When you obtain a surety bond, it constitutes a contract between three parties. The principal is either you or your business entity, the party that requires you to get bonded is the obligee, and the surety is the underwriter of the bond. By signing this contractual agreement, the surety grants its financial backing in your name, so that you can meet the requirements of the obligee.
Often, when getting bonded, you will be also required to complete a surety bond indemnity agreement. The difference between the general indemnity agreement (GIA) and the bond itself is subtle, but important to grasp.
The surety bond GIA is an additional contract between the principal and the surety that transfers risk from the latter to the former. It guarantees that the surety is financially protected and will receive all due payments from you, the bonded entity. As the principal, you take the role of an indemnitor who assumes full liability, while the surety is the indemnitee, which is freed from financial obligations.
Why is the GIA needed? While the bond outlines your responsibilities in front of the obligee, it does not clearly state your relationship to the surety. With the indemnity, however, the surety obtains legal protection in case it has to pay out a proven claim on your bond. This additional document confirms that you are solely in charge of reimbursing the full costs that the surety incurs due to your violations of the bond.
As the indemnity contains enforceable legal rights, it is a preferred way for sureties to have extra security that they won't suffer any losses by providing you with a bond. Instead of relying on general laws, the GIA provides actionable tools for sureties, to ensure your financial responsibility towards them.
Who needs to complete an indemnity agreement during bonding?
While obtaining a surety bond, most bond companies will require you to sign an indemnity agreement. However, there are certain cases where a signed indemnity agreement will not be required, such as for bonds that do not require credit checks. As a rule of thumb, if you're purchasing a higher risk bond, you should expect a GIA requirement.
A number of people will need to sign the indemnity agreement beyond the main bond applicants. These include all business owners and stakeholders possessing more than 10% of the company, as well as the spouse of the principal.
Owners need to sign the GIA both as individuals and in the name of their company. The reasoning is that in case the business does not have sufficient funds to cover claim costs to the surety, personal finances may be used for this purpose.
As for spouses, it's a common practice that they also need to sign the indemnity for further security. Why? In case of a proven claim, an owner may want to transfer their money to their spouse to avoid paying their obligations towards the surety. The spousal indemnity thus gives protection in such circumstances.
What are the typical obligations of a principal under an indemnity agreement?
Before you sign your surety bond indemnity agreement, it's important to get thoroughly acquainted with your duties under it. Every surety has a different version of this agreement, but there are still some common provisions you should know about.
The basic statement in the indemnity is the so-called indemnity provision. It describes the transferral of financial risk from the surety to you as the principal of the bond. Usually this provision is broad, so that it can cover different types of potential liabilities.
Another typical component of the indemnity agreement is the right to enforce the indemnity. It states, in essence, that the indemnitor guarantees full coverage of financial loss to the surety, including attorney's fees and any other expenses in relation to enforcing the GIA.
Next in the list is the right to settle provision. It transfers to the surety the right to make the final decision on whether to pay, settle, or defend a claim. By signing this, the principal agrees that the surety has full discretion and is bound by it.
Other common provisions include the right of the surety to examine your company's books and records, as well as your duty to cooperate in the investigation of claims.
How is the indemnity agreement enforced?
The main purpose of the indemnity is to secure fair compensation to the surety in case of a claim against your bond. If the principal undergoes a claim procedure and does end up having to reimburse claimants, the bond underwriter is the one who will cover the costs at first. That's why in some cases, the surety will also require a collateral that backs up your duties under the agreement.
Generally, if the bonded party defaults on its repayment towards the surety, or does not comply with other provisions in the GIA, the indemnity is the protection that the bond provider can use. It may take legal action by bringing the case to court. In that case the indemnity will be used as the basis for suing the principal. That's how the surety will be able to recover the funds it has used for the bond claim. Enforcement of the indemnity also includes the fees and expenses connected with the court case.


text:
Q: how to remove '\x01' from the result of pandas.read_csv()? Got '\x01' While reading csv file using pandas.read_csv().
Original value in csv:  width 18'' x 18'' log  "is measured A or B."   "C"   "DFG"   ""   ""
Output :  width 18\'\' x 18\'\' log\x01""is measured\x01A or B.""\x01""C""\x01""DFG""\x01""""\x01""""
pandas version : 0.25.0
python 3.6
import pandas as pd
path='data.csv'
dataframe = pd.read_csv(path,   sep="," )

I have upgraded pandas to latest version and gone through some answers, but its not working in my case.
Adding a line-terminator in pandas ends up adding another \r
https://github.com/pandas-dev/pandas/issues/7989

redpajama_set_name: RedPajamaStackExchange


text:
Currently viewing: 001 Weight of evidence | Experimental result002 Weight of evidence | Experimental result003 Weight of evidence | Experimental result004 Weight of evidence | Experimental result005 Weight of evidence | Experimental result006 Weight of evidence | Experimental result
other: see 'Remark'
Experimental data was reviewed by the ECETOC Task Force, author of the JACC Report No. 53, "Cyanides of Hydrogen, Sodium and Potassium, and Acetone Cyanohydrin (CAS No. 74-90-8, 143-33-9, 151-50-8 and 75-86-5)", 2007. The report is a weight of evidence approach to an extensive body of literature, much of which was undertaken prior to development of guidelines. The report was peer reviewed by the scientific non-governmental ogranization (NGO), which judged the data to be reliable with rescriptions.
review article or handbook
cohort study (prospective)
no guideline available
measurement of thyroid gland size, serum measurements of thyroid hormone
Hydrogen cyanide is delivered as a component of cigarette smoke.
Several scientists have studied goitre in European and African populations in relation to the thiocyanate level in serum and/or the urinary iodide excretion per day (Bourdoux et al, 1978; Cliff et al, 1986; Knudsen et al, 2000). Knudsen et al (2000) studied two Danish cohorts with different iodine excretion levels, both of which were iodide deficient. They observed a higher incidence of thyroid enlargement with decreasing urinary iodide excretion. Knudsen et al (2002) found an association between smoking and thyroid enlargement that was more pronounced at higher iodine deficiency. It is not possible to draw a simple correlation between the incidence of goitre and blood thiocyanate levels without considering the impact of dietary iodide. This general conclusion is consistent with the work of Hennart et al (1982), who suggested that thyroid effects were critically dependent on the ratio of iodine and thiocyanate intake and proposed that a urinary iodinethiocyanate ratio (as μg Iodide ion/mg SCN ion) of greater than 4 would indicate no concern for thiocyanateinduced goitre.
The data of Knudsen et al (2002) seem to suggest that, in heavy smokers (> 30  40 cigarettes/d), serum thiocyanate levels of 150 ± 50 μmol/l led to an increase in thyroid size. In nonsmokers, similar serum thiocyanate levels resulted in increases to about 14 ml in the case of a mild iodine deficiency and to 17 ml in the case of moderate iodine deficiency. The latter group would just reach the borderline of a normal adaptive response in the case of females (no gender differentiation was made in the publication). Interestingly, the authors also reported that the thyroid size in exsmokers was approximately the same as in nonsmokers, indicating reversibility of the effect.
Knudsen et al, 2002 has correlated increased incidences of thyroid enlargement to heavy smoking, in particular when combined with iodine deficiency. However, these studies often did not provide information on the corresponding thiocyanate levels.
Information on thiocyanate serum levels in smokers can be drawn from large studies that have determined serum thiocyanate concentrations in smokers and nonsmokers in order to get an objective measure of cigarette consumption (Scheuermann et al, 1991 cited by Knudsen et al, 2000, 2002; Tsuge et al, 2000).
There is a high variation of serum thiocyanate in nonsmokers (55 ± 30 μmol/l, Scheuermann et al, 1991 cited by Knudsen et al, 2002). This wide distribution means that the range of measured data is between 18 and 128 μmol/l serum (i.e. 2.5 and 97.5 percentile, respectively). This high variation obviously did not lead to thyroid malfunctioning. The reason for this high variation was probably related to diet.
The definition of goiterasused by different authors is not identical and has been a matter of debate. Thyroid enlargement is essentially an adaptive and reversible process. A pathological enlargement of thyroid is defined as 4 to 5 times the normal thyroid size. The technique of ultrasonography enables determination of the thyroid size more accurately in comparison with palpation and visible enlargement. Differences in volume of a few ml (10% to 20%) can be measured as a significant change. Nevertheless, if the thyroid is visibly enlarged with or without extended neck, the thyroid size has been increased by a factor of 4 to 5 and is called goitre (Delange 1999; Knudsen et al, 2002). Knudsen et al (2000) defined the diagnosis 'thyroid enlargement' by a thyroid volume of more than 25 ml in men and more than 18 ml in women.
Thiocyanate is a competitive inhibitor of iodide absorption by the thyroid. The effect of thiocyanate is compensated for by an increase in TSH release from the pituitary in order to maintain the appropriate T3 and T4 thyroid hormonelevelsin the blood. This isachievedby increasing the thyroid volume by increasing the thyrocyte volume.
In order to better define the borderline between adaptive and pathological changes in thyroid size in connection with thiocyanate exposure, the ECETOC Task Force compared the reported changes in thyroid size and related them to the serum thiocyanatelevelsand the iodine status. The normal thyroid size in a population with borderline iodine deficiency (70 μg iodide/l urine) was reported to be about 12 ml for men and 10 ml for women (Knudsen et al, 2000). Barrère et al (2000) observed a strong relation between thiocyanate level in the urine and the thyroid size in the healthy French population with borderline iodine deficiency. The thiocyanate level in serum was strongly related to smoking. These authors developed a regression equation which describes the increase of thyroid size with increasing urinary thiocyanate excretion under the condition of borderline iodine deficiency.
Thiocyanate is a competitive inhibitor of iodide absorption by the thyroid. The effect of thiocyanate is compensated for by an increase in TSH release from the pituitary in order to maintain the appropriate T3 and T4 thyroid hormone levels in the blood. This is achieved by increasing the thyroid volume by increasing the thyrocyte volume.
In order to better define the borderline between adaptive and pathological changes in thyroid size in connection with thiocyanate exposure, the ECETOC Task Force compared the reported changes in thyroid size and related them to the serum thiocyanate levels and the iodine status. Barrère et al (2000) observed a strong relation between thiocyanatelevelin the urine and the thyroid size in the healthy French population with borderline iodine deficiency. The thiocyanate level in serum was strongly related to smoking. These authors developed a regression equation which describes the increase of thyroid size with increasing urinary thiocyanate excretion under the condition of borderline iodine deficiency.
Itseemsthat small changes in iodide supply (assumed to be in equilibrium with urinary excretion)havea measurable impact on thyroid size. If the urinary iodide excretion is less than 20 μg/d, the incidence of goitre increases to more than 60%. The influence of thiocyanate on the thyroid size is marginal in comparison with lack of iodine. The data of Knudsen et al (2002) suggests that, in heavy smokers (> 30  40 cigarettes/d), serum thiocyanate levels of 150 ± 50 μmol/l led to an increase in thyroid size. In nonsmokers, similar serum thiocyanatelevelsresulted in increases to about 14 ml in the case of a mild iodine deficiency and to 17 ml in the case of moderate iodine deficiency. The latter group would just reach the borderline of a normal adaptive response in the case of females(no gender differentiation was made in the publication).
Interestingly, the authors also reported that the thyroid size in exsmokers was approximately the same as in nonsmokers, indicating reversibility of the effect. The findings of Knudsen et al are in accordance with the data of Cliff et al (1986) who reported small adaptive changes in thyroid hormones, but no increased goitre incidence, in a cassavaeating noniodine deficient population with serum levels of about 250 μmol SCNion/l (14.5 μg/ml). They also agree with the data of Barrère (2000), who reported an increased thyroid volume of 15.1ml in male French smokers (compared to 12.1 ml in non smokers) in a slightly iodine deficient population. According to the criteria above, this would also be regarded as an adaptive response rather than a pathological change.
Hennart et al (1982) suggested that thyroid effects of cyanide were critically dependent on the ratio of iodine and thiocyanate intake and proposed that a urinary iodinethiocyanate ratio (as μg I ion/mg SCN ion) of greater than 4 would indicate no concern for thiocyanateinduced goitre.
However, the impact of an increase of thyroid size through thiocyanate exposure will depend on the size of the thyroid before exposure. If the thyroid is small, the increase of volume will not be visible. If, due to lack of iodine uptake, the volume of the thyroid is already 24 ml, then an increase in thyroid size of 25% will increase the volume to 30 ml, which would be diagnosed as a thyroid enlargement. So, increased thiocyanate in serum may increase the incidence of thyroid enlargement and ultimately of goitre at low iodine intake. In the case of sufficient iodine supply, the influence of increased thiocyanate will not result in malfunction of the thyroid pituitary axis. Hence, changes in thyroid size might be regarded as a physiological adaptation to variable levels of thiocyanate in blood.
This is an epidemiologic study which underscores the importance of baseline dietary iodine levels in susceptibility to cyanide associated goitre. Populations of unexposed Danes were monitored for their iodine and thiocyanate levels. The authors of the study found a wide distribution in the range of measured data, between 18 and 128 μmol/l serum (i.e. 2.5 and 97.5 percentile, respectively), in the unexposed population. This variation did not lead to thyroid abnormalities. Smoking about 30  40 cigarettes per day increased serum thiocyanate levels to 150 ± 50 μmol/l, and led to goitre development. However, a baseline deficiency of iodine was more critical to thyroid gland enlargement than was inhaled cyanide from cigarette smoking.

