text:
CeBIT 2003 Show Coverage
Mar 15,2003	 0
22. NEC
2. AccessTek
3. Asus
4. Ricoh
5. Waitec
6. DVD+RW Alliance
7. AOpen
8. Primera
9. ReWritable Products Promotion Initiative (RWPPI)
10. MET
11. Plextor
12. BenQ
13. CMC Magnetics
14. LG
15. INcoder
16. Mitsumi
17. BTC
18. Intenso
19. LiteON
20. Maxell
21. MSI
23. Panasonic
24. Sanyo
25. Prodisc
26. Plasmon
27. Ritek
28. Verbatim
30. SKC
31. Sony
32. Teac
33. Toshiba
34. Nero
35. TraxData
36. Pinnacle
NEC demonstrated the latest ND-1300A multi-format DVD Recorder. The drive supports 4x DVD-R and DVD+R writing, 2x DVD-RW and 2.4x DVD+RW recording, and 12x DVD reading. The drive also behaves as a 16x/10x/40x CD-RW recorder. The cache memory of the drive is set to 2MB.
NEC designed and manufactured both the pickup and basic chipset for the ND-1300A. The drive uses two different laser beams for writing on DVD and	CD media, while for reading the laser beam is focused on the same lens for all formats.
NEC also demonstrated a single format DVD+R/RW drive. The ND-1100A supports 4x DVD+R and 2.4x DVD+RW writing, and 12x DVD reading. As in the case of the ND-1300A, the drive is also a 16x/10x/40x CD-RW recorder. The ND-1100A is illustrated in the picture below:
The top NEC CD burner is the NR-9300. This supports 48x CD-R and 24x CD-RW writing, and 48x CD-ROM reading.
In the following picture you can see the CD-3002A 52x CD-ROM and the DV-5800C which is a 16x DVD-ROM and 48x CD-ROM.
NEC is among the first companies which launched a DVD+R/RW recorder for notebooks. The ND-5100 supports 4x DVD+R and 2.4x DVD+RW writing, and 8x DVD-ROM reading. For the CD format, the drive offers 24x CD-R writing, 10x rewriting and 24x CD-ROM reading. The supported burst transfer rate is PIO mode 4/Ultra DMA 33 and the average access times for the DVD and CD discs is 150ms and 130ms, respectively.
For sure, the next product is the most exciting demonstrated by NEC this year. This is the first Blue Laser DVD recorder. The technology is being developed jointly by Toshiba and NEC. The capacities that can be	archived	reach approximately 20GB.
It is not clear when the drive will hit the market. What is sure is that we will have to wait a couple of more years. More information about the new technology will be available soon.
In the following picture you can see the internals of the new (prototype) drive.
Philips JR32RWDV
52X CD-RW Roundup Vol2


Leicester City striker Jamie Vardy has been named the Barclays Premier League Player of the Month for October.
The in-form Foxes forward has been in irresistible form so far this term and leads the top flight scoring charts with a remarkable haul of 12 goals in 12 games.
He collects the October award after scoring in each of City's four games in the month, hitting five goals in total and extending his scoring streak to eight consecutive matches.
Having kicked off November with another goal in Saturday's 2-1 win over Watford, Vardy now has Ruud Van Nistelrooy's Premier League record of scoring in 10 consecutive games in his sights, ahead of City's trip to Newcastle United on 21 November.
A Leicester player takes the Player of the Month honours at the third time of asking this season, following Vardy's nomination in September and Riyad Mahrez's in August.
Vardy topped the October vote ahead of Arsenal duo Mesut Özil and Olivier Giroud, Manchester City's Kevin De Bruyne, Watford's Odion Ighalo and Stoke City's Jack Butland.
Meanwhile, City boss Claudio Ranieri was edged out in the race for the Manager of the Month award by Arsenal's Arsène Wenger.
City's record of three wins and a draw from October had earned our Italian manager a place on the shortlist alongside Wenger and Manchester City's Manuel Pellegrini.
But it was the Gunners' boss that took the honours – Arsenal having won all four of their Premier League outings in the month.


text:
Michael Hopmeier
Unconventional Concepts, Inc.
Michael Hopmeier is the President of Unconventional Concepts, Inc. He has been a technical advisor and operational consultant to numerous governmentaland international agencies and organizations, including the DARPA Defense Sciences Office, U.S. Army Medical Research and Materiel Command, United States Surgeon General, the Deputy Assistant to the Secretary of Defense for Chemical and Biological Defense, the World Health Organization, and several foreign governments. He was one of the primary developers of the Bioterrorism Preparedness Program at the CDC, served as the Science and Technology Advisor to the USAF Surgeon General, and was the first S&T Advisor to the United States Marine Corps Chem/Bio Incident Response Force (CBIRF). He has been active in the development and deployment of numerous guidelines and procedures, including guidelines for policy development and operations related to counterterrorism and response, security and public health issues associated with mass gatherings, and preparedness and response programs supporting population response to disasters and critical incidents.
Hopmeier is an internationally recognized expert on countering suicide terrorism, counter- and anti- terrorism, disaster/crisis response, public health and national security programs, and emergency management and preparedness. He is a founding and current member of the Executive Board of the International Counter-Terrorism Academic Community and is an Associate Researcher of the Institute for Counter-Terrorism. He has been a member and/or task force Chair for numerous senior advisory panels including the Defense Science Board and the National Academy of Sciences and chaired the Joint Staff External Red Team for Joint Concepts for the Chairman. He has authored numerous papers and presentations on topics ranging from biological model development andbiotechnology research, to emergency response training and suicide bombing. He is also an expert on Federal Acquisition Programs.

redpajama_set_name: RedPajamaCommonCrawl


text:
\section{Introduction\label{intro}}

Ken Wilson introduced the exact renormalization group (ERG) to define
continuum limits in quantum field theory.\cite{wk} Using a theory with
a finite ultraviolet (UV) cutoff, we can construct a continuum limit
with the expense of keeping an infinite number of terms in the action.
The idea was subsequently applied to perturbation theory by Joe
Polchinski.\cite{joe} The purpose of this paper is to apply
Polchinski's version of ERG to construct QED perturbatively.

Before writing anything about gauge theories, we would like to clarify
our terminology.  The ``action'' we have mentioned above is a
functional of field variables.  The momenta of the fields are
restricted to the range below a UV cutoff $\Lambda$.  The interaction
vertices of the action are obtained by integrating out the
fluctuations of fields with momenta larger than $\Lambda$.  Hence, the
correlation functions calculated with this action contain the physics
of all momentum scales.  The action with a UV cutoff is often called a
``Wilson action'' in the literature, and we will follow this practice
here even though an ``action with a UV cutoff'' is perhaps more
descriptive.  The reason is that we wish to avoid confusion with the
``effective action'' with an infrared (IR) cutoff $\Lambda$ that
consists of the 1PI parts of the vertices of the Wilson action.  In
the limit $\Lambda \to 0$, the ``effective action'' with an IR cutoff
reduces to the standard effective action.  ERG determines the UV
cutoff dependence of the Wilson action or the IR cutoff dependence of
the ``effective action''.  Except for this introduction, we will
consider only the Wilson action in this paper.

The construction of gauge theories in the framework of ERG has been
discussed by various authors.  To the author's knowledge the first
person who applied ERG systematically to construct (non-abelian) gauge
theories is Becchi.\cite{becchi} (There is an even earlier work by
Warr \cite{warr}, who treated ERG mainly as a method of
regularization.)  Becchi showed how to construct a BRST invariant
Wilson action by introducing sources that generate BRST
transformations.  Alternatively gauge theories can be formulated for
the effective action with an IR cutoff.  This was initiated by
Ellwanger \cite{ellwanger} under the name of the ``modified'' Ward (or
Slavnov-Taylor) identities.

Whether we study a Wilson action with a UV cutoff or an effective
action with an IR cutoff, the form of the Ward identities depends on
the cutoff $\Lambda$ explicitly.  (This is the reason for the
adjective ``modified.'')  But ERG guarantees the $\Lambda$
independence of the identities: once the identities are satisfied for
some $\Lambda$, it is satisfied for any $\Lambda$.  It is this
property which simplifies the study of gauge symmetry within the ERG
framework.

The first explicit construction of QED using ERG was done in
\cite{bonini}.  They computed the effective action with $\Lambda = 0$
by solving ERG differential equations starting from a set of initial
conditions at a very large cutoff $\Lambda_0$.  They showed how to
fine tune the initial conditions so that the effective action with
$\Lambda = 0$ satisfies the Ward identities.  There, ERG is merely a
device for loop calculations, and they did not take advantage of the
simplicity of the Ward identities at large $\Lambda$.  Except for the
original work of Becchi, most later works seem to share the same
short-coming: the Ward identities are always checked at $\Lambda = 0$.

The main purpose of this paper is to construct the Wilson action of
QED by satisfying the Ward identities at large UV cutoff $\Lambda$.
As advocated by Becchi \cite{becchi}, the Ward identities get
simplified at large $\Lambda$, and to take advantage of this we need
to parameterize the Wilson action in terms of its asymptotic behavior
at large $\Lambda$.  Such parameterization scheme has been introduced
in refs.~\cite{integral,erg}, and we apply it here to QED.

We organize this paper as follows.  In sect.~2, we briefly review
Polchinski's ERG differential equation by applying it to QED.  In
sect.~3 we parameterize the Wilson action in terms of its behaviors at
large cutoff.  This is an application of the scheme explained in
\cite{erg}.  (The reader unfamiliar with perturbative applications of
ERG may find a casual reading of \cite{erg} helpful.)  In sects.~4 and
5 we give a new derivation of the Ward identities for the Wilson
action.  The result we obtain is equivalent to what has been derived
before by Becchi \cite{becchi} and Ellwanger \cite{ellwanger} and
others for YM theories. Our starting point is the Ward identities in
the continuum limit of QED.  A crucial observation, which has not been
emphasized or clearly understood in the previous literature on ERG, is
that the continuum limit can be constructed using a Wilson action with
any finite UV cutoff.  (This is derived for the real scalar theory in
appendix A.)  Hence, we can rewrite the Ward identities in the
continuum limit as the identities for the Wilson action.  We will end
up with an operator equation (\ref{id}), an equality between two
composite operators.  In sect.~6, we explain how we can satisfy
(\ref{id}) by fine tuning the parameters of the theory order by order
in loop expansions.  We give 1-loop calculations in sect.~7.  After
giving brief remarks about how to rewrite the Ward identity (\ref{id})
as BRST invariance in sect.~8, we conclude the paper in sect.~9.  Some
detailed calculations are given in appendix B.

Before closing we mention some relevant past works.  Besides
\cite{bonini}, construction of QED using ERG has been done
by others, and we mention only a couple here.  In \cite{scalar,fw} the
background field method was applied to scalar QED.  More recently, a
manifestly gauge invariant formulation has been constructed not only
for QED \cite{arnone} but also for general YM theories.\cite{rosten}

Throughout the paper we use the euclidean metric.

