimately , the filament will accrete into the halo , be heated to the halo temperature , and never accrete onto the galaxy itself . galaxy g1 has likely not had new gas to fuel star formation for several gigayears and will likely not acquire new gas via accretion as it evolves . apart from the possibility of dry minor mergers @xcite building the stellar mass of galaxy g1 , it is likely that the galaxy has experienced secular stellar evolution since @xmath86 . if galaxy g3 is at @xmath760 , one might ask if the filament is associated with this lower mass @xmath761 galaxy . with the data in hand , it is nearly impossible to claim any relationship between galaxy g3 , the complex , and galaxy g1 . however , a virial shock is not predicted for lower mass galaxies , which have cooling times shorter than their dynamical times . as such , it would be expected that a filament accreting onto galaxy g3 would not show the signature of shocked gas with conductive interfaces as seen in the complex . it could be speculated that galaxy g3 is embedded in the filament , perhaps contributing to some in situ metal enrichment , and might eventually be a dry minor merger ( 2% mass ratio ) with galaxy g1 . this scenario for the evolution of galaxy g1 is in stark contrast to the evolution of spiral galaxy g2 , which is observed to have on - going star formation at @xmath26 , likely due to on - going multiphase accretion that is feeding the galaxy @xcite . to the limit of @xmath762 , there is no indication in the cos spectrum of absorbing gas that bridges these two galaxies , which are separated by @xmath763 ( in the frame of the galaxies ) . the scenario of a shock heated filament for which the accretion onto galaxy g1 is quenched is very different than the favored scenarios for the lower redshift complexes toward h1821 + 643 , pks 2155304 , and hs 0624 + 6907 @xcite . none of these complexes are in the vicinity of a massive elliptical galaxy , and as such it would be expected that they represent physical scenarios other than the one we propose for the q1317 + 277 complex . that is , absorbing complexes , though filamentary in nature , likely trace various environments around galaxies and their relationships with the intergalactic medium . we have studied the gas properties of and the luminous environment around a remarkable absorbing complex over the range @xmath764@xmath765 having a velocity spread of @xmath766 towards the quasar q1317 + 277 . to constrain the gas absorption properties , we have analyzed cos , stis , and hires spectra of the quasar to examine the lyman series , , , and absorption using voigt profile fitting and photo+collisional ionization modeling . the galaxy properties in the quasar field have been measured using a wfpc2/f702w image , and multi - band apo / spicam and kpno / irim ground - based images . stellar population modeling and halo abundance matching were employed to estimate the stellar ages , metallicities , mass , and virial mass , radii , and temperatures of the galaxies . _ absorption properties : _ the complex is characterized by five contiguous absorbing regions , comprising 21 subcomponents , or clouds . ionization models suggest that the kinematics are not due to the local hubble flow , but are consistent with a @xmath767 mpc by @xmath768 kpc structure with a total gas mass on the order of @xmath739 m@xmath118 . we find a hot @xmath769 cloud , which we attribute to shock heated gas . this cloud is bordered by multiphase , cool , warm , and hot layers gas suggestive of a conductive interface in which metal line absorption ( , , and ) is detected . the low metallicity of the gas ( @xmath724 ) is more consistent with enrichment levels of the high redshift intergalactic medium ( e.g. , * ? ? ? * ; * ? ? ? * ) , perhaps with low levels of in situ enrichment , than with the metallicities observed in the intracluster medium at @xmath743 @xcite . _ galaxy properties : _ we find that the galaxy g1 ( @xmath770 at impact parameter @xmath2 kpc ) is consistent with a massive ( @xmath771 ) elliptical galaxy that is metal - rich ( @xmath772 ) , and formed at @xmath86 ( 6 gyr stellar population ) . the magnitudes and colors of the other galaxies in the field , limits on the x - ray luminosity , and the low metallicity of the absorbing gas are consistent with galaxy g1 being a field galaxy with an evolutionary scenario in which the cold accretion has been shut down by shock heating . the redshift of galaxy g1 ( @xmath770 ) is bracketed by the redshifts of the collisionally ionized gas ( @xmath773 , @xmath774 ) and the multiphase gas with detected metals consistent with a conductive interface ( @xmath775@xmath776 , @xmath777 to @xmath778 ) in the complex . _ interpretation : _ based upon our data and analysis , we favor the scenario in which the complex is a filamentary structure accreting into the halo of galaxy g1 that is experiencing virial shock heating and dynamical disruption . consistent with predictions of both theoretical treatment ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) and cosmological simulations ( e.g. , * ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? ? * ; * ? ? ? * ; * ? ? ? * ; * ? ? ? * ) of massive galaxies ( i.e. , @xmath779 ) , our observations and analysis indicate that the gas accreting into the halo of galaxy g1 at times after its formation epoch have not accreted onto the galaxy itself and that the complex will also not accrete onto the galaxy . as such , the star formation of galaxy g1 has likely been quenched for gigayears . though it is difficult to definitively determine the nature of the absorbing complex , the scenario we favor is highly plausible and consistent with simulations and theory . in fact , the data appear to provide convincing evidence that theory and simulations correctly predict by @xmath7 , cold accretion via filaments in high mass galaxies is shock heated as it accreted into the virialized hot halos and that this gas then grows the halos , but does not fuel further star formation . continued growth of the stellar mass would then necessarily occur via dry mergers of minor galaxies . we thank daniel ceverino for several stimulating and informative discussions during his visit to new mexico state university and for helpful comments on an early draft of this paper . we also thank kyle stewart for several informative email exchanges with regard to halo abundance matching methods . this research was primarily support through grant hst - go-11667.01-a provided by nasa via the space telescope science institute , which is operated by the association of universities for research in astronomy ( aura ) under nasa contract nas 5 - 26555 . cwc thanks ggk , and michael t. murphy , and swinburne faculty research grants for providing funding for a visit to swinburne university of technology . some observations are obtained with the apache point observatory 3.5-meter telescope , which is owned and operated by the astrophysical research consortium ( arc ) . additional data were obtained at kitt peak national optical astronomy observatory , which is operated by aura under cooperative agreement with the national science foundation . some data presented herein were obtained at the w.m . keck observatory , which is operated as a scientific partnership among the california institute of technology , the university of california and nasa . the observatory was made possible by the generous financial support of the w. m. keck foundation . the authors wish to recognize and acknowledge the very significant cultural role and reverence that the summit of mauna kea has always had within the indigenous hawaiian community . this research has made use of the nasa / ipac extragalactic database ( ned ) which is operated by the jet propulsion laboratory , california institute of technology , under contract with nasa . this research has also made use of the simbad database , operated at centre de donnes , strasbourg , france .

using _ hst_/cos / stis and hires / keck high - resolution spectra , we have studied a remarkable absorbing complex at @xmath0 toward the quasar q1317 + 277 . the absorption has a velocity spread of @xmath1 , comprises 21 voigt profile components , and resides at an impact parameter of @xmath2 kpc from a bright , high mass ( @xmath3 ) elliptical galaxy that is deduced to have a 6 gyr old , solar metallicity stellar population . ionization models suggest the majority of the structure is cold gas surrounding a shock heated cloud that is kinematically adjacent to a multi - phase group of clouds with detected , and absorption , suggestive of a conductive interface near the shock . the deduced metallicities are consistent with the moderate _ in situ _ enrichment relative to the levels observed in the @xmath4 forest . we interpret the complex as a metal - poor filamentary structure being shock heated as it accretes into the halo of the galaxy . the data support the scenario of an early formation period ( @xmath5 ) in which the galaxy was presumably fed by cold - mode gas accretion that was later quenched via virial shocking by the hot halo such that , by intermediate redshift , the cold filamentary accreting gas is continuing to be disrupted by shock heating . thus , continued filamentary accretion is being mixed into the hot halo , indicating that the star formation of the galaxy will likely remain quenched . to date , the galaxy and the absorption complex provide some of the most compelling observational data supporting the theoretical picture in which accretion is virial shocked in the hot coronal halos of high mass galaxies .

Advertisement Continue reading the main story MOSCOW — Responding to a new round of economic sanctions by the United States, President Vladimir V. Putin of Russia lashed out late Wednesday against what he called America’s “aggressive foreign policy,” which he said had caused havoc in the Middle East, and accused the United States of pushing the Ukrainian government to continue fighting rather than encouraging peace. Mr. Putin, speaking to reporters in Brasília, where he is winding up a trip through central and South America, warned that the American sanctions would backfire. “I have already said they tend to have a boomerang effect, and without any doubt, in this case they are driving Russian-American relations to an impasse, causing very serious damage,” Mr. Putin said, according to a Kremlin transcript. “And I am convinced that this is harmful to the national long-term strategic interests of the American state, the American people.” Mr. Putin said that rather than imposing sanctions like those announced in Washington on Wednesday against Russian banks and energy companies in retaliation for Moscow’s intervention in Ukraine, the Obama administration should be working to end the bloodshed in Ukraine, where pro-Russian separatists have been fighting the government since early April. Although there is evidence that Russia has been supporting the insurgents with weapons, tanks and other equipment, and some of the leaders of the insurgency have identified themselves as Russian citizens, Mr. Putin said that the United States should do more to assist Russian efforts to achieve a peace agreement. “This must be done together — it must be jointly, of course, to encourage all sides in the conflict in Ukraine to an immediate end to hostilities and negotiate,” Mr. Putin said. “Unfortunately, we don’t see this on the side of our partners, especially the American partners, who it seems to me on the contrary are pushing the Ukrainian authorities to the continuation of this fratricidal war and the continuation of this punitive operation. This policy has no prospects.” Mr. Putin, who has never hidden his disdain for American foreign policy in the Middle East, once again held up the region as evidence of failed interventionism on the part of Washington. “In general I would say that those who are planning foreign policy actions in the United States — unfortunately we are not seeing it only in recent times, but say, the last 10-15 years — they conduct quite aggressive foreign policy and, in my opinion, very unprofessional,” Mr. Putin said. “Look: In Afghanistan, problems. Iraq is falling apart, Libya is falling apart. If General Sisi had not taken Egypt in hand, Egypt no doubt would now be wasted and feverish. In Africa, there are problems in many countries. They touched Ukraine, and there are problems.” Mr. Putin said that he remained open to negotiations with the United States. “It is a pity that our partners are going on this way, but we have not closed the door to negotiations, to resolve this situation,” he said. Advertisement Continue reading the main story Advertisement Continue reading the main story While Mr. Putin seemed unbowed, even bellicose, in his response, the Russian financial markets had a different reaction. The benchmark Russian stock index, MICEX, fell 2.5 percent at opening Thursday, while shares in two of the companies targeted by sanctions — the oil giant Rosneft and the energy company Novatek — declined even further. Analysts said the American sanctions would carry a sharp bite. “This represents a seismic hit to Russia, and to Russian markets,” wrote Timothy Ash, a market analyst with Standard Bank in London, who follows Russia and Ukraine closely. “With such prominent companies sanctioned, questions will now be asked which other Russian companies will next be on the list.” Mr. Ash said he believed that the Obama administration was hoping to prevent Russia from intervening further in Ukraine and to give President Petro O. Poroshenko’s military operation more time to quash the insurrection. Mr. Ash also played down the importance of the European Union’s decision to not to impose additional sanctions of its own immediately. “It does not really matter what the E.U. itself does, but the fact that these Russian companies are being sanctioned by the U.S. will force European companies with business interests in the U.S. to comply,” he wrote. “Every Western business is ultimately forced to comply.” ||||| Image copyright Reuters Image caption The West imposed the sanctions in response to what it says is Russia's backing for Ukrainian separatism Russian President Vladimir Putin has denounced the latest US sanctions against his country, saying they will damage relations and hurt businesses from both countries. The president said that bilateral relations were reaching a "dead end". He was speaking after the US and EU bolstered sanctions against Russia over its support for separatists in Ukraine. As shares in Russian interests hit by the sanctions fell sharply, markets also fell by more than 2.5%. Media playback is unsupported on your device Media caption The US blames Russia for arming separatist rebels in Ukraine, as Tom Esslemont reports Shares in the energy companies Rosneft and OA Novatek - who are both now barred from obtaining long-term loans from the US - fell 5.4% and 6.8% respectively. In addition the rouble has plunged against the euro and dollar. The sanctions do not target the whole energy sector, the BBC's Daniel Sandford reports from Moscow, but the creation of Rosneft was a personal project of President Putin and it is run by one of his closest allies, Igor Sechin. Another company targeted - the gas producer Novatek - is part-owned by friends of Vladimir Putin. 'Long-term damage' Shares in the energy companies Rosneft and OA Novatek - who are both now barred from obtaining long-term loans from the US - fell 5.4% and 6.8% respectively. Image copyright Reuters Image caption Fighting in the east of Ukraine has been raging while the US and Russia disagree over the sanctions question Image copyright Reuters Image caption More than 1,000 civilians and combatants have been killed since mid-April, when Ukrainian security forces moved to regain control of the eastern regions In comments made on television on Thursday while in Brazil, Mr Putin said the sanctions were driving relations between Russia and the US "into a corner". He said the penalties would only serve to generate a backlash against American companies working in Russia and were not in the interests of American companies and "the long-term national interests of the US government and people". The Russian president said Rosneft had a multibillion-dollar deal with US company ExxonMobil to develop lucrative oil fields in Russia. "So, what, the United States does not want it to work there now?" he asked. Russia's foreign ministry called the US move "outrageous" and a "primitive attempt at revenge". Deputy Foreign Minister Sergei Ryabkov said Russia would retaliate but gave no details. The new round of US sanctions announced by the US treasury significantly expands previous penalties by Washington, which were limited to individuals in Russia and Ukraine and a number of companies. As well as major banks and energy firms, the weapons manufacturer Kalashnikov Concern is also on the list. Two self-proclaimed rebel entities in eastern Ukraine - the Donetsk People's Republic and the Luhansk People's Republic - are also targeted. Speaking in Washington, US President Barack Obama said the sanctions were imposed because Russia had failed to fulfil its promises to de-escalate the crisis in Ukraine. Image copyright Reuters Image caption Shares in the energy companies Rosneft have fallen since the announcement of tougher US sanctions Image copyright AFP Image caption Fighting in eastern Ukraine has intensified in recent days The US penalties stop short of a complete disengagement with sectors of the Russian economy - a step that US officials said was being held in reserve in case Moscow launches a military invasion of Ukraine. In Brussels, the EU leaders agreed to beef up their own sanctions against Russia. The EU leaders said they would ask the EU-owned European Investment Bank (EIB) to suspend new investments in Russia. They would, they added, also seek a suspension of new lending by the European Bank for Reconstruction and Development (EBRD), which includes both EU and non-EU shareholders. More than 1,000 civilians and combatants have been killed since mid-April, when Ukrainian security forces moved to regain control of the eastern regions, while tens of thousands of people have fled. The crisis has led to the most serious standoff between Russia and the West since the end of the Cold War.