redpajama_set_name: RedPajamaCommonCrawl


Investor Overview | Meta Financial Group, Inc.
Meta Financial Group, Inc.® (NASDAQ Global Market®: CASH), headquartered in Sioux Falls, S.D., is the holding company for MetaBank®, a federally chartered savings bank, Member FDIC.
SIOUX FALLS, S.D. , April 10, 2019 (GLOBE NEWSWIRE) -- Meta Financial Group, Inc. ® (Nasdaq: CASH) ("Meta" or the "Company") announced that it will release financial results for the second quarter of fiscal 2019 on Thursday, April 25, 2019 , after market close.


Any form of X-ray exposure should be carefully monitored and controlled, so that the patient is only exposed to safe amounts. Even though X-ray users are extremely careful when exposing their patients to diagnostic tests, where radiation is involved, it is important to bear in mind how low the risks really are, especially when compared to other forms of radiation exposure. As with any kind of medical procedure, X-rays are safe when they are used properly. When clinically indicated, properly conducted imaging with the smallest risk should be performed. In this study, the optical densities, OD, of adult mammograms, undergoing X-ray exposures was measured from the radiology department of the University of Benin Teaching Hospital (UBTH), Benin City, Edo State, Nigeria, with the aid of a densitometer, model MA 5336. The measured optical densities were used to estimate the X-ray radiation dose to patients, undergoing mammography, for the purpose of Quality Assurance (QA) and Quality Control (QC), in diagnostic and screening. A total of fifty (50) adult mammograms were collected for use in the radiology department of the hospital. The optical densities were measured five times at different spots across the image of each of the mammograms and the mean were obtained, in other to estimate the absorbed dose. The results obtained showed that the mean dose was 0.48 mGy, minimum dose 0.04 mGy, maximum dose 1.07 mGy, range of dose 1.03 mGy, SD 0.24, kurtosis 2.77, 1st Q 0.34 and 3rd Q 0.66. These results were in agreement with those of the International Atomic Energy Agency (IAEA), guidance levels in X-ray guided medical interventional procedures.
Akinlade, B. I., Odefemi, F. B. and Farai, I. P. (2016). Overview of radiation dose to patients from medical X – ray examinations in Nigeria. Afr. J. Med. Sci. 45, 23 – 29.
NCRP (National Council on Radiation Protection and Measurement) (1987). Ionizing radiation exposure of the population of the United States. NCRP 1987, report 93.
Ajayi, I. R. and Akinwumi, A. (2000). Measurement of entrance skin doses to patients in four common diagnostic examinations by thermo luminescence dosimetry in Nigeria. Radiat. Prot. Dosim. 2000; 87(3): 213 – 220.
Boerma M, Nelson GA, Sridharan V, Mao XW, Koturbash I, Hauer-Jensen M. Space radiation and car-diovascular disease risk. World J Cardiol. (2015). 7(12):882–8. Epub 2016/01/06. https://doi.org/10.4330/wjc.v7.i12.882 PMID: 26730293.
Lu T, Zhang Y, Wong M, Feiveson A, Gaza R, Stoffle N, et al. Detection of DNA damage by space radiation in human fibroblasts flown on the International Space Station. Life Sciences in Space Research. (2017). 12 (Supplement C):24–31. https://doi.org/10.1016/j.lssr.2016.12.004.
Dobrzynski L, Fornalski KW, Feinendegen LE. Cancer Mortality Among People Living in Areas With Various Levels of Natural Background Radiation. Dose Response. (2015). 13(3):1559325815592391. Epub 2015/12/18. https://doi.org/10.1177/1559325815592391 PMID: 26674931.
Medlin D, Heffron W, Siegel A, Wilson K, Klingenberger A, Gall A, et al. Development of an x-ray irradiation port for biomedical applications at the CUEBIT facility. Journal of Physics: Conference Series. (2015). 583(1):012048.
Mykyta Sokolov and Ronald Neumann (2016). Global Gene Expression Alterations as a Crucial Constituent of Human Cell Response to Low Doses of Ionizing Radiation Exposure. Int. J. Mol. Sci. (2016). 17, 55.
Mervyn D Cohen (2018). Is there a risk of getting cancer from radiation from medical diagnostic imaging? J Radiol Med Imaging. 2018; 1: 1005.
GAMMEX (2016). Film Densitometer Peripheral Technical Manual, Model 5336. GAMMEX Middleton, WI, USA.
Scarlat, F., Scarisoreanu, A., Oane, M., Mitre, E., Badita, E. (2008). Determination of Absorbed Dose Using a Dosimetric Film. IX Radiation Physics & Protection Conference, 15 – 19 November, 2008, Nasr City, Egypt. 313 – 321.
Artur, T. (2003). Determination of Absorbed X-ray Radiation Dose in X-ray Diagnostics and Imaging. J. Med. Sci. 1 (2); 31-36.
IAEA (International Atomic Energy Agency) (Safety Reports Series No. 59). Establishing Guidance Levels in X – ray Guided Medical Interventional Procedures: A Pilot Study. Safety Reports Series No. 59.
NBIRR (Nigeria Basic Ionizing Radiation Regulation) (2003).
ICRP (International Commission on Radiological Protection) (1996). Radiological Protection and safety in Medicine, Publication 73 (Oxford and New York: Pergamon Press).


text:
Q: data manipulation with na values My code are like that df2 DataFrame (toy data) :
import pandas as pd
import numpy as np

end = '20201117'

np.random.seed(107)
df = pd.DataFrame()
for i in range(10):
    start = np.random.choice(['20000101', '20100101', '20160101', '20121010'])
    df_tempo = pd.DataFrame({'product': 'p'+str(i),
                             'category': 'cat'+str(np.random.choice(4))
                             },
                            index=pd.bdate_range(start=pd.to_datetime(start),
                                                 end=end,
                                                 freq=np.random.choice(['D', 'W'])))

    df_tempo['valeur1'] = np.random.randint(50, 100, df_tempo.shape[0])
    df_tempo['valeur2'] = np.random.randint(100, 200, df_tempo.shape[0])
    df = pd.concat([df, df_tempo])
df = df.reset_index().rename(columns={'index': 'date'})

df2 = df.pivot(index='date', columns=['category', 'product'], values=['valeur1', 'valeur2'])

from this I would like to calculate the growth rate for 2020, 2019,..years
I tried :
df2.apply([
    lambda x: 100*x.valeur1[x.valeur1['2020'].last_valid_index()]/x.valeur1[x.valeur1['2019'].last_valid_index()]-100,
         ])

but get an error message with is (I would like to calculate different stat for valeur1 and valeur2) :
AttributeError: 'Series' object has no attribute 'valeur1'

so I did (it's not what I would like to do because as I said I would like to apply different stat on valeur1 and valeur2) :
df2['valeur1'].apply([
    lambda x: 100*x[x['2020'].last_valid_index()]/x[x['2019'].last_valid_index()]-100,
    lambda x: 100*x[x['2010'].last_valid_index()]/x[x['2009'].last_valid_index()]-100,

         ])

It works except that
lambda x: 100*x[x['2010'].last_valid_index()]/x[x['2009'].last_valid_index()]-100

because I have data series that have no data for 2010 and so return an error.
I tried then a dropna()but not help
Any ideas to help on these 2 problems ?