\section{Polchinski's equation}

The Wilson action of QED is given as the sum of free and
interaction parts:
\begin{equation}
S (\Lambda) = S_{\mathrm{free}} (\Lambda) + S_{\mathrm{int}} (\Lambda)
\end{equation}
where
\begin{eqnarray}
S_{\mathrm{free}} (\Lambda) &\equiv& - \frac{1}{2} \int_k A_\mu (k) A_\nu (-k)
\frac{1}{K(k/\Lambda)} \left( k^2 \delta_{\mu\nu} - \left(1 -
\frac{1}{\xi} \right) k_\mu k_\nu \right) \nonumber\\ && \, - \int_p
\frac{1}{K (p/\Lambda)} \bar{\psi} (-p) \left( \fmslash{p} + i m
\right) \psi (p)
\end{eqnarray}
We use a sign convention so that the weight of functional integration
is given by $\exp [S (\Lambda)]$ instead of the more usual $\exp [-
S(\Lambda)]$.  The momentum cutoff $\Lambda$ is introduced via a
positive cutoff function $K(x)$, which is $1$ for $x^2 < 1$ and decays
rapidly (e.g., exponentially) for $x^2 > 1$.  The free propagators are
given by
\begin{eqnarray}
\vev{A_\mu (k) A_\nu (-k)}_{S_{\mathrm{free}} (\Lambda)} &=& \frac{K(k/\Lambda)}{k^2} \left(
\delta_{\mu\nu} - (1-\xi) \frac{k_\mu k_\nu}{k^2} \right)\\
\vev{\psi (p) \bar{\psi} (-p)}_{S_{\mathrm{free}} (\Lambda)} &=&
\frac{K(p/\Lambda)}{\fmslash{p} + i m}
\end{eqnarray}
Throughout the paper we consider only the connected part of the
correlation functions.  For notational simplicity we omit the overall
factor of the delta function for momentum conservation.

We can construct the continuum limit using a Wilson action $S(\Lambda)$
with a finite $\Lambda$.  But this comes with a price: we must keep an
increasing number of terms in the Wilson action as we go to higher orders
in perturbation theory.  The $\Lambda$ dependence of the interaction
part $S_{\mathrm{int}} (\Lambda)$ is given by Polchinski's ERG differential
equation \cite{joe}:
\begin{eqnarray}
  &&- \Lambda \frac{\partial S_{\mathrm{int}} (\Lambda)}{\partial \Lambda} = \int_k
  \frac{\Delta (k/\Lambda)}{k^2} \left( \delta_{\mu\nu} - (1-\xi)
    \frac{k_\mu k_\nu}{k^2} \right)\nonumber\\
&& \qquad\qquad\qquad
 \times \frac{1}{2} \left( \frac{\delta S_{\mathrm{int}} (\Lambda)}{\delta A_\mu
      (k)} \frac{\delta S_{\mathrm{int}} (\Lambda)}{\delta A_\nu (-k)} + \frac{\delta^2 S_{\mathrm{int}}
      (\Lambda)}{\delta A_\mu (k) \delta A_\nu (-k)} \right)
  \nonumber\\ &&
\qquad\qquad - \int_p \Delta (p/\Lambda) \,\mathrm{Sp}~ \Bigg[
  \frac{1}{\fmslash{p}+im} \nonumber\\
&& \qquad \times \left\lbrace \ld{-p} S_{\mathrm{int}} (\Lambda) \cdot S_{\mathrm{int}}
    (\Lambda) \rd{p} + \ld{-p} S_{\mathrm{int}} (\Lambda) \rd{p}\right\rbrace
  \Bigg]
\label{joe}
\end{eqnarray}
where
\begin{equation}
\Delta \left(\frac{p}{\Lambda}\right) \equiv \Lambda
\frac{\partial}{\partial \Lambda} K \left(\frac{p}{\Lambda}\right)
\end{equation}
is a non-negative function which is zero for $p^2 < \Lambda^2$, has an
appreciative value only for $p^2 \sim \Lambda^2$, and decays rapidly
as $p^2$ grows.  The minus sign in front of the second integral of
(\ref{joe}) is due to the Fermi statistics.

It is common to think that $S(\Lambda)$ describes only the physics of
low momentum $p < \Lambda$ correctly.  On a close inspection, however,
we find that $S(\Lambda)$ contains the physics of all momentum scales.
To be precise, the renormalized two-point functions are given by
\begin{eqnarray}
\vev{A_\mu (-k) A_\nu (k)} &=& \frac{1 - K(k/\Lambda)^{-1}}{k^2}
\left( \delta_{\mu\nu} - (1-\xi) \frac{k_\mu k_\nu}{k^2} \right)
\nonumber\\ && \qquad + \frac{1}{K(k/\Lambda)^2} \vev{A_\mu (-k) A_\nu
(k)}_{S (\Lambda)} \label{aa}\\
\vev{\psi (p) \bar{\psi} (-p)} &=& \frac{1 -
  K(p/\Lambda)^{-1}}{\fmslash{p} + i m} + \frac{1}{K(p/\Lambda)^2}
  \vev{\psi (p) \bar{\psi} (-p)}_{S (\Lambda)}\label{psipsibar}
\end{eqnarray}
where $\vev{\cdots}_S$ is the correlation function calculated with
$S$.  The renormalized higher point functions are more simply given by
\begin{eqnarray}
  &&\vev{A_{\mu_1} (k_1) \cdots A_{\mu_M} (k_M) \psi (p_1) \cdots \psi
    (p_N) \bar{\psi} (-q_1) \cdots \bar{\psi} (-q_N)}\nonumber\\ && =
  \prod_{i=1}^M \frac{1}{K(k_i/\Lambda)} \prod_{i=1}^N \frac{1}{K
    (p_i/\Lambda) K(q_i/\Lambda)} \nonumber\\
  && \qquad \cdot \vev{A_{\mu_1} (k_1) \cdots
    A_{\mu_M} (k_M) \psi (p_1) \cdots \psi (p_N) \bar{\psi} (-q_1)
    \cdots \bar{\psi} (-q_N)}_{S(\Lambda)}\label{higher}
\end{eqnarray}
To make sense of the division by $K (p/\Lambda)$, we assume that
$K(p/\Lambda)$ is strictly positive and that it vanishes only in the
limit $p^2 \to \infty$.  As long as the Wilson action $S(\Lambda)$
satisfies (\ref{joe}), the right-hand sides of
(\ref{aa},\ref{psipsibar},\ref{higher}) are independent of the cutoff
$\Lambda$.  Since the results (\ref{aa},\ref{psipsibar},\ref{higher})
may not be widely known, we derive analogous results for the real
scalar field theory in appendix A.

\section{Parameterization}

Let us next discuss how to parameterize the solutions of (\ref{joe}).
We are only interested in those solutions corresponding to
renormalized theories.  (See \cite{integral, erg} for a similar
analysis for the $\phi^4$ theory.)  We evaluate the functional derivatives
of $S(\Lambda)$ at vanishing fields.  The asymptotic behaviors at
large $\Lambda$ are obtained by expansions in powers of the electron
mass and external momenta:
\numparts
\begin{eqnarray}
&&\frac{\delta^2 S_{\mathrm{int}}}{\delta A_\mu (k) \delta A_\nu (-k)}\Bigg|_0 =
\delta_{\mu\nu} \Bigg\lbrace a_2 \left(\ln \Lambda/\mu\right)
\Lambda^2 \nonumber\\
&&\quad + b_2 \left( \ln \Lambda/\mu \right) m^2 + c_2
\left(\ln \Lambda/\mu\right) k^2 \Bigg\rbrace + d_2 \left(\ln
\Lambda/\mu \right) k_\mu k_\nu + \cdots \label{asymp-aa}\\
&&\ld{-p} S_{\mathrm{int}} \rd{p}\Bigg|_0 = a_f \left( \ln \Lambda/\mu \right)
\fmslash{p} + b_f \left( \ln \Lambda/\mu \right) i m + \cdots\\
&&\ld{-p-k} \frac{\delta S}{\delta A_\mu (k)} \rd{p}\Bigg|_0 = a_3 \left( \ln
\Lambda/\mu \right) \gamma_\mu + \cdots \label{asymp-vertex}\\
&&\frac{\delta^4 S}{\delta A_\alpha (k_1) \delta A_\beta (k_2) \delta
  A_\gamma (k_3) \delta A_\delta (k_4)}\Bigg|_0 \nonumber\\
&& \qquad\qquad = a_4 \left( \ln
\Lambda/\mu \right) \left( \delta_{\alpha\beta} \delta_{\gamma\delta}
  + \delta_{\alpha\gamma} \delta_{\beta\delta} + \delta_{\alpha
  \delta} \delta_{\beta \gamma} \right) + \cdots \label{asymp-aaaa}
\end{eqnarray}
\endnumparts
where an arbitrary momentum scale $\mu > 0$ is introduced to make
$\frac{\Lambda}{\mu}$ dimensionless.  The vertical line with subscript
$0$ is a reminder that the derivative is evaluated at vanishing
fields.  (The extraction of the asymptotic parts is similar to the
$\mathcal{T}$ operation in \cite{becchi}.)

For the renormalizable theories, the dotted parts are suppressed by
negative powers of $\Lambda$, hence vanishing in the limit
$\Lambda/\mu \to \infty$.  The higher order derivatives have negative
dimensions, and vanish also in the limit $\Lambda/\mu \to \infty$.

In solving (\ref{joe}), the seven functions
\begin{equation}
\begin{array}{c}
b_2 (\ln \Lambda/\mu), c_2(\ln \Lambda/\mu) , d_2(\ln
\Lambda/\mu),\\ a_f(\ln \Lambda/\mu) , b_f(\ln
\Lambda/\mu) , a_3(\ln \Lambda/\mu) ,a_4 (\ln \Lambda/\mu)
\end{array}
\end{equation}
are ambiguous by additive constants.  (Note that the quadratically
divergent $\Lambda^2 a_2$ has no such
ambiguity.)  Therefore, in order to specify a unique solution of
(\ref{joe}), we must introduce seven conditions.  To begin, we can
adopt the following three normalization conditions:
\begin{equation}
c_2 (0) = a_f (0) = b_f (0) = 0
\end{equation}
($c_2 (0)$ normalizes the gauge field, $a_f (0)$ the spinor fields,
and $b_f (0)$ the mass parameter $m$.)  It is one of the main purposes
of this paper to show how the Ward identities determine the remaining
four constants
\begin{equation}
b_2 (0), d_2 (0), a_3 (0), a_4 (0) \label{four}
\end{equation}
in terms of the elementary charge $e$, which itself is introduced
through the Ward identities.

\section{The Ward identities}

Let us recall the renormalized Ward identities in QED.  They have two
parts.  The first part is the identity for the two-point function of
the gauge field:
\begin{equation}
\frac{1}{\xi} k_\mu \vev{A_\mu (-k) A_\nu (k)} = \frac{k_\nu}{k^2}
\label{ward-1}
\end{equation}
The second part is the Ward identities for the higher-point functions:
\begin{eqnarray}
&&\frac{1}{\xi} k_\mu \vev{A_\mu (-k) A_{\mu_1} (k_1) \cdots A_{\mu_M}
  (k_M) \psi (p_1) \cdots \psi (p_N) \bar{\psi} (-q_1) \cdots
  \bar{\psi} (-q_N)} \nonumber\\ &&= \frac{e}{k^2} \sum_{i=1}^N \left[
  \vev{A_{\mu_1} (k_1) \cdots \psi (p_i - k) \cdots} - \vev{A_{\mu_1}
  (k_1) \cdots \bar{\psi} (-q_i-k) \cdots} \right] \label{ward-2}
\end{eqnarray}
where $e$ is interpreted as the elementary charge defined at scale
$\mu$.  The Ward identities can be also written as the conservation
law:
\begin{eqnarray}
&&k_\mu \vev{J_\mu (-k) A_{\mu_1} (k_1) \cdots A_{\mu_M}
  (k_M) \psi (p_1) \cdots \psi (p_N) \bar{\psi} (-q_1) \cdots
  \bar{\psi} (-q_N)} \nonumber\\ &&= e \sum_{i=1}^N \left[
  \vev{A_{\mu_1} (k_1) \cdots \psi (p_i - k) \cdots} - \vev{A_{\mu_1}
  (k_1) \cdots \bar{\psi} (-q_i-k) \cdots} \right] \label{cvc}
\end{eqnarray}
where $J_\mu$ is the charge current.  The goal of this section is to
find a concrete expression of $J_\mu$ in terms of the interaction
action $S_{\mathrm{int}} (\Lambda)$.