– Predictably, Vladimir Putin is none too pleased with the White House's decision to slap tough new sanctions on Moscow's energy firms, major banks, and a weapons manufacturer. Speaking from Brazil yesterday, Putin slammed America's "aggressive foreign policy" and accused the US of encouraging Ukraine to continue fighting rather than promoting peace. In fact, as bilateral relations near a "dead end," Putin warned that the sanctions would backfire, the BBC reports. "I am convinced that this is harmful to the national long-term strategic interests of the American state, the American people," he said, per the New York Times. Putin also appeared to blame a host of conflicts on the US. "Look: In Afghanistan, problems. Iraq is falling apart, Libya is falling apart. In Africa, there are problems in many countries. They touched Ukraine, and there are problems." Despite all this, "we have not closed the door to negotiations, to resolve this situation," Putin said. His focus? "To encourage all sides in the conflict in Ukraine to an immediate end to hostilities and negotiate." Russian markets fell 2.5% following news of the sanctions, while the energy companies hit, Rosneft and OA Novatek, fell 5.4% and 6.8% respectively, the BBC notes.

it is well established that active life style is associated with improved quality of life . however , skin wound is one of the most common causes of inactivity ( lack of movement ) . the skin wound healing is a complicated process requiring coordination of different tissues and cells , to ensure successful healing . adipose mesenchymal stem cells ( amscs ) have the ability to repair skin damage and promote wound healing it is believed that the secretome of amscs plays an important role in skin wound healing [ 2 , 3 ] . the conditioned medium of amscs ( amscs - cm ) accelerated wound closure with increased reepithelialization , cell infiltration , and angiogenesis . recent research showed that the low oxygen concentration could improve the effects of paracrine of the bone mesenchymal stem cells on murine skin wound healing . in this study , we performed experiments using concentrated hypoxia - preconditioned amscs - cm ( conc . hypo - amscs - cm ) to evaluate the effects of concentration and nonconcentration of hypo - amscs - cm on the rat 's full - thickness skin defect model . the abdominal subcutaneous adipose tissue was collected from the female sprague - dawley rats ( 250300 g ) . the adipose tissue was minced and digested with collagenase ( 0.12 u / ml , gibco , usa ) at 37c for 40 min under constant shaking . after centrifugation ( 400 g for 10 min ) , the cellular pellet was resuspended in dulbecco 's modified eagle medium/10% fetal bovine serum placed in concentration 24 10 cells / cm . the analysis ( fluorescence - activated cell sorting , facs ) was performed using cd29 , cd34 , cd71 , and cd90 as primary fluorescent antibodies and using igg - fitc and igg - pe as secondary antibodies . the negative control was cells without primary antibodies . to induce osteogenic and adipogenic differentiation , the medium was replaced with adipogenic or osteogenic differentiation medium , as described before ( when amscs as passage 3 grew to approximately 90% confluence ) . the differentiated amscs were stained with oil red o for analysis of lipid droplet in adipogenic induction or alizarin red for calcium in osteogenic induction . as described previously , cells were cultured in the sealed box with an anaeropack , a disposable oxygen - absorbed and co2 generator , for 24 h at 37c . the anaeropack starts to absorb oxygen within 1 min ; oxygen tension inside the box drops to 1 mm hg within 1 h. the final concentration of oxygen was less than 1% , and the concentration of carbon dioxide was about 20% . the amscs culture dishes were washed three times with pbs and cultured overnight in culture medium consisting of dmem / f-12 , 0.4% rat serum . after 24 hours of incubation , the cultured medium was collected and then the fresh low - serum medium was added . the cultured medium of amscs was filtered using a 0.22 m filter and then centrifuged at amicon - ultra-15 ml ( mwco 3 kd , millipore ) at 4c 4000 g for 30 minutes . the medium was concentrated about 5 times using ultrafiltration membrane of 3.5 kd with polyethylene glycol at 4c . freezing - dried powder was prepared in the sterilized penicillin bottle using the lyophilizer ( boyikang corp . , the concentration of protein in conditioned medium was measured by nanodrop 2000 ( thermo , ma , usa ) . all animal experiments were conducted with the approval of nanjing medical university ethics committee and were performed in accordance with the guide for the care and use of laboratory animals published by the us national institutes of health ( nih publication number 86 - 23 , revised 1996 ) . the full - thickness skin defect model used in this study is identical to the model previously described . thirty adult female sprague - dawley rats , weighing 200 g , were used . full - thickness skin incisions , 30 mm in diameter , were made on the back of each rat ( figure 2(a)(1 ) ) . thirty rats were randomly divided into 3 groups : ( 1 ) concentrated hypoxia - preconditioned adipose mesenchymal stem cells - conditioned medium group ( conc . hypo - amscs - cm group ) ; ( 2 ) asc - conditioned medium group ( hypo - amscs - cm group ) ; ( 3 ) control group ( 0.4% rat serum medium ) . the location of skin injury in all experimental groups was covered with concentrated and normal hypo - amscs - cm , which contains 1% hyaluronic acid ( ha ) . all medium was attached to the surface of wound completely and fixed on the skin with sterile transparent patches . statistical analysis was performed using analysis of variance ( anova ) test by spss17.0 , as appropriate . the t - test analysis was applied for measuring the data , and the regression analysis was used for the relationship between the time and the percentage of wound healing . the average number of adipose mesenchymal stem cells isolated was 1.4 0.5 10/ml from abdominal fat . primary amscs were cultured for 7 days ( figure 1(a)(1 ) ) and showed a typical fibroblast - like morphology at passage 3 after 27 days ( figure 1(a)(2 ) ) . the result of flow cytometry confirmed that amscs expressed cd29 ( figure 1(b)(1 ) ) , cd90 ( figure 1(b)(3 ) ) , and cd105 ( figure 1(b)(4 ) ) , but not cd34 ( figure 1(b)(2 ) ) . oil red o staining showed the lipid vacuoles appearance in cells ( figure 1(c)(2 ) ) and alizarin red staining obviously revealed calcium in cells , as observed from red staining ( figure 1(c)(4 ) ) . meanwhile , the oil red o staining of noninduced cells ( before staining , ( c)(5 ) ; after staining , ( c)(6 ) ) and the alizarin red staining of noninduced cells were also shown in figure 1 ( before staining , ( c)(7 ) ; after staining , ( c)(8 ) ) . the hypo - amscs - cm was collected and lyophilized in the sterilized penicillin bottle . in application , hypo - amscs - cm was diluted with 1 ml sterilized water or hyaluronic acid ( figure 2(a)(2 ) ) . the protein concentration of hypo - amscs - cm is 0.389 0.04 mg / ml , the conc . hypo - amscs - cm is 5.989 0.07 mg / ml , and the 0.4% rat serum medium is 0.350 0.04 mg / ml . the average healing time of the three groups was measured , of which the conc . hypo - amscs - cm group was 16.2 0.98 days , hypo - amscs - cm group was 17.7 0.78 days , and medium control group was 21.3 1.10 days ( figure 3(a ) ) . hypo - amscs - cm and hypo - amscs - cm groups ( p = 0.002 ) and between hypo - amscs - cm and control groups ( p < 0.001 ) . percentage of wound healing was evaluated by measurement of healing area / initial wound area 100% on 7 , 14 , and 21 days after treatment in three groups ( figure 3(b ) ) . in the regression analysis , the equation of relationship between the time and the percentage of wound healing in conc . hypo - amscs - cm group was y = 0.0455x + 0.127 ( r = 0.9043 , p < 0.01 ) ; that in hypo - amscs - cm group was y = 0.0444x + 0.1108 ( r = 0.9122 , p < 0.01 ) ; and that in the control group was y = 0.0442x + 0.0688 ( r = 0.9589 , p < 0.01 ) . hypo - amscs - cm and hypo - amscs - cm groups ( p = 0.299 ) . the conc . hypo - amscs - cm treatment improved wound healing when compared with that of the hypo - amscs - cm group at 7 ( p < 0.001 ) and 14 ( p < 0.001 ) days ( figures 2(b ) and 3(b ) ) . the hypo - amscs - cm group 's wound healing was also significantly different from that of the control groups at 7 ( p < 0.001 ) , 14 ( p < 0.001 ) , and 21 days ( p = 0.0005 ) ( figures 2(b ) and 3(b ) ) . for hematoxylin and eosin stain , biopsies of three groups were harvested from center of wound at 21 days after wound . hypo - amscs - cm showed well organized epidermis , thick cuticular layer , and increased collagen content ( figure 2(b ) ) , whereas wound areas treated with hypo - amscs - cm showed immature epidermal regeneration , weak cuticular layer , and less collagen content ( figure 2(b ) ) . hypo - amscs - cm treatment has better effects on wound repair than hypo - amscs - cm treatment . it has been shown that amscs can differentiate into adipogenic and osteogenic lineages in the particular medium . in this study , amscs showed the same immune - phenotypes as described previously [ 6 , 10 ] . they expressed the mesenchymal stem cell markers cd29 , cd90 , and cd105 , but not hematopoietic marker cd34 . the applications of culture medium of other cells have also been widely used in wound healing . we searched the medline and embase databases , using the conditioned medium and skin wound as search terms . all eligible studies were parallel - controlled trials about conditioned medium of stem cell in skin wound healing ( see supp . we first freeze - dried the conditioned medium of amscs , so the multiple concentration of conditioned medium could be made for clinical application . however , the umbilical cord wharton 's jelly cells and bone marrow mesenchymal cells were used frequently , and the adipose mesenchymal stem cells were selected in this research not only because of extensive sources , but also because of the fact that the fat tissue plays an important role in reepithelialization of damaged tissue and reconstruction of skin appendage . subcutaneous adipose cells , which demonstrate the dynamic regeneration parallel to the activation of skin stem cell , are necessary and sufficient to drive follicular stem cell activation and support lanugo growth . the hypo - amscs - cm has been shown to promote hair growth in c(3)h / neh mice . amscs were located in perivascular niches , close to vascular structure in fat . in vivo the lower oxygen environment is an important factor for maintaining the self - renewal and plastic characterization of amscs . in vitro , the oxygen concentration is considered a driver of cell function , and it helps maintain stem cell pluripotency , induces angiogenesis , and regulates the signaling of stem cell . the hypo - amscs - cm could enhance the wound healing via angiogenesis , increasing the collagen 1 expression , migration of fibroblasts , vascular endothelial cell and keratinocytes , and recruiting the circulating stem cells . therefore , response of hypoxia - preconditioned amscs may be invaluable for the development of novel wound healing and skin regeneration strategies . skin is the first line of body 's defense in the protection of foreign invasion , as the skin is exposed to pathogens in the macroenvironment . the unexpected skin injury may affect circulative exercise training , thus disrupting normal training rhythm . serious injury could potentially end athlete 's whole sports career . according to the skin wound severity , the healing takes around 2 weeks generally . many treatments have been proven to accelerate the healing , such as tissue engineering , stem cell , prp , and gene therapy . however , the cost and safety are major challenges . the results from this study showed that there are no statistical differences between the concentrated and nonconcentrated groups . the process of concentration may be important for wound healing because of difference in day 7 and day 14 . additionally , the hypo - amscs - cm has several advantages in skin wound healing : ( 1 ) being without nucleic acid and suitable for allogeneic application , ( 2 ) terminal sterilization by filtration , ( 3 ) easiness in producing and maintaining , and ( 4 ) a variety of concentrations of amscs - cm that could be obtained from freezing - dried powder . the hypo - amscs - cm could be powdered through the concentrated and lyophilized process , and the high concentrated hypo - amscs - cm , made by the powder , may be more effective in the skin wound treatment of the rat model .

in recent years , the bioactive factors were utilized in exercise and athletic skin injuries . in this research , the concentrated conditioned medium of hypoxia - preconditioned adipose mesenchymal stem cells , which is rich in bioactive factor , is applied in full - thickness skin defect model to evaluate the therapeutic efficacy . adipose mesenchymal stem cells were harvested from the abdominal subcutaneous adipose tissues . the surface markers and the potential of differentiation were analyzed . the conditioned medium of hypoxia - preconditioned stem cells was collected and freeze - dried and then applied on the rat full - thickness skin defect model , and the healing time of each group was recorded . haematoxylin and eosin staining of skin was assessed by microscope . the characteristics of adipose mesenchymal stem cells were similar to those of other mesenchymal stem cells . the concentration of protein in freeze - dried conditioned medium in 1 ml water was about 15 times higher than in the normal condition medium . in vivo , the concentrated hypoxia - preconditioned conditioned medium can reduce the wound size and accelerate the skin wound healing . the concentrated hypoxia - preconditioned adipose mesenchymal stem cell - conditioned medium has great effect on rat model of wound healing , and it would be an ideal agent for wound care in clinical application .