A: Since date is already the index of df2, pd.Grouper(freq="Y").last() can be used to retrieve the value on the last date. Is this what you are expecting?
Note: df2 = df2.groupby(pd.Grouper(freq="Y")).ffill() will fill the last date of each year with previous valid value(s). For this sample dataset, however, no difference was introduced.
Code
df_last = df2.groupby(pd.Grouper(freq="Y")).last()
out = df_last.diff() / df_last.shift() * 100

Result
print(out)

              valeur1                        ...    valeur2
category         cat0                  cat2  ...       cat0                  cat2
product            p0         p1         p2  ...         p7         p8         p9
date                                         ...
2000-12-31        NaN        NaN        NaN  ...        NaN        NaN        NaN
2001-12-31        NaN  62.000000 -35.869565  ...        NaN -37.113402        NaN
2002-12-31        NaN   8.641975  28.813559  ...        NaN  13.934426        NaN
2003-12-31        NaN -40.909091  19.736842  ...        NaN  30.935252        NaN
2004-12-31        NaN  25.000000 -30.769231  ...        NaN -18.131868        NaN
2005-12-31        NaN -20.000000  57.142857  ...        NaN -18.791946        NaN
2006-12-31        NaN  19.230769 -15.151515  ...        NaN  14.049587        NaN
2007-12-31        NaN  25.806452 -40.476190  ...        NaN  -5.072464        NaN
2008-12-31        NaN  -1.282051   4.000000  ...        NaN  32.824427        NaN
2009-12-31        NaN   7.792208  38.461538  ...        NaN  -9.770115        NaN
2010-12-31        NaN -33.734940 -26.388889  ...        NaN  12.738854        NaN
2011-12-31        NaN  29.090909  83.018868  ...        NaN -12.994350  43.442623
2012-12-31        NaN -19.718310 -40.206186  ...        NaN  -5.194805  13.142857
2013-12-31        NaN  17.543860  34.482759  ...        NaN  12.328767 -19.696970
2014-12-31        NaN   8.955224  23.076923  ...        NaN -22.560976 -18.867925
2015-12-31        NaN  -6.849315 -14.583333  ...        NaN  43.307087  23.255814
2016-12-31        NaN  33.823529  -7.317073  ...        NaN -22.527473  -6.289308
2017-12-31 -22.580645 -35.164835  -2.631579  ...  -8.176101  10.638298 -22.818792
2018-12-31  -6.944444  55.932203   5.405405  ... -30.821918   1.923077  35.652174
2019-12-31  14.925373  -8.695652  -1.282051  ...  70.297030  -6.918239  19.230769
2020-12-31   2.597403   8.333333 -20.779221  ... -28.488372  -6.081081 -17.204301

[21 rows x 20 columns]


text:
Main Area and Open Discussion > Living Room
Microsoft ending TechNet subscription activations effective august 2013
<< < (6/6)
40hz:
If MS cracks down harder it'll be rats off a sinking ship time for sure.
-Stoic Joker (July 12, 2013, 04:17 PM)
--- End quote ---
I'd liken it more to: The eagles take flight, leaving the ship - with it's unfortunate complement of rats and domestic animals - to face their tragic fate.
Ah...poetry! :-* And before my first cup of coffee no less. It's gonna be a good day! :Thmbsup:
Renegade:
-40hz (July 13, 2013, 10:11 AM)
I rather like that! :D
Actually, it reminds me of Ben Franklin's take on the eagle, but lets not sully the moment. :D
:Thmbsup:
wraith808:
Well, sooner or later, unless they start reversing course like they did for the XBone, they're going to start seeing more and more of this as others take advantage of their arrogance...
x16wda:
Ooh, look. Finally they have come to their senses. Yay.
We have extended your TechNet Subscription for an additional 90 days.
On July 1, 2013, Microsoft announced the retirement of the TechNet Subscriptions program. Since then, we've been listening to your feedback on how we can better support the IT professional community through this transition.
More background on Microsoft's decision to retire the TechNet Subscription service and the implications for current subscribers is available on the TechNet Subscriptions FAQ.
Two of the most common pieces of feedback we heard are that you need more time to prepare for this change, and ongoing access to prior versions of Microsoft software. As a result, we're announcing the following updates:
•Eligible subscribers with active accounts as of September 1, 2013 will receive a free, one-time, 90 day subscription extension. You can continue to access your product downloads, use your professional support calls*, and get priority support in TechNet Forums through your updated expiration date, which you can find on the My Account page of the TechNet Subscriptions benefits portal.
•As TechNet Subscriptions customers begin to transition to the free evaluation resources Microsoft provides, we're improving the TechNet Evaluation Center by making prior versions of products available for trial. Windows 7, Windows Server 2008 R2, and others are available now. We will add additional products over time.
We appreciate your feedback and will continue to invest in free evaluation, learning, and support resources to meet your business needs and career goals.
- TechNet Subscriptions Team
* The professional support calls benefit is only available to TechNet Subscription Professional subscribers.
Microsoft respects your privacy. Review our online Privacy Statement.
One Microsoft Way
Redmond, WA, USA 98052


The 34th All India Conference on "Communication Strategies for Travel and Tourism" organised from 29th September to 1st October, 2012 in Shimla by Public Relations Society of India was a unique conference of its kind. The participants from different parts of the country and abroad took part in the conference and PR practitioners, communicators more than 200 in number from Government, Private and Public Sector Undertakings participated in the Conference and renowned experts from various parts of the country from renowned institutions, Media Institutions and abroad expressed their views in six business sessions organised during 3 day conference. Perhaps this was for the first time that such meaningful conference had been held in Shimla.
From the deliberations of the Conference it emerged that tourism has become integral part of economy of the world and the facilities and tourism destinations should be promoted in the right perspective and it is the need of the hour to sell the experiences not the destination. For this, right communication strategies would have to be adopted.
A. Juggessuer, the High Commissioner of Mauritius, Chief Guest at the inaugural session of conference highlighted the tourism development in Mauritius. He said that tourism had vital impact on local and national economy and now, various organizations were taking services of Travel and Tourism Agencies for branding their image. He said that tourism contributed 8.4 percent in the total GDP of Mauritius and political stability, sustainable environment effective policy had resulted to boost tourism in the country.
Ajay Mittal, Additional Chief Secretary who presided over the inaugural session stressed upon the need of development of tourism and highlighted the role of communicators in it. During this three day conference, six sessions were organised and more than 200 delegates from various parts of India and abroad expressed their views.
Bhim Sen, Chief Information Commissioner said that the role of Public Relations had become more important in the era of globalization and liberalization and it has become important part of every institution. He said that tourism had become most important source of livelihood.
Ajit Pathak, National Chairman, PRSI said that job of PR was building images and the PR professionals should abstain from indulging in unethical practices which may harm the organizations.
Dr.C.V. Narsimha Reddy former National President, PRSI and Editor of 'Public Relations Voice' said that tourism development can be successful only when there was effective PR of any organization.
MJA Sheehan, Editor, Asia Pacific Public Relations Journal, School of Communication and Creative Arts, Deakin University, Australia expressed his views on 'The Language of Tourism: Perfecting Soft Skills in a flat world. Prof. Vibhavari Kumar, Chairperson, Fashion Communication Department, NIFT New Delhi expressed her views on 'Fashion Tourism'.
Shri R.P. Singh, Chairman and Managing Director, Satluj Jal Vidyut Nigam, Shimla and Shri N.L. Sharma, Director (Personnel), SJVNL spoke on 'Corporate Social Responsibility: Launching Pad for Repositioning Corporate Image while Shri Tej Bahadur Mathur, Head, Corporate Communication and CSR, Hindalco, Renukoot expressed his views on 'Employees as Ambassadors of Corporate Organizations'.
Shri Unmesh Dikshit, Vice President (West), PRSI stressed the role of communicators in the promotion of tourism. Ms. Monisha Mitra, Managing Director, White Paper Consulting, New Delhi spoke on 'Communication that can hold your tourists back with you'. Shri Anuj Dayal, Head (Corporate Communication) of Delhi Metro, New Delhi delivered on 'International Tourism Potential of Metro Trains. Shri Madan Bahal, Managing Director, Adfactors PR Pvt. Ltd., Mumbai expressed his views on 'Financial Communication'.
Shri Dinesh Kumar, Associate Editor, The Tribune and Shri Himangshu Vatts, Senior Editor, The Economic Times, New Delhi expressed their views on 'Making Corporate Communications more saleable to Media' while Shri Philip Abraham, Head (Corporate Strategy and Marketing) REI Six Ten Retail Ltd., New Delhi delivered on 'Social Media as a PR tool in travel and tourism sector'. Shri Manjul Tiwar from NTPC, New Delhi spoke on 'Sustainability and Branding'.
Shri Y Babji, Vice President (South), PRSI expressed views on role of media and Smt. Manju Wadhwalkar, Head Corporate Communications, PGI, Chandigarh expressed views on 'Medical Tourism-Strengthening International Bonds'. Shri Sanjay Roy, Vice President (Corporate Communications), DLF, Gurgaon spoke on 'Golf as a tool for Tourism Promotion'. Prof. Ram Ji Tripathi, Makhan Lal University, Bhopal expressed his views on 'Catalyst Role of Media in Tourism Promotion'.
It is pertinent to mention here that PRSI, Shimla Chapter came to existence in 2006 and has been conferred PRSI National Awards for three times. Shri B.D. Sharma, Chairman, PRSI, Shimla Chapter had been conferred Best Chairman Award twice in 2009 and 2012.


Anette Freytag, ed., The Gardens of La Gara: An 18th-Century Estate in Geneva with Gardens Designed by Erik Dhont and a Labyrinth by Markus Raetz (Zurich: Scheidegger and Spiess, 2017), 272 pages, ISBN: 978 38588 18027, $99 / £85.
La Gara is an 18th-century country estate in Jussy, a village near Geneva, Switzerland. The buildings have been carefully restored by Swiss architect Verena Best, who also added inspired touches to the interior design. The renowned Belgian landscape designer Erik Dhont reinterpreted and subtly redesigned the gardens and surrounding grounds, completed by a palindrome-like labyrinth designed by Swiss artist Markus Raetz. This new book tells the story of the La Gara estate and illustrates its beauty. The essays investigate its preservation and restoration of buildings and gardens and the contemporary interventions. They highlight features such as the historic watering system for the gardens and the fishponds and look at the specific Genevan garden tradition and characteristics of the rural landscape around Jussy with its biodiversity. Moreover, they contextualise La Gara with the 'ferme ornée', a villa with agricultural and ornamental features following ancient Roman models. The beautiful volume is rounded out with newly commissioned photographs by renowned Swiss photographer Georg Aerni.
Anette Freytag is Professor of Landscape Design at Rutgers University in New Brunswick, New Jersey.


Firefox 3+ version has always been promising and got better always, and now its the next version Firefox 3.6 going to be released soon, and you can download the release candidate which is the version just prior to the public release. The preview version is available for free, and more than 75% of the add-ons are going to come with upgrades that are compatible with the 3.6 version.
There are a lot more changes and improvements made from the earlier versions. To get a sneak peak and try the new version, download the Firefox 3.6 release candidate from here.
Upgrading is one feature of Mozilla Firefox that makes it more special than other Web browsers.


text:
De Vorobjovy Gory (Russisch: Воробьёвы горы; mussenheuvels), tussen 1935 en 1999 Leninskie Gory (Ленинские горы: Leninheuvels), zijn een hoogte ten zuidwesten van het centrum van Moskou en zijn daarmee een van de hoogste punten van de stad. De hoogte ligt op 220 meter boven zeeniveau; de relatieve hoogte ten opzichte van de Moskva bedraagt ongeveer 65 meter.

De hoogte bevindt zich niet ver van het Olympisch Stadion Loezjniki, waar de openings- en sluitingsceremonie, alsmede de atletiekwedstrijden van de Olympische Spelen van 1980 plaatsvonden. Ook het Novodevitsjiklooster met de Novodevitsjibegraafplaats zijn vlakbij. Het gelijknamige metrostation Vorobyovy Gory is een van de weinige metrostations van Moskou die bovengronds liggen. Het metrostation Vorobjovy Gory
bevindt zich ín een brug boven de Moskva. Het bekendste gebouw op de heuvels is het hoofdgebouw van de Staatsuniversiteit van Moskou.