We first examine (\ref{ward-1}).  Using (\ref{aa}), we can
rewrite (\ref{ward-1}) as
\begin{equation}
\frac{1}{\xi} k_\mu \vev{A_\mu (-k) A_\nu (k)}_{S(\Lambda)} = K(k/\Lambda)
\frac{k_\nu}{k^2} \label{ward-1a}
\end{equation}
Since
\begin{eqnarray}
&&\vev{A_\mu (-k) A_\nu (k)}_{S(\Lambda)} \nonumber\\
&& \quad= \frac{K(k/\Lambda)}{k^2}
\left( \delta_{\mu\alpha} - (1-\xi) \frac{k_\mu k_\alpha}{k^2} \right)
\cdot \left( \delta_{\alpha\nu} +
\vev{\frac{\delta S_{\mathrm{int}}}{\delta A_\alpha (k)} A_\nu (k)}_{S(\Lambda)}
\right)\label{firstrelation}
\end{eqnarray}
(see appendix A for an analogous result for the real scalar theory), we
can rewrite (\ref{ward-1a}) as
\begin{equation}
k_\mu \vev{\frac{\delta S_{\mathrm{int}}}{\delta
    A_\nu (k)} A_\nu (k)}_{S(\Lambda)} = 0 \label{ward0}
\end{equation}

Next, we examine (\ref{ward-2}).  Using (\ref{higher}) and
\begin{eqnarray}
&&\vev{A_\mu (-k) A_{\mu_1} (k_1) \cdots \psi (p_1) \cdots \bar{\psi}
  (-q_1) \cdots}_{S(\Lambda)} \nonumber\\ && = \frac{K(k/\Lambda)}{k^2}
  \left( \delta_{\mu\alpha} - (1-\xi) \frac{k_\mu k_\alpha}{k^2}
  \right)\nonumber\\
&&\qquad\cdot \vev{\frac{\delta S_{\mathrm{int}}}{\delta A_\alpha (k)}
  A_{\mu_1} (k_1) \cdots \psi (p_1) \cdots \bar{\psi} (-q_1)
  \cdots}_{S(\Lambda)}\label{secondrelation}
\end{eqnarray}
(again see appendix A), we can rewrite
(\ref{ward-2}) as
\begin{eqnarray}
&& k_\mu \vev{\frac{\delta S_{\mathrm{int}}}{\delta A_\mu (k)} A_{\mu_1} (k_1)
    \cdots A_{\mu_M} (k_M) \psi (p_1) \cdots \psi (p_N) \bar{\psi}
    (-q_1) \cdots \bar{\psi} (-q_N) }_{S(\Lambda)}\nonumber\\ &&
    \qquad \times \frac{1}{\prod_{i=1}^M K(k_i/\Lambda) \prod_{j=1}^N
    K(p_i/\Lambda) K(q_i/\Lambda)} \nonumber\\ && = e \sum_{n=1}^N
    \Bigg[ \vev{ A_{\mu_1} (k_1) \cdots \psi (p_n - k) \cdots} -
    \vev{A_{\mu_1} (k_1) \cdots \bar{\psi}(-q_n-k) \cdots}
    \Bigg]\label{ward}
\end{eqnarray}

To summarize so far, we can replace (\ref{ward-1},\ref{ward-2}) by
(\ref{ward0},\ref{ward}).  Note that (\ref{ward0}) is a special case
$M=1$, $N=0$ of (\ref{ward}).  Hence, (\ref{ward}) for arbitrary $M,
N$ is equivalent to (\ref{ward-1},\ref{ward-2}).

We now define a vector current by
\begin{equation}
J_\mu (-k) \equiv \frac{\delta S_{\mathrm{int}} (\Lambda)}{\delta A_\mu (k)} \label{jmu}
\end{equation}
This is a composite operator since its correlation functions
\begin{eqnarray}
&&\vev{J_\mu (-k) A_{\mu_1} (k_1) \cdots \psi (p_1) \cdots
    \bar{\psi}(-q_1) \cdots}\nonumber\\ && \equiv \vev{J_\mu (-k)
    A_{\mu_1} (k_1) \cdots \psi (p_1) \cdots \bar{\psi}(-q_1)
    \cdots}_{S(\Lambda)}\nonumber\\ && \qquad \times
    \frac{1}{\prod_{i=1}^M K (k_i/\Lambda) \prod_{j=1}^N
    K(p_j/\Lambda) K (q_j/\Lambda)} \label{Jcorr}
\end{eqnarray}
are independent of $\Lambda$.  (See Appendix A for an explanation on
composite operators.)  To show this, we differentiate
(\ref{joe}) with respect to $A_\mu (k)$ to obtain
\begin{equation}
- \Lambda \frac{\partial}{\partial \Lambda} J_\mu (-k) = \mathcal{D}
  \cdot J_\mu (-k) \label{operator}
\end{equation}
where $\mathcal{D}$ is a linear differential operator defined by
\begin{eqnarray}
&& \mathcal{D} \cdot \mathcal{F} \equiv \int_l \frac{\Delta (l/\Lambda)}{l^2}
\left( \delta_{\mu\nu} - (1-\xi) \frac{l_\mu l_\nu}{l^2} \right)
\nonumber\\ &&\qquad\qquad\qquad\qquad \cdot \left( \frac{\delta
S_{\mathrm{int}}}{\delta A_\mu (-l)} \frac{\delta \mathcal{F}}{\delta A_\nu (l)} +
\frac{1}{2} \frac{\delta^2 \mathcal{F} }{\delta A_\mu (l) \delta A_\nu (-l)}
\right) \nonumber\\ && \qquad\quad - \int_p \Delta (p/\Lambda) \, \mathrm{Sp}~
\frac{1}{\fmslash{p} + i m} \Bigg\lbrace \ld{-p} S_{\mathrm{int}} \cdot \mathcal{F}
\rd{p}\nonumber\\ &&\qquad\qquad\qquad + \ld{-p} \mathcal{F} \cdot S_{\mathrm{int}} \rd{p}
+ \ld{-p} \mathcal{F} \rd{p} \Bigg\rbrace
\end{eqnarray}
acting on any functional $\mathcal{F}$.  (\ref{operator}) guarantees
that the correlation functions (\ref{Jcorr}) are independent of
$\Lambda$.  Thus, from (\ref{ward}--\ref{Jcorr}), we can
rewrite the Ward identities as (\ref{cvc}) where $J_\mu$ is defined by
(\ref{jmu}).  (For a discussion of composite operators in $\phi^4$
theory, see \cite{erg}.)

\section{Ward identity as an operator identity \label{opid}}

In this section we wish to rewrite the Ward identities
(\ref{cvc}) as a single operator equation.  For this purpose we
construct a composite operator $\Phi (-k)$ whose correlation functions
give the right-hand side of (\ref{cvc}):
\begin{eqnarray}
&&\vev{\Phi (-k) A_{\mu_1} (k_1) \cdots A_{\mu_M} (k_M) \psi (p_1)
  \cdots \psi (p_N) \bar{\psi} (-q_1) \cdots \bar{\psi} (-q_N)}
  \nonumber\\
&&  = e \sum_{i=1}^N \left( \vev{A_{\mu_1} (k_1) \cdots \psi (p_i-k)
  \cdots} - \vev{A_{\mu_1} (k_1) \cdots \bar{\psi} (-q_i - k) \cdots}
  \right) \label{Phicorr}
\end{eqnarray}
Once we construct $\Phi (-k)$, the Ward identities (\ref{cvc}) are
equivalent to the single operator equation:
\begin{equation}
k_\mu J_\mu (-k) = \Phi (-k) \label{id}
\end{equation}
The construction of $\Phi (-k)$ is essential, but it involves a fair
amount of technicality.  The derivation will be given in appendix B.
There, we show that $\Phi (-k)$ is given by
\begin{eqnarray}
\Phi (-k) &\equiv& \int_p \mathrm{Sp}~ U (-p-k,p) \nonumber\\ &&\qquad \cdot
\left\lbrace \ld{-p} S \cdot S \rd{p+k} + \ld{-p} S \rd{p+k}
\right\rbrace \nonumber\\ && + e \int_p \Bigg[ - S \rd{p}
\frac{K(p/\Lambda)}{K\left((p-k)/\Lambda\right)} \psi (p-k)\nonumber\\
&&\qquad\qquad + \frac{K(p/\Lambda)}{K\left((p+k)/\Lambda\right)} \bar{\psi}
(-p-k) \ld{-p} S \Bigg] \label{Phi}
\end{eqnarray}
where the matrix $U$ is defined by
\begin{eqnarray}
&&U (-p-k, p) \nonumber\\ && \equiv e \left[ K \left( (p+k)/\Lambda
\right) \frac{1 - K(p/\Lambda)}{\fmslash{p} + i m} - \frac{1 - K
\left( (p+k)/\Lambda \right)}{\fmslash{p} + \fmslash{k} + i m} K
(p/\Lambda) \right] \label{U}
\end{eqnarray}
$\Phi$ is a composite operator, satisfying
\begin{equation}
- \Lambda \frac{\partial}{\partial \Lambda} \Phi (-k) = \mathcal{D}
  \cdot \Phi (-k)
\end{equation}
Hence, if (\ref{id}) is valid asymptotically for large $\Lambda \gg
\mu$, then it is valid for any $\Lambda$.  As explained in sect.~1,
this is the most important feature of the Ward identity in ERG.  A
Ward identity similar to (\ref{id}) has been obtained for the scalar
QED in equation (7) of \cite{fw}, using the background field formalism.

\section{Fine tuning}

We now show how to satisfy the Ward identity (\ref{id}) for $\Lambda
\gg \mu$ by fixing the four constants (\ref{four}).