determining the nature and origin of the dark matter dominating almost all clustered systems in the universe remains , some 40 years after strong evidence of the existence of dark matter was first presented , one of most important outstanding questions in physics and cosmology . while light neutrinos were the first natural non - baryonic candidate for dark matter , there is now ample evidence that this material , while definitely non - baryonic as i shall describe , must also be cold , i.e. non - relativistic at the time the first large scale structures in the universe began to form . perhaps the favored cold dark matter candidate is the lightest supersymmetric particle ( lsp ) , which not only arises naturally in extensions of the standard model , but also has a mass scale and interaction strength ( making it a wimp - weakly interacting massive particle ) which naturally falls in the range allowing it to possibly dominate the mass density of the universe today . nevertheless , as collider experiments continue to constrain the scale of susy breaking , the lsp allowed range is shrinking , and questions of fine tuning have arisen . for this reason , as i shall describe , extensions of the minimal supersymmetric standard model are now being considered . for all such wimps , there has been potential excitement associated with possible indirect signatures from annihilation in the galaxy , and i review why such excitement is misplaced . at the same time , as the second generation of wimp detectors is coming online and beginning to seriously probe the lsp parameter space , it is worth considering how the uncertainties associated with our lack of knowledge of our galactic halo might impact upon such experiments , and also how one might design experiments that can separate astrophysical uncertainties from particle physics uncertainties . next , as i shall describe , axions , the other well motivated cdm candidate are once again returning from obscurity , as particle physicists are finding new ways of making unnatural acts natural . finally , of course , there are a host of unmotivated dark matter candidates that are being discussed , demonstrating once again that beauty , even in science , is in the eye of the beholder . from the moment that dark matter was first inferred , using the motion of galaxies in clusters , and then , more solidly , by the rotation curves of spiral galaxies , the natural suspicion was that it could easily be explained as being due to non - luminous baryons , like snowballs , planets , or brown dwarfs . over time these possibilities became more and more constrained . by the 1990 s , one of the most severe constraints came from big bang nucleosynthesis ( bbn ) . observations of absorption of light from distant quasars by intervening hydrogen gas clouds allowed for the first time a measurement of the fraction of primordial deuterium in these clouds . while the measurements are quite difficult , and subject to large possible systematic uncertainties , the measured deuterium to hydrogen fraction settled on a value of approximately @xmath0 . comparing this to the predictions of standard bbn calculations yields a baryon fraction ( compared to the critical density ) of @xmath1 , where @xmath2 represents the hubble constant in units of @xmath3 , and hst values suggest @xmath4 . at the same time , separate astrophysical observations , ranging from x - ray studies of galaxy clusters to gravitational lensing observations of these system began to converge on an inferred dark matter fraction that was statistically incompatible with this fraction , in the range @xmath5 . while this inconsistency was apparent , there were still loopholes . first , could bbn estimates be trusted ? second , large scale structure observations had often been subject to large systematic uncertainties that had caused cosmologists to refine estimates of @xmath6 on numerous occasions . happily , whatever nagging doubts may have existed have largely been laid to rest following the wmap observations of the cmb , which have independently confirmed both of the above estimates for @xmath7 and @xmath6 @xcite . as a result , we now have definitive evidence that dark matter _ can not _ be baryonic , and therefore is likely composed from a gas of more exotic elementary particles . i like to categorize non - baryonic dark matter candidates by the different mechanisms by which they may have arisen . in this case , dark matter candidates fall into one of the following categories : * * born to be dark * , * * achieve dark matterdom * * * have dark matterdom thrust upon them * the prototypical such candidate is a light neutrino . present in roughly the same thermal equilibrium numbers in the early universe as photons , which have an energy fraction of roughly @xmath8 , if @xmath9 then neutrinos will automatically close the universe . unfortunately they do nt . or rather , fortunately , they do nt , because if they did it is not clear that galaxies would have formed in time for us to be here today . here , wimps are the prototypical candidate . like neutrinos , they were present with thermal equilibrium densitys comparable to photons at early times . however , their annihilation cross - sections , which scale with their mass , are much larger . as a result , before their interactions freeze out , the temperature of the universe would have decreased below their mass . as a result , their number density will be suppressed by a factor of roughly @xmath10 $ ] compared to photons . this produces a roughly critical mass today if @xmath11 and @xmath10 \approx 1/20 $ ] , which requires interaction cross sections that are roughly comparable to weak interaction cross sections . axions are the prototypical candidate in this regard . with predicted masses much less than 1 @xmath12 , axions by all rights should be cosmologically irrelevant . however , cosmic axions are not be produced just thermally . since axions are the pseudo - goldstone boson associated with a global phase transition , they can exist as a bose condensate at early times . if , for example , the peccei - quinn phase transition happens before inflation , the axion field , described by an angular variable , @xmath13 , where @xmath14 is the pq symmetry breaking scale , can have a non - zero expectation value throughout the entire universe . while the potential is strictly flat , when qcd effects break the symmetry , the axion field gets a mass . this induced curvature implies that there is non - zero energy density stored in the coherent axion field . it is miniscule at early times , but if the axion mass is very small , the axion field does not begin to relax down the potential until late times . until it relaxes , the energy density stored in the field looks like a cosmological term , and remains constant , while the matter density of the rest of the universe falls as @xmath15 . once the field starts to relax , the coherent field energy gets converted into non - relativistic matter , whose energy begins to redshift . ultimately , if the initial value of @xmath16 is @xmath17 then the axion can dominate the energy density of the universe , with a contribution to @xmath18 of @xmath19 the minimal supersymmetric standard model ( mssm ) provides an elegant framework in which to attempt to understand two central issues in elementary particle physics , the hierarchy problem , and the possibility of grand unification . it is remarkable that at the same time the energy scale associated with low energy supersymmetry breaking can naturally result in stable particles whose interaction strength is precisely in the range described above as required for wimps . and if nature were an impressionist painting the mssm would , without question , be considered the most likely candidate for physics beyond the standard model . however , when examined in detail , certain issues arise which suggest some fine tuning might be necessary . these are : * the @xmath20 problem : a susy conserving mass term for the two higgs superfields in the mssm with mass parameter @xmath20 can have values ranging from zero to the planck scale . why it should be fine - tuned at the electroweak scale is not clear * non observation of the higgs : the upper bound on a neutral higgs in the mssm at lep requires that the higgs exist very close to its upper bound , requiring fine tuning * how to get @xmath21 ? : because annihilation of lsp s determines their remnant abundance , in order to get sufficient annihilation for relatively heavy lsp s , one has to have light intermediate annihilation channels . but collider constraints on sleptons and squarks , as well as the higgs particles make this increasingly difficult . * small flavor changing rates require fine tuning * parameter space squeezed : the parameter space of the mssm is being increasingly squeezed , especially if dark matter lsp s is desired within the context of the mssm , a number of authors have examined what the implications of existing collider constraints are for dark matter searches . it has been claimed that constraints on @xmath18 , combined with collider constraints drive the allowed range of models to be those with small @xmath20 parameter . in some cases this gives a lower bound on the wimp spin - independent cross section with nucleons , the parameter of relevance to direct dark matter detectors @xcite . it has also been claimed @xcite that tevatron searches for the neutral higgs , which are sensitive to large @xmath22 and small @xmath23 are precisely the parameter range probed by dark matter experiments like the cdms experiment @xcite . thus , direct dark matter constraints will impact on what is observable at the tevatron . as an alternative to this possibility , a number of authors have examined a next - to - minimal version of the ssm , in which a gauge singlet higgs superfield is added . if this superfield gets a vev of the order the the susy breaking scale , it leads to an effective @xmath20 parameter that is also of the order of the ew scale . it also allows the upper bound on the neutral higgs to be increased , and allows for a very light higgs boson which is not experimentally excluded , and which also provides an additional annihilation channel for susy wimps , increasing the allowed parameter space as a function of lsp mass @xcite . in particular , very light lsp dark matter masses are now possible . recently , my collaborators and i carried out a comprehensive examination of the possibility that these additional phenomenological attractions in the nmssm might lead to new indirect signatures for the detection of susy dark matter . we have found that extra one - loop amplitudes for nmssm annihilation into photons and gluons is enhanced , and that low mass antimatter experiments should be a good probe of such nmssm wimps , and that the possibility of the detection of a monochromatic gamma - ray line within the nmssm is more promising than the mssm @xcite . it is also possible that nmssm wimps might form an additional solar system dark matter contribution which could enhance detection of annihilation in the earth @xcite . while the direct and indirect signatures for susy wimps in the mssm and nmssm are exciting , motivation for considering the added flexibility of light wimps allowed by the nmssm was provided by several claimed direct and indirect hints of halo dark matter in experiments . the dama experiment , for example , claimed to observe an annual modulation signal in excess of noise in their sodium iodide scintillation experiment . this , however , was inconsistent with limits from the original cdms experiment unless the wimp mass was very small . however , this rationale turns out to have been misplaced , as it now appears that the dama experiment , which has its own consistency problems , appears inconsistent improved limits from direct search experiments , even for low mass wimps . at the same time , positron annihilation signals have been observed from the galactic core @xcite , which was thought might be possibly due to annihation of very light wimps in the sub - gev range . it turns out however that detailed analyses have shown that wimp annihilation can not account for this signature . in particular , any mechanism which produces energetic positrons will also be accompanied by internal bremsstrahlung photon emission , and if the positrons are created with an energy greater than 20 mev , this will violate the comptel / egret constraints @xcite . moreover , if positrons are produced a mildly relativistic energies , then higher energy gamma rays will be produced due to in - flight annihilations , requiring that the positrons must be injected with @xmath24 @xcite . at the opposite susy extreme of very high wimp masses , a claimed signature of dark matter annihilation came from claims of an excess in high energy gamma rays in the 100 gev - tev range . however , a careful analysis of the energy spectrum expected from such annihilations does not match the observed flux @xcite . thus , for the moment at least , it appears that there is as of yet no compelling direct or indirect evidence for signatures for susy wimps , and that the next generation of direct and indirect detectors , searching for the signals described in the last section , provide our best bet of constraining the susy parameter space in a way that will complement the upcoming searches at the lhc . if direct search experiments ever do detect a signal , it will in fact resemble noise . indeed this fact is one of the reasons that the dama claimed detection is so difficult to interpret . clearly it will be necessary to consider a second generation of experiments that will be more sensitive to the halo properties of the dark matter , in particular the fact that the earth and sun are moving with respect to the galactic rest frame . a detector with full directional information would be optimal in order to distinguish a preferred direction for nuclear recoils from wimp interactions . there are , however , no detectors with such sensitivity . happily , we have recently explored the efficacy of using detectors with a two dimensional directional sensitivity , as may be achieved by the proposed drift experiment . we have shown , as can be seen in the table below @xcite , that _ if and only if _ forward backward sensitivity is possible , i.e. the head of the recoil track can be distinguished from the tail , that 2d detectors which can rotate in the laboratory frame are almost as efficient as full 3d detectors for distinguishing motion through an isothermal halo from a flat laboratory background . .the number of events required to identify a wimp signal above a flat background for different types of detectors and a wimp mass of @xmath25 . [ cols="<,^,^,^ " , ] axions , while by far the most elegant solution of the strong cp problem , have been less favored of late as dark matter candidates because the parameter range for allowed axion masses does naturally lie in the range in which axions would be dark matter . if the peccei - quinn scale is near the gut scale then if @xmath26 , axions would close the universe today . moreover , constraints from axion emission by supernovae , red giants and white drwarfs put a limit on axion masses of less than @xmath27 , so that axion masses are being squeezed from the high end as well . however , it is true that if @xmath28 in our universe then gut scale axions could be dark matter . until recently this possibility was viewed as unnatural . however , recently , due to the inability to naturally explain what appears to be a cosmological constant dominating the energy density of the universe with an absurdly small and non - zero value , theorists have been driven to the last refuge of scoundrels , namely the anthropic principle . while much of the discussion regarding anthropics is tantamount to metaphysics , it is true that if inflation occurs after the pq transition , then the value of @xmath16 will be a random variable over different causally disconnected regions . recently it has been argued that if one is to average over universes with sufficient clustered matter , then the expected value of @xmath16 that is favored is such that the axion dark matter density would be comparable to the observed density of dark matter today @xcite . this is amusing , but like all anthropic arguments , far from compelling . nevertheless , it has boosted axion stock on futures markets around the world . light susy wimps and axions remain as highly motivated and potentially detectable dark matter candidates . the possibility of future discoveries in direct and indirect dark matter searches can complement the range accessible at terrestrial accelerators , meaning that the beautiful complementarity between non - accelerator and accelerator physics continues . of course , as mentioned , beauty is in the eye of the beholder , and the possibility of dark matter that might arise naturally in particle physics has not stopped theorists from imagining a host of dark matter particles that are both undetectable and unmotivated . i see no good reason to review these possibilities here . * acknowledgments * i thank the organizers of neutrino 2006 for producing a very interesting meeting , and my collaborators , in particular francesc ferrer and craig copi , for their important contributions to our projects , and for educating me about many things . my research is supported in part by doe and nasa grants . 9 spergel , d.n . , et al , 2006 , astro - ph/0603449 , 2006 kitano , r , nomura , y. , 2006 , _ phys . d * 73 * , 095004 carena , m , hooper , d , skands , p. , 2006 lett . _ * 97 * , 051801 akerib , d.s . , et al , 2006 , _ phys . lett . _ * 96 * , 011302 belanger , g. , et al , 2005 _ j. cosm . and astropart . phys _ * 9 * , 001 gunion , j. f. , hooper , d. , mcelrath , b. , 2006 , _ phys . d * 73 * , 005011 ferrer , f , krauss , l.m . , profumo , s. , 2006 , _ phys . d * 74 * , 115007 damour , t , krauss , l.m . , 1999 , _ phys . _ d * 59 * , 3509 knodlseder , j. , et al , 2003 , astro - ph/0309442 , knodlseder , j. , et al , 2005 , _ astr . _ , * 441 * , 513 beacom , j.f . , bell , n. , bertone g. , 2005 , _ phys . rev . lett . _ * 94 * , 171301 beacom , j.f.,yuksel h. , 2006 , _ phys . lett . _ * 97 * , 071102 zaharijas , g , hooper , d , 2005 , _ phys . _ d * 73 * , 103501 copi , c. , krauss , l.m.,simmons - duffin , d , stroiney , s. , 2007 , _ phys . _ d * 75 * , 023514 tegmark , m. , et al , 2006 , _ phys . _ d * 73 * , 023505

in this brief review of recent theoretical developments associated with the search for dark matter i describe the following : why baryons are now ruled out as dark matter candidates ; susy wimps and signatures in the mssm and nmssm why claimed indirect signatures are probably not wimp related , why axions may be of new interest , how wimp detection might tell us about the galactic halo , and how theorists are preparing to avoid the next generation of experimental constraints . ( invited review talk , neutrino 2006 , santa fe 2006 )