De heuvels spreken een belangrijke rol in de roman De Meester en Margarita van Michail Boelgakov.

Berg in Rusland
Heuvel
Moskou

redpajama_set_name: RedPajamaWikipedia


I turned to a favorite food blog for a little inspiration, Pinch of Yum. Keeping up with the food blogs I read regularly had also fallen by the wayside as I grieved during December, and I vaguely remembered that when I last read POY, Lindsay, the author, had announced her pregnancy with a baby boy. As I pulled up her page and realized that her most recent posts were a 10 part series chronicling the loss of that same sweet baby boy at 23 weeks I felt absolutely devastated. I sobbed as I read through her posts. Her photographs were so beautiful and her words so eloquent and they mirrored so many of those same feelings I had and continue to feel. It was a very surreal moment, sitting on my couch, weeping for someone I've never met but suddenly felt very close to. The internet is both weird and wonderful in that way, I suppose.
One of the things that struck me about Lindsay's writing was how hope permeated her grief. I am a natural worrier, so hope is sometimes… difficult… for me. The anxiety and worry manifests itself differently but lately and predictably it has centered around what if I can't get pregnant again? Understandable, perhaps, but as of yet unfounded, and although I know this logically I've thought about it many, many times over the last few months. A few days after reading Lindsay's blog I stumbled across a totally unrelated news article. The article was on one of those news sites that is formatted so that you scroll down from one article to the next with no page breaks. As soon as you finish whatever article you're reading you're hit with the headline for the next one. I am clearly the intended audience for this strategy as I often find myself still reading 5 articles later after the initial one I clicked on. I finished the unrelated article and was struck by the headline of the one just below it: Mom Stuns Doctors By Beating Deadliest Brain Cancer.
The woman in the article was 6 years cancer free after being diagnosed with a stage 4 glioblastoma. When asked why she thought she was still alive today, her answer was two fold. First, and I would have to agree, she believes God has a bigger plan for her. Second, and this is the part that really struck me, she never thought cancer would kill her. She claims that she never lost hope, that she never once thought she would die from cancer, and she hasn't. Mind over matter in the most extreme sense. I finished that article (and didn't scroll down to the next one) and felt like a little light bulb went off. I know my mind is powerful. I have literally worried myself sick before and in the same sense, physical symptoms have sometimes disappeared as my mind has been put at ease. I don't doubt that believing she would live is one of the main reasons that woman is alive today. I want my mind to have that kind of positive power too.
This past week, I have tried very hard to keep that article in mind, and not to worry quite so much, especially about getting pregnant again. It's a struggle, but I am trying, and I will continue to. I think worrying less means living in the moment more. So I'm trying to fully enjoy the things that I can do in this moment because I'm not pregnant, like drink champagne, eat sushi and plan a trip somewhere far away. I'm also trying to slow down and enjoy that I am feeling more like myself again, physically and mentally, urge to cook included, because that truly is a blessing in and of itself.
So what did I make? I wanted something comforting (and easy) so soup it was. It was delicious soup, and I do plan to share it, but first things first, the chicken.
I believe it's a dough blade but since I don't make bread (yet) I use it to shred chicken. Unlike a metal blade which will turn your chicken into mush, this plastic one shreds it perfectly every time. I pop my chicken breasts in the crock pot on low for 6-8 hours, and when they are done they go into the food processor where I pulse them about 10 times or until you reach your desired level of shred. I know, two forks are somewhat easier to clean but this literally takes a fraction of the time and is so worth it if you already have the equipment.


text:
The Head of ICE Just Admitted Immigrants Are No More Dangerous Than Native-Born Americans
And that same day, the House of Representatives passed a bill that would cut funding to sanctuary cities.
Kate Wheeling
People walk through John F. Kennedy airport on June 26th, 2017.
(Photo: Spencer Platt/Getty Images)
In an off-camera White House briefing on Wednesday afternoon, Thomas Homan, the acting director of Immigration and Customs Enforcement, admitted that undocumented immigrants do not, in fact, commit more crimes than Americans.
Homan's statement, while backed by decades of research, undermines the Trump administration's contention that unauthorized immigrants are more likely to be dangerous or violent compared to native-born Americans. President Donald Trump went so far as to create a new office in the Department of Homeland Security—the Victims of Immigration Crime Engagement—for the victims of crimes committed by undocumented immigrants.
First- and second-generation immigrant offending trajectories.
(Chart: Justice Quarterly/Pew Research Center)
Homan's acknowledgement does not mean that ICE, or the administration more broadly, will be backing off of its aggressive immigration agenda. "If you're in this country illegally and you committed a crime by being in this country, you should be uncomfortable, you should look over your shoulder," Homan said earlier this month before the House Appropriations Committee.
Also on Wednesday, the House of Representatives passed the No Sanctuary for Criminals Act, which would cut funding to sanctuary cities. The House is expected to vote on Kate's Law later this week, which would introduce mandatory minimums for undocumented immigrants who re-enter the United States after deportation.
"These bills can restore sanity and common-sense to our system by ending abusive attempts to undermine federal law, and they can prevent future tragedies by empowering law enforcement," Attorney General Jeff Sessions said in a statement in support of the bills. "I urge the House of Representatives to put the American people first before another family loses their child."
Immigration And Customs EnforcementNEWSImmigrationDonald TrumpCrimeCharts
Kate Wheeling is a staff writer at Pacific Standard, where she specializes in criminal justice and the environment.
Starry, Starry Skies
California desert town takes back the night, wins rare "Dark Sky" award
What Is the Future of Paid Parental Leave in America?
The U.S. has a rough track record with how it treats new parents, but there are reasons to believe that this could soon be a thing of the past.
These Maps Show What Graham-Cassidy Would Mean for Your State
A new report concludes that the Graham-Cassidy proposal would reduce federal funding to states by $215 billion by 2026.
The Fault in Our Star Names
The International Astronomical Union has established a committee to finalize a list of official star names. Some companies offer unofficial naming rights for purchase. But the voices of certain communities are often left behind.
How Much Can Dietary Changes and Food Production Practices Help Mitigate Climate Change?
Food policy experts weigh in on the possibilities of individual diet choices and sustainable production methods.
Unseen America
Las Manos Jóvenes Que Nos Alimentan
Se calcula que 524,000 niños trabajan inimaginables largas horas en los agotadores campos agrícolas de Estados Unidos, y todo es perfectamente legal.


text:
Home> Distributed Computing
by Ryan Smith on April 16, 2020 10:00 AM EST
Oh god oh god we're all going to die
Just under a month ago, I put out the call: AnandTech's readers were needed once more to defend the honor of the site in the most nerdy of contests: a Folding@Home race.
The distributed computing platform has been around for over a decade now, and it has taken on a new life as the novel coronavirus, SARS-CoV-2, has shut down a significant part of society. In light of the now global pandemic, the project has turned its eyes to trying to simulate the virus and potential treatment avenues for it, in order to hopefully speed up the development of a cure. A task that has been met with great enthusiasm from the public, as the combined power of the Folding@Home project has recently surpassed 2.4 ExaFLOPS, making it over an order of magnitude more powerful than any supercomputer in the world.
Overall, the project's coronavirus research has come not a moment too soon, as many of us find ourselves essentially confined to our homes. And, after more than a month of this, we're all starting to go more than a little mad. So mad, in fact, that AnandTech and Tom's Hardware agreed to race each other over a four week period to see who could contribute the most to the Folding@Home project.
Those four weeks are finally up, and I am proud to report that Team AnandTech has emerged victorious, defeating our loyal opposition by over a billion points. It was, perhaps, never too close of a race, but I also know that the Tom's Hardware readership (and its leadership) is never one to underestimated. So while Team AnandTech can take this moment to enjoy a victory lap in defeating its favorite punching bag for the third time in a row, it was a hard-fought race on both sides, and ultimately it all went to a good cause.
Folding@Home Race Results
Team Points
Team AnandTech 5,513,255,966
Tom's Hardware 4,419,576,007
As always, I'd like to thank the AnandTech readers who chipped in to help with this race, as well as the Team AnandTech members who supplied their own computing power, as well as contributing to the stats tracking and other functions needed to host a proper race. To say that AnandTech couldn't have done it without all of you is an understatement, and this is ultimately your victory.
Meanwhile, although we're still not out of our home quite yet, hopefully the combined 9.9 billion points worth of work completed by Team AnandTech and Tom's Hardware gets us one step closer to developing effective treatments for COVID, and getting everything at least a little bit back to normal.
Carousel Image Courtesy of: CDC/Alissa Eckert, MS
blaktron - Thursday, April 16, 2020 - link
Gamer's Nexus is doing 7m a day with a single box lol.
hehatemeXX - Thursday, April 16, 2020 - link
I'm not here to call you out, but what box is doing 7m a day? My 32/64t server doesn't even get that.
drexnx - Thursday, April 16, 2020 - link
two tesla V100s and a 3990x, iirc
"We recently saw Linus getting involved in Folding @ Home with 6 Titan Vs doing 15-16 million points per day, so we decided to turn on two of our Tesla V100 video cards and contribute about 7.6 million points per day. We're hoping that we can soon follow-up with an extreme overclocking F@H challenge" -GN news article
mode_13h - Friday, April 17, 2020 - link
Maybe AT should team up with Toms against Linus. If we'd still be hopelessly outmatched, maybe enlist STH or others.
TennesseeTony - Thursday, April 16, 2020 - link
A single RTX2080Ti gets just over 3M ppd under Linux. Likewise an EPYC Rome with 128 threads also gets about 3M ppd.
blckgrffn - Thursday, April 16, 2020 - link
Considering how hard it was to get consistent WU's, this was far from a set it and forget it race. Great work everyone :)
nandnandnand - Thursday, April 16, 2020 - link
The race isn't over until a vaccine is created and deployed, in around 36 months.
Drumsticks - Thursday, April 16, 2020 - link
Anandtech's team was generating 196M points a day, on average, it looks like. Toms generating 157M a day. There was plenty of trouble getting work units too, I think, so it's hard to say what the true potential of any given setup was.
It might not be a single box, but every computer piling in helps!
(repost because I meant this to be a top level comment)
LordanSS - Thursday, April 16, 2020 - link
Indeed... left alone my machines would go hours (sometimes over 12-14hrs!!) without receiving a new WU.
I was happy to help AT a bit and will keep churning whenever I can for the next several months.


text:
En calcul de propositions, la barre de Sheffer, nommée d'après Henry M. Sheffer, notée « | » (voir barre verticale, à ne pas confondre avec « || » qui est souvent utilisé pour représenter la disjonction), « Dpq », ou « ↑ » (une flèche pointant vers le haut), désigne une opération logique qui est équivalente à la négation de la conjonction logique, exprimée « pas les deux à la fois » dans le langage ordinaire. Il est aussi appelé nand (« non et »), car il dit en effet qu'au moins l'un de ses opérandes est faux. En algèbre booléenne et en électronique numérique, il est connu sous le nom de lopération NON-ET.

