bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonsymmetric conical upper density and 𝑘-porosity
Authors: Käenmäki Antti , Suomala Ville
Published: November 2010

We study how the Hausdorff measure is distributed in nonsymmetric narrow cones in

R

n

\mathbb {R}^n

. As an application, we find an upper bound close to

n
−
k

n-k

for the Hausdorff dimension of sets with large

k
k

-porosity. With

k
k

-porous sets we mean sets which have holes in

k
k

different directions on every small scale.
Magnetic monopoles on manifolds with boundary
Authors: Norbury Paul
Published: November 2010

Kapustin and Witten associate a Hecke modification of a holomorphic bundle over a Riemann surface to a singular monopole on a Riemannian surface times an interval satisfying prescribed boundary conditions. We prove the existence and uniqueness of singular monopoles satisfying prescribed boundary conditions for any given Hecke modification data confirming the underlying geometric invariant theory principle.
Boundary partitions in trees and dimers
Authors: Kenyon Richard W. , Wilson David
Published: November 2010

Given a finite planar graph, a grove is a spanning forest in which every component tree contains one or more of a specified set of vertices (called nodes) on the outer face. For the uniform measure on groves, we compute the probabilities of the different possible node connections in a grove. These probabilities only depend on boundary measurements of the graph and not on the actual graph structure; i.e., the probabilities can be expressed as functions of the pairwise electrical resistances between the nodes, or equivalently, as functions of the Dirichlet-to-Neumann operator (or response matrix) on the nodes. These formulae can be likened to generalizations (for spanning forests) of Cardy’s percolation crossing probabilities and generalize Kirchhoff’s formula for the electrical resistance. Remarkably, when appropriately normalized, the connection probabilities are in fact integer-coefficient polynomials in the matrix entries, where the coefficients have a natural algebraic interpretation and can be computed combinatorially. A similar phenomenon holds in the so-called double-dimer model: connection probabilities of boundary nodes are polynomial functions of certain boundary measurements, and, as formal polynomials, they are specializations of the grove polynomials. Upon taking scaling limits, we show that the double-dimer connection probabilities coincide with those of the contour lines in the Gaussian free field with certain natural boundary conditions. These results have a direct application to connection probabilities for multiple-strand

SLE
2

\operatorname {SLE}_2

,

SLE
8

\operatorname {SLE}_8

, and

SLE
4

\operatorname {SLE}_4

.
Heteroclinic travelling waves of gradient diffusion systems
Authors: Alikakos Nicholas , Katzourakis Nikolaos
Published: November 2010

We establish the existence of travelling waves to the gradient system

u
t

=

u

z
z

−
∇
W
(
u
)

u_t = u_{zz} - \nabla W(u)

connecting two minima of

W
W

when

u
:

R

×
(
0
,
∞
)
⟶

R

N

u : \mathbb {R} \times (0,\infty ) \longrightarrow \mathbb {R}^N

; that is, we establish the existence of a pair
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="left-parenthesis upper U comma c right-parenthesis element-of left-bracket upper C squared left-parenthesis double-struck upper R right-parenthesis right-bracket Superscript upper N times left-parenthesis 0 comma normal infinity right-parenthesis">

(
U
,
c
)
∈
[

C
2

(

R

)

]
N

×
(
0
,
∞
)

(U,c) \in [C^2(\mathbb {R})]^N \times (0,\infty )

, satisfying
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout Enlarged left-brace 1st Row upper U Subscript x x Baseline minus nabla upper W left-parenthesis upper U right-parenthesis equals minus c upper U Subscript x Baseline comma 2nd Row upper U left-parenthesis plus-or-minus normal infinity right-parenthesis equals a Superscript plus-or-minus Baseline comma EndLayout">

{

U

x
x

−
∇
W
(
U
)
=
−
c

U
x

,

U
(
±
∞
)
=

a

±

,

\left \{\begin {array}{l} U_{xx} - \nabla W ( U ) = - c\; U_x,\\ U(\pm \infty ) = a^{\pm }, \end {array}\right .

\]
where

a

±

a^{\pm }

are local minima of the potential

W
∈

C

loc

2

(

R

N

)

W \in C_{\textrm {loc}}^2(\mathbb {R}^N)

with

W
(

a
−

)
>
W
(

a
+

)
=
0

W(a^-)> W(a^+)=0

and

N
≥
1

N \geq 1

. Our method is variational and based on the minimization of the functional
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper E Subscript c Baseline left-parenthesis upper U right-parenthesis equals integral Underscript double-struck upper R Endscripts left-brace one half StartAbsoluteValue upper U Subscript x Baseline EndAbsoluteValue squared plus upper W left-parenthesis upper U right-parenthesis right-brace e Superscript c x Baseline d x">

E
c

(
U
)
=

∫

R

{

1
2

|

U
x

|

2

+
W
(
U
)

}

e

c
x

d
x

E_c (U) = \int _{\mathbb {R}}\Big \{ \frac {1}{2}|U_x|^2 + W( U ) \Big \}e^{cx} dx

in the appropriate space setup. Following Alikakos and Fusco (2008), we introduce an artificial constraint to restore compactness and force the desired asymptotic behavior, which we later remove. We provide variational characterizations of the travelling wave and the speed.
Dynamics for the energy critical nonlinear wave equation in high dimensions
Authors: Li Dong , Zhang Xiaoyi
Published: November 2010

T. Duyckaerts and F. Merle (2008) studied the variational structure near the ground state solution

W
W

of the energy critical wave equation and classified the solutions with the threshold energy

E
(
W
,
0
)

E(W,0)

in dimensions

d
=
3
,
4
,
5

d=3,4,5

. In this paper, we extend the results to all dimensions

d
≥
6

d\ge 6

. The main issue in high dimensions is the non-Lipschitz continuity of the nonlinearity which we get around by making full use of the decay property of

W
W

.
Duality in spaces of finite linear combinations of atoms
Authors: Ricci Fulvio , Verdera Joan
Published: November 2010

In this paper we describe the dual and the completion of the space of finite linear combinations of

(
p
,
∞
)

(p,\infty )

-atoms,

0
>
p
≤
1

0>p\leq 1

. As an application, we show an extension result for operators uniformly bounded on

(
p
,
∞
)

(p,\infty )

-atoms,

0
>
p
>
1

0>p > 1

, whose analogue for

p
=
1

p=1

is known to be false. Let

0
>
p
>
1

0 > p >1

and let

T
T

be a linear operator defined on the space of finite linear combinations of

(
p
,
∞
)

(p,\infty )

-atoms,

0
>
p
>
1

0>p > 1

, which takes values in a Banach space

B
B

. If

T
T

is uniformly bounded on

(
p
,
∞
)

(p,\infty )

-atoms, then

T
T

extends to a bounded operator from

H
p

(

R

n

)

H^p(\mathbb {R}^n)

into

B
B

.
Precise finite speed and uniqueness in the Cauchy problem for symmetrizable hyperbolic systems
Authors: Rauch Jeffrey
Published: November 2010

Precise finite speed, in the sense of the domain of influence being a subset of the union of influence curves through the support of the initial data, is proved for hyperbolic systems symmetrized by pseudodifferential operators in the spatial variables. From this, uniqueness in the Cauchy problem at spacelike hypersurfaces is derived by a Hölmgren style duality argument. Sharp finite speed is derived from an estimate for propagation in each direction. Propagation in a fixed direction is proved by regularizing the problem in the orthogonal directions. Uniform estimates for the regularized equations are proved using pseudodifferential techniques of Beals-Fefferman