in low - dimensional semiconductor nanostructures ( ldsn ) the motion of electrons can be confined spatially , from one , two , and even three spatial directions . in the latter case , such nanostructures are known as quantum dots and often termed by physicists as 0-dimensional structures , reflecting the fact that the motion of carriers is constrained from all three spatial directions . these structures have been receiving an increasing interest due to new technological advances and fascinating applications they offer . indeed , they can be used as biological tags in cell biology and biomedicine , be used in constructing quantum bits for quantum computing , and be applied in a wide range of more traditional structure- and device - like applications , including photodectors , laser - based emitters , etc . while in many such applications the focus is on optical properties of future devices , it is important to remember that the formation of ldsns , and in particular quantum dots , is a competition between the surface energy in the structure and strain energy . hence , mechanical properties are essential in designing quantum - dot - based devices and structures . further , many quantum dot structures have a well pronounced piezoelectric effect which does contribute to their overall properties in a non - trivial manner . these coupled electromechanical effects will become increasingly important for the current and future applications of such nanostructures . in designing stable strained nanostructures , computational modelling provides a major tool for predicting their optoelectromechanical properties . during the last decade , the attention of the science and engineering community to the influence of strain effects on quantum mechanical properties of ldsns has been growing rapidly @xcite . a majority of the published works were focusing on strain effects only , without taking into account electromechanical interactions due to the piezoelectric effect . those authors who did account for the piezoeffect based their considerations on the minimization of uncoupled , purely elastic energy functionals with respect to displacements . under this approach , the maxwell equation for piezoelectric solids and the equations of elasticity were effectively solved in either uncoupled or semicoupled manner . pan with his collaborators @xcite were the first who have attracted the attention of the bandstructure engineering community to the importance of coupled effects . based on his semi - analytical green s function approach applied to an idealized half - space structure @xcite , he demonstrated that only the fully coupled model can lend a reliable prediction . further , based on a combination of analytical ( for the 1d case ) and numerical ( for the 2d case ) techniques , the idea was generalized to the device level @xcite , but no details of the numerical procedure were given . all the above studies were based on the linear theory only . furthermore , the nature of the analyzed problem allowed a number of simplifications , including those related to the wetting layer . the inclusion of the wetting layer in a consistent manner not only increase the computational complexity of the problem in several times due to different spatial scales , but may also require the formulation of non - trivial boundary conditions @xcite . in this paper , we base our consideration on the coupled schrodinger - poisson model where we account consistently for the piezoelectric effect and analyze the influence of different nonlinear terms in strain components . we structure the paper as follows . in section 2 , we analyze two fundamental approaches in bridging the scales in mathematical models for the description of optoelectromechanical properties of nanostructures . in section 3 , we provide the core model for the description of coupled electromechanical interactions in piezoelectric semiconductor solids . the model is exemplified for hexagonal ( wz ) and cubic ( zb ) materials used in our computational experiments . in section 4 , we give details of the model for bandstructure calculations , focusing on the @xmath0 approximation as a convenient framework for incorporating strain and piezoelectric effects . a general procedure for modelling quantum dot nanostructures , based on the variational formulation of the problem , is outlined in section 5 . in section 6 we provide details of numerical experiments demonstrating the influence of the piezoelectric effect and analyzing contributions of nonlinear terms in strain components . conclusions are given in section 7 . waves propagation in anisotropic media has always been a topic in the heart of scientific inquiries and a source of new ideas for engineers . this topic is of immense practical importance in the context of both solid and fluid mechanics . purely elastic waves in shells and other structures have been studied in the context of fluid - solid interactions at least since the late 1950ies , providing many meaningful examples where coupling effects become essential . around the same time , an increasing interest to coupled problems was also generated by the analysis of dynamic thermal stresses in structures , in particular by the famous danilovskaya problem , first formulated in 1950 . since then , coupled effects , in particular in anisotropic materials , have continued to fuel interest to their studies due to both , theoretical challenges and an increasing range of practical applications . in what follows , we will focus on the coupling between electric and mechanical fields in low - dimensional semiconductor nanostructures . the core of the mathematical models dealing with this sort of coupling contains the equations for coupled electromechanical motion of piezoelectric solids . the experience accumulated in mechanics of solids in solving such equations becomes now invaluable in the area known as bandstructure engineering and in the modelling semiconductor quantum structures in general . at the same time , the experience accumulated in fluid dynamics applications is equally important in this area . indeed , the hydrodynamic approach in the analysis of semiconductor devices , superlattices , and other semiconductor structures has been an important tool in semiconductor modelling for a number of years . fluid - dynamics - like hydrodynamic approximations have been widely utilized in this area and more recently several their extensions have been proposed to account for quantum effects . the importance of such semiconductor systems as quantum wells , wires , dots , and superlattices @xcite will continue to grow in nanoscale electronics , photonics , and bioengineering . new technological advances in applications of these structures require to have a fresh look at their modelling aspects , in particular in the context of their optoelectromechanical properties . while strain effects are fundamental to such properties , in the bandstructure engineering literature their influence is still typically analyzed with simplified linear models based on the minimization of uncoupled , purely elastic energy functionals with respect to displacements . the applicability of such models is limited as coupled effects related , e.g. , to built - in spontaneous and piezoelectric polarization become essential . new models accounting for these effects need to be developed . the modelling experience accumulated in both mechanics of solids and fluid mechanics can help in achieving this task . to get started , note that in semiconductor systems we are dealing with , both classical and quantum effects are interlinked , and the analysis of such systems and the choice of modelling tools depend critically on the spatio - temporal scales required for specific applications . we can start constructing a model for the analysis of such systems from the fundamental quantum level by specifying the hamiltonian of the system within the schrodinger framework . however , then we should incorporate additional effects , pronounced at larger scales , such as piezoelectric , into the obtained approximate model . this is _ the bottom - up approach _ to modelling semiconductors , applied actively today for the analysis of nanostructures . alternatively , we can attempt to carry out some physics - based averaging right from the beginning , applying _ the top - down approach _ to modelling semiconductors . a good example , clarifying conceptually the applicability and limitations of these approaches , can be provided by considering models for superlattices . based on the underlying physical assumptions , there are two major classes of such structures , classical and quantum . these structures have additional periodicity on a scale larger than atomic . the idea of creating quantum superlattices is due to l. keldysh ( 1962 ) . experimentalists reported the creation of such objects about a decade later ( l. esaki , 1970 ; zh . alferov et al , 1971 ) . it has been the domain of solid state physics where tools of solid mechanics are essential and well established . on the other hand , the idea of creating classical semiconductor superlattices was originated from a fluid mechanics analogy . it is well known ( e.g. , @xcite and references therein ) that a fluid under gravity can reach its equilibrium if its temperature depends on the height only . if the temperature gradient , directed down , exceeds certain critical value , we observe a free convection of the fluid . if we assume that this process takes place between two infinitely long horizontal planes heated to different temperatures ( temperature of the lower plane is higher ) , under a sufficiently high temperature gradient the fluid becomes unstable and we observe stationary convective motion . due to the underlying assumptions , in the horizontal plane the motion is expected to be periodic . based on this hydrodynamic analogy , a similar idea was proposed in early 1970ies in the context of carrier motion in semiconductors , where the role of gravitational field could be played by the electric field with heating produced by , e.g. , light ( @xcite and references therein ) . the analogy between wave phenomena in classical superlattices and the behaviour of wave functions of an electron moving in a periodic potential field of a quantum superlattice can be exploited when developing a hierarchy of models for the analysis of semiconductor structures . in both cases , we have an additional periodicity of the structure . however , the difference between these two cases lies in the fact that while for classical superlattices such an additional periodicity leads to the quantization of wave energy , in quantum superlattices it leads to the quantization of carrier energy . if the period of the potential field exceeds the length of free carrier runs , so that on this specific spatio - temporal scale carriers will not be affected by the action of the additional periodic field , semiconductor superlattices behave like classical structures . in the latter case , many ( fluid - mechanics analogy based ) techniques developed for semiconductor device modelling at sub - micron scales can often be applied . the study of quantum superlattices requires more fundamental approaches to account for atomic scales . note that already at the classical level we have to construct a multiscale hierarchy of the models . indeed , the standard drift - diffusion approximation may not be an appropriate modelling tool even for classical superlattices , while hydrodynamic and kinetic models provide quite useful tools for the analysis of such structures . based on relaxation time approximations , a classification of the hierarchy of mathematical models for these structures was discussed in @xcite . at the top of this hierarchy is the liouville equation framework which leads to substantial difficulties in practical realization of this approach . hence , most practical approaches stem from the kinetic - type models such as the semi - classical boltzmann equation . in these models , scattering of carriers on each other is not essential . however , the scattering of carriers on imperfections of the lattice plays the dominant role . hence , charge carriers under this approach can not be considered as an independent thermodynamical system . based on the moment methodology or the hilbert expansion method , a range of macroscopic models can be derived , among which hydrodynamic - type models play a prominent role . in such models the electron - hole `` plasma '' can be considered as an almost independent thermodynamical system that only weakly interacts with the crystal lattice . this group of models as well as quasi - hydrodynamic models can account for non - equilibrium and non - local behaviour of semiconductor carrier `` plasma '' . further details of the developed computational techniques for such models can be found in @xcite . we note that the equations we deal with in such situations are similar to , but differ from , the hydrodynamic equations of fluid mechanics . they consist of the poisson equation , equations of continuity ( for carrier concentrations ) and energy transfer . furthermore , re - distributions of charge carriers lead to an additional field , a phenomenon absent in the fluid mechanics . attempts to apply these types of models to other semiconductor structures and devices at smaller scales have led recently to the development of extended hydrodynamic models that should incorporate quantum corrections @xcite . the important observation is that all the models we have discussed above within the top - down approach are intrinsically nonlinear . at the other end of the spectrum of model hierarchy are the models developed with the bottom - up approach . surprisingly , up to date the majority of research efforts in this area has been concentrated on linear models . in what follows , we focus on the analysis of quantum dot structures and show that the conventional approaches to the analysis of these structures based on linear models need to be augmented to account for coupled nonlinear effects . mechanical effects profoundly influence electronic and optical properties of the nanostructures . two points should be mentioned in this context . firstly , we note that the key to intrinsic properties of quantum dot structures lies with strain effects arising from lattice mismatch . following @xcite , where the authors started their reasoning from the total helmholtz free energy function , we assume that there is the local equilibrium value of the lattice constant . hence , the lattice mismatch can be incorporated in the models for bandstructure calculations by defining the strain associated with it as a mismatch between two material layers @xmath1 and by accounting for it in the strain - displacement relationships . in ( [ eq1 ] ) , @xmath2 and @xmath3 are lattice constants of two different material layers , respectively , while @xmath4 is the position vector responsible for tracking the interface . this aspect of mechanical effect contributions has been actively incorporated into the theory of bandstructure calculations since early 1970s , starting from fundamental works by pikus , bir , rasba , sheka and many others @xcite . secondly , semiconductors are piezoelectric materials and the piezoelectric effect contributions to the overall properties can not be ignored in bandstructure engineering , neither for hexagonal ( wurtzite ) structures ( often due to the principle strain components ) nor for cubic ( zinc - blende ) structures ( often due to the shear strain components ) . piezoelectrics represent anisotropic media and wave interactions in such media have been a topic of immense practical importance . while purely elastic waves in structures have been studied intensively for many decades , the study of coupled electromechanical interactions in anisotropic materials is of more recent origin . one reason for that lies with the fact that dealing with problems of coupled electroelasticity usually requires the development and implementation of effective numerical techniques @xcite . hence , the experience that has been accumulated in solving problems of coupled electroelasticity for piezoelectric structures becomes invaluable in the area of bandstructure engineering and modelling semiconductor quantum structures . as in the other areas where modelling piezoelectric solids is an essential component , we consider the following general model ( e.g. , @xcite ) , describing coupled electromechanical interactions in the cartesian system of coordinates @xmath5 : @xmath6 where @xmath7 is the displacement vector , @xmath8 is the stress , @xmath9 is the density of the piezoelectric material , @xmath10 and @xmath11 are body and electric forces on the piezoelectric , if any , @xmath12 and @xmath13 are the electric field and electric displacement , and @xmath14 is the electrostatic potential . the conventional procedure applied in modelling ldsns is based on the minimization of the purely elastic functionals ( e.g. , @xcite ) , rather than on the solution of the fully coupled problem . the effect of coupling has been analyzed rigorously in a general setting in @xcite ( see also references therein ) , while in the context of nanostructure modelling it has recently been demonstrated that such an effect could be quite substantial @xcite . the core component of our model for analyzing the properties of quantum dot nanostructures will be the equilibrium equations of the coupled theory of electroelasticity which are simplified in this case to @xmath15 where the coordinate subindeces in the timoshenko - karman notions are obtained by changing @xmath16 , @xmath17 , @xmath18 in the tensorial representation above . the type of coupling between the mechanical and electric fields is determined by the type of the crystallographic symmetry of the material . in particular , for the wz semiconductors we have @xmath19 & & \sigma_{yy } = c_{12 } \varepsilon_{xx } + c_{11 } \varepsilon_{yy } + c_{13 } \varepsilon_{zz } - e_{31 } e_z , \quad \sigma_{yz}= c_{44 } \varepsilon_{yz } - e_{15 } e_y , \nonumber \\[10pt ] & & \sigma_{zz } = c_{13 } ( \varepsilon_{xx } + \varepsilon_{yy } ) + c_{33 } \varepsilon_{zz } - e_{33 } e_z , \quad \sigma_{zx } = c_{44 } \varepsilon_{zx } - e_{15 } e_x , \quad \nonumber \\[10pt ] & & d_x = e_{15 } \varepsilon_{zx } + \epsilon_{11 } e_x , \quad d_y = e_{15 } \varepsilon_{yz } + \epsilon_{11 } e_y , \nonumber \\[10pt ] & & d_z= e_{31 } ( \varepsilon_{xx } + \varepsilon_{yy } ) + e_{33 } \varepsilon_{zz } + \epsilon_{33 } e_z + p_{\rm sp } , \label{eq4}\end{aligned}\ ] ] where @xmath20 and @xmath21 are piezoelectric and dielectric coefficients ; @xmath22 is the spontaneous polarization . while for the wz materials the built - in spontaneous polarization and the principal components of strain are main contributors to the piezoelectric effect contributions , in zb materials it is the shear strain components that may contribute noticeably to the overall properties . for such materials we have the following constitutive relationships that couple ( [ eq3 ] ) : @xmath23 & & \sigma_{zz}=c_{12}\varepsilon_{xx } + c_{12}\varepsilon_{yy}+c_{11}\varepsilon_{zz } , \quad \sigma_{yz}=4c_{44}\varepsilon_{yz}-e_{14}e_x , \nonumber \\[10pt ] & & \sigma_{zx}=4c_{44}\varepsilon_{zx}-e_{14}e_y , \quad \sigma_{xy}=4c_{44}\varepsilon_{xy}-e_{14}e_z , \nonumber \\[10pt ] & & d_x = e_{14}\varepsilon_{yz}+\epsilon_{11}e_x , \quad d_y = e_{14}\varepsilon_{zx}+\epsilon_{22}e_y , \quad d_z = e_{14}\varepsilon_{xy}+\epsilon_{33}e_z . \label{eq5}\end{aligned}\ ] ] the issue of coupling via boundary conditions remains largely untouched in the area of modelling piezoelectric semiconductor nanostructures , in particular when the wetting layer is taken into account . the formulation of correct boundary conditions in the latter case was discussed in @xcite . recall that the model we presented in @xcite accounted for electron states with arbitrary kinetic energies in the wetting layer . effectively , the model we derived for the quantum dot structure with wetting layer allowed us to demonstrate several important observations . in particular , electron states that correspond to a single quantum dot structure with wetting layer will asymptotically approach one of the two limiting situations : either `` pure '' quantum well states far away from the quantum dot region or zero in the case of a `` pure '' quantum dot state . this observation must be used , as explained in @xcite , for the formulation of general boundary conditions for the combined quantum - dot / wetting - layer structure . the resulting problem we deal with in this paper is a boundary value problem that is solved with respect to @xmath24 . from a mechanics point of view , the model is derived from a variational principle applied to the total potential energy which includes both deformational energy and piezoelectric field functionals as described in @xcite . variational difference schemes developed in @xcite , as well as the finite element formulation developed for computations in this paper , follow from such a variational representation . finite element methodologies have been previously applied to bandstructure analysis in @xcite . however , in these papers the contribution of piezolectric effect was not accounted for . all works in this area we are aware of are based so far on the linear theory of elasticity . taking into account piezoelectric effect contributions , in the subsequent sections we will compare the results for bandstructure calculations and the prediction of optoelectromechanical properties of nanostructures that are obtained with linear and nonlinear strain models . already today , quantum effects play an important role in many optoelectronic devices and structures . this trend will persist into the future as device miniaturization continues . therefore , ideally the full bandstructure transport description is required . however , at present it is not possible in practice , in particular at the device / structure level . the reason is simple : transport should be computed with a many - particle hamiltonian for the carriers and the atomic structures of the device / structure material . this is a task of enormous computational complexity , not feasible to complete today . hence , some simplifications need to be made . one approach is to account for quantum mechanical ( and statistical ) effects via the wigner - boltzmann model . although such a model also involves substantial computational difficulties , it allows us to construct a hierarchy of the macroscopic models in a way similar to those involving fluid dynamics problems and semiconductor device theory where the continuity ( fluid - like ) analogy is used for the model classification ( e.g. , @xcite and references therein ) . at present , most of the quantum corrected macroscopic models are in their infancy as they are usually not able to adequately include interactions between the electrons and other particles . new efforts in this direction are currently being undertaken by a number of authors ( e.g. , @xcite ) . since the problem we are addressing is a _ problem , a natural way to approach its solution in the above framework could be to apply a domain decomposition technique . for example , one can use the quantum mechanical approach in the regions where quantum mechanical effects are dominant and use continuum - like ( e.g. , hydrodynamic ) models in other regions . however , the issue of coupling such models , e.g. , via an interface condition of a typical domain decomposition methodology or by using other techniques , is far from trivial and remains