Comme son dual, l'opérateur NON-OU, NON-ET peut être utilisé par lui-même, sans aucun autre opérateur logique, pour constituer un système formel logique. Cette propriété rend la porte NON-ET cruciale pour l'électronique numérique moderne, y compris son utilisation dans la mémoire flash NAND et la conception d'un processeur d'ordinateur.

Définition
L'opération NON-ET est une fonction logique sur deux valeurs logiques. Elle produit une valeur vrai, si — et seulement si — au moins une des propositions est fausse.

Table de vérité
La table de vérité de A NON-ET B (aussi noté A | B, Dpq, ou A ↑ B) est la suivante :

Histoire
La barre est nommée d'après Henry M. Sheffer, qui en 1913 a publié un document dans les Transactions of the American Mathematical Society (Sheffer 1913) fournissant une axiomatisation des algèbres booléennes en utilisant cette barre, et a prouvé son équivalence. Moses Schönfinkel a étendu l'idée de Scheffer au calcul des prédicats dans sa tentative de minimiser le nombre de concepts de base en logique.
Russell et Whitehead ont utilisé la barre de Sheffer en 1927 lors de la deuxième édition des Principia Mathematica.

Charles Sanders Peirce (1880) avait découvert la complétude fonctionnelle de NON-ET ou NON-OU plus de 30 ans auparavant, mais il n'a jamais publié ses résultats.

Introduction, élimination, et équivalences

La barre de Sheffer  est la négation de la conjonction :

Exprimés en fonction de , les opérateurs habituels de la logique propositionnelle sont :

Articles connexes
 Liste des symboles logiques

 Domaine booléen
 Porte logique
 NAND gate
 NOR gate
 NOT gate
 Fonction OU
 Fonction NON-ET
 Fonction NON
 Calcul des propositions

Notes et références

Notes

Références
 Bocheński, Józef Maria (1960), Précis of Mathematical Logic,  translated from the French and German editions by Otto Bird, Dordrecht, South Holland:  D. Reidel.
 Church, Alonzo, (1956) , Vol. 1, Princeton:  Princeton University Press.

 Charles Sanders Peirce, 1880, "A Boolian[sic] Algebra with One Constant", in Hartshorne, C. and Weiss, P., eds., (1931–35) Collected Papers of Charles Sanders Peirce, Vol. 4: 12–20, Cambridge:  Harvard University Press.