The asymptotic behavior of $k_\mu J_\mu$ is easily obtained from the
asymptotic behavior of the Wilson action, which is given by
(\ref{asymp-aa},\ref{asymp-vertex},\ref{asymp-aaaa}):
\numparts
\begin{eqnarray}
&&\frac{\delta k_\mu J_\mu (-k)}{\delta A_\nu (-k)}\Bigg|_0 = k_\nu
\Bigg\lbrace a_2 (\ln \Lambda/\mu) \Lambda^2 \nonumber\\
&&\qquad\qquad\qquad + b_2 (\ln \Lambda/\mu) m^2 + \left(c_2 +
d_2\right) (\ln \Lambda/\mu) k^2 \Bigg\rbrace + \cdots\\ && \ld{-p-k}
k_\mu J_\mu (-k) \rd{p}\Bigg|_0 = a_3 (\ln \Lambda/\mu) \fmslash{k} + \cdots\\
&&\frac{\delta^3 k_\mu J_\mu (-k)}{\delta A_\alpha (k_1) \delta
A_\beta (k_2) \delta A_\gamma (k_3)}\Bigg|_0 \nonumber\\ &&\qquad\qquad\qquad
= a_4 (\ln \Lambda/\mu) \left( k_{\alpha} \delta_{\beta\gamma} +
k_\beta \delta_{\alpha\gamma} + k_\gamma \delta_{\alpha\beta} \right)
+ \cdots
\end{eqnarray}
\endnumparts

The composite operator $\Phi (-k)$ is a dimension $4$ scalar operator
of momentum $-k$, odd under charge conjugation, and vanishing at
$k=0$.  Hence, its asymptotic behavior has the same form as above:
\numparts
\begin{eqnarray}
&&\frac{\delta \Phi}{\delta A_\nu (- k)}\Bigg|_0 \nonumber\\
&& \quad = k_\nu \Bigg\lbrace \bar{a}_2 (\ln \Lambda/\mu) \Lambda^2
 + \bar{b}_2 (\ln \Lambda/\mu) m^2 + \bar{d}_2 (\ln
\Lambda/\mu) k^2 \Bigg\rbrace + \cdots\\
&& \ld{-p-k} \Phi (-k) \rd{p}\Bigg|_0 = \bar{a}_3 (\ln \Lambda/\mu)
 \fmslash{k} + \cdots\\
&&\frac{\delta^3 \Phi (-k)}{\delta A_\alpha
  (k_1) \delta A_\beta (k_2) \delta A_\gamma (k_3)}\Bigg|_0\nonumber\\
&& \qquad\qquad = \bar{a}_4 (\ln \Lambda/\mu) \left( k_{\alpha}
  \delta_{\beta\gamma} + k_\beta \delta_{\alpha\gamma} + k_\gamma
  \delta_{\alpha\beta} \right) + \cdots
\end{eqnarray}
\endnumparts
The values of the four dimensionless functions $\bar{b}_2$,
$\bar{d}_2$, $\bar{a}_3$, $\bar{a}_4$ at $\ln \Lambda/\mu = 0$
determine $\Phi (-k)$ uniquely.  Therefore, the operator equation
(\ref{id}) is equivalent to the following four equations:
\begin{equation}
\begin{array}{c@{~=~}c}
b_2 (0) & \bar{b}_2 (0)\\
d_2 (0) & \bar{d}_2 (0)\\
a_3 (0) & \bar{a}_3 (0)\\
a_4 (0) & \bar{a}_4 (0)
\end{array}\label{recursion}
\end{equation}
where we have used the convention $c_2 (0) = 0$.

Now, $\Phi$ is defined by (\ref{Phi}, \ref{U}) in terms of the Wilson action
$S (\Lambda)$.  Therefore, we obtain
\numparts
\begin{eqnarray}
&&\frac{\delta \Phi}{\delta A_\nu (- k)}\Bigg|_0 = \int_q \mathrm{Sp}~ U (-q-k,
 q) \ld{-q} \frac{\delta S}{\delta A_\nu (-k)} \rd{q+k}\Bigg|_0
 \label{Phi-1}\\ && \ld{-p-k} \Phi (-k) \rd{p} \Bigg|_0 = e \left(1 - a_f
 (\ln \Lambda/\mu) \right) \fmslash{k}\nonumber\\ &&\quad + \int_q
 \ld{-p-k} \mathrm{Sp}~ \left\lbrace U(-q-k,q) \ld{-q} S \rd{q+k} \right\rbrace
 \rd{p} \Bigg|_0 \label{Phi-2}\\ &&\frac{\delta^3 \Phi (-k)}{\delta
 A_\alpha (k_1) \delta A_\beta (k_2) \delta A_\gamma
 (k_3)}\Bigg|_0\nonumber\\ && \, = \int_q \mathrm{Sp}~ U (-q-k,q) \ld{-q}
 \frac{\delta^3 S}{\delta A_\alpha (k_1) \delta A_\beta (k_2) \delta
 A_\gamma (k_3)} \rd{q+k} \Bigg|_0\label{Phi-3}
\end{eqnarray}
\endnumparts
Expanding the right-hand sides in powers of the electron mass and
external momenta, we can obtain $\bar{b}_2$, $\bar{d}_2$, $\bar{a}_3$,
$\bar{a}_4$.  On the right-hand sides one extra loop is given
explicitly by the integral over $q$, and it is sufficient to know $S
(\Lambda)$ only up to $(l-1)$-loop level to determine the four
constants $\bar{b}_2 (0), \bar{d}_2 (0), \bar{a}_3 (0), \bar{a}_4 (0)$
at $l$-loop level.  (Note $a_f (0) =0$ by convention.)  In other
words, with $b_2 (0), d_2 (0), a_3 (0), a_4 (0)$ determined up to
$(l-1)$-loop level, we can determine the $l$-loop values of $b_2 (0),
d_2 (0), a_3 (0), a_4 (0)$ by demanding (\ref{recursion}).  We can
thus construct QED using the Ward identities.  This recursive nature
of the Ward identities has been observed by Becchi \cite{becchi} and
Morris and D'Attanasio \cite{md} among others.  We have taken
advantage of it using our particular parameterization of the theory.

\section{1-loop calculations}

Using the results of the previous section, let us do 1-loop
calculations.  We start from the tree-level values:
\begin{equation}
 b_2 (0) = d_2 (0) = a_4 (0) = 0,\quad a_3 (0) = e
\end{equation}

At 1-loop, (\ref{Phi-1}) gives
\begin{equation}
\frac{\delta \Phi}{\delta A_\nu (-k)}\Bigg|_0 = e^2 \int_q \mathrm{Sp}~
  \gamma_\nu U (-q-k,q)
\end{equation}
Changing the integration variable as
\begin{equation}
q \longrightarrow \Lambda q \label{change}
\end{equation}
we obtain
\begin{eqnarray}
&& \frac{\delta \Phi}{\delta A_\nu (-k)}\Bigg|_0 = e^2 \Lambda^2 \int_q
  \mathrm{Sp}~ \gamma_\nu \nonumber\\ &&\qquad\qquad \cdot \left\lbrace K\left( q +
  \frac{k}{\Lambda} \right) \frac{1 - K (q)}{\fmslash{q} + i
  m/\Lambda} - \frac{1 - K\left( q +
  \frac{k}{\Lambda}\right)}{\fmslash{q} + \fmslash{k}/\Lambda + i
  m/\Lambda } K(q) \right\rbrace\nonumber\\ &&\quad\simeq e^2 k_\nu \left[ - 2
  \Lambda^2 \int_q \frac{1}{q^2} \Delta (q) \left( 1 - K(q) \right) +
  \left( m^2 + \frac{k^2}{3} \right) \int_q \frac{\Delta (q)}{(q^2)^2}
  \right]
\end{eqnarray}
where we have expanded the integral in powers of $m/\Lambda$
and $k_\mu/\Lambda$.  Using
\begin{equation}
\int_q \frac{ \Delta (q) K(q)^n}{(q^2)^2}  = \frac{1}{n+1}
\int \frac{d^4 q}{(2 \pi)^4} \frac{- 2}{q^2} \frac{d}{d q^2} K( q )^{n+1} =
\frac{1}{(4 \pi)^2} \frac{2}{n+1}
\end{equation}
(independent of the choice of $K$), we obtain
\begin{equation}
b_2 (0) = \frac{2 e^2}{(4 \pi)^2},\quad
d_2 (0) = \frac{2 e^2}{3 (4 \pi)^2}
\end{equation}

Next we consider (\ref{Phi-2}) at 1-loop:
\begin{eqnarray}
&&\ld{-p-k} \Phi (-k) \rd{p} \Bigg|_0 - e (1 - a_f (\ln \Lambda/\mu))
\fmslash{k} \nonumber\\
&& = - e^2 \int_q \gamma_\mu U (-q-k,q) \gamma_\nu\nonumber\\
&& \qquad \cdot \frac{1 - K ((q-p)/\Lambda)}{(q-p)^2} \left(
\delta_{\mu\nu} - (1-\xi) \frac{(q-p)_\mu (q-p)_\nu}{(q-p)^2}
\right)\nonumber\\
&& \simeq - e^3 \fmslash{k} \int_q \frac{1}{(q^2)^2} \left\lbrace \xi
K(q) \left(1 - K(q) \right)^2 + \frac{3 - \xi}{4} \left(1 -
K(q)\right) \Delta (q) \right\rbrace
\end{eqnarray}
where we have used the change of variables (\ref{change}), and
expanded the integral in powers of $k_\mu/\Lambda$, $p_\mu/\Lambda$.
Hence,
\begin{equation}
a_3 (0) - e = - e^3 \left( \xi \int_q \frac{1}{(q^2)^2} K(q) (1 -
K(q))^2 + \frac{3 - \xi}{4 (4\pi)^2} \right)
\end{equation}

Finally, we consider (\ref{Phi-3}):
\begin{eqnarray}
&&\frac{\delta^3 \Phi (-k)}{\delta
 A_\alpha (k_1) \delta A_\beta (k_2) \delta A_\gamma
 (k_3)}\Bigg|_0\nonumber\\
&& = e^3 \int_q \mathrm{Sp}~ U (-q-k,q) \nonumber\\
&&\quad \cdot \Bigg\lbrace \gamma_\gamma \frac{1 - K \left( (q-k_3)/\Lambda
 \right)}{\fmslash{q} - \fmslash{k}_3 + i m} \gamma_\beta
\frac{1 - K\left( (q-k_2-k_3)/\Lambda \right)}{\fmslash{q} -
 \fmslash{k}_2 - \fmslash{k}_3 + i m} \gamma_\alpha\nonumber\\
&& \qquad\qquad + (\textrm{5 permutations}) \quad\Bigg\rbrace\nonumber\\
&& \simeq 2 e^4 \left( k_\alpha \delta_{\beta\gamma} + k_\beta
  \delta_{\gamma \alpha} + k_\gamma \delta_{\alpha\beta} \right)
\int_q \frac{\Delta (q/\Lambda)}{(q^2)^2} \left(1 - K(q/\Lambda)\right)^2
\end{eqnarray}
Hence, we obtain
\begin{equation}
a_4 (0) = \frac{4}{3} \frac{e^4}{(4 \pi)^2}
\end{equation}

\section{BRST invariance}

To elucidate the gauge structure of QED further, we introduce ghost
and antighost fields $c, \bar{c}$.  These fields are non-interacting,
and we define the total Wilson action by
\begin{equation}
\bar{S} (\Lambda) \equiv S (\Lambda) - \int_k \bar{c} (-k) c(k)
\frac{k^2}{K (k/\Lambda)}
\end{equation}
We now define the BRST transformation as follows:
\numparts
\begin{eqnarray}
\delta_\epsilon A_\mu (k) &=& k_\mu \epsilon c (k)\\
\delta_\epsilon c (k) &=& 0\\
\delta_\epsilon \bar{c} (-k) &=& - \frac{1}{\xi} k_\mu A_\mu (-k) \epsilon\\
\delta_\epsilon \psi (p) &=& \int_k \epsilon c(k) \Bigg( e \frac{K(p/\Lambda)}{K\left(
  (p-k)/\Lambda \right)} \psi (p-k) \nonumber\\
&& \qquad\qquad - U(-p,p-k) \ld{-p+k} \bar{S} \Bigg)\\
\delta_\epsilon \bar{\psi} (-p) &=& - \int_k \epsilon c(k)
e \frac{K(p/\Lambda)}{K\left( (p+k)/\Lambda \right)} \bar{\psi} (-p-k)
\end{eqnarray}
\endnumparts
where $\epsilon$ is an arbitrary Grassmann variable.  The transformation of
$\psi$ is highly non-linear due to the second term.  The Ward identity
(\ref{id}) is equivalent to the following BRST invariance:
\begin{equation}
\delta_\epsilon \bar{S} + \int_k \epsilon c (k) \int_p \mathrm{Sp}~
  U(-p-k,p) \ld{-p} \bar{S} \rd{p+k}
 = 0 \label{brst}
\end{equation}
The first term is the change of the Wilson action $\bar{S}$ under the
transformation.  The second term is the change of the fermionic
integration measure.  Note that the non-vanishing $\delta_{\epsilon}
\bar{S}$ implies the non-invariance of the action under the BRST
transformation.  For example, the non-invariance due to the photon
mass term is cancelled precisely by the jacobian.