largely open . in this paper we follow another route . while the application of ab initio and atomistic methodologies are inheritably problematic from a computational complexity point of view , we resort to averaging procedures over atomic scales . this can be achieved by a variety of procedures , including various empirical tight - binding , pseudopotential , and @xmath0 approximations . in what follows , we focus on the latter approximation as a tool for averaging over atomic scales . the procedure stems from the original work by luttinger - kohn and is based on the effective mass approximation and the subsequent development of the @xmath25 theory . as with any model , the one we develop here relies on a set of assumptions some of which may not be always fulfilled . for example , a typical assumption of the @xmath0 theory that potentials change slowly on the length scale of the lattice constant could be questionable for metal - oxide - semiconductor field - effect ( mosfe ) devices , e.g. nevertheless , in bandstructure calculations of ldsns , the theory provides a remarkably flexible tool . furthermore , while we do not address this issue in detail in this paper , it is worthwhile mentioning that a recent refined approximation of the luttinger - kohn hamiltonian , known as the burt - foreman correction , has been developed and tested ( see examples and further details in @xcite ) . this correction allows us to put the effective mass theory formalism related to the behaviour of the envelope functions across interfaces on a much more rigorous mathematical foundation . for the benefit of the reader , we recall the main premises of the @xmath0 approximation . although a number of methodologies quoted above ( such as tight - binding and pseudo - potential ) can provide us with the global dispersion relationships over the entire brillouin zone for the bulk material , to know the main electronic characteristics of the semiconductor , such as wave functions , we need only the dispersion relationship over a small wave vector @xmath26 around the band extrema @xcite . indeed , it is well known that most processes in semiconductors take place near the top of the valence band and at the bottom of the conduction band @xcite . the wave functions , characterizing wave propagation in the box volume @xmath27 , are assumed to be in the form @xmath28 = \nonumber \\ & & ( l_x l_y l_z)^{-1/2 } \exp ( i { \bf k } \cdot { \bf r}),\end{aligned}\ ] ] where the allowed values of @xmath26 @xmath29 form a 3d @xmath26 space with the origin denoted as @xmath30 point . based on this assumption , the application of bloch s theorem in the context of semiconductor crystals leads to the following ( bloch ) representation of the wave function in a crystal @xmath31 with @xmath32 being periodic . since it is easier to find approximate solutions for the function @xmath32 ( assumed to be slowly varying over a small region of @xmath26 space ) than for @xmath33 @xcite , we attempt to write the schrodinger equation in terms of @xmath32 . in doing so , the derivatives of the momentum operator @xmath34 acting on the plane waves are simplified to @xmath35 , leading to a simplification of the schrodinger equation for the bloch functions of the crystal , @xmath33 , where the terms depending on @xmath26 are treated as perturbations away from the solution at @xmath36 . the presence of the operator @xmath37 in the resulting expression renders the name of the underlying local methodology . in this way , the standard parabolic approximations of the bands are refined locally in the @xmath0 theory . this is important for the conduction band , but even more so for the valence band due to degenerating light and heavy holes at the @xmath30 point . it is worthwhile mentioning that another major reason for this particular choice of averaging lies with the fact that the @xmath38 treats the bandstructure in a continuum - like manner , albeit allowing to incorporate many important effects acting at different scales which is very important for the problems like ours . this includes mechanical and electromechanical effects . as strain and piezoeffect are key contributors to changes in optoelectromechanical properties , the models described in the previous section must be incorporated in the bandstructure calculation . in order to do that , we first remind the reader that the accuracy of approximations based on the @xmath0 theory depends on the functional space where the envelope function is considered . in fact , we put subbands within conduction and valence bands of the semiconductor material into correspondence to the basis functions that span such a space . the number of such functions varies in applications , but typically ranges from 1 to 8 to ensure computational feasibility of the problem . for wz materials , 8 functions should usually be included due to spin - orbit , crystal - field splitting , as well as conduction / valence band mixing effects . this corresponds to 6 valence subbands and 2 conduction subbands that account for spin up and spin down situations . given that the hamiltonian in the @xmath0 theory can be represented as @xmath39 the problem at hand can be formulated as an eigenvalue partial differential equation problem @xmath40 the standard kohn - luttinger representation of the hamiltonian in the form of ( [ eq6 ] ) is well documented in the literature and we refer the reader interested in details to books by g. bastard and j. singh , e.g. @xcite . the problem ( [ eq7 ] ) should be solved with respect to eigenpair @xmath41 , where @xmath42 is the electron / hole energy and @xmath43 is the wave vector with dimensionality of the functional space chosen . for example , in the situation discussed above we have @xmath44 where the subindex s denotes the wave function component of the conduction band and @xmath45 is the wave function component that corresponds to the x bloch function of the valence band when the spin function of the missing electron is up . in the hamiltonian representation ( [ eq6 ] ) @xmath46 is the energy functional , defined either by the standard kohn - luttinger hamiltonian ( as mentioned above ) or by the burt - foreman modification @xcite . it represents the kinetic energy plus a nonuniform potential field @xmath47 and other effects contributing to the total potential energy of the system , as specified further in section 4 . other notations are standard : @xmath48 is the planck constant , @xmath49 is the free electron mass , @xmath50 , while the superindeces @xmath51 are used to denote the basis of the space for the wave function , which in the case discussed above ( 6 valance and 2 conduction subbands ) would lead to an @xmath52 hamiltonian . four equations ( [ eq3 ] ) of coupled electromechanics and the eigenvalue pde problem ( [ eq7 ] ) constitute a coupled schrodinger - poisson model that provides a general framework for incorporating nonlinear effects . similar to the top - down approach , where coupling procedures are well established , in the bottom - up approach applied here the coupling between schrodinger and poisson equations is essential , in particular at the level of quantum device modelling . since the fundamental work @xcite , strain effects firmly took their place in the models for bandstructure calculations of semiconductor structures . many important examples of such calculations based on strained rasba - sheka - pikus hamiltonian have recently been provided in the context of low - dimensional semiconductor nanostructures , including quantum dots ( e.g. , @xcite ) . however , all current models we are aware of have been based on linear theories . the first question to ask is whether material nonlinearities , expressed by stress - strain relationships , may become important for such calculations . the usual argument for using the linear stress - strain relationships in this field of applications is based on the fact that strain is indeed of order of magnitudes smaller of the elastic limits . although this argument may fail at the device level modelling , it remains valid for the structures of interest in the present paper . at a more fundamental level , however , elastic and dielectric coefficients may become nonlinear due to geometry of the structure which will lead to nonlinear stress - strain relationships . to address this issue rigorously , one has to look critically at the standard keating model where the parameters of the model are unit - cell dimension dependent . in the general case , we may need to account for many body interactions of higher order to reflect asymmetry of the interatomic potential . this issue is outside of the scope of the present paper . instead , we will focus on a consequence of this issue that leads to geometric nonlinearities . indeed , one of the major drawbacks of the current models for bandstructure calculations is that they are not able to resolve adequately strain nonhomogeneities due to the application of the original representation of @xcite based the infinitesimal theory with cauchy relationships between strain and displacements . as we demonstrate in the next section , this approximation is inadequate when we have to deal with geometric irregularities of low - dimensional semiconductor structures . in the latter case , by using the variation of deformation @xmath53 which is induced by the variation in displacements @xmath54 , we describe the new position @xmath55 of the material particle ( with initial coordinates @xmath56 ) after deformation . this leads naturally to the formulation of the problem where the general nonlinear green - lagrange relationship for strain can be accounted for . as we pointed out , the variational formulation of the problem at hand has been used before in the context of finite element implementations ( e.g. , @xcite ) . two new features that have been developed in this paper include ( a ) consistent coupled treatment of the piezoelectric effect and ( b ) the ability to incorporate geometric nonlinearities into the model . as we demonstrate in the next section , the influence of these features on the bandstructure calculations , and therefore optoelectromechanical properties of the modelled structures , could be substantial . the case of weakly coupled piezoelectricity was analyzed previously in @xcite where convergence results in sobolev classes of generalized solutions were established . indeed , in some special cases , in particular for simple boundary conditions , the problem can be addressed semi - analytically . in the context of quantum dots , this has been done in @xcite by using green s function approach . strongly coupled problems of piezoelectricity have been analyzed previously from variational scheme perspectives in @xcite . in the latter case , the steady - state formulation given by ( [ eq3 ] ) should be understood in a variational sense as : @xmath57 d v = 0 , \label{eq9}\end{aligned}\ ] ] where both piezoelectric stress and the nonlinear part of strain are taken into account via constitutive relationships with the total variation of deformation given by its linear and nonlinear parts @xmath58 . the above problem is coupled to the eigenvalue pde problem , also understood in a weak sense . that is we seek the solution to the following problem @xmath59 where the hamiltonian is given by ( [ eq6 ] ) . as usual in the @xmath0 theory , formal representation can be reduced to the sum of constant and @xmath26-dependent energies ( @xmath60 ) : @xmath61 where @xmath62 , derived from the standard kane hamiltonian at @xmath63 ( e.g. , @xcite ) , accounts for the spin - splitting effects ; @xmath64 is the contribution due to the kinetic part of the microscopic hamiltonian unit cell averaged by the respective bloch functions , s , x , y , or z ; @xmath65 is the strain - dependent part of the hamiltonian , and @xmath66 is the energy of unstrained conduction / valence band edges . in what follows we consider an example of modelling nanostructures based on the model described above . the main emphasis is given to a pyramidal quantum dot residing on a wetting layer . in @xcite it was demonstrated that the electronic states in the wetting layer may influence electronic states in the dot and vice versa and , hence , the thin layer on which the quantum dot resides can not be excluded from the computational domain as it is often done in the literature . this brings additional difficulties in the computational implementation of this multiscale problem . our representative example in this section concerns inas / gaas quantum dot structures of pyramidal shape . such self - assembled structures are grown experimentally via stranski - krastanov methodology and have been studied before with simplified models of linear elasticity ( e.g. , @xcite ) . as we have already mentioned , the present study has a number of new features . firstly , we take the full electromechanical coupling as well as the wetting layer into account . secondly , we analyze the influence of nonlinear strain components in modelling such quantum dot structures . all our computational examples below are for the quantum dot structure presented in fig . [ figure1 ] where geometric dimensions are also given . pyramidal shapes of quantum dot structures , such as the one we analyze , have been confirmed by experimental techniques , including high resolution electron microscopy . the entire structure , consisting of the inas dot sitting on the wetting layer , is embedded in a ( spherical ) gaas matrix . in such semiconductor materials one expects changes in the optoelectromechanical properties due to strain effects . however , up until now , such changes have been quantified with linear theories only . hence , as the first step , in fig . [ figure2 ] we present energy levels for both conduction and valence bands by using the conventional methodology based on the linear approximation . this result is given at the center of the dot ( @xmath67 ) along vertical z - axis . a straightforward generalization of the linear theory in our context is to account for the large deformation gradient @xmath68 . this gradient is responsible for the dominant nonlinear strain effect due to the lattice mismatch in the growth direction . while in the x and y directions the strain components will be identical in this case to the von karman type model , in the z - direction they differ . as all the shear strain components are assumed in this case [ case i ] to be linear , the green - lagrange strain components in this model take the form : @xmath69 & & \varepsilon_{zz}=\frac{\partial u_3}{\partial z } + \frac{1}{2}\left(\frac{\partial u_3}{\partial z}\right)^2 \;. \label{eq12}\end{aligned}\ ] ] in this case , closer to the base of the dot , the behaviour of the energy levels are the same as in the linear case . however , the situation changes at the tip of the dot as can be seen from fig . [ figure3 ] . as before , the result is presented at the center of the dot ( @xmath67 ) along vertical z - axis . next , we have analyzed and quantified the difference between this nonlinear case and the linear case , conventionally used in these calculations . in fig . [ figure4 ] we present the difference in the band edge potential for the conduction and valence bands . this result demonstrates that nonlinear strain contributions could be substantial in calculating energy levels , and hence in predicting optoelectronic properties of nanostructures . in our case these contributions are particular pronounced for the conduction band . the comparisons indicate the maximum deviation from the linear theory near the top vertex of the pyramid of @xmath70 high , not at the wetting layer . indeed , due to the lattice mismatch at the wetting layer and pyramid interface , components like @xmath71 and @xmath72 will become important , rather than @xmath73 or @xmath74 which are due mainly to the poisson effect in this problem . these differences between the results produced with the linear and nonlinear models are hard to quantify without the band edge potentials , as presented above . indeed , we have calculated a number of other characteristics , including biaxial strain @xmath75 and isotropic strain @xmath76 in fig . [ figure5 ] we present biaxial and isotropic strains in the y=0 plane . these characteristics are shown also just above the wetting layer , at z=1.5 nm , in fig . [ figure6 ] . in both of the above situations we chose to present the results of calculations produced with the conventional methodology , while noting that calculations obtained with nonlinear contributions look very similar . in fig . [ figure7 ] we present the distribution of the piezoelectric potential in the quantum dot under consideration ( as well as its projection from the top ) . recall that results with uncoupled or semi - coupled models usually demonstrate maxima of the piezopotential outside of zb quantum dot structures only , in particular when the dot is truncated . this is , of course , not the case for the coupled model applied in the current situation . the local extrema of the piezoelectric potential near the qd top can be well reproduced , as demonstrated by fig . [ figure7 ] . as expected , the distribution is symmetric at the bottom and at the top of the pyramid . we note also that predicting optoelectromechanical properties of hexagonal ( wz ) materials usually requires to account for an additional effect of spontaneous polarization , typically negligible in zb materials . as described in section 2 , our model is capable of dealing with both types of the materials . next , we have calculated eigenstates of the structure . the ground state , presented in fig . 8 , has been calculated accounting for strain and piezoelectric effects . as seen from the figure , the state is fully confined . in fig . 9 the next four eigenstates of the nanostructure are presented . as confinement visualization looks similar for both linear and nonlinear cases , we shall provide calculated numerical values that demonstrate the influence of piezoelectric effect as well as nonlinear contributions on electronic states . + before doing that , we recall that the only nonlinear model we considered so far was the model accounting for the large deformation gradient in the growth direction . we have also analyzed the case where we account for the large deformation gradients @xmath77 and @xmath78 , responsible for the dominant nonlinear strain effects due to the lattice mismatch in the @xmath79 plane , normal to the growth direction . in this case [ case ii ] the green - lagrange strain components are : @xmath80 \varepsilon_{yy}=\frac{\partial u_2}{\partial y } + \frac{1}{2}\left(\frac{\partial u_1}{\partial y}\right)^2 + \frac{1}{2}\left(\frac{\partial u_2}{\partial y}\right)^2 \ ; , \nonumber \\[10pt ] \varepsilon_{zz}=\frac{\partial u_3}{\partial z } + \frac{1}{2}\left(\frac{\partial u_1}{\partial z}\right)^2 + \frac{1}{2}\left(\frac{\partial u_2}{\partial z}\right)^2 \ ; , \label{eq15}\end{aligned}\ ] ] while all the shear strain components remain linear . as expected in this case , the results show nonlinear effect contributions due to the nonlinear relaxation of the interfacial strain between the inas wetting layer and the gaas matrix . next , we implemented the full nonlinear strain model [ case iii ] in the developed finite element code , based on the general green - lagrange strain @xmath81 where @xmath10 is the deformation gradient and @xmath82 is the identity matrix . in figs . 1012 the results are presented along the z - axis ( y=0 ) for the three cases : x=0 , 30 , and 60 @xmath83 , respectively . although differences with calculations obtained with the linear model are clearly observed , we quantify them in table 1 . the first column in the table is the number of the corresponding eigenstate . the second column gives eigenstates obtained with the linear theory , accounting for strain only ; the third column gives eigenstates obtained with the linear theory , accounting for strain and piezo effects . the remaining columns give the results obtained with the nonlinear models based on cases i , ii , and iii , respectively , as described above . all values are given in ev . in all finite element computations reported here we applied tetrahedral elements with quadratic lagrangian interpolation function . the global convergence was analyzed by refining the finite element mesh and ensuring that the difference between the last two subsequent refinements is negligible in @xmath84 . for the solution of the discretized equations we used gmres with incomplete cholesky factorization . the maximum number of iteration was set to 500 and the @xmath84 error tolerance was set as @xmath85 . the pyramid was embedded into a sphere . the loading conditions were simulated by subjecting the outer surface of the sphere to dirichlet boundary conditions in displacement . the pyramid structure was allowed to equilibrate under the combined effect of lattice misfit induced strain and piezoelectric polarization . .the influence of strain , piezoeffects , and nonlinear contributions on eigenstates of the structure . [ cols="^,^,^,^,^,^",options="header " , ] finally , we calculate the bandstructure with our finite element method code and compare the band edge potential due to the above three nonlinear strain models in the presence of piezoelectricity . the difference for each of these three cases of band edge potentials with respect to that of the linear case is computed and plotted along the z - axis for ( a ) @xmath67 , ( b ) @xmath86 , and ( c ) @xmath87 in figs . 1315 , respectively . it is clear from the plots that the fully nonlinear strain model ( case iii ) captures the large inhomogeneous strain - induced band edge potential as a cumulative effect of the potentials for cases i and ii . the band edge potentials along the presented [ 001 ] direction ( z - axis ) for each of these three cases have been computed with the fully coupled model . in this contribution , we analyzed two fundamental approaches in bridging the scales in mathematical models for the description of optoelectromechanical properties of nanostructures . we demonstrated that the conventional application of linear models to the analysis of properties of nanostructures in bandstructure engineering could be inadequate . by accounting consistently for the piezoelectric effect , we considered three nonlinear strain models and analyzed contributions of quadratic nonlinear terms induced by the deformation gradient in the growth direction , as well as in the plane normal to that direction . the core of our model was based on the shrodinger - poisson system which was presented in the variational form and implemented with finite element methodology . in this framework , we presented also the full nonlinear strain model and quantify the differences between the conventional linear and developed here nonlinear models for bandstructure calculations . generalizations of the existing models and the examples provided for quantum dot nanostructures emphasized the importance of coupled effects in predicting optoelectromechanical properties of such structures . this work was supported by nserc . the authors thank profs m. willatzen ( denmark ) , l.c . lew yan voon ( usa ) , and dr b. lassen ( sweden ) for fruitful discussions on ldsn modelling issues and the anonymous referees for a number of useful suggestions incorporated in the final version of this paper . rudan m , gnani e , reggiani s , baccarani g. a coherent extension of the transport equations in semiconductors incorporating the quantum correction . ieee transcations on nanotechnology . 2005 ; 4(5 ) : 495 - 509 .