Connecteur logique
Symbole


text:
Report| Volume 11, ISSUE 3, P344-350, April 21, 2015
Behavioral Disturbances in Estrogen-Related Receptor alpha-Null Mice
Huxing Cui
Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
Yuan Lu
Michael Z. Khan
Rachel M. Anderson
Department of Psychology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
Latisha McDaniel
Hannah E. Wilson 5
5 Present address: West Virginia University, MD/PhD Program, Robert C. Byrd Health Science Center, P.O. Box 9104, Morgantown, WV 26506-9104, USA
Hannah E. Wilson
Terry C. Yin
Jason J. Radley
Interdisciplinary Neuroscience Program, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
Andrew A. Pieper
Department of Neurology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
Michael Lutter
Open AccessPublished:April 09, 2015DOI:https://doi.org/10.1016/j.celrep.2015.03.032
Previous ArticleRibosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice
Next ArticleIrreplaceability of Neuronal Ensembles after Memory Allocation
Esrra expression in the mouse brain is regulated by energy status
Loss of Esrra reduces response to a high-fat diet
Esrra-null mice display behavioral compulsivity and social impairments
Esrra knockdown in mPFC and OFC recapitulates feeding and grooming deficits
Eating disorders, such as anorexia nervosa and bulimia nervosa, are common and severe mental illnesses of unknown etiology. Recently, we identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA) that is associated with the development of eating disorders. However, little is known about ESRRA function in the brain. Here, we report that Esrra is expressed in the mouse brain and demonstrate that Esrra levels are regulated by energy reserves. Esrra-null female mice display a reduced operant response to a high-fat diet, compulsivity/behavioral rigidity, and social deficits. Selective Esrra knockdown in the prefrontal and orbitofrontal cortices of adult female mice recapitulates reduced operant response and increased compulsivity, respectively. These results indicate that Esrra deficiency in the mouse brain impairs behavioral responses in multiple functional domains.
While eating disorders (EDs) are known to result from a complex interaction of environmental stress and genetic vulnerability (
Kaye et al., 2013
Kaye W.H.
Wierenga C.E.
Bailer U.F.
Simmons A.N.
Bischoff-Grethe A.
Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa.
Trends Neurosci. 2013; 36: 110-120
), the specific neural substrates that mediate development of EDs remain poorly understood. To elucidate molecular pathways that lead to the development of EDs, we previously conducted next-generation sequencing of two large families with multiple members affected by EDs (
Cui et al., 2013
Cui H.
Moore J.
Ashimi S.S.
Mason B.L.
Drawbridge J.N.
Han S.
Hing B.
Matthews A.
McAdams C.J.
Darbro B.W.
Eating disorder predisposition is associated with ESRRA and HDAC4 mutations.
J. Clin. Invest. 2013; 123: 4706-4713
). In that study, we identified rare missense mutations in the estrogen-related receptor alpha (ESRRA) and histone deacetylase 4 (HDAC4) genes that significantly increase the risk of having an ED (
). Specifically, the ESRRAR188Q mutation reduces induction of known ESRRA-target genes in vitro, while the HDAC4A786T mutation increases transcriptional repression of ESRRA by HDAC4. As both mutations result in decreased ESRRA transcriptional activity, we hypothesized that loss of ESRRA activity confers specific susceptibility to developing an ED.
While ESRRA is known to be expressed in the CNS, relatively little is known about its function in neurons. Esrra is also required for induction of mitochondrial biogenesis in the brain, in response to the peroxisome proliferator-activated receptor gamma agonist rosiglitazone (
Strum et al., 2007
Strum J.C.
Shehee R.
Virley D.
Richardson J.
Mattie M.
Selley P.
Ghosh S.
Nock C.
Saunders A.
Roses A.
Rosiglitazone induces mitochondrial biogenesis in mouse brain.
J. Alzheimers Dis. 2007; 11: 45-51
). Furthermore, parkin, a protein associated with the development of Parkinson's disease, regulates Esrra levels through ubiquitination and degradation of Esrra by the proteasome, which decreases expression of the Esrra-target genes monoamine oxidase A and B (
Ren et al., 2011
Ren Y.
Jiang H.
Ma D.
Nakaso K.
Feng J.
Parkin degrades estrogen-related receptors to limit the expression of monoamine oxidases.
). Recently, Esrra has also been implicated in mediating increased expression of the Fdnc5 and Bdnf genes in mouse hippocampus following endurance exercise (
Wrann et al., 2013
Wrann C.D.
White J.P.
Salogiannnis J.
Laznik-Bogoslavski D.
Wu J.
Lin J.D.
Greenberg M.E.
Spiegelman B.M.
Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway.
Cell Metab. 2013; 18: 649-659
). Taken together, these findings suggest that tight control of Esrra levels in the CNS may regulate multiple metabolic processes critical to neuronal function. In the present study, we examine Esrra function in mouse brain by using genetic methods to examine the behavioral consequences of loss of Esrra expression.
To study the role of Esrra in the brain, we performed immunohistochemistry to determine its expression pattern in the whole mouse brain. Esrra is abundantly expressed in several cortical regions, including orbitofrontal cortex, medial prefrontal cortex (mPFC), and cingulate cortex (Figures 1A–1C). Additionally, Esrra is highly expressed in the primary and secondary somatosensory cortex, piriform cortex, retrosplenial granular cortex, hippocampus, thalamus, mammillary nucleus, cerebellum, and several brainstem nuclei involved in transmission of sensory information (Figures S1A–S1C). Moderate levels of expression are observed in dorsolateral aspects of the striatum, septum, global pallidus, lateral hypothalamic area, and some midbrain structures including tegmentum and substantia nigra. Very limited expression was observed in the bed nuclei of stria terminalis, amygdala, and the remainder of the hypothalamus, regions that have been traditionally associated with a role in feeding regulation. Double-immunohistochemistry staining of Esrra and glial fibrillary acid protein failed to reveal colocalization of Esrra in glia (data not shown).
Figure 1Esrra-Null Mice Display Impaired Behavioral Responses to Calorie Restriction
(A–C) Expression of Esrra in 14-week-old C57BL6/J mice in lateral orbitofrontal, mPFC, and cingulate cortex.
(D and E) 60% calorie restriction for 10 days increases Esrra expression in mouse brain. Magnification shows retrosplenial region of cingulate cortex.
(F and G) Wild-type (n = 7) and Esrra-null (n = 6) littermate mice were trained to lever press for a HFD pellet on a fixed ratio and then tested for total lever presses (F) and reward earned (G) on a progressive ratio under calorie restriction and ad lib feeding conditions.
Data are presented as mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 indicate significant differences between groups (Student's t test). See also Figure S1.
Upregulation of Esrra expression has been observed in peripheral tissues following calorie restriction (
Ranhotra, 2009
Ranhotra H.S.
Up-regulation of orphan nuclear estrogen-related receptor alpha expression during long-term caloric restriction in mice.
Mol. Cell. Biochem. 2009; 332: 59-65
). Thus, we examined whether Esrra expression in brain would also be increased in this same condition. Ten days of 60% calorie restriction significantly increased the intensity of Esrra staining throughout the brain, including the cortex (Figures 1D, 1E, S1D, and S1E), indicating that Esrra activity may be involved in the response to energy balance. To quantify this effect, we performed quantitative real-time PCR to measure the relative abundance of Esrra mRNA in the cortex. Consistent with immunohistochemical analysis, 60% calorie restriction induced a significant increase in Esrra mRNA abundance in the cortex compared to that in mice housed under ad lib feeding conditions (2.48 ± 0.59 versus 4.93 ± 0.50, n = 6/group, p = 0.0098).
After determining Esrra expression in several mouse brain regions and that Esrra expression is regulated by metabolic status, we examined the behavioral consequences of Esrra loss. A previous study reported that chow-fed male and female Esrra-null mice were ∼15% smaller than wild-type littermates and displayed reduced weight gain on a high-fat diet (HFD), which is consistent with the clinical diagnosis of anorexia nervosa where body weight is maintained at or below 85% of ideal body weight (
Luo et al., 2003
Luo J.
Sladek R.
Carrier J.
Bader J.A.
Richard D.
Giguère V.
Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.
Mol. Cell. Biol. 2003; 23: 7947-7956
). We also verified that Esrra-null mice were ∼15% smaller than wild-type littermates and consumed less chow and HFD (data not shown); however, these phenotypes were identified in animals on an ad libitum diet. As the magnitude of ad libitum food intake primarily reflects intra-meal satiety independent of any component of behavioral effort (
Perello et al., 2010
Perello M.
Chuang J.C.
Scott M.M.
Lutter M.
Translational neuroscience approaches to hyperphagia.
J. Neurosci. 2010; 30: 11549-11554
), we utilized instrumental responding as a more sensitive measure of motivation to obtain a HFD.
Following a fixed-ratio training session, wild-type and Esrra-null mice were advanced to a progressive-ratio schedule in which obtaining each successive HFD pellet required an increased number of lever presses. Effortful responding for a HFD was then assessed during both caloric restriction and ad libitum feeding conditions by measuring the total number of lever presses and total number of pellets earned during the 2-hr session. During caloric restriction, Esrra-null mice exhibited reduced total lever presses and number of reward obtained compared to wild-type littermates (Figures 1F and 1G). Following re-feeding, total lever presses and reward obtained decreased for both groups as expected, and no significant differences were noted between treatment groups. At the end of testing, we measured fasting glucose and body composition to control for differences in energy reserves that might account for the decreased responding in Esrra-null mice. Fasting glucose levels (Figure S1F) and body composition (Figure S1G) were not different for both groups, indicating that reduced effortful responding observed in Esrra-null mice was not secondary to differences in energy reserves.
In separate cohorts of female mice, we performed a battery of behavioral tasks relevant to mental illness including locomotor activity, depression/anxiety, compulsivity/behavioral rigidity, and impairments in social functioning. Esrra-null mice have recently been reported to have reduced locomotion in both treadmill exercise and voluntary activity in a metabolic cage assessment (
Perry et al., 2014
Perry M.C.
Dufour C.R.
Tam I.S.
B'chir W.
Estrogen-related receptor-α coordinates transcriptional programs essential for exercise tolerance and muscle fitness.
Mol. Endocrinol. 2014; 28: 2060-2071
). As locomotor activity varies greatly depending on the context, we measured activity under three conditions: voluntary wheel running, home-cage activity, and exploration of a novel environment. When given free access to a running wheel for 5 days, Esrra-null mice exhibited normal circadian patterns of activity but also a reduction in total revolutions (Figure 2A). Using the Laboras system, we assessed home-cage activity and found a modest reduction in locomotion in Esrra-null mice compared to wild-type littermates (Figure 2B). Finally, we evaluated exploration of a novel environment by measuring distance traveled in the elevate-plus-maze model of anxiety-like behavior and found no significant difference between the groups (Figure 2C). This finding is important as the majority of behavioral tests that we performed involved activity within a novel environment.
Figure 2Behavioral Deficits in Esrra-Null Mice
(A) Voluntary wheel-running activity for female wild-type (WT) and Esrra-null mice for 5 days (n = 3 WT, 6 Esrra null).
(B) Time spent active in home cage as measured by vibration plate (n = 17 WT, 5 Esrra null).
(C and D) Distance moved and time spent on the open arm of the elevated-plus-maze (n = 8 WT, 14 null).
(E) Time immobile in the forced-swim test (n = 8 WT, 14 null).
(F) Home-cage grooming as measured by vibration plate (n = 17 WT, 5 Esrra null).
(G) Number of marbles buried within 30 min (n = 7 WT, 12 Esrra null).
(H) Time spent near old target and new target in Barnes maze (n = 5 WT, 6 Esrra null).
(I) Time spent with novel mouse in three-chamber test (n = 8 WT, 10 Esrra null).
(J) Time spent with novel object (n = 9 WT, 11 Esrra null).
(K) Percentage of victories in the social dominance test (n = 24 unique pairings).
Data presented as mean ± SEM with ∗p < 0.05, ∗∗p < 0.01 indicating significant differences between groups (two-way ANOVA [A] or Student's t test [B–I and K]), except for (J), which is presented as a percentage of total victories with ∗∗∗p < 0.001 indicating significant differences between groups (chi-square test).
We assessed anxiety- and depression-like behaviors using the elevated-plus-maze and forced-swim test models. Female Esrra-null mice do not display any differences in overall activity or time on the open arm in the elevated-plus-maze (Figures 2C and 2D); however, they did exhibit reduced immobility in the forced-swim test (Figure 2E). Several tasks modeling aspects of perseveration and behavioral rigidity in mice have been used to study related neuropsychiatric disorders, such as autism and obsessive-compulsive disorder, including compulsive grooming (
Shmelkov et al., 2010
Shmelkov S.V.
Hormigo A.
Jing D.
Proenca C.C.
Bath K.G.
Milde T.
Shmelkov E.
Kushner J.S.
Baljevic M.
Dincheva I.
Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice.
Nat. Med. 2010; 16: 598-602
Welch et al., 2007
Welch J.M.
Lu J.
Rodriguiz R.M.
Trotta N.C.
Peca J.
Ding J.D.
Feliciano C.
Chen M.
Adams J.P.
Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice.
Xu et al., 2013
Xu P.
Grueter B.A.
Britt J.K.
McDaniel L.
Huntington P.J.
Hodge R.
Lee C.
Vong L.
Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice.
Proc. Natl. Acad. Sci. USA. 2013; 110: 10759-10764
), marble burying (
Angoa-Pérez et al., 2013
Angoa-Pérez M.
Kane M.J.
Briggs D.I.
Francescutti D.M.
Kuhn D.M.
Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice.
J. Vis. Exp. 2013; : 50978
), and reversal learning (
Kim J.I.
Lee H.R.
Sim S.E.
Baek J.
Yu N.K.
Choi J.H.
Ko H.G.
Lee Y.S.
Park S.W.
Kwak C.
PI3Kγ is required for NMDA receptor-dependent long-term depression and behavioral flexibility.
Nat. Neurosci. 2011; 14: 1447-1454
). Using a vibration-plate based system to quantify 24-hr home-cage grooming, we observed that loss of Esrra increases grooming in female mice (Figure 2F). The fact that chronic fluoxetine treatment has been shown to reduce repetitive grooming in several other genetic models of compulsivity (
) led us to assess whether this treatment could also ameliorate the increased repetitive grooming in female Esrra-null mice. Separate groups of Esrra-null female mice were tested for baseline grooming and then randomized into two equal groups that received either fluoxetine or saline vehicle. Following 1 week of treatment, no effect of fluoxetine was noted (saline 88.2% ± 12.1% versus fluoxetine 93.0% ± 8.9%, n = 6/group, p = 0.71). We also assessed behavioral compulsivity in Esrra-null mice using the marble-burying test. Consistent with the compulsive grooming results, female Esrra-null mice showed a significantly greater degree of marble-burying behaviors after 30 min than wild-type littermates (Figure 2G). Mice were trained for 4 days to find an escape hole in the Barnes maze to assess hippocampal-dependent memory formation. On the fifth day, a probe trial was performed showing that both wild-type and Esrra-null mice spent more time in the area of the escape hole without a significant difference noted between the groups. Following this initial training, mice were next subjected to an additional 4 days of training in which the escape hole was relocated to the opposite position. Another probe trial was then performed, and time spent at the old and new target was measured. While both groups learned the location of the new escape hole, Esrra-null mice spent significantly more time at the original target (Figure 3H), an indication of behavioral rigidity.
Figure 3Knockdown of Esrra Expression by shRNA in Cortex Produces Region-Specific Behavioral Deficits
(A) Body-weight gain in female C57BL6/J mice on a HFD after AAV delivery into cingulate (n = 10 scramble and 9 shRNA-Esrra), orbitofrontal (n = 9 scramble and 10 shRNA-Esrra), or mPFC (n = 9 scramble and 11 shRNA-Esrra).
(B) Intake of a HFD after Esrra knockdown in mPFC.
(C) A separate cohort of mice received AAV into mPFC and was tested for total lever presses and reward earned.
(D and E) Mice from (A) were tested for home-cage grooming (D) and immobility in the forced-swim test (E).
Data presented as mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 indicate significant differences between groups (ANOVA [A] or Student's t test [B–E]). See also Figure S2.
Several tasks modeling social dysfunction in mice have been designed, including the three-chamber social interaction, social dominance, and novel object recognition. Using this battery of tasks, we also found that Esrra-null mice displayed reduced preference for interaction with a novel social target (Figure 2I), increased social subordination (Figure 2J), and no differences in novel object recognition as compared with wild-type littermate mice. Together these behavioral findings indicate that Esrra-null mice exhibit behavioral deficits in multiple domains including decreased motivation for HFD, perseveration/ behavioral rigidity, and impaired social functioning.
We next interrogated the neural circuits underlying the behavioral phenotypes exhibited by Esrra-null mice by abrogating expression of this gene in a region-specific manner in wild-type female mice. Using viral-mediated gene transfer to selectively knockdown expression of Esrra by short hairpin RNA (shRNA)-mediated silencing (Figures S2A–S2D), we selected several cortical regions implicated in the development of EDs and ED-related behaviors, including cingulate cortex, orbitofrontal cortex, and medial prefrontal cortex (mPFC) (
Frank G.K.
Altered brain reward circuits in eating disorders: chicken or egg?.
Curr. Psychiatry Rep. 2013; 15: 396
). While knockdown of Esrra in the cingulate and orbitofrontal cortex had no effect on HFD-induced weight gain in female mice, knockdown in the mPFC reduced weight gain (Figure 3A) via reduced intake of a HFD (Figure 3B). We tested a separate cohort of mice to assess whether knockdown of Esrra in the mPFC disrupted operant responding for HFD. Consistent with our observations in Esrra-null mice, knockdown of Esrra in mPFC was sufficient to reduce total lever presses and reward earned (Figure 3C). Subsequent analyses also examined the capacity of knockdown of Esrra within selected cortical fields to reproduce other behavioral phenotypes observed in null mutants. Increased grooming was observed only after knockdown of Esrra in orbitofrontal cortex, whereas no differences in grooming were observed following either cingulate or mPFC knockdown (Figure 3D). Reduced immobility was observed only after knockdown of Esrra in the cingulate cortex (Figure 3E). Together, these findings identify specific neural substrates accounting for the behavioral alterations observed in Esrra-null mice.
Finally, we determined whether there was a sexual dimorphism in any of the changes we observed in female Esrra-null mice by conducting all of the testing on male mice as well. Table 1 summarizes the differences in behavioral phenotypes in female and male Esrra-null mice. Similar to female mice, male Esrra-null mice display reduced locomotor activity, decreased operant responding, and reduced immobility in the forced-swim test, but do not exhibit deficits in the compulsive/behavioral rigidity battery of tasks or the three chamber social interaction test.
Table 1Summary of Behavioral and Electrophysiological Phenotypes in Female and Male Esrra-Null Mice
Results for female mice from Figures 1 and 2.
Results for male wild-type and Esrra-null littermate mice (n = 6–11/group) tested under identical protocols.
Operant responding
Lever presses decrease decrease
Rewards decrease decrease
Wheel running decrease no difference
Home-cage activity decrease decrease
Elevated plus maze
Distance traveled no difference no difference
Time on open arm no difference no difference
Forced-swim test decrease decrease
Grooming increase no difference
Marble burying increase no difference
Reversal learning decrease no difference
Three chamber test decrease no difference
Social dominance decrease decrease
Novel object no difference no difference
See also Table S1.
a Results for female mice from Figures 1 and 2.
b Results for male wild-type and Esrra-null littermate mice (n = 6–11/group) tested under identical protocols.
In the current study, we examine the forebrain distribution and function of Esrra, a gene identified in human genetic studies of EDs. We report that Esrra-null mice display behavioral impairments relevant, including maintaining body weight at 15% below normal, impaired behavioral responses to caloric restriction, compulsivity/behavioral rigidity, and impaired social functioning. Furthermore, knockdown of Esrra expression within selected cortical subfields distinguished regional specificity for circuitry underlying behavioral deficits identified in Esrra-null mutants. These findings show that Esrra dysfunction in select forebrain regions impairs behaviors relevant to psychiatric disorders and offer insight into the potential role of Esrra dysfunction in the development of eating disorders, such as anorexia nervosa.
Esrra expression in brain is increased during calorie restriction and loss of Esrra by conventional knockout or shRNA-mediated knockdown in the mPFC results in decreased consumption of a HFD and decreased operant responding for a HFD. These results suggest that increased expression of Esrra is important for mediating behavioral responses to negative energy balance. As the ESRRAR188Q mutation that was found to be associated with an increased risk of developing anorexia nervosa results in decreased transcriptional activity (
), our results suggest that loss of ESRRA activity in humans may predispose to the development of anorexia nervosa by impairing behavioral responses to calorie restriction.
Identifying the neural circuit that mediates the reduced effortful responding for HFD after fasting is another question of great clinical relevance. Esrra activity in the mPFC seems to be at least partially required for this effect, as viral-mediated knockdown of Esrra expression in the mPFC produces a similar reduction in responding (Figure 3C). Stimulation of glutamatergic neurons in the mPFC by pharmacological (
Mena et al., 2013
Mena J.D.
Selleck R.A.
Baldo B.A.
Mu-opioid stimulation in rat prefrontal cortex engages hypothalamic orexin/hypocretin-containing neurons, and reveals dissociable roles of nucleus accumbens and hypothalamus in cortically driven feeding.
) or optogenetic (
Land et al., 2014
Land B.B.
Narayanan N.S.
Liu R.J.
Gianessi C.A.
Brayton C.E.
Grimaldi D.M.
Sarhan M.
Guarnieri D.J.
Deisseroth K.
Aghajanian G.K.
DiLeone R.J.
Medial prefrontal D1 dopamine neurons control food intake.
Nat. Neurosci. 2014; 17: 248-253
) approaches potently induces food intake in rodents. However, the site of this action is unclear as mPFC neurons project to multiple sites, including the amygdala, lateral-perifornical hypothalamic area, and nucleus accumbens that have been implicated in this behavioral response (
). Recently developed chemogenetic and optogenetic approaches to the study of feeding may ultimately be required to deconstruct these circuits.
Additionally, the behavioral deficits we observe in Esrra-null mice might have important implications for other symptoms associated with the development of eating disorders. Neuropsychological testing has consistently found that patients with EDs display increased perseveration and behavioral rigidity (
Roberts et al., 2010
Roberts M.E.
Tchanturia K.
Treasure J.L.
Exploring the neurocognitive signature of poor set-shifting in anorexia and bulimia nervosa.
J. Psychiatr. Res. 2010; 44: 964-970
). Patients with EDs display deficits in social functioning as well including insecure attachment, reduced emotional awareness, increased avoidance of emotion, and increase sense of social inferiority (
Caglar-Nazali et al., 2014
Caglar-Nazali H.P.
Corfield F.
Cardi V.
Ambwani S.
Leppanen J.
Olabintan O.
Deriziotis S.
Hadjimichalis A.
Scognamiglio P.
Eshkevari E.
A systematic review and meta-analysis of 'Systems for Social Processes' in eating disorders.
Neurosci. Biobehav. Rev. 2014; 42: 55-92
Our findings may also be relevant to the basis of sex differences observed in neuropsychiatric disorders. Many psychiatric disorders, including EDs, major depression, and most anxiety disorders, predominantly affect women although the neural basis of this sexual dimorphism remains unclear. Our data suggest that females may be more susceptible to the loss of Esrra function, as female knockout mice exhibited more behavioral impairments than male mice. The mechanism for the observed sex differences remains unclear. There is an estrogen response element in the promoter of the Esrra gene, and previous studies have indicated that estrogen receptor signaling affects expression of Esrra in peripheral tissues (
Bonnelye et al., 2002
Bonnelye E.
Kung V.
Laplace C.
Galson D.L.
Aubin J.E.
Estrogen receptor-related receptor alpha impinges on the estrogen axis in bone: potential function in osteoporosis.
Endocrinology. 2002; 143: 3658-3670
Liu et al., 2003
Liu D.
Zhang Z.
Gladwell W.
Teng C.T.
Estrogen stimulates estrogen-related receptor alpha gene expression through conserved hormone response elements.
), although we did not observe any change in Esrra mRNA levels in mPFC 4 weeks after ovariectomy in young adult female mice (data not shown). Alternatively, estrogen receptors alpha and beta have been localized to dendritic spines in the hippocampus and may have a direct, non-genomic signaling effect on synaptic plasticity (
Sala and Segal, 2014
Sala C.
Segal M.
Dendritic spines: the locus of structural and functional plasticity.
Physiol. Rev. 2014; 94: 141-188
). Delineating the roles of Esrra and estrogen receptor activity will have important implications in understanding sex-based differences in mental illness.
Several limitations of the current study should be noted. Esrra-null mice have reduced locomotor activity, which can confound the interpretation of certain behavioral tasks like operant responding and the forced-swim test. This hypolocomotor phenotype appears to be most severe for endurance activity, such as treadmill exercise (
) or voluntary wheel running (Figure 2A). The phenotype is less severe for home-cage activity (Figure 2B) and absent in the exploration of a novel environment (Figure 2C), which represents the majority of our tasks. Also, we have tried to select a balanced set of tasks to control for differences in locomotor activity. For instance, the increased activity of Esrra-null mice in the forced-swim test, marble-burying test, and grooming assay is in the opposite direction of an expected hypolocomotor effect.
Finally, there are limitations with the two methods used to decrease Esrra activity. We selected the Esrra-null mouse because the ESRRAR188Q mutation that predisposes to the development of eating disorders in human populations decreases transcriptional activity of Esrra in vitro (
). While we believe that the Esrra-null mouse is a reasonable first approach to testing our hypothesis that reduced Esrra activity increases the risk of developing ED-related behaviors, we cannot be certain that the R188Q mutation does not induce an unanticipated change in the activity of the Esrra protein. Additionally, the use of shRNA-mediated gene knockdown has been questioned for possible off-target effects (
Baek et al., 2014
Baek S.T.
Kerjan G.
Bielas S.L.
Lee J.E.
Fenstermaker A.G.
Novarino G.
Gleeson J.G.
Off-target effect of doublecortin family shRNA on neuronal migration associated with endogenous microRNA dysregulation.
Neuron. 2014; 82: 1255-1262
). While this concern is offset by our limited use of shRNA in the context of mapping behavioral deficits originally identified in Esrra-null mice, the use of more targeted genetic models, such as conditional deletion of Esrra expression with a Cre-lox approach, will further expand our understanding of the genetic necessity of Esrra within discrete neural circuits.
In conclusion, we show that loss of the transcription factor Esrra results in behavioral deficits in multiple functional domains, including maintenance of a low body weight, reduced effortful responding for HFD after calorie restriction, compulsivity/behavioral rigidity, and impaired social functioning. These findings offer insight into the neurobiological function of Esrra and have potential implications for understanding the neurobiological basis of eating disorders.
Esrra-null and C57BL/6J mice were obtained from Jackson Laboratory and backcrossed more than five generations onto C57BL/6J. All animal procedures were performed in accordance with University of Iowa Institutional Animal Care and Use Committee guidelines. Mice heterozygous for Esrra+/− alleles were bred to generate wild-type (Esrra+/+) and Esrra-null (Esrra−/−) littermate mice. Mice were weaned and genotyped at 3–4 weeks of age. See Supplemental Experimental Procedures for housing and animal husbandry conditions.
Behavioral Studies
Twelve- to 16-week-old animals were used for behavioral studies. Some mice were used after completing body-weight monitoring and had previously been exposed to a high-fat diet (42.8% calories from fat, TD.88137, Harlan-Teklad). No behavioral differences, however, were noted between chow- and HFD-fed animals and groups (data not shown). Separate cohorts of mice not exposed to a HFD were used for wheel running and operant responding, respectively, so that no mouse included in the other behavioral tasks had been exposed to increase physical activity or calorie restriction. See Supplemental Experimental Procedures for full methodology for behavioral experiments.
Immunohistochemistry was performed as previously reported (
Sohn J.W.
Gautron L.
Funahashi H.
Williams K.W.
Elmquist J.K.
Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area.
J. Comp. Neurol. 2012; 520: 4168-4183
). Rabbit monoclonal anti-Esrra antibody was used (04-1134; Millipore) at 1/1,000 dilution. The specificity of anti-Esrra antibody was confirmed by both immunohistochemistry (Figure S1B) and immunoblotting (Figure S1C) in Esrra-null mice. Quantification of immunohistochemistry was performed as previously described (
Yin et al., 2014
Yin T.C.
De Jesús-Cortés H.
Lu Y.
Genova R.M.
Khan M.Z.
Voorhees J.R.
Shao J.
Katzman A.C.
P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.
Cell Rep. 2014; 8: 1731-1740
Viral Preparation
An shRNA sequence targeting nucleotides 1203–1223 of mouse Esrra (NM_007953) or scramble control were commercially prepared (Vector Laboratories). See Supplemental Experimental Procedures for full description of viral preparations.
Viral Delivery
Twelve-week-old female C57BL/6J (The Jackson Laboratory, #00664) mice were randomly assigned into two groups to receive either adeno-associated virus 2 (AAV) encoding both mEsrra-shRNA and GFP or AAV encoding scrambled sequence and GFP as control into the following regions: mPFC (AP +1.8 mm, ML +0.8 mm, DV −2.8 mm, 10-degree angle), lateral orbitofrontal (AP +2.8 mm, ML +1.7 mm, DV −2.0 mm, 10-degree angle), and cingulate (AP +0.2 mm, ML +0.6 mm, DV −1.7 mm, 10-degree angle). See Supplemental Experimental Procedures for surgical procedures.
Data are presented as mean ± SEM. GraphPad Prism 6 software (GraphPad) were used to perform all statistical analyses. For feeding and wheel-running studies, comparisons between groups were made by two-way ANOVA with time as the repeated measure. The chi-square test was used to determine significance in the social dominance test. Student's t test was used for all other measures. p < 0.05 was considered to be statistically significant.
This material is based upon work supported by the Dylan Tauber Researcher Award from the Brain and Behavior Foundation (M.L.), the Klarman Family Foundation Grants Program in Eating Disorder Research (M.L.), and MH-095972 (J.J.R.).
Document S1. Supplemental Experimental Procedures, Figures S1 and S2, and Table S1
Accepted: March 12, 2015
Received: December 22, 2014


Humility is a response to the character of God.
God has no beginning and no end. God is the creator and sustainer of the universe. He deserves all of our worship and praise for what He has done and continues to do in our life.
On the other hand, we are humans created by God. And while we are the crowns of God's creation, we are nothing without our Creator God.
Yet so often, we act like we are God. We allow our pride to take over and forget that any of our strengths or accomplishments would not exist without God. The only proper response in light of God's greatness is to respond with humility in our interactions with the people around us.
Jesus is the ultimate example of humility.
Jesus is the Son of God. And in the beginning, Jesus was part of creating the heavens and the earth. As the Son of God, there is nothing in Heaven of on the earth that isn't under Jesus' command. Yet Jesus chose to become one of us. He was born as a baby and walked among us. He developed calloused hands as He worked in a carpenter's shop. The dirt of the road caked His feet as He traveled to show love to others. Jesus willingly left the majesty and glory of Heaven to laugh and cry as He was fully human.
Jesus' ultimate act of humility on Earth was sacrificial death. He could have called down an angel army to protect him, but instead allowed Himself to be wrongly accused and arrested. He could have been worshiped with a gold crown and royal robes, but instead wore a crown of thorns. Jesus deserved praise and adoration, but sacrificed Himself for us.
We live in a world that's all about putting ourselves first. Jesus lived in a world like that, too. He could have looked out for Himself, called 10,000 angels to come and rescue Him. But He didn't. Out of his love for us, He chose the humble route and put us first. It cost Him everything.
Putting others first will cost you something: your time or money. Maybe it will cost you some pride. But when we choose to follow Jesus with our lives, believing that His death an resurrection made it possible for us to be right with God, the least we can do is put others first even if it's a bit uncomfortable and cost us something.
We think it's important, especially at Easter, for us to help our kids and families discover more about humility - putting others first by giving up what you think you deserve.
The verse is part of a passage that describes Jesus' humility. Jesus left everything He deserved to humble himself to save us. As we respond to Jesus' love, we can show humility as we love on those around us.
As we celebrate Jesus' life, death, and resurrection this Easter season, we'll be taking a closer look at the way humility shows up throughout the end of Jesus' time on Earth.


The Plaintiffs' Steering Committee represents oystermen, fishermen, restaurateurs, and hoteliers who claim that their businesses were damaged by the 2010 Gulf of Mexico oil spill. They have filed a lawsuit against the oil company, BP, in order to gain damages and compensation for their loss of business.
According to reports, BP may be close to reaching a settlement with the committee, in order to avoid going to court. The lawsuit is set to begin in court on March 5. BP is considering using part of the $14 billion fund that they set up in order to benefit fishermen and businesses that were damaged during the oil spill to pay the settlement.
The trial was delayed by a week in order for settlement talks to be discussed between the two parties. Sources close to the case believe that a deal could be announced as early as this week.
If your oil spill claim was denied, you need experienced representation on your side in order to secure the compensation you deserve. Please contact the oil spill denied claims lawyers of Williams Hart by calling 800-821-1544 today.


I booked a number of estate agents in to have my property valued prior to selling and Preston Baker was one of them. What set Claire and Preston Baker apart from the rest was the friendly communication and honest feedback. The other agents had a quick look round, 5 minutes and gave a figure. Clare came round had a proper look in detail at the property suggested things to do to it there and then in order to improve the valuation and the chances of a sale then gave a presentation about what they would do and how detailing the different channels to market the house would be available through. Head and shoulders above the rest.


Woke up this morning to see the fishermen bringing in their first catch of the day at Tokeh Beach, Sierra Leone.
With every wave the boat is pulled in.
"We tell God tenki!" The catch is in and ready to smoke, sell and eat.


text:
30Dec By adminNo Comments
Reviews, Business, Information, Internet, Opinion
CVMarkets Review | Why Do You Need This Broker?
I enjoy forex trading. That being said, when the moment comes and you have to choose a platform, I am extremely specific about it. It doesn't make a difference if the platform is new or old, what you have to focus on is if the platform offers top-notch security and a huge variety of features. These days something else that has jumped up is getting multiple account types options and technological tools from the platform. There are countless things that the cutting-edge trader is presently anticipating from the more innovatively progressed platforms that now has everybody scrambling around searching for some specific administrations that are up to current trends and have the most features. I am exceptionally mindful of the issue that finding a platform is intense for many people. We a...
21Dec By Muhammad HassanNo Comments
Entertainment, Information, Internet, Life Style, Opinion
The Joker Torrent – Watch Movie for Free
Joker is a 2019 movie, directed by Todd Phillips and starring Joaquin Phoenix and Robert De Niro, which follows the titular character and his descent to full-blown insanity, which fuels a counter-culture and a class struggle revolution in the fictional city of Gotham. Described as a superhero movie for the decaying 21st century and the creation of Batman from the Joker's viewpoint, the psychological thriller has remained engrained in the PC culture of late 2010's and has earned a whopping $1.07 billion from sales, to become one of the most talked-about and the most commercially successful film of 2019. Want to get in on the hype but can't watch it in cinemas or Netflix? Don't worry, because you have the Joker torrent, which will allow you to watch the movie for free and download it...
Entertainment, Information, Internet, Opinion
EliteTorrent – How to Fix Error and Download Torrents
One of the most visited sites on the internet are torrenting sites, websites that allow peer-to-peer file sharing. This is because they provide free stuff; free games, movies and TV series. Where there's free, there's a crowd. Among the most popular torrent sites is EliteTorrent, which provides the largest archive and directory for Spanish movies and TV series and boasts a hefty internet traffic, and rightfully so. This passage will get you up to speed with the EliteTorrent website; how you can download movies from it and how you can resolve common errors like 500 internal error in EliteTorrent. When we state torrents in Spanish, it includes both that come within the ambit of the phrase; Hollywood movies and shows subbed or dubbed in Spanish or Spanish movies and telenovelas made in...
Entertainment, Information, Internet, Opinion, Reviews
How to Use u Torrent?
Watching movies for free today is no big deal. That's because the advent of peer-to-peer file sharing and torrenting websites has made pirating an easy enough task for a 9-year-old kid to download a cracked version of GTA 5, play it and then keep it as a souvenir from an era rampant with torrenting and illegal filesharing. But what good is a website with lots of healthy torrents and tons of pirated content when you can't download it and use it? Fortunately, software like µTorrent and/or BitTorrent exist in the grey spaces between illegal and legal software, and it is this type of torrent-downloading clients that help us get from a 11kb .torrent file to a whole 3GB Blu-Ray movie. God bless this torrent protocol. But the newbies and the ones who have just don their pirate hats and th...
Land of the Lustrous Season 2 – Release Date
Many anime lovers, or as they would like to be called, otakus, have been waiting for a lot of sequels or continuations in the form of seasons. But the wait goes on and yet another series joins the waiting line; this time, it's the hit anime series Land of the Lustrous (Japanese: Houseki no Kuni), which has its fans all around the world waiting for a season 2. While there is still no word or rumor's of it flying around, right off the bat, there is a good chance that Land of the Lustrous season 2 will be released somewhere in 2021. Land of the Lustrous is an anime series that deals with a unique storyline and conceptual existence; where instead of normal human beings, there are creatures known as Lustrous, who are described as the rare gemstones personified; humanoid figures resembling th...
My London-Gates Review | Why should you trust London-Gates? (london-gates.com)
Today, I decided to review one broker that aims to turn into the pioneer in the trading business. I am truly excited to compose this London-Gates survey since when I see an assertion like that, I expect only the best assistance. So, how about we look into how dedicated London-Gates is and how it intends to satisfy this objective. The initial move towards being the best in the market is to have amazing trading conditions. Since this broker guarantees super tight spreads, quick request execution, exceptional help, and cutting-edge innovation, I need to say that it picked the most ideal approach to catch my complete consideration. On the off chance that you choose to open an account, more than 200 tradable assets will be available to you. You can pick between CFDs, Forex, Indices, S...
15Dec By adamstNo Comments
Travel, Information, Life Style, Opinion, Reviews
The World's Most Spectacular Deserts are Definitely a Sight To Experience
A list of famous and splendid deserts around the globe that will amaze your senses. Mother earth is full of wonders and nerve-wracking experiences. Out of so many splendid things worldwide, deserts are the landscapes that stun us the most. The barren lands of sand are isolated, yet they have an undefined beauty inside them. They can be hot, cold, or both(days and nights are different in deserts). One-third of Earth's surface area is covered with Deserts. You will be presented with the most diverse scenery and vast beauty if you visit all of these deserts. Therefore, take a look at the list of desserts in the world that are most spectacular. Amaze your senses visiting these beautiful deserts The Sahara Desert, Africa The Sahara covers most of Africa's Northern region and spread over 3.6...
Showbox Alternative – The Best Sites
For those of us who like to save money here and there, nothing is better than free entertainment, because of the way corporations like Disney and Hollywood have turned good, old-fashioned entertainment into money-milking machines. So, by becoming a pirate and sailing the uncharted waters of The Pirates Bay or using websites like 123Movies to watch free movies online, you can get back at the system. But what if the aforementioned sites aren't working (which is fairly common)? What is your Saturday night plans are threatened by Hollywood lawyers working to keep such sites down? Enter Showbox, the streaming platform that hosts movies for free, and just like other free websites, has had its fair share of a turbulent history. We'll talk about Showbox and what is a good alternative to Showbo...
25Nov By marketinghubsNo Comments
Information, Education, Opinion
Tops Cool Unique Boy Name For Boys
If you want to find a cools unique boy name for your son, there are many resources available online. If you have trouble finding the right name for your son, you can ask friends and family for some help. There are some cools unique boy names for boys in the U.S. and Canada as well. If you're looking for cools unique boy name in the USA, you can start with the popular choices that are popular in North America. Names like Hunter, Sam, and Jayden are popular. These are three of the most common cools unique boy name for boys in the United States and Canada. You can also find unique boy name for boys in other countries. In Canada, names like Hunter, Sam, and Jayden are very popular. If you're looking for a cools unique boy name for your son in the United Kingdom, you might c...
23Nov By pweastNo Comments
Reviews, Life Style, Opinion
THE BENEFITS OF SOURSOP
Soursop is a fruit that's popular for its delicious flavor and impressive health benefits. It's also very nutrient-dense and provides a good amount of fiber and vitamin C for very few calories. What Is Soursop? Soursop, also known as graviola, is the fruit of Annona muricata, a type of tree native to tropical regions of the Americas (1Trusted Source). This prickly green fruit has a creamy texture and a strong flavor that is often compared to pineapple or strawberry. Soursop is typically eaten raw by cutting the fruit in half and scooping out the flesh. Fruits range in size and can be quite large, so it may be best to divide it into a few portions. A typical serving of this fruit is low in calories yet high in several nutrients like fiber and vitamin C. A 3.5-ounce (100-gram) serv...
Iron-Bits Reviews | Why Is This Broker Trustworthy?
At thatviralfeedcdn.com you can get news around the global about all the trendy topics in different industries. We are your the most trusted source for latest trendy news.
admin@thatviralfeedcdn.com
https://thatviralfeedcdn.com