Due to the electron number conservation, the transformation of $\psi,
\bar{\psi}$ under BRST is not unique.  Alternatively, we can define
the BRST transformation which is symmetric between $\psi$ and
$\bar{\psi}$: \numparts
\begin{eqnarray}
\delta_\epsilon \psi (p) &=& e K(p/\Lambda) \int_k \epsilon c(k) \Psi (p-k)\\
\delta_\epsilon \bar{\psi} (-p) &=& - e K(p/\Lambda) \int_k \epsilon c(k)
\bar{\Psi} (-p-k)
\end{eqnarray}
\endnumparts
where
\numparts
\begin{eqnarray}
\Psi (p) &\equiv& \psi (p) + \frac{1 - K(p/\Lambda)}{\fmslash{p} + i m}
\frac{\overrightarrow{\delta}}{\delta \bar{\psi} (-p)} S_{\mathrm{int}}\\
\bar{\Psi} (-p) &\equiv& \bar{\psi} (-p) + S_{\mathrm{int}}
\frac{\overleftarrow{\delta}}{\delta \psi (p)} \frac{1 -
  K(p/\Lambda)}{\fmslash{p} + i m}
\end{eqnarray}
\endnumparts
are composite operators.  The transformations of $A_\mu, c, \bar{c}$
are the same as before.  The BRST invariance is now given as
\begin{equation}
\delta_\epsilon \bar{S} - \int_k \mathrm{Sp}~ \left[
 \delta_\epsilon \psi (p) \frac{\overleftarrow{\delta}}{\delta \psi (p)} +
  \frac{\overrightarrow{\delta}}{\delta \bar{\psi} (-p)} \delta_\epsilon
  \bar{\psi} (-p) \right] = 0
\end{equation}

The first form of BRST invariance has been extended further using the
antifield formalism in the joint work with Igarashi and Itoh.\cite{IIS}

\section{Conclusions}

For some time the compatibility of a smooth cutoff with gauge
invariance has been established by the previous works
(\cite{becchi},\cite{ellwanger},\cite{bonini},\cite{scalar}--\cite{rosten}
and references therein) on ERG.  Nevertheless, the contrary viewpoint
is still prevalent among the practitioners of quantum field theory.
A main task of this paper was to introduce a concrete application of
ERG to convince the reader of the compatibility.  In particular we
have shown how to construct QED using ERG.  The Wilson action with a
finite momentum cutoff has exactly the same gauge invariance as the
continuum limit.  Nothing is compromised.  The crucial observation for
our construction is that with a Wilson action we can compute the
correlation functions in the continuum limit.  (See
(\ref{aa}--\ref{higher}) and appendix A.)

As we have mentioned in sect.~\ref{intro}, it is some time since the
ground work was laid down for incorporation of gauge symmetries in the
ERG formalism.  As far as formalism goes, Becchi's results in
\cite{becchi} are seminal, if not final.  A merit of the present paper
is in the use of a particular parameterization of the theory, based on
the asymptotic behavior of the Wilson action at a very large cutoff.
The Ward identities of the Wilson action simplify for a large cutoff,
and we were able to take advantage of it using our parameterization
scheme.  In a future publication we wish to apply the same scheme to
YM theories.

\ack

I thank Profs. Y.~Igarashi and K.~Itoh for the observation that the
Ward identity (\ref{id}) can be interpreted as the BRST invariance
(\ref{brst}).  Without their help I would have missed the BRST
invariance.  I also thank Prof. K.~Higashijima for a comment which
helped me to simplify the presentation of this paper.  This work was
partially supported by the Grant-In-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science, and Technology,
Japan (\#14340077).

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text:
Neuvila (en francès Neuville) és un municipi francès, situat al departament de la Corresa i a la regió de la Nova Aquitània.

Referències

Municipis de la Corresa

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The present invention relates to a method for screening a new drug candidate using a liquid chromatography/microfluidic device/mass spectrometry system, and to a liquid chromatography/microfluidic device/mass spectrometry system. The present invention involves the detection of an interaction between molecules on a real-time basis through adjustment of a microreaction between traces of natural material or synthesized new drug candidates and a target material (protein or cell, etc.), thus developing materials for new drug candidates at a lower cost and with high efficiency, while improving quality of life and reducing medical costs. The present invention can be valuably used in increasing new scientific technology through the convergence of nanotechnology, biotechnology, and analytical chemistry technology.
The present invention relates to a Liquid chromatography(LC)-microfluidic device(MFR)-mass spectrometry(MS)-based method and apparatus for screening a new drug candidate.
New drug development generally consists of new drug material screening stage, preclinical stage, clinical stage (phase 1, phase 2, phase 3), and commercialization stage, and requires at least five years for the development stage and more than a billion dollars for the development and clinical tests. However, once the efficacy and safety are verified, this potential blockbuster drug can generate several trillion dollars of revenues (see FIG. 1). However, many new drug candidate materials do not pass the preclinical and clinical trial stages due to safety and toxicity problems. Accordingly, it is required to drop out the materials that have low possibility for commercialization or drugs with toxicity as early as possible to save cost and time for development of new drugs.
In order to resolve the above-mentioned problems, screening may generally be performed to select the new drug candidate materials. The screening method of new drug material generally involves in-vitro assay and cell-based assay, and it is generally necessary that low molecular compounds which act on the proteins that have an established correlativity to specific genes and diseases are developed. Accordingly, faster and more efficient screening techniques are necessary, which can ensure that the candidate materials for new drug development are obtained as many as possible.
Meanwhile, the focus of new drug development and research has recently extended from the synthesized to natural drugs. The natural drugs, which can be obtained from plants or marine microorganisms, are widely known as being free of side-effect even with a long period of use.
Particularly in South Korea where infrastructure for new drug development has not been built completely, the field of new drug development using natural materials has gained a place as the Blue Ocean strategy. The synthesized drugs can also use the natural extract as a starting material. Considering the fact that approximately 25% of new drug materials fail the toxicity test, the drugs using natural materials are expected to have higher possibility to be free of toxicity than synthetic counterpart. Given the above-mentioned situation, the natural drugs have been steadily developed for commercialization thereof, and the Korean government and science field have legislated related laws to promote and encourage natural drug development. Since the natural materials generally include a trace of candidate material with other compounds, it may be desirable that the screening incorporates a method for isolating and purifying only the reactant material, to thereby shorten time for development.
In order to discover new drug candidate from the natural extract, it is necessary to confirm interaction between the separated candidate with proteins related to disease-associated protein.
The interaction between biomaterial such as protein with separated candidate can generally be measured using bioluminescence resonance energy transfer (BRET), fluorescence resonance energy transfer (FRET), fluorescence polarization (FP), etc., which utilize the principle of energy transfer according to interaction between the materials. These methods can observe changes in cells or proteins with relatively high degree of speed and accuracy, and thus are used in the screening of new drug materials that can react with the same.
BRET uses luciferin, which is extracted from firefly, as a light-emitting resonator to detect interaction between molecules when the molecules approach, i.e., when the resonance energy between donor and acceptor materials is transferred.
FRET is capable of measuring and detecting the energy transferred to the acceptor molecule based on fluorescent energy transferred as the resonance energy from the interaction between molecules is transferred.
FP is particularly utilizable in the field of new drug substance screening, since FP can acquire physical information regarding molecular movement including protein-ligand binding, protein-nucleic aid interaction, protein degradation, or the like.
Like BRET or FRET, in FP, resonance energy, instead of energy by photon, is transferred to cause variation in fluorescence when the substances are in vicinity to each other. One of the advantages of FP is lower dependency on the fluorescent material than FRET, which allows test to be conducted under a variety of biological environments. Due to anisotropy, FP varies depending on rotation and mass of the molecules, and macromolecules such as protein exhibit high degree of fluorescence polarization during rotation. By utilizing the such characteristics, it is possible to measure interaction between the molecules. That is, it is possible to find that whether a material binds to the protein or not by measuring the interaction between ligand and protein with fluorescence or fluorescent polarization. Therefore, it is possible to selectively differentiate the new drug candidate substances using the above-explained assays.
Accordingly, the present inventors have designed a microfluidic device which can adjust micro-reaction between natural material containing a new drug candidate material or synthetic new drug with a target material, and detect interaction between molecules based on an increase of fluorescence, and developed and completed a screening method, according to which the new drug candidate separated with the liquid chromatograph is fed into the microfluidic device and a mass spectrometer, so that the microfluidic device carries out detection at multi levels using only a trace of substance, and also according to which analysis result is provided in real-time basis, and an apparatus for implementing said method.
An object of the present invention is to provide a method for screening a new drug candidate using liquid chromatography/microfluidic device/mass spectrometry system.
Another object of the present invention is to provide the microfluidic device.
Yet another object of the present invention is to provide a liquid chromatography/microfluidic device/mass spectrometry system to implement the method for screening the new drug candidate.
Further another object of the present invention is to provide a method for constructing a library of new drug candidate materials according to which a mixture of the new drug candidate materials is separated with liquid chromatograph and reacted.
Yet another object of the present invention is to provide a method for identifying a reaction between the new drug candidate material and a target material.
Further another object of the present invention is to provide an apparatus for identifying a reaction between the new drug candidate material and a target material.
In order to accomplish the above-mentioned object, the present invention provides a method for screening a new drug candidate material using a liquid chromatography/microfluidic device/mass spectrometry system.
Also, the present invention provides the microfluidic device.
Further, the present invention provides a liquid chromatography/microfluidic device/mass spectrometry system to implementing the method for screening.
Also, the present invention provides a method for constructing a library of new drug candidate materials according to which a mixture of the new drug candidate materials is separated with liquid chromatograph and reacted.
Further, the present invention provides a method for identifying a reaction between the new drug candidate material and a target material.
Also, the present invention provides an apparatus for identifying a reaction between the new drug candidate material and a target material.
The present invention involves the detection of an interaction between molecules on a real-time basis through adjustment of a micro-reaction between traces of natural material or synthesized new drug candidates and a target material, thus developing materials for new drug candidates at a lower cost and with higher efficiency, while improving quality of life and reducing medical costs. The present invention can also be useful in increasing new scientific technology through the convergence of nanotechnology, biotechnology, and analytical chemistry technology.
FIG. 16 is a microscopic image showing fluorescence of a new drug material screened in Experimental example 3 fluoresces, according to an embodiment of the present invention.
The present invention will be explained in detail below.
The present invention provides a method for screening a new drug candidate material using a liquid chromatography/microfluidic device/mass spectrometry system, the method comprising: separating a natural material containing the new drug candidate material or a synthesized new drug material using a liquid chromatograph (step 1); injecting the new drug candidate material separated at step 1 into inlets of a mass spectrometer and of a microfluidic device at the same time through a splitter (step 2-1); injecting a target material into an inlet of a target material channel designed to be connected to a new drug candidate material channel for the new drug candidate material separated at step 1 (step 2-2); reacting the new drug candidate material and the target material injected at steps 2-1 and 2-2 respectively in a reaction channel connected with the channels of steps 2-1 and 2-2 (step 3); injecting an oil through an oil channel connected to the reaction channel of step 3 to form droplets (step 4); and detecting the droplets in fluorescence or emitting light from among the droplets of step 4, using the mass spectrometer (step 5).
The present invention will be explained in greater detail below with reference to the respective steps.
First, the step 1 according to present invention is a step separating natural material containing a new drug candidate material or a synthesized new drug candidate material using liquid chromatograph.
In particular, the step 1 according to present invention is a step separating a single new drug candidate material from the natural materials containing the new drug candidate materials or the synthesized new drug material using chromatography. Each new drug candidate material may be separated at different discharge time due to varying moving speed in columns.
Next, the step 2-1 according to the present invention is a step injecting the new drug candidate material separated at step 1 into the mass spectrometer and the new drug candidate material inlet of the microfluidic device through the splitter.
At step 2-1, the new drug candidate material may desirably be injected to the new drug candidate material inlet and the mass spectrometer of the microfluidic device at the same time, to find a new drug candidate material which is injected into the microfluidic device and reacted with the target material, and also to confirm the material injected into the mass spectrometer for analysis at the discharge time of the new drug candidate material separated at step 1.
Next, the step 2-2 according to the present invention is a step injecting the target material into the inlet of the target material channel which is designed to be connected to the new drug candidate material channel of step 2-1.
The new drug candidate material of step 2-1 or the target material of step 2-2 may preferably be injected in a flow rate of 1 to 20 μl/hour. If the flow rate is below 1 μl/hour, the new drug candidate material or the target material may not flow along the microchannel, while if the flow rate exceeds 20 μl/hour, the new drug candidate material or the target material may be accelerated too much to allow the reaction to occur between the two substances, according to which illumination or fluorescence sufficient to result in detection may not occur.
The target material of step 2-2 may preferably be a DNA, protein, cell or disease-associated material, and may be the one that can induce or increase fluorescence or illumination from a reaction with the new drug candidate.
Wherein, the target material may have a concentration from 0.1 to 10 mg/ml. If the concentration is less than 0.1 mg/ml, detection can be difficult.
It is also preferable that steps 2-1 and 2-2 are carried out concurrently so that appropriate reaction mixture can be provided to the reaction channel of step 3.
Next, step 3 according to the present invention is a step reacting the new drug candidate material and the target material injected at steps 2-1, 2-2 respectively with each other in a reaction channel which is connected to the new drug candidate material channel and the target material channel.
To be specific, the step 3 provides sufficient reaction between the new drug candidate material and the target material as injected to allow energy transfer including bioluminescence resonance energy transfer (BRET), fluorescence resonance energy transfer (FRET), or fluorescence polarization (FP) to occur, in which the reaction channel may be designed in a letter U configuration to ensure sufficient moving distance within a narrow space occupied by the microfluidic device. For example, the reaction may include immunological reaction such as antigen-antibody reaction (e.g., virus antigen-virus antibody, pathogenic microorganism-pathogen microorganism antibody, etc.), biotin-avidin, immunoglobulin G-protein A; hormone-hormon receptor reaction; DNA-DNA receptor reaction; RNA-RNA receptor reaction; or drug-drug receptor reaction, but not limited thereto.
Next, step 4 is a step injecting oil through the oil channel connected to the reaction channel of step 3 to form droplets.
To be specific, step 4 may injected the oil into a channel where the mixture of the new drug candidate material and the target material which have been reacted to each other flows, to thereby form reaction droplets of constant volume.
The oil may preferably have viscosity ranging from 5 to 20 cSt. If the oil has the viscosity less than 5 cSt, droplets may not form, and if the viscosity exceeds 100 cSt, the oil may not flow in the channel.
The oil may preferably include a silicon oil, mineral oil, or hexadecane, but not limited thereto.
The oil further may include a surfactant. By using the surfactant, it can be formed more stable droplets.
Wherein, the oil may be injected under pressure two to ten times greater than the pressure under which the mixture is injected. As the pressure of the injected oil is considered to be an important variable that plays an important role in the formation of the droplets, the size of the droplets may decrease as the pressure of injecting the oil is increased. If the injection pressure of the oil is less than the injection pressure of the mixture, the droplets may not form, while if the injection pressure of the oil exceeds the injection pressure of the mixture, the mixture may not be injected into the channel.
The droplets of step 4 may be sized to have 0.01 to 0.10 mm in length, and 1 nl to 100 pl in volume.
Next, step 5 is a step detecting the droplets exhibiting fluorescence or illumination from among the droplets formed at step 4, using the mass spectrometer. Using the mass spectrometer, it is possible to obtain mass-to-charge ratio of the reaction fluorescent material, define structure of a compound using high resolution spectrometer and also identify the structure of the new drug candidate material using multi-dimensional mass spectrometer.
Further, the present invention provides a microfluidic device, comprising: a new drug candidate material inlet to which a new drug candidate material is injected; a new drug candidate material channel through which the injected new drug candidate material is moved; a target material inlet to which a target material is injected; a target material channel through which the fed target material is moved; a reaction channel connected to the new drug candidate material channel and the target material channel so that reaction and moving of the new drug candidate material and the target material are carried out therein; an oil channel connected to the reaction channel, and comprising an oil inlet to which the oil is injected to form reaction droplets by blocking a flow of the new drug candidate material and the target material; and an outlet through which the reaction droplets and the oil are discharged.
FIG. 2 depicts a microfluidic device according to an embodiment of the present invention.
Referring to FIG. 2, in the microfluidic device according to an embodiment of the present invention, the new drug candidate, separated from the liquid chromatograph, is injected into an inlet and moved along the new drug candidate material channel, the target material is injected through the inlet and moved along the target material channel, and the new drug candidate material and the target material are mixed and reacted with each other in the reaction channel which is connected to the respective channels.
The mixture of the new drug candidate material and the target material may form reaction droplets due to the oil injected thereto. The reaction droplets may move along the reaction channel, with exhibiting illumination or fluorescence which is detectable through a detector. The reaction droplets and the oil may be discharged through the outlet connected to an end of the reaction channel.
To ensure a sufficient moving distance of the mixture of the new drug candidate material and the target material inside a narrow space occupied by the microfluidic device, the reaction channel may preferably be formed into U-shape (see FIGS. 3 and 4).
The reaction channel according to the present invention may desirably be connected to the oil channel in T-, Y-, X- or +-shaped structure, but not strictly limited thereto.
In addition, the oil channel according to the present invention may include a neck designed to reduce the width of the oil channel by 5 to 20% at a connecting portion to the reaction channel. The neck reduces the width of the oil channel at a connecting portion to the reaction channel, to thereby partially increase the flow rate of the oil and still facilitate the formation of the reaction droplets.
The channel may preferably be 1 to 100 μm in width, and 1 to 100 μm in height. If the width is less than 10 μm, the pressure of the fluid in the channel may increase more than necessary, while if the width exceeds 100 μm, the size of the droplets may increase more than necessary.
The microfluidic device according to the present invention may be made from an optically transparent material to detect illumination and fluorescence expressed by a reaction between the new drug candidate material and the target material. Any material with optical transparency may be used as the optically transparent material without limit, which may include glass, quartz, polydimethylsiloxane (PDMS), polymethylmethacrylate, polyacrylate, or polycarbonate or polyurethane.
The microfluidic device may use glass as a substrate through surface and also use polymer as a material for the channel, and modificating and rinsing by chemical and physical methods, to thereby provide more reinforced bonding and also facilitated flow of the fluids along the channel.
Furthermore, the present invention provides a liquid chromatography/microfluidic device/mass spectrometry system, comprising: a liquid chromatograph which separates a new drug candidate material from a natural materials or synthesized new drug candidate materials; a splitter which is connected to the liquid chromatograph and splits into a microfluidic device and a mass spectrometer; the microfluidic device which allows the new drug candidate material separated from the splitter to react with a target substance; a detector which detects illumination or fluorescent reaction within the microfluidic device; and the mass spectrometer which analyzes the new drug candidate material separated from the splitter.
FIG. 5 illustrates a conceptual view of the liquid chromatography/microfluidic device/mass spectrometry system according to an embodiment of the present invention, and FIG. 6 illustrates the liquid chromatography/microfluidic device/mass spectrometry system according to an embodiment of the present invention as actually constructed.
Referring to FIG. 5, the splitter of the liquid chromatography/microfluidic device/mass spectrometry system according to an embodiment of the present invention may separately feed the new drug candidate separated from the liquid chromatograph into the microfluidic device and the mass spectrometer, respectively. The liquid chromatography/microfluidic device/mass spectrometry system constructed as explained above according to an embodiment of the present invention may concurrently feed the fraction separated from the liquid chromatograph into the microfluidic device and the mass spectrometer, detect illumination or fluorescent reaction within the microfluidic device with fluorescent microscopic probe, or the like, and find a substance as analyzed at the mass spectrometer to thereby screen the new drug candidate in a real-time basis.
The mass spectrometer may additionally include a nano-column at the inlet. The nano-column may reduce the flow rate fed into the mass spectrometer through the splitter to the same level as that of the flow fed into the microfluidic device. Accordingly, the nano-column operates to maintain the time at which the fraction of the liquid chromatograph is discharged, the time at which the fraction is analyzed at the mass spectrometer, and the time at which the fraction after reaction is detected within the microfluidic device.
Wherein, the nano-column may preferably reduce the flow rate of the flow fed from the splitter in a range of 1/350 and 1/250, and a shortcoming may occur if the flow rate diverges from the above range. That is, it may be difficult to detect the substance with accuracy due to difference between the time of analysis at the mass spectrometer and the time of detection.
Further the present invention provides a method for screening a new drug candidate using a liquid chromatography/microfluidic device/mass spectrometry system including: separating a natural material containing the new drug candidate material or a synthesized new drug material using a nano liquid chromatograph and injecting into the microfluidic device (step A); splitting the new drug candidate material injected into the microfluidic device at step A in the microfluidic device and injecting into a new drug candidate material channel (step B-1); injecting a target material into an inlet of a target material channel designed to be connected to a new drug candidate material channel for the new drug candidate material split at step B-1 (step B-2); injecting the new drug candidate material split at step B-1 into the mass spectrometer (step B-3); reacting the new drug candidate material injected at step B-1 with the target material injected at step B-2 in a reaction channel to which the channels of steps B-1 and B-2 are connected (step C); injecting an oil through an oil channel connected to the reaction channel of step C to form droplets (step D); and detecting the droplets in fluorescence or emitting light from among the droplets of step D, using the mass spectrometer (step E).
An embodiment of the present invention will be explained in greater detail below with reference to the respective steps thereof.
In one embodiment, the step A is a step separating a natural materials containing the new drug candidate materials or synthesized new drug materials using a nano liquid chromatograph and injecting into the microfluidic device.
At step A, the natural material containing the new drug candidate materials or the synthesized new drug materials is separated into a single new drug candidate material using chromatograph, and injected into the microfluidic device. The respective new drug candidates material may be separated at different time of discharge due to varying moving speed in columns. The chromatograph may desirably be a liquid chromatograph, or more preferably, nano-liquid chromatograph. The new drug candidates separated using chromatograph may be injected directly into the microfluidic device.
Next, the step B-1 is a step splittings the new drug candidate material injected into the microfluidic device and injecting the split material into the new drug candidate material channel.
The new drug candidate material injected into the microfluidic device may be injected into the new drug candidate material channel in the microfluidic device via a splitter provided in the microfluidic device.
Next, the step B-2 is a step injecting a target material into an inlet of a target material channel which is designed to be connected to the channel of the new drug candidate material split at step B-1. Step B-2 may be performed in the same manner as step 2-2.
Next, the step B-3 is a step injecting the new drug candidate material split at step B-1 into the mass spectrometer. It is preferable that step B-3 is performed concurrently with steps B-1, and B-2. Steps B-1, B-2 and B-3 may preferably be performed concurrently to provide appropriate reaction mixture to the reaction channel of step C.
Next, the step C is a step reacting the new drug candidate material injected at step B-1 with the target material injected at step B-2 in a reaction channel to which the channels of steps B-1 and B-2 are connected. Step C may preferably be performed in the same manner as in step 3.
Next, the step D is a step injecting an oil through an oil channel connected to the reaction channel of step C to form droplets. Step D may be performed in the same manner as step 4.
Next, the step E is a step detecting the droplets in fluorescence or emitting light from among the droplets of step D, using the mass spectrometer. Step E may be performed in the same manner as in step 5.
Furthermore, the present invention provides a microfluidic device including: a new drug candidate material inlet to which a new drug candidate material is injected from a nano liquid chromatograph; a splitter which splits the injected new drug candidate material into a mass spectrometer and a new drug substance material channel; a target material inlet to which a target material is injected; a target material channel through which the injected target material is moved; a reaction channel connected to the new drug candidate material channel and the target material channel so that reaction and moving of the new drug candidate material and the target material are carried out therein; an oil channel connected to the reaction channel, and comprising an oil inlet to which the oil is injected to form reaction droplets by blocking a flow of the new drug candidate material and the target material; and an outlet through which the reaction droplets and the oil are discharged.
In the microfluidic device according to an embodiment of the present invention, the new drug candidate material separated from the nano-liquid chromatograph is injected into the inlet, and the injected new drug candidate material is separated into the mass spectrometer and the new drug candidate channel inside the microfluidic device using the splitter. Wherein, the new drug candidate material moves to the new drug candidate material channel, the target material is injected into the inlet and moved to the target material channel, and the injected new drug candidate and the target substance are mixed and reacted with each other in the reaction channel to which the respective channels are connected. The mixture of the new drug candidate and the target substance may form reaction droplets due to oil as injected. The reaction droplets move along the reaction channel, during which illumination or fluorescence appears, and such can be detected via the detector. The reaction droplets and oil may be discharged through the outlet connected to an end of the reaction channel.
To ensure a sufficient moving distance of the mixture of the new drug candidate material and the target material inside a narrow space occupied by the microfluidic device, the reaction channel may preferably be formed into U-shape (see FIG. 7).
Wherein, the reaction channel according to the present invention may desirably be connected to the oil channel in a combination of two or more of T-, Y-, X- or +-shaped structures, but not strictly limited thereto.
Furthermore, the present invention provides a liquid chromatography/microfluidic device/mass spectrometry system including: a nano liquid chromatography which separates a new drug candidate material from natural materials or synthesized new drug candidate materials; a microfluidic device connected to the nano liquid chromatography; a splitter which separates an inside of the microfluidic device the mass spectrometer and a new drug candidate material channel; a detector which detects illumination or fluorescent reaction within the microfluidic device; and a mass spectrometer which analyzes the new drug candidate separated from the splitter.
FIG. 8 illustrates a conceptual view of a liquid chromatography/microfluidic device/mass spectrometry system according to the present invention.
Referring to FIG. 8, the liquid chromatography/microfluidic device/mass spectrometry system according to the present invention injects a fraction separated from the nano-liquid chromatography into the microfluidic device, and separates the fraction in the microfluidic device into the mass spectrometer and the new drug candidate material channel in the microfluidic device using the splitter. The liquid chromatography/microfluidic device/mass spectrometry system constructed as above may detect illumination or fluorescence within the microfluidic device using microscopic fluorescence probe or the like, and at the same time, find a material analyzed at the mass spectrometer, to thereby screen the new drug substance in a real-time basis.
The mass spectrometer may additionally include a nano-column at the inlet. The nano-column may reduce the flow rate of the flow injected into the mass spectrometer through the splitter to the same level as that of the flow injected into the microfluidic device. Accordingly, the nano-column operates to maintain the time at which the fraction of the liquid chromatograph is discharged, the time at which the fraction is analyzed at the mass spectrometer, and the time at which the fraction after reaction is detected within the microfluidic device.
Where, the nano-column may preferably reduce the flow rate of the flow fed from the splitter in a range of 1/350 and 1/250, and a shortcoming may occur if the flow rate diverges from the above range. That is, it may be difficult to detect the substance with accuracy due to difference between the time of analysis at the mass spectrometer and the time of detection.
The liquid chromatography/microfluidic device/mass spectrometry system may have an integrated splitter within the microfluidic device, in which case the system may not require a separate splitter.
Furthermore, in one embodiment of the present invention, a splitter device may be provided, which separates nano-fluid in the microfluidic device and injects the nano-fluid into the mass spectrometer and the new drug candidate channel in the microfluidic device respectively.
In addition, the present invention provides a method for constructing a library in order to separate mixture of new drug candidate materials with liquid chromatography and to react the separated new drug material using the microfluidic device and illuminating phenomenon, when the new drug candidate material is discovered, and the method including: mixing mixture of pure compounds in a solvent to obtain a mixture solution (step 1); and identifying structures and information of the compounds contained in the mixture solution obtained at step 1 (step 2).
The method for constructing a library will be explained in greater detail below with reference to the respective steps.
The step 1 according to the present invention is a step mixing mixture of pure compounds in a solvent to obtain a mixture solution.
The compounds are reactable with the target material, and may preferably include synthesized compounds or natural materials. If the compounds are natural, natural extract is used for the library. It is preferable to prepare the mixture solution by mixing from 100 to 300 compounds to reduce the number of possibilities that the compounds may react with the target material. Further, it is preferable to use a compound with a known structure.
Next, the step 2 according to the present invention is a step is a step identifying structures and information of the compounds contained in the mixture solution obtained at step 1.
The library according to the present invention may be constructed by repeatedly performing steps 1 and 2. The library may be constructed by: performing re-separating with liquid chromatography; reacting with target material; and detecting compound reacted with the target material using mass spectrometer.
Furthermore, the present invention provides a method for identifying a reaction material when the new drug candidate material is reacted with the target material in the microfluidic device, by recording optically a reaction between a new drug candidate material and a target material and tracking a movement of the droplets and automatically detecting a change in brightness of the fluorescence in the droplets and tracking reaction time, in which the method including: filtering a fluorescence using a microscope and capturing a video image of the same using a CCD camera (step 1); stacking the video image having fluorescence progressed therein from among the video image acquired at step 1 into a single-layer image (step 2); setting a limited area within a fluid passage of a microfluidic device and measuring a change in luminous flux of pixels within the set area image by image (step 3); and exporting the luminous flux acquire at step 3 onto a spreadsheet to thereby detect a time at which the fluorescence appears (step 4).
Wherein, it is possible to detect the reaction material in which fluorescence appears, by matching the time at which the fluorescence appears at step 4 with the time of the mass spectrometer. The fluorescent image of step 3 and the spreadsheet of step 4 according to the identification method is showed in FIG. 9. More specifically, FIG. 9( a) illustrates an image which represents measurement of variation of luminous flux of the pixels at three regions (i.e., regions 1 to 3) in the fluorescent image where the fluorescence is progressed, and FIG. 9( b) represents variations of luminous flux at regions 1 to 3 compared with respect to time divisions, in which the time detected as having appearance of fluorescence is identified. Referring to FIG. 9( b), region 1 has fluorescence generated at about 6.62 sec, region 2 at about 6.33 sec, and region 3 about at 6.40 sec The above result indicates that the material detected at about 6.62 second by the mass spectrometer corresponds to the reaction material of region 1, the material detected at about 6.53 sec corresponds to the reaction material of region 2, and the material detected at about 6.40 sec corresponds to the reaction material of region 3.
a microscopic fluorescent probe which filters a fluorescence; a CCD camera which captures the fluorescence into a video image; an image program which stacks the video image into a single-layer image; and a program which measures a change in luminous flux of pixels.
Hereinbelow, the present invention will be explained in greater detail with reference to exemplary embodiments and the accompanying drawings. It should be noted that the exemplary embodiments are written only for illustrative purpose, and therefore, should not be construed as limiting the present invention.
A microfluidic device was fabricated using negative photolithography which will be explained below.
Photoresist was evenly applied on a silicon wafer under vacuum using spin coater, and activated by the light while using a photomask image. A master was fabricated by leaving only the channels. The channels were formed into a pattern according to which the channel for feeding a mixture and a channel for feeding oil form a Y-shaped structure.
Trimethylcholrosilane (TMCS) was coated on the prepared master to prevent binding between the silicon wafer and PDMS, on which the mixture of polydimethylsiloxane (PDMS, Sylgard 184) oligomer and cross-linker in 4:1 ratio was poured. The above was hardened in the oven for 30 minutes at 75° C., a portion with the channels is removed, and connecting holes were bored so that solution can be inserted into the channel therethrough.
Solution, in which PDMS oligomer and hardner were mixed in 20:1 ratio, was spin-coated on a glass substrate. After hardening in the oven for 30 minutes, the PDMS with the channels prepared in advance was adhered to the lower substrate, and underwent hardening for additional 30 minutes in the oven. As a result, PDMS microfluidic reaction device was fabricated. A connecting line, through which solution is fed, is connected to the fabricated chip as illustrated in FIG. 2. The microfluidic device fabricated in the manner explained above was illustrated in FIG. 10.
Silicon oil (viscosity: 10 cSt, KF-96, ShinEtsu) was injected into the microfluidic device at a flow rate of 10 μl/hour, and aqueous solution containing blue pigment was injected at a flow rate of 15 μl/hour into the microfluidic device fabricated in the manner explained above, so that the pressure of the oil and the mixture reached an equilibrium value after which it was confirmed that the uniform droplets as illustrated in FIG. 10 are continuously generated.
The microfluidic device was fabricated in the same manner as used in Example 1, except that a channel pattern is formed so that the channel for feeding a mixture and a channel for feeding oil form a T-shaped structure. Then, aqueous solution containing blue pigment was injected into the microfluidic device fabricated in the manner explained above, under 1 psig, and at a flow rate of 10 μl/hour. Mineral oil (21 cSt) with viscosity approximately two times greater than that of silicon oil, was injected at a flow rate of 15 μl/hour to form droplets. As illustrated in FIG. 11( a), droplets were formed. FIG. 11( b) illustrates uniform-sized droplets formed.
The PDMS surface was treated with O2 plasma for 20 seconds to directly bond the PDMS with the channel pattern fabricated in Example 1 to the glass substrate, then it was joined with the glass substrate was followed by bonding in the oven for 12 hours. Wherein, the glass substrate was treated with a mixture of sulfur and hydrogen peroxide or plasma treated so that organic matter was removed from the surface and the microfluidic device was bonded more firmly when completed.
The microfluidic device was fabricated in the same manner as explained above in Example 1 or Example 2, except that surfactant SPAN 80 was additionally mixed with oil and used.
The microfluidic device was fabricated using negative photolithography which will be explained below.
Photoresist was evenly applied under vacuum on a silicon wafer using spin coater, and activated by the light while using a photomask image. A master was fabricated by leaving only the channels. The channels were formed in such a pattern that a channel for feeding a mixture and a channel for feeding oil are connected with each other in a Y-shaped structure. Additionally, a Y-shaped channel pattern is formed within the microfluidic device to thereby integrate the Y-shaped splitter which separates the nano fluid fed from the nanofluidic chromatograph into feeds into the mass spectrometer and the mixture feeding channel within the microfluidic device. In Examples 1 to 3 explained above, the flow rate of the fluid fed from the liquid chromatograph into the microfluidic device is regulated by the valve. In Example 4, the valve may be omitted by integrating the splitter within the microfluidic device, since the nano fluid fed from the liquid chromatograph can be directly separated and fed without requiring use of a valve.
Solution, in which PDMS oligomer and hardner were mixed in 20:1 ratio, was spin-coated on a glass substrate. After hardening in the oven for 30 minutes, the PDMS with the channels prepared in advance was adhered to the lower substrate, and underwent hardening for additional 30 minutes in the oven. As a result, PDMS microfluidic reaction device was fabricated.
Except for the fact that a T-shaped channel pattern was formed to connect the mixture feeding channel and the oil feeding channel, the microfluidic device was fabricated in the same manner as explained above with reference to Example 5.
In order to directly bond the PDMS in which the channel is formed according to Example 5, to a glass substrate, the PDMS surface was treated with O2 plasma for 20 seconds, joined to the glass substrate and bonded in an oven for 12 hours. By treating the glass substrate with a mixture of sulfur and hydrogen peroxide, or plasma to remove organic substance from the surface, a more firmly bonded microfluidic device was fabricated.
Except that a surfactant was mixed with the oil, a microfluidic device was fabricated in the same manner as that of Example 5 or 6.
A mixture of DAPI(4′6-diamidino-2-phenylindole, excitation wavelength of 345 nm, emission wavelength of 458 nm) and acrydine orange (excitation wavelength of 500 nm, emission wavelength of 530 nm) was injected to a new drug candidate material inlet of a microfluidic device in a flow rate of 10 to 15 μl/hour, and herring DNA in concentration of 8 mg/ml was injected into a target substance inlet in a flow rate of 10 to 15 μl/hour. At this time, inside of the reaction channel was maintained to be under 1 psig of pressure, and the oil was injected under 2.5 psig of pressure to form droplets. The formed droplets were detected using fluorescent microscope (Nikon inverted microscope, Eclipse Nikon TS100, 4×10 UV lens, 100 W Nikon Intensilight epi-fluoresence lamp). FIG. 12 shows the microfluidic device mounted on the fluorescent microscope, and FIG. 13 illustrates the result of detecting fluorescence using the above.
Referring to FIG. 13, the droplets formed according to the present invention fluoresced and were formed uniformly.
Herring DNA in concentration of 8 mg/ml was fed in a flow rate of 10 to 15 μl/hour into the target material inlet of the screening device constructed as explained above with reference to FIGS. 5 and 6 using the microfluidic device as shown in FIG. 1, 2 or 4, and a mixture of DPI and acrydine orange was separated with a liquid chromatography (Finnigan Surveyor LC), and the separated fraction was injected into the splitter. The fraction injected into the splitter was reduced in its flow rate to 1/300 through the nano column (Polymicro OD 359/ID250/tube coat 17.5) and then injected into the new drug candidate material inlet and the mass spectrometer (Finnigan TSQ MS Quantum Ultrainnigan TSQ MS Quantum Ultra).
FIG. 14 illustrates the process of observing the microfluidic device using the microscopic fluorescence probe, and FIG. 15 illustrates the Total Ion Chromatography (TIC) obtained as a result of screening in the manner explained above.
Referring to FIG. 14, the fraction fed into the microfluidic device reacted with the target material (i.e., Herring DNA) to fluoresce at the fluorescence probe.
Further, referring to FIG. 15, the mixture of DAPI and acrydine orange was separated trough the liquid chromatography into DAPI at 12.55 minute and acrydine orange at 17.18 minute, and the mass spectrometer confirmed that the separated fractions were DPI and acrydine oranges, respectively, thereby indicating that the new drug candidate material can be screened in real-time basis as these are separated at the liquid chromatography.
Dronpa (emission wavelength 520 nm) in concentration approximately of 1 mg/ml was injected into a new drug candidate material inlet of the microfluidic device of Examples 5 to 8 in a flow rate of 10 to 15 μl/hour. The inside of the reaction channel was maintained under 1 psig of pressure, and the oil was fed under 2.5 psig of pressure to form droplets. The formed droplets were detected using fluorescent microscope (Nikon inverted microscope, Eclipse Nikon TS100, 4×10 UV lens, 100 W Nikon Intensilight epifluorescence lamp), and FIG. 16 illustrates the result of the detection.
Referring to FIG. 16, the droplets formed according to the present invention fluoresced and were formed uniformly.
injecting an oil through an oil channel connected to the reaction channel of step 3 to form droplets (step 4); and detecting the droplets in fluorescence or emitting light from among the droplets of step 4, using the mass spectrometer (step 5).
2. The method according to the claim 1, wherein the new drug candidate material of step 2-1 or the target material of step 2-2 are injected in 1 to 20 μl/hour.
3. The method according to the claim 1, wherein the target material of step 2-2 is a disease-associated substance selected from a group consisting of DNA, protein and cell.
4. The method according to the claim 3, wherein the target material is a material which can induce or increase fluorescence or illumination by reacting with the new drug material.
5. The method according to the claim 1, wherein processes at steps 2-1 and 2-2 are carried out at the same time.
6. The method according to the claim 1, wherein the target material of step 2-2 is in concentration of 0.1 to 10 mg/ml.
7. The method according to the claim 1, wherein the oil of step 4 is non-polar, and has viscosity ranging from about 5 to about 20 cSt.
9. The method according to the claim 1, wherein the oil of step 4 further include a surfactant.
10. The method according to the claim 1, wherein the oil of step 4 is injected under 2 to 10 times greater pressure than the pressure of a mixture of the new drug candidate material and the target material.
an outlet through which the reaction droplets and the oil are discharged.
12. The microfluidic device according to the claim 11, wherein the reaction channel has a densely-repeating U-shaped channel structure to ensure a length of the channel.
13. The microfluidic device according to the claim 11, wherein the reaction channel and the oil channel are connected to each other in a T, Y, X or +-shaped structure.
14. The microfluidic device according to the claim 11, wherein the oil channel comprises a neck designed at a linking portion with the reaction channel to reduce a width of the oil channel by 5 to 20%.
15. The microfluidic device according to the claim 11, wherein the microfluidic device is formed from an optically-transparent material.
16. The microfluidic device according to the claim 15, wherein the optically-transparent material is one selected from a group consisting of glass, quartz, polydimethylsiloxane (PDMA), polymethylmethacrylate, polyacrylate, polycarbonate, and polyurethane, or a mixture thereof.
a mass spectrometer which analyzes the new drug candidate material separated from the splitter.
18. The system according to the claim 17, wherein the mass spectrometer further comprises a nano column at an inlet thereof.
19. The system according to the claim 18, wherein the nano column reduces a flow rate of the new drug candidate fed via the splitter to 1/350 to 1/250.


Once ranging north into the Sky Islands of Arizona and New Mexico, thick-billed parrots are today limited to Mexico's Sierra Madre Occidental, where ~2,000–2,800 mature birds remain in the wild. Scientists suspect that breeding pairs may produce fewer than 100 active nests each year.
Thick-billed parrots eat primarily pine nuts, and nest in the cavities of old-growth trees. In Mexico as throughout the world, old-growth forests are rapidly disappearing, with logging having eliminated more than 99% of the old-growth habitat in the Sierra Madre Occidental. Because of habitat loss, thick-billed parrots currently breed in only 2 areas.
In 2000, a landmark conservation initiative spearheaded by Wildlands Network, Naturalia, and Pronatura protected almost 6,000 acres of mature spruce-pine forest in Chihuahua from future logging. This area is the largest nesting ground for thick-billed parrots in the world.
Map showing location of ejido Tutuaca, where Las Cebadillas parcel has been protected for thick-billed parrots.
Owners of Las Cebadillas parcel within the communal land, ejido Tutuaca, agreed to halt logging for at least 15 years. Conservation groups reciprocally committed to compensating members of the ejido for lost revenue while helping to foster sustainable community development. The ejidatarios (members of the commune) are now convinced of the merits and benefits of conservation management and are willing to devote their parcel to conservation in perpetuity. A new agreement will be finalized in 2017.
Cebadillas hosts ancient pines reaching 60 meters in height, and fir trees that have stood for as much as a millennium. This parcel also comprises one of Mexico's most important watersheds, where multiple springs and waterfalls feed the rivers Tutuaca, Papigochic, Sehuayo, and Aros Rivers—eventually forming the majestic Yaqui River in Sonora.
Four years after Wildlands Network helped to establish the thick-billed parrot sanctuary in ejido Tutuaca, Pronatura signed a 15-year contract to protect an additional 4,918 acres of old-growth forest north of and adjacent to Tutuaca—in ejido Conoachi.
The ejidos Tutuaca and Conoachi both lie within the limits of a federal Natural Protected Area (Área de Protección de Flora y Fauna Tutuaca), which was, until recently, a so-called paper park. In 2001–2002, however, Mexico's federal park agency re-categorized the joint Tutuaca-Conoachi thick-billed parrot sanctuary as part of the reserve's core area, and awarded the sanctuary its highest protections.
Eventually, we will help to reconnect this network of conservation lands with the Sky Islands in the U.S.—restoring an unbroken system of cores and linkages to protect one of North America's most scenic and biologically diverse places.


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Setting the NDP record straight
SETTING THE NDP RECORD STRAIGHT…. We talked earlier about President Obama breaking with Bush's habit of recognizing the National Day of Prayer. In the past few hours, though, the bizarre lies from the right about the president's decision have been remarkable.
Let's quickly summarize. In the early 1950s, when lawmakers were adding "under God" to the Pledge and changing all American money to include the phrase "In God We Trust," Congress created an official annual Prayer Day for the nation. Congress, under pressure from the religious right, changed the law in 1988 to set the National Day of Prayer as the first Thursday in May. Obama, like his predecessors, issued a proclamation (pdf) honoring the "holiday."
So, what's the problem? Unlike George W. Bush, Obama didn't open up the White House to the self-appointed National Day of Prayer Task Force, run by religious right activists, which has hosted exclusive events for the last eight years.
This has led a variety of conservatives to make a variety of demonstrably false claims.
Lie #1: Rush Limbaugh said Obama tried to "cancel" the National Day of Prayer.
That's obviously not true; Obama issued a proclamation acknowledging the day. No effort was made to "cancel" anything.
Lie #2: Fox News' online project, Fox Nation, said the president "won't celebrate" the National Day of Prayer.
Again, the proclamation proves otherwise.
Lie #3: Fox News' Gretchen Carlson said the president's decision to participate in "private" prayer on "National Prayer Day" is evidence of Obama "giving in to the PC society that we live in."
No one pressured Obama to keep the National Day of Prayer Task Force out of the White House; it was just the obvious thing to do. As for the knock on "private" prayer, I might recommend Gretchen Carlson read Matthew 6:6.
Lie #4: Fox News' Steve Doocy said Reagan and George H. W. Bush held events similar to that of George W. Bush.
As hard as this is to believe, Doocy has it backwards. Reagan largely ignored the NDP for his first seven years in office.
Lie #5: Elisabeth Hasselbeck said on Fox News that the National Day of Prayer "has been a huge tradition" in the U.S.
That's just nonsense, since most presidents, like most Americans, have largely ignored the "holiday." Besides, Obama is keeping the "tradition" going by doing what his predecessors have done — he issued a proclamation. [Update: And if we're really going to talk about American "traditions," it's also worth remembering that Thomas Jefferson and James Madison explicitly rejected state-sponsored prayer days. And all Madison did was write the Constitution.]
Hasselbeck — who is she again? — concluded, "We should be able to gather and pray as we see fit." What I'll never understand about conservative activists is why they think they need government to get involved in spiritual matters. Hasselbeck could get together with others to pray as they see fit yesterday, today, and tomorrow. Whether the Dobsons get to hang out in the East Room of the White House is irrelevant.
Honestly, I'm not sure which is more annoying — the conservatives' prayer-related dishonesty or their prayer-related whining.


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