we demonstrate that the conventional application of linear models to the analysis of optoelectromechanical properties of nanostructures in bandstructure engineering could be inadequate . such linear models are usually derived from the traditional bottom - up approach applied to the analysis of nanostructure properties . at the same time , in the hierarchy of mathematical models for semiconductor device modelling constructed on the basis of the top - down approach , we deal predominantly with models where nonlinearity is essential . in this contribution , we analyze these two fundamental approaches in bridging the scales in mathematical models for the description of optoelectromechanical properties of nanostructures . the focus of the present paper is on a model based on the coupled schrodinger - poisson system where we account consistently for the piezoelectric effect and analyze the influence of different nonlinear terms in strain components . the examples given in this paper show that the piezoelectric effect contributions are essential and have to be accounted for with fully coupled models . while in structural applications of piezoelectric materials at larger scales , the minimization of the full electromechanical energy is now a routine in many engineering applications , in bandstructure engineering conventional approaches are still based on linear models with minimization of uncoupled , purely elastic energy functionals with respect to displacements . generalizations of the existing models for bandstructure calculations are presented in this paper in the context of coupled effects . coupled effects , fluid - dynamics approximations , nonlinear strain , nanostructures , piezoelectric materials .

recently , economy has become an active research area for physicists . physicists have attempted to apply the concepts and methods of statistical physics , such as the correlation function , multifractal , spin models , complex networks , and information theory to study economic problems @xcite . from the economic system , many empirical data reflecting the economic conditions can be obtained . among them the time series of composite stock price index is one of the best data reflecting economics conditions well . the index data is used to analyze and predict the perspective of markets . the scientific interest in studying financial markets stems from the fact that there is a large amount of reasonably well defined data . information is an important keyword in analyzing the market or in estimating the stock price of a given company . it is quantified in rigorous mathematical terms @xcite , and the mutual information , for example , appears as meaningful choice replacing a simple linear correlation even though it still does not specify the direction . the directionality , however , is required to discriminate the more influential one between correlated participants , and can be detected by the transfer entropy @xcite . in many case , traders in the stock market refer to the index to invest in stocks . therefore , we can guess that prices of stocks is affected by the composite stock index of the market . however , no attempt to measure the influence of index quantitatively has been accomplished , while it is found evident that the interaction therein is highly nonlinear , unstable , and long - ranged from many previous research on econophysics using financial time series . schreiber @xcite introduced the transfer entropy which measures dependency in time between two variables . we focus quantitatively on the direction of information flow between the index data and the price of individual companies using the method of the transfer entropy . this concept of the transfer entropy has been already applied to the analysis of financial time series by marschinski and kantz @xcite . they calculated the information flow between the dow jones and dax stock indexes and obtained conclusions consistent with empirical observations . while they examined interactions between two huge markets , we construct its internal structure between stock index and individual stocks . the transfer entropy which measures directionality of variable with respect to time has been recently introduced by schreiber @xcite based on the probability density function ( pdf ) . let us consider two discrete and stationary process , @xmath0 and @xmath1 . the transfer entropy relates @xmath2 previous samples of process @xmath0 and @xmath3 previous samples of process @xmath1 is defined as follows : @xmath4 where @xmath5 and @xmath6 represent the discrete states at time @xmath7 of @xmath0 and @xmath1 , respectively . @xmath8 and @xmath9 denotes @xmath2 and @xmath3 dimensional delay vectors of two time consequences @xmath0 and @xmath1 , respectively . the joint pdf @xmath10 is the probability that the combination of @xmath11 , @xmath8 and @xmath9 have particular values . the conditional pdf @xmath12 and @xmath13 are the probability that @xmath11 has a particular value when the value of previous samples @xmath8 and @xmath9 are known and @xmath8 are known , respectively . the transfer entropy with index @xmath14 measures how much the dynamics of process @xmath1 influences the transition probabilities of another process @xmath0 . the reverse dependency is calculated by exchanging @xmath15 and @xmath16 of the joint and conditional pdfs . the transfer entropy is explicitly asymmetric under the exchange of @xmath5 and @xmath6 . it can thus give the information about the direction of interaction between two time series . the transfer entropy is quantified by information flow from @xmath1 to @xmath0 . the transfer entropy can be calculated by subtracting the information obtained from the last observation of @xmath0 only from the information about the latest observation @xmath0 obtained from the last joint observation of @xmath0 and @xmath1 . this is the main concept of the transfer entropy . therefore , the transfer entropy can be rephrased as @xmath17 where @xmath18 we analyze daily records of the s&p 500 index ( gspc ) , dow jones index ( dji ) and stock price of selected 125 individual companies . the dataset consists of about 4,000 simultaneously recorded data points during the period june 1 , 1983 to may 31 , 2007 . we use logarithmic price difference as follows : @xmath19 where @xmath20 means index or stock price of _ n_-th trading day . the first step in analysis for the transfer entropy is to discretize the time series by some coarse graining . quite often , statistical studies which use the entropy assume that the variables of interest are discrete , or may be discretized in some straightforward manner . we partitioned the real value @xmath21 into discretized price change @xmath22 . in the concrete , @xmath23 for @xmath24 ( decrease ) , @xmath25 for @xmath26 ( intermediate ) , @xmath27 for @xmath28 ( increase ) are chosen . when data is discretized , it is important to determine the size of @xmath29 because probability of each state is varied by @xmath29 . in case of very small @xmath29 , most of return value is belonged not to the intermediate state but to the increase or decrease states . therefore , the data can be regarded as two - states practically . also , when @xmath29 is very high , the greater part of return is fallen under intermediate state . so data is able to be considered in one - state system . as the value of @xmath29 , the range of intermediate state , is changed , the probability of each state is varied . [ fig : pstate ] represents the probability of each state . the probabilities of increase and decrease states are almost same . therefore , the probability of intermediate state increases as @xmath29 is increasing , while those of increase and decrease are reduced . around @xmath30 , the probabilities of three states are approximately same for both of composite stock index . on the other hand , individual stocks represent the same probability at @xmath31 . the reason , why the value of @xmath29 which makes the same probability for composite stock index is not same to that for individual stock prices , is that index usually does not change its value abruptly in a day compare with individual stocks , because composite stock index is average or weighted average of individual stock prices . [ fig : meante - d ] shows the mean value of the transfer entropy between composite stock index ( @xmath0 ) and price of individual stocks ( @xmath32 ) for the gspc and the dji as a function of @xmath29 with @xmath33 and @xmath34 . the transfer entropy from the stock index to the stock prices , @xmath35 , is almost higher than that from the stock prices to the stock index , @xmath36 . at @xmath37 , discretized data is fallen into two - states because the intermediate state is disappeared . therefore , it has smaller value of the transfer entropy compared with that for three states . as @xmath29 is increasing , the number of state turns to three , and the transfer entropy is maximized around @xmath38 . above @xmath29 which makes maximized the transfer entropy , the larger @xmath29 , the larger probability of the intermediate state . moreover , above about 0.02 , @xmath39 for the index goes close to 1 . therefore , the transfer entropy is deceasing and finally goes to 0 because all data is fallen into the intermediate state at very large @xmath29 . open squares ( @xmath40 ) and triangles ( @xmath41 ) of fig . [ fig : meante - d ] represent the transfer entropy from shuffled data . as expected , the transfer entropy from shuffled data is smaller than that from the original data , and also the difference between @xmath35 and @xmath42 is disappeared below @xmath43 and above @xmath44 in both indices . in the range from around 0.02 to around 0.04 , number of states for the indices is 1 , while it is still 3 for individual stocks . therefore , this difference between them triggers discrepancy of the transfer entropy between the indices and stocks . figs . [ fig : dtestocks](a ) and [ fig : dtestocks](b ) show the frequency of the transfer entropy between composite stock index and stock prices at @xmath38 . frequency distribution of the transfer entropy from index to stocks is more skewed to right than that from stocks to index [ fig : dtestocks](c ) and [ fig : dtestocks](d ) show the difference between @xmath45 and @xmath42 . for the majority of companies , the transfer entropy from index to stocks are larger than the transfer entropy for the reverse . however , about 35% companies gives information to index of the next day . .the top 10 companies of the transfer entropy . [ cols="<,<,<,<,<",options="header " , ] fig . [ fig : relation ] shows the positive relation between @xmath45 and @xmath42 . the value of correlation between them is 0.51(9 ) for the gspc and 0.40(9 ) for the dji . in table [ table : company ] , the top 10 companies of the transfer entropy is listed . among the top 10 companies , xerox corp . , entergy corp . , consolidated edison inc . , centerpoint energy inc . , and pg & e belong to the top 10 companies for both @xmath45 and @xmath42 . both fig . [ fig : relation ] and table [ table : company ] show that the higher @xmath35 , the higher @xmath42 , though the average value of @xmath35 is higher than one of @xmath42 . consequently , individual stocks are able to be divided into highly connected stocks and lowly connected stocks to the market . the concept of the transfer entropy has been proposed for finding direction of casuality . using the measure , we are able to investigate the information flow between stock index and individual stocks . our results indicate that there is a stronger flow of information from the stock index to the individual stocks than vice versa , and the transfer entropy for both direction has positive correlation . moreover , we expect similar result to the u.s . market for other stock markets . as a matter of fact , the result of the information flow in japan stock market also produces the same directional casuality although it is not shown in this paper . we have desire to find the correlations between the direction of information flow and company profile . however , we could not find it yet . the division of individual stocks due to the direction of casuality between composite stock index and companies may be useful for the stock investment strategies . this work is supported in part by creative research initiatives of the korea ministry of science and technology ( o.k . ) , the second brain korea 21 project ( j .- s.y . ) , and grant no . r01 - 2004 - 000 - 10148 - 1 from the basic research program of kosef ( j .- s.y . ) .

we investigate the strength and the direction of information transfer in the u.s . stock market between the composite stock price index of stock market and prices of individual stocks using the transfer entropy . through the directionality of the information transfer , we find that individual stocks are influenced by the index of the market . , transfer entropy , information flow , econophysics , stock market + 05.45.tp , 89.65.gh , 89.70.+c

basic science has advanced our understanding of nociception and suggests numerous receptors that can be targeted by drugs for pain relief in humans . unfortunately , few novel compounds have emerged as clinically useful analgesics ( mogil , 2009 ) . opioids are the mainstay for the management of acute pain ( wu and raja , 2011 ) and in palliative care ( portenoy , 2011 ) , where the duration of treatment is limited . the role of opioids for the treatment of chronic non - malignant pain remains debatable ( chou et al . , 2009a ) . chronic pain , by definition , persists beyond 3 months . in many patients , the fluctuations in the severity of such pain there are concerns that opioid - based medications may fail to maintain their efficacy when used indefinitely to relieve such pain . robust data on opioid treatment efficacy in these patients are lacking ( noble et al . , 2010 ) , and concerns have grown over the escalating death rates from prescription - opioid overdose reported in the united states ( okie , 2010 ) . nonetheless , there is still general consensus amongst clinicians , that long - term management of pain with opiates can be beneficial , or at least safe with appropriate patient selection and dose titration ( british pain society , 2010 ; chou et al . , 2009b ; kahan et al . experimental studies have demonstrated analgesic effects via stimulation of opioid receptors that are peripheral or centrally located ( dickenson and kieffer , 2013 ) . there are key spinal and supraspinal actions of opioids and the latter involves descending pathways . furthermore , recent clinical trials with methyl - naltrexone , a peripherally restricted mu - opioid - receptor antagonist , suggest that the effects within the central nervous system are important to pain relief afforded by systemic delivery of opioids in palliative care and chronic non - malignant pain ( anissian et al . , 2012 ; michna et al . , 2011 ; thomas et al . , 2008 ) . thus , human brain neuroimaging studies may further our understanding of the central processes through which opiates operate to provide pain relief . most human neuroimaging research in humans far less is known about the effects of chronic opioid analgesic therapy on the central nervous system in humans . more recent data now suggests that chronic opioid administration or withdrawal cause a hyperalgesic state ( bannister and dickenson , 2010 ) where opioids can paradoxically worsen pain . furthermore , there may be risks of cognitive decline ( kendall et al . , 2010 ) and medication misuse , particularly in the vulnerable ( pergolizzi et al . , 2012 ) . here , we discuss how far human neuroimaging research has come in translating mechanistic data from other species , suggest avenues for further studies that are relevant to the long - term management of pain with opioids . neuroimaging research suggests that the experience of pain emerges from an extensive network of brain regions ( apkarian et al . , 2005 ) , which is unsurprising given how complex pain really is ( tracey , 2005 ) . the international association for the study of pain ( iasp ) defines pain as an unpleasant sensory or emotional experience associated with actual or potential tissue damage , or described in terms of such damage ( iasp , 1994 ) . this definition is based on the concept of pain as a specific consciousness comprising of sensory , emotional and cognitive aspects . brain imaging has provided evidence for neural mechanisms that contribute to pain perception and its modulation , but the neuro - signature of pain itself remains elusive ( tracey and mantyh , 2007 ) . nearly all neuroimaging studies of opioid analgesia have been performed in healthy volunteers , in whom the effects of opioids on pain from brief non - injurious noxious stimuli are examined ( adler et al . , 1997 ; oertel et al . , 2008 ; petrovic et al . , 2002 ; wagner et al . , 2007 ; wise et al . , 2002 ) . experimentally induced pain can not replicate the distress experienced by patients with long - term pain that is often difficult to treat . nonetheless , studies in healthy volunteers allow for more precise stimulation of the nociceptive system and pharmacological modulation of the resultant experience of pain without illness , disease and treatment confounds . in these highly controlled experiments , short - acting intravenous opioids , for example remifentanil or alfentanil , the early pharmacodynamic fmri studies from our laboratory revealed that opioids decrease pain - related activations in a specific and dose dependent manner ( wise et al . activations within the intra - calcarine cortex that are related to visual stimulation , a control task employed in these experiments , were not significantly affected by opioid administration . this finding suggests that the suppression of sensory - limbic activations was related to specific effects on neural processing , rather than global vascular effects from hypercarbia related to hypoventilation during opioid analgesia ( wise and tracey , 2006 ) . furthermore , an investigation of the acute effects of remifentanil on fmri activations after controlling for hypercarbia have not revealed direct effects of remifentanil on cerebral vascular reactivity itself ( pattinson et al . , 2007 ) . interestingly , we found that activations evoked within the insular regions by noxious stimuli were particularly susceptible to remifentanil ( wise et al . the data are consisted with the known role of insular cortex in nociception and pain perception ( craig , 2003 ; mazzola et al . , 2009 ; ostrowsky et al . ( 2008 ) have further demonstrated that opioid analgesic dose response functions differ between the posterior and anterior insula cortex . in their study , the posterior insula and other regions that encode the sensory aspects of pain , also demonstrate a linear reduction of activity with increasing intravenous opioids dose . however , they report that activations in the amygdala , anterior insula and cingulate cortices , which are regions implicated in the affective aspects of pain ( craig , 2009 ) , are maximally suppressed at the lowest opioid dose . their findings suggest that the limbic regions are exquisitely sensitive to opioid effects , consistent perhaps with their high opioid receptor densities ( fig . 1 ) . nonetheless , the fmri data suggest that opioid analgesics can directly influence emotional responses at low doses that do not alter sensory aspects of pain ( fig . 2 ) . wagner and colleagues found increased activation in the perigenual anterior cingulate cortex ( acc ) and the periaqueductal grey ( pag ) activations during opioid analgesia ( wagner et al . , 2007 ) . converging evidence suggests that these regions comprise the neural circuit for the descending modulation of nociception , which include frontal - limbic and brainstem regions ( tracey , 2010 ) . baseline fluctuations of activity within regions in this circuit can predict moment - to - moment variation in the threshold of pain sensation within individuals , and relates to differences in trait anxiety and pain vigilance between individuals ( ploner et al . endogenous opioids are known to contribute to the function of this descending neural circuit ( bencherif et al . opioids can activate this same neural circuit for analgesic effects ( petrovic et al . , 2002 ) , which is shown to be active across fmri studies during noxious stimulation itself ( fig . 2 ) interestingly , pain from noxious stimulation is also associated with activations in the several brain regions that are better known for their roles in processing rewards , such as monetary gain , palatable food , drugs and pleasurable social interactions ( becerra et al . , 2001 ) . these regions include the orbitofrontal cortex ( ofc ) , nucleus accumbens ( na ) and the ventral tegmental area ( vta ) , all of which are densely populated by opioid receptors . fmri activations of these reward regions during noxious stimulation may reflect increased endogenous opioidergic transmission for the regulation of pain . this increased opioidergic tone has been considered an opponent - process ( pain - opposing ) that persists briefly after cessation of the noxious stimulation to explain the experience of relief ( from pain ) ( leknes and tracey , 2008 ; seymour et al . , 2005 ) . supporting the opponent - theory of pain are studies from our group and others studies demonstrating increased activations in similar reward regions when pain relief is experienced from the cessation or diminution of noxious stimulation ( baliki et al . , 2010 ; leknes et al . , 2011 ) . more recently , we demonstrated that pain relief related to opioids could be predicted from the baseline reactivity of reward - regions within the brain in an fmri study ( wanigasekera et al . , 2012 ) . in that study , activations within the ofc , na and vta evoked by painful noxious stimulation prior to opioid administration were positively correlated to reductions in subjective reports of pain intensity from identical noxious stimulation during opioid administration in healthy individuals . opioid analgesia was also positively correlated with a psychometric measure of reward responsiveness , though neuroimaging data better accounted for the variance in opioid effects on pain ratings . interestingly , activity in these reward regions evoked by noxious stimulation during opioid administration did not correlate with analgesic effect , suggesting that exogenous opioids do not directly modulate these reward regions for analgesic effect but may operate on shared mechanisms that are further downstream . for example , the baseline reactivity of the vta also significantly predicted the opioid - induced changes in neuronal activity in the right amygdala and the left hippocampus , which may in turn influence the expression of behavioural analgesia in the study . as with any treatment for pain , opioid analgesia can be influenced by the belief ( expectancy ) of efficacy held by the individual . expectancy is often used to explain the placebo effect , which is now substantiated by neuroimaging research as a genuine psychobiological event . endogenous opioids are known to contribute to placebo effect ( scott et al . , 2008 ; opioidergic mechanisms for placebo analgesia operate within the neural circuit for the descending control of pain , including the acc , the pag and the spinal dorsal horn ( eippert et al . , 2009 ) . more recently , we investigated whether effects from positive and negative expectancies of opioid analgesia engaged similar brain regions in healthy subjects ( bingel et al . , 2011 ) . subjects reported slightly lower pain compared to baseline when the infusion commenced but knowledge of that was hidden . pain relief became significantly superior when subjects were told that the infusion had commenced . when informed that the infusion had ceased ( though in reality the infusion was continued ) , their ratings of pain returned to baseline . the fmri data revealed that effects of positive and negative expectancies on opioid analgesia involve distinct neuroanatomical substrates . expectation of poor analgesic effect was accompanied by activation of the entorhinal cortex , a hippocampal region that mediates the exacerbation of pain through anxiety , through inhibition of perigenual acc activity ( ploghaus et al . , 2001 ) . conversely , positive expectation of analgesic effect was associated with increased perigenual acc activation , suggesting the descending mechanisms of pain inhibition were engaged . specific , activations within the primary somatosensory , insular and mid - anterior cingulate cortices regions followed subjective reports of pain that was modulated by expectancy under a fixed remifentanil dose . it should be noted , though , that activations in those regions did not return to baseline levels during the nocebo arm unlike the subjectively reporting pain ratings . hence , they reflect the true pharmacodynamic action that occurred and illustrate nicely the value of imaging that is not a simple surrogate marker of pain rating slavishly following the subjective report but are something additional . however , activations in many of these same somatosensory , insular and cingulate regions also correlate with pain modulated by varying doses of remifentanil without psychological manipulation ( wise et al . , 2002 , 2004 ) . this raises the question about whether placebo and intrinsic opioid effects might interact significantly to impact estimates of drug effectiveness in placebo - controlled clinical trials , where a brain on drug might not be able to mount the same placebo effect and mechanism as a brain off drug. atlas ( 2012 ) employed a full factorial experimental design in their recent study to investigate potential interaction effects between remifentanil and expectation on pain ratings as well as brain activity . instead , expectancy and remifentanil effects were distinguishable because they influenced different brain regions . additionally , expectancy and remifentanil effects had different onsets . expectancy effects occurred soon after the subjects became aware the infusion had started , whereas remifentanil effects become prominent only after peak blood concentrations were achieved from the infusion . these studies on drug and expectancy effects suggest that expectancy effects possess distinct functional neuro - anatomies . further research is needed to explore the possibility of isolating the contribution of placebo or nocebo effects on pain based on neuroimaging data during clinical drug trials . neuroimaging studies on the effects of opioids are scant in patients with chronic non - malignant pain . hence data regarding the distribution of opioid - receptors in the brain in patient populations can be instructive ( fig . 1 ) . clinical trials have not revealed any particular clinical pain syndrome for which opioids are particularly efficacious . the earliest pet study suggests that opioid - receptor binding is decreased during a period of increased pain related to inflammation in a small group of patients with rheumatoid arthritis ( jones et al . , 1994 ) . an interpretation for the decreased opioid - receptor binding observed in the longitudinal study is increased occupancy by release of brain endorphins ; possibly centrally regulated pain caused by the joint inflammation . control designs in their pet studies of individuals with well - characterized neuropathic pain . in general , they demonstrate decreased opioid - receptor binding in patients compared to age - matched healthy controls ( jones et al . , 2004 ; maarrawi et al . , 2007 ; complex regional pain syndrome ( crps ) and fibromyalgia are currently diagnoses of exclusion : the contributing pathologies remain unclear in symptomatic individuals . in these pain syndromes , opioid - receptor binding is again altered primarily in the frontal and limbic regions , and further accounts in part for the variance observed in the self - reports of affect and mood related to pain in patients ( harris et al . a reduced opioid - receptor density has been proposed as an explanation for the efficacy of exogenous opioids or the lack thereof in patients ( harris et al . however , binding potential is an estimate of available receptors , which depends on the affinity and selectivity of ligand ( henriksen and willoch , 2008 ) . a change in binding potentials may be related to receptor occupancy by endogenous opioid peptides or change in absolute quantity of receptors . additionally , the action of different opioids varies depending on the selectivity of their binding to opioid - receptor subtypes ( melichar et al . , opioid - induced tolerance is simply described as a shift to the right in the dose response curve : a higher dose is required over time to maintain analgesic effect . progressive disease may lead to higher opioid requirements . tolerance also results from pharmacokinetic change , for example , when the drug up - regulates the activity of a metabolic process that facilitates its elimination from the body . for this review , opioid tolerance refers to pharmacodynamic tolerance , which reflects drug - activated changes in the response of the neural systems . mechanisms for analgesic tolerance include altered molecular signalling pathways and down - regulation of opioid receptors ( nagi and pineyro , 2011 ) . data regarding opioid tolerance in animal models of inflammation , injury and disease are few and inconsistent . some behavioural studies suggest that tolerance to the anti - nociceptive effects ( withdrawal effects ) of opioids develop more slowly in inflammatory ( vaccarino et al . , 1993 ; zollner et al . , 2008 ) , cancer ( urch et al . , 2005 ) and neuropathic models ( iwai et al . , 2012 ) other studies demonstrate enhanced development of analgesic tolerance , particularly in neuropathic models ( raghavendra et al . , 2002 ) . the inconsistencies appear related to the species , disease model and the opioid and dose administered ( mogil , 2009 ) . distinct from tolerance , the excitatory effects of opioids at the cellular level are thought to cause opioid - induced hyperalgesia ( muscoli et al . , 2010 ; simonnet and rivat , 2003 ; van dorp et al . , 2009 ; waxman et al . , 2009 ) . in clinical practice , opioid - induced hyperalgesia is diagnosed when generalised pain develops and worsens with escalating opioid dose ( tompkins and campbell , 2011 ) . improvement following opioid dose reduction is recommended to help distinguish between opioid tolerance and excitatory effects ( baron and mcdonald , 2006 ) . however , discomfort related to drug withdrawal can negatively influence the overall pain experienced and cloud the diagnosis . opioid - induced hyperalgesia is mainly demonstrated after prolonged administration of opioids in healthy animal models ( bannister and dickenson , 2010 ; heinl et al . , 2011 ) . these data appear consistent with findings of decreased tolerance of noxious stimuli in human individuals maintained on long - term methadone to manage opioid dependence ( compton et al . , 2000 ; however , a recent study in which oxycodone was administered orally over days in healthy volunteers without a history of drug misuse revealed no analgesic tolerance or hyperalgesia ( cooper et al . , 2012 ) . hence , the development of tolerance or hyperalgesia may vary with the duration of administration , dose and opioid chemistry ( angst and clark , 2006 ) . in healthy volunteers , cessation of remifentanil ( after about 40 min of infusion ) can induce ( jensen et al . , 2009 ; luginbuhl et al . , 2003 ; wanigasekera et al . , the phenomenon of opioid post - infusion hyperalgesia has been investigated recently in a combined psychophysical - fmri study ( wanigasekera et al . , only half of all subjects recruited developed post - infusion hyperalgesia to noxious thermal stimuli , implying considerable inter - individual variation for the phenomenon , possibly related to genetic susceptibility ( jensen et al . midbrain reticular formation activation was significantly increased only in hyperalgesic subjects but correlated negatively with the degree of hyperalgesia , which suggest that brainstem activity regulates , rather than drives sensitisation effects during opioid withdrawal . in that human fmri study ( wanigasekera et al . , 2011 ) , subjects who developed opioid post - infusion hyperalgesia were indistinguishable from the rest of study cohort during the remifentanil infusion itself : decreases in subjective ratings of pain during opioid infusion were similar in both groups . in subjects who subsequently developed post - infusion hyperalgesia , fmri revealed increased activation in the midbrain reticular formation during the opioid infusion , suggesting initiation of pro - nociceptive process in that brief period . this was an acute administration study with an hour of opioid infusion , it remains unclear whether opioid - induced hyperalgesia would have occurred eventually had the infusion been prolonged in the susceptible individuals . in contrast to opioid - induced hyperalgesia in healthy animals , relatively few animal studies demonstrate opioid - induced hyperalgesia in the presence of tissue injury ( celerier et al . liang et al . , 2008 ) , inflammation ( rivat et al . , 2009 ) or cancer ( king et al . , 2007 ) , suggesting that these pathological states are protective . notably , the doses of opioids used to induce hyperalgesia appear higher than those employed to study opioid tolerance . several clinical investigators have reported increased post - surgical pain scores and analgesic requirements following intra - operative remifentanil administration ( guignard et al . , 2000 ; rauf et al . , 2005 ) . however , the effects are small and are not reproduced in other comparable studies ( cortinez et al . , 2001 ; lee et al . , 2005 ) , leading to questions about the relevance of opioid tolerance or withdrawal - induced hyperalgesia in peri - operative pain management ( fishbain et al . , 2009 ) . quantitative sensory testing in patients whose pain is managed by chronic opioid therapy reveals decreased pain thresholds to noxious stimuli during opioid therapy ( chen et al . , 2009 ; again , the findings are difficult to interpret , as the patients were heterogeneous in terms of pain phenotypes . also , the relevance of qst findings to the clinical pain state is yet to be fully established . in laboratory settings , unrestrained and healthy rats exposed to morphine by chance will subsequently self - administer opiates regularly ( gardner , 2000 ) . this behavioural model has long been employed as a tool for studying neurobiology of addiction ( weeks , 1962 ) . there are less data on how inflammatory or neuropathic pain might modulate volitional opioid self - administration . opioid self - administration decreased with alleviation of inflammation by indomethacin or dexamethasone treatment ( colpaert et al . also , opiates do not seem to act as reinforcers in neuropathic models of pain ( ozaki et al . , 2003 , 2004 ) . sustained activation of the kappa - opioidergic system within the nucleus accumbens is observed in the inflammatory pain state , and is thought to suppress drug - rewarding effects ( narita et al . , 2005 ) . more recently , ewan and colleagues compared the effects of morphine and cocaine on intracranial electrical self - stimulation ( icss ) of the vta in the nerve - ligated rat , a model of neuropathic pain ( ewan and martin , 2011 ) . icss is an operant paradigm in which rats will press a lever repeatedly in order to receive intracranial electrical stimulation , which is highly rewarding by itself . in healthy rats , cocaine and opioids in contrast , cocaine facilitated icss in nerve - ligated rats but opioids , which produced analgesic effects , did not . a subsequent experiment by the same investigators revealed opposite effects of these drugs on icss of the paraventricular nucleus ( pvn ) of the hypothalamus : opioids facilitate icss to a greater extent than cocaine ( ewan and martin , 2012 ) . the reinforcing properties of opioids are modulated by neuropathic pain and appear to be mediated differently from those of cocaine , a clearly non - analgesic but addictive drug . overall , the experimental data suggest that opioids do not act as primary reinforcers in the presence of pain that is clearly attributable to peripheral or central pathology . this is consistent with the bulk of clinical experience of opioid use for post - surgical ( wu and raja , 2011 ) , and cancer - related pain ( portenoy , 2011 ) . the positive subjective effects induced by opioids are thought to be reinforcing in humans but there is evidence that pain modulates these effects . in healthy subjects without clinical pain or history of recreational drug dependence , positive subjective effects of opioids are decreased during pain caused by hand - immersion in icy - cold water ( conley et al . the subjective effects of opioids may differ in the presence of chronic pain , or when there is continued exposure of opioids . an early study in the 1950s reported that in contrast to healthy controls and in the opioid dependent subjects , most chronically ill patients reported the drug as pleasant only because it reduced pain ( lasagna et al . , 1955 ) . a later study found that opioid - dependent subjects reported more positive effects ( liking and good drug effects ) , and had lower ratings for negative effects ( coasting and tired or sluggish ) ( azolosa et al . , 1994 ) . the rate of drug delivery to the central nervous system is widely held to be a key predictor of the reinforcing strength of a drug . extensive data in non - human species suggest that rapid delivery is associated with increased addictive potential for several recreational drugs , including opioids ( samaha and robinson , 2005 ) . in humans , under well - controlled experimental settings , more rapid infusions of opioids produced increased positive effects of the drug in healthy volunteers ( marsch et al . , 2001 ) as well as opioid - dependent subjects ( comer et al . , 2009 ) . it remains unclear whether the positive subjective reactions of rapid drug administration are modulated in the presence of pain . also subjective reactions to opioids do not themselves explain differences in self - administration in the presence of a painful stimulus . a recent study found that opioid use was linked to the presence of painful stimulation in the control group but not in the drug - dependent group even though the positive subjective effects of opioids ( oxycodone ) were similar in opioid - dependent and control groups ( comer et al . , 2010 ) . there are relatively few data on the neural correlates of subjective or reinforcing effects of opioids per se in healthy drug - nave volunteers . several pet studies have revealed significant changes in regional cerebral blood flow particularly in the acc and ofc following acute administration ( single dose ) of opioids in healthy volunteers ( firestone et al . , 1996 ) . similar activity is observed in other mr - perfusion - based studies ( leppa et al . , 2006 ; zelaya et al . , 2012 these changes might be anticipated given the distribution of opioid receptors in the brain , and are likely neural correlates to the subjective effects of the drug in the absence of pain ( leppa et al . , 2006 ; zelaya et al . , 2012 there are as yet no published data regarding how the brains of patients with pain respond to long - term opioid therapy . the decreased opioid receptor binding in pet studies suggest that brain responses to opioids should differ and account for clinically relevant effects ( see previous section ) . further support for the hypothesis comes from the numerous mr - based studies that suggest volumetric changes in the reward - circuitry in several clinical pain populations compared to healthy controls ( schmidt - wilcke , 2008 ) . however , it remains unclear whether these findings from neuroimaging ( pet or mri ) studies relate to chronic pain or to effects from long - term medication use ( including opioids ) . the issue was partly addressed in a recent longitudinal mr study ( younger et al . , 2011 ) . individuals with chronic low back pain were administered oral morphine daily for 1 month , and compared to those who used placebo . significant volumetric differences were observed in several regions , including the amygdala , and anterior cingulate cortex between patients who were treated with opioids compared to those who received placebo . however , patients who were treated with morphine reported significant reduction of reported pain scores , compared to those who were on placebo . thus , the mr findings may relate to pain relief in general , rather than to the effects of opioid specifically . interestingly , the volumetric changes in the morphine group persisted for months after cessation of opioids but no data regarding pain at that stage were reported . it is still unclear whether structural changes in the limbic system determine the subjective effects of exogenous opioids . a recent fmri study explored activity in the na in patients with chronic back pain ( baliki et al . , 2010 ) . this limbic structure forms part of the mesostriatal dopamine pathway of the reward - circuitry . it encodes information that helps determine motivation and hence the behavioural response to external stimuli ( leknes and tracey , 2008 ) . in that study , noxious heat stimulation engendered na responses in patients with chronic pain that were diametrically opposite to those of controls suggesting differences in motivational value assigned to the experimental stimulus . whether these findings generalise to other salient stimuli , or influence the reinforcing effects of exogenous opioids await further investigation . pain relief or comfort from opioid therapy does not necessarily lead to improvements in other aspects of health . adverse effects can lead to significant physical deterioration and unintended respiratory depression and death can occur when opioid therapy is poorly monitored ( braden et al . tolerance and opioid - induced hyperalgesia further limits the effectiveness of opioid - based analgesia in patients . current animal data do show that tolerance and hyperalgesia are slow to develop in the presence of overt pathology that induces pain . however , the direct relevance of these mechanistic data for clinical practice remains to be established . consequently , caution is being urged when initiating or escalating opioid therapy in patients for pain that is disproportionate to the disease process , or in the pain syndromes where pathology can not as yet be demonstrated ( ngian et al . , 2011 ) . addictive potential is now cited as a concern when opioids are used for treating chronic non - malignant pain ( dhalla et al . , 2011 ; okie , 2010 ) . however , defining or diagnosing opioid misuse in patients with pain remains perplexing ( weissman and haddox , 1989 ) and currently relies on behaviour that is also observed when pain is poorly treated ( bell and salmon , 2009 ) . physicians are expected to distinguish between the use of opioids as medications to relieve pain , and the illegitimate use of opioids as drugs to get high(fields , 2011 ) . unfortunately , there is no objective tool that can clarify motivation for opioid use in patients with pain . human neuroimaging studies of opioid pharmacology now exist , but most data pertain to single dose opioids in healthy volunteers . there is a clear need for studies that are relevant to the complex issues clinicians face in prescribing long - term opioids for analgesia ( bruehl et al . , 2013 ) .

opioids play an important role for the management of acute pain and in palliative care . the role of long - term opioid therapy in chronic non - malignant pain remains unclear and is the focus of much clinical research . there are concerns regarding analgesic tolerance , paradoxical pain and issues with dependence that can occur with chronic opioid use in the susceptible patient . in this review , we discuss how far human neuroimaging research has come in providing a mechanistic understanding of pain relief provided by opioids , and suggest avenues for further studies that are relevant to the management of chronic pain with opioids.this article is part of the special issue section entitled neuroimaging in neuropharmacology.

studies of mouse -herpesvirus 68 ( mhv-68 ) have shown that cd4 t cells can control a herpesvirus infection and its malignant consequences in vivo , independent of cd8 t cells and b cells . mhv-68 establishes asymptomatic chronic infection in mice after respiratory challenge due to an immune response that contains but does not eliminate the virus . immune control of mhv-68 infection can be established in the absence of cd8 t cells , but depletion of both cd4 and cd8 t cells leads to a fatal primary infection ( 1 ) . depletion of cd8 t cells resulted in higher virus loads in lung and spleen , suggesting that cd4 t cells were more efficient at controlling mhv-68 infection in the presence of cd8 t cells . in addition to causing chronic infections , mhv-68 is oncogenic ( although more weakly so than several of the human -herpesviruses ) . virus - specific cd4 t cells , but not cd8 t cells , have been shown to eliminate tumors that were induced by injection of a mhv-68infected b cell lymphoma cell line into t cell deficient ( nude ) mice ( 2 ) . after adoptive transfer of both cd4 and cd8 t cells , tumor - infiltrating lymphocytes were found to be primarily cd4 positive . more recently , cd4 t cell mediated immune control of mhv-68 has been shown to be independent of b cells ( in addition to cd8 t cells ) ( 3 ) . there is also in vitro evidence that the human -herpesvirus epstein barr virus ( ebv ) and its malignant consequences are controlled by cd4 t cells . ebv establishes persistent infection in more than 90% of the human adult population and is associated with tumors of epithelial and b cell origin , which fortunately develop in less than 10 per 100,000 individuals annually in most populations . usually ebv - transformed b cells can not grow out from peripheral blood mononuclear cells ( pbmcs ) of healthy ebv carriers unless the cultures are subject to immune suppression , for example , with cyclosporine a , which indicates that these individuals harbor immune cells that can target ebv - transformed b cells . depletion of cd4 t cells abolished this immune control ( 4 ) , and addition of cd4 t cells to t cell depleted , ebv - infected pbmcs inhibited b cell transformation by ebv more efficiently than unsorted t cells . in agreement with this initial study , cd4 t cell clones specific for nuclear antigen 1 or 2 of ebv ( ebna1 and ebna2 ) were found to inhibit outgrowth of ebv - transformed b cells ( 5 , 6 ) . these studies suggest that memory cd4 t cells specific for ebv antigens can control b cell transformation by ebv . b cell transformation by ebv can also be inhibited by ebv - specific cd4 t cells derived from the purified cd4 t cells of ebv seronegative donors that were primed in vitro by dendritic cells ( dcs ) ( 7 ) . control over transformed latently infected b cells was evident in these cultures after 12 days , i.e. , with the slow kinetics typical for primary immune responses . together these findings show that ebv infection in vitro can be controlled by virus - specific cd4 t cells primed in vitro ( i.e. , a primary response ) and by virus - specific cd4 memory cells primed in vivo ( i.e. , a secondary response ) . it appears that this control can be exerted by cd4 t cells directly , independent of cd8 effector cells , which suggests that cd4 t cells can mediate virus - specific immune control as effectors in their own right . although it is widely accepted that cd4 t cells provide helper functions for antigen - presenting cells and can restrict viral replication by secreting cytokines ( 1 ) , there is also data that virus - specific cd4 t cells can directly kill infected cells . ebv - specific cells were among the first cd4 cytolytic t lymphocytes ( ctls ) to be isolated , using ebv - transformed b cells , such as lymphoblastoid cell lines ( lcls ) , as targets . the initial ebv - specific cd4 ctls to be studied were clones derived from healthy donors ' pbmcs after prolonged in vitro expansion with lcls ( 8) , and therefore , there was the possibility that these had acquired cytolytic behavior in culture . however , subsequent studies described cd4 ctls in pbmcs without the need for prolonged in vitro expansion . ebna1 ( 9 ) , ebna2 ( 10 ) , ebna3c ( 10 ) , and latent membrane protein 2 ( lmp2 ) ( 11)and lytic bhrf1 ( 12 ) , balf4 , and bllf1 ( 13)stages of ebv infection . apoptosis induced by the ligand of the death receptor fas ( fasl ) ( 5 , 9 ) and killing by the death effector molecule perforin ( 11 ) were both identified as cytotoxic mechanisms of ebv - specific cd4 ctls . interestingly , the ebna1-specific cd4 ctls and the bllf1- and balf4-specific cd4 ctls described in this issue were found to target burkitt 's lymphoma , an ebv - associated b cell lymphoma which resists recognition by cd8 t cells due to down - regulation of the mhc class i antigen processing machinery . therefore , particularly in humans where nearly all tissues can express mhc class ii molecules after immune activation , virus - specific cd4 ctl could fill the gap left by viral immune escape from cd8 ctl recognition . the presence of cd4 ctl is neither rare nor exclusive to ebv immunity and to in vitro for example , in mice infected with the murine lymphocytic choriomeningitis virus ( lcmv ) , killing by cd4 ctls was observed in vivo after injection of fluorescent - labeled target cells coated with viral peptides ( 14 ) . this lcmv - specific cd4 t cell cytotoxicity was at least in part due to fasl - induced apoptosis . in addition , human peripheral blood contains cd4 t cells that are positive for the cytotoxic effector molecules perforin and granzyme ( 15 ) . these cd4 ctl are fully differentiated effector cells and some are specific for the -herpesvirus human cytomegalovirus ( hcmv ) . therefore , cytotoxic cd4 t cells the new concept of direct immune control by cd4 ctl raises questions on the pathways that lead to presentation of viral antigens on mhc class ii molecules by target cells . however , for cd4 t cell recognition of virus - infected cells , both exogenous and endogenous pathways for peptide loading of mhc class ii molecules have been described ( fig . 1 ) . uptake of virus particles or fragments of infected cells has been found to mediate cd4 t cell recognition of ebv - associated tumor cell lines . the early lytic ebv antigen bhrf1 elicited cd4 t cell mediated cytolysis of ebv - transformed b cells ( 16 ) . mhc class ii presentation of bhrf1 was most likely due to uptake of antigen - containing fragments ( fig . 1 , pathway 1 ) from the few lcls where ebv spontaneously entered lytic replication ( typically less than 5% ) . however , the cytolysis was only moderately effective ( 4080% of lcls were killed ) , and 21 days were required for antigen transfer . cd4-mediated lysis that is much more efficient with respect to processing kinetics and required antigen amount is reported by adhikary et al . in this issue ( p. 995 ) , who examined targeting of the late lytic ebv antigens and envelope proteins bllf1 and balf4 ( 13 ) . transfer of less than 1 ebv virion per target cell was sufficient to trigger ifn secretion by bllf1- and balf4-specific cd4 t cells as early as 12 hours after infection . ebv virion uptake for this mhc class ii presentation was mediated by the interaction of bllf1 with the b cell surface receptor cd21 ( fig . presentation of transferred bllf1 and balf4 even led to lysis of burkitt 's lymphoma cell lines , an ebv - associated malignancy that can support higher levels of lytic replication than lcls in vitro and might , therefore , be especially well targeted via this pathway . exogenous and endogenous mhc class ii antigen processing pathways lead to direct recognition of virus - infected cells by cd4 t cells . uptake of infected cell fragments ( 1 ) or virions ( 4 ) leads to mhc class ii presentation of viral antigens . in addition , viral envelope as well as cytosolic or nuclear antigens reach the miic via the secretory pathway from the endoplasmic reticulum ( er ) ( 2 ) or after macroautophagy of cytoplasm ( 3 ) , respectively . after transport to the cell surface , the complexes of mhc class ii molecules and viral antigen fragments are recognized by cd4 t cells , which then either secrete ifn to restrict viral replication or kill the infected cell via fasl and perforin - granzyme dependent mechanisms . in addition to these exogenous pathways for mhc class ii presentation of viral antigens from infected cells , efficient sensitization of virally infected cells for cd4 t cell recognition and killing has also been demonstrated after intracellular transport of viral antigens . endogenous pathways for presentation of viral antigens include co - migration of viral membrane proteins with mhc class ii molecules to mhc class ii loading compartments ( miics ) via the secretory pathway ( fig . 1 , pathway 2 ) . two prominent examples of viral proteins following the secretory pathway to intersect with miics are the hcmv envelope protein gb ( 17 ) and the influenza envelope protein hemagglutinin ( ha ) ( 18 ) . glial , epithelial , and endothelial cells were shown to present low levels of hcmv gb to cytolytic cd4 t cells ( 17 ) . similarly , mutated influenza ha , which was retained in the golgi apparatus , sensitized human lymphoblastoid cells to killing by cd4 t cells after processing of ha through the secretory pathway ( 18 ) . later , it was proposed that association of ha with mhc class ii molecules directs ha from the golgi apparatus to the miic for efficient mhc class ii loading . however , it remains unclear how efficient this pathway is since most cells block mhc class ii loading in the endoplasmic reticulum by the invariant chain ( 19 ) . the second endogenous mhc class ii antigen processing pathway that has been shown to elicit cd4 t cell recognition of virus - infected cells involves macroautophagy . during this degradation pathway , the cell engulfs its own cytoplasm by forming autophagosomes , which are then transported to lysosomes . the nuclear ebv antigen ebna1 was found to accumulate in autophagosomes after inhibition of lysosomal degradation , and ebna1-specific cd4 t cell recognition of ebv - transformed b cells could be down - regulated by pharmacological or sirna - mediated inhibition of macroautophagy ( 20 ) . together , these experiments show that cytosolic , nuclear , and membrane - bound viral antigens can sensitize cells for cd4 t cell mediated cytolysis in vitro . whether these endogenous and exogenous antigen presentation pathways contribute to the immune control of infections and tumors in vivo remains to be established . the discovery of a cytolytic effector function of virus - specific cd4 t cells indicates that cd4 t cells can do more than simply help other lymphocytes . cytolytic cd4 t cells have been targeted in recent approaches to rational vaccine design , a good example being the development of vaccines specific for ebv . earlier immunization attempts focused on inducing cd8 ctls against the viral antigens present in ebv - associated malignancies , for example lmp2 , which is expressed in nasopharyngeal carcinomas ( npcs ) . dcs pulsed with cd8 t cell epitopes of lmp2 were injected into inguinal lymph nodes of npc patients , where they induced detectable but transient lmp2-specific cd8 ctls . unfortunately , as with other antitumor vaccines that have focused solely on the induction of cd8 t cells , the epitope - specific responses were either too weak or too transient to achieve clinical responses ( 21 ) . since cd4 t cells are necessary to maintain protective cd8 t cell immunity and can target infected cells directly , more recent vaccine attempts against ebv - associated tumors have focused on inducing both cd4 and cd8 t cells . npc cells also express ebna1 , which is a strong immunogen for cd4 t cells in healthy ebv carriers . to achieve simultaneous stimulation of cd4 and cd8 t cells against npc , a modified vaccinia virus vector encoding a fusion between the cd4 t cell epitope - rich c - terminal domain of ebna1 and the full - length lmp2 protein was constructed . dcs infected with this vector were able to reactivate both lmp2-specific cd8 and ebna1-specific cd4 t cell responses from blood of healthy virus carriers in vitro ( 22 ) . furthermore , in order to directly target viral epitopes to the miic , a polyepitope protein incorporating multiple class ii restricted viral epitopes of ebv , including ebna1 peptides , was fused to the lysosomal - targeting sequence of the lysosome - associated membrane protein , lamp1 . when the gene encoding this fusion protein was delivered to pbmcs with recombinant vaccinia viruses , activation of virus - specific cd4 memory ctls was observed ( 23 ) . stimulation of cd4 ctls against ebv - infected tumors is crucial especially for burkitt 's lymphoma , where ebna1 is the only viral protein expressed and mhc class i antigen presentation for cd8 t cell recognition is severely impaired . ( 13 ) shows that vaccines against burkitt 's lymphoma and other ebv - associated malignancies should stimulate not only ebna1-specific cd4 ctls , but also bllf1- and balf4-glycoprotein specific cd4 ctls . indeed , vaccination with bllf1 encoding recombinant vaccinia viruses protected cottontop tamarins from lethal ebv challenge , and part of this protection might have been due to bllf1-specific cd4 ctl ( 24 ) . whether any of the therapeutic immunization approaches that have stimulated cd4 ctls in vitro will work in vivo remains to be seen . one caveat of the current vaccine approaches is that , although many of them use dcs to stimulate t cells in vitro , they do not target dcs in vivo . novel immunization approaches ( 25 ) that target antigens directly to endocytic receptors of dcs in vivo promise to achieve a more robust stimulation of cd4 ctls , which in turn might lead to a direct attack on infected cells as well as efficient establishment of t cell memory .

cd4 + t cells are classically thought to orchestrate adaptive immune responses . but recent studies demonstrate that they can also kill infected cells directly . a new paper shows that highly efficient processing of epstein barr virus ( ebv ) glycoproteins for presentation on mhc class ii makes virus - transformed b cells susceptible to lysis by cd4 + t cells . thus , antiviral vaccines should aim to stimulate both helper and cytolytic cd4 + t cells .

this study took place in the women s ambulatory health services ( wahs ) clinic at hartford hospital , an inner - city , tertiary care hospital in hartford , conn . in july 2011 , the wahs clinic changed its routine gdm screening from the 50-g , two - step process to the 75-g , one - step process . routine management included testing all nondiabetic pregnant women for gdm between 24 and 28 weeks gestation . high - risk women ( patients with a history of gdm or macrosomia or who were obese ) were screened at their initial prenatal visit . if that screening was negative , they were screened again between 24 and 28 weeks gestation . using the two - step method , women were considered to have screened positive for gdm if they had a serum glucose value 135 mg / dl 1 hour after the nonfasting 50-g challenge test . the threshold values used for the ogtt were : fasting 95 mg / dl , 1-hour 180 mg / dl , 2-hour 155 mg / dl , and 3-hour 140 mg / dl , based on the criteria of carpenter and coustan , with two abnormal values required for diagnosis . women with a 50-g test result > 183 mg / dl were not given the ogtt and were diagnosed with gdm . for the one - step screening , the criteria used for this method were based on the hyperglycemia and adverse pregnancy outcome ( hapo ) study . the threshold values were : fasting 92 mg / dl , 1-hour 180 mg / dl , and 2-hour 153 mg / dl . all women diagnosed with gdm were treated in a similar manner throughout the study period with dietary modification and/or insulin depending on their capillary blood glucose values . glucose screening and outcome data from the 9 months ( 1 october 2010 to 30 june 2011 ) preceding the change in screening method were collected and compared to data from the first 6 months ( 1 july 2011 to 31 december 2011 ) of the one - step screening process . for patients who had glucose testing performed at the end of the study period , data collection continued for an additional 3 months ( 1 january 2012 to 30 march 2012 ) to include delivery outcomes . included records were those of female patients 18 years of age who were seen at the wahs clinic during the allotted time period . excluded records were those of female patients who were < 18 years of age , had preexisting diabetes , or had a history of gastric bypass surgery . maternal data included race , bmi , weight gain during pregnancy , and mode of delivery . neonatal outcomes included birth weight , apgar score , neonatal intensive care unit ( nicu ) admission , small - for - gestational - age ( sga ) status , large - for - gestational - age ( lga ) status , hypoglycemia , hyperbilirubinemia , respiratory distress syndrome ( rds ) , intraventricular hemorrhage , culture - proven sepsis , and necrotizing enterocolitis ( nec ) . data were compared using student s t test , test , and fisher s exact test . a total of 832 patients delivered during the study period ; 10 had preexisting diabetes , 1 had a history of gastric bypass , and 9 were < 18 years of age , leaving 812 patients meeting inclusion criteria . no differences were found between the two groups regarding average bmi , prepregnancy weight , parity , pregnancy weight gain , or race . of all study patients , 60.4% were overweight or obese , 29.1% were overweight with a bmi of 2529.9 kg / m , and 31.3% were obese with a bmi 30 kg / m . the overall distribution of race was hispanic 74% , african american 16.7% , and caucasian 7% . the 1-hour , 50-g ( two - step ) screening was performed in 458 patients , and 75 patients ( 16.4% ) required a 3-hour screening . the 2-hour , 75-g ( one - step ) screening was performed in 257 patients . of the patients who had the 1-hour screening , 32 ( 7% ) ultimately tested positive for gdm after a 3-hour ogtt . of the 257 patients who had the 2-hour screening , 30 ( 11.7% ) tested positive . of the women who were seen during the 1-hour screening period , 49 ( 9.9% ) were not compliant with gdm testing compared to 52 ( 16.4% ) seen during the 2-hour screening period . with regard to delivery outcome , there were no differences between the two groups for mode of delivery , average birth weight , or apgar score ( table 1 ) . the rates of nicu admission , sga , lga , rds , nec , hyperbilirubinemia , sepsis , and length of nicu stay were similar between the two groups ( figure 1 ) . we also evaluated for a difference in composite neonatal outcome among infants admitted to the nicu and did not find a difference between the two groups . the rate of hypoglycemia was lower during the one - step screening process , but this was not statistically significant ( p = 0.056 ) . debate continues about the best screening and diagnostic method for gdm . in our high - risk patient population , we did not find a difference in delivery or neonatal outcomes when the one - step screening was used , despite a 4.7% increase in gdm ( from 7 to 11.7% ) . others have found an even higher incidence ( ranging from 16 to 27% ) of gdm using the one - step screen and the thresholds proposed by the hapo study and the international association of the diabetes and pregnancy study groups . the lack of a difference in outcome and a lower - than - expected increase in gdm may be related to decreased compliance with testing . the one - step screening is less convenient because patients must be fasting , and it takes longer to complete than the nonfasting , 1-hour test for the first part of the two - step testing protocol . a decrease in compliance may not be seen in other pregnancy populations and would potentially affect delivery or neonatal outcomes . decreased compliance would likely be seen in similar obstetrical practices with high minority rates and decreased overall health care compliance . although not statistically significant , the rate of hypoglycemia was lower in patients in the one - step protocol . with increased compliance , the rate of hypoglycemia may be lower for women who undergo the one - step screening . if no other differences in neonatal outcome are seen with the one - step screening , the impact of this may not be considered clinically significant if the infants with hypoglycemia do not require more than minimal intervention or monitoring . for example , women who are employed may be required to take time off to complete fasting blood work , whereas they could complete the 50-g screening at a more convenient time . a limitation to this study is a lack of data on compliance with therapy . at wahs , women diagnosed with gdm are referred to a nutritionist and instructed to check both fasting and 2-hour postprandial blood glucose levels . they are started on oral or insulin therapy if their blood glucose is consistently > 95 mg / dl fasting and > 120 mg / dl postprandially . another limitation is the historical nature of the data collected , although both groups , the health care providers , and the practices were similar throughout the study period . the one - step , 2-hour screening for gdm appears to be associated with an increased rate of gdm , despite decreased rates of screening , without improving maternal or neonatal outcomes . an increase in the rate of gdm using the one - step screening would also be expected to increase health care costs by increasing doctor visits , ultrasounds , nutrition and diabetes team counseling , and home glucose testing .

in briefscreening for gestational diabetes mellitus is controversial . in their high - risk obstetrical practice , the authors did not find a difference in delivery or neonatal outcomes when using a one - step versus a two - step screening process . they did find lower rates of compliance with screening when using the one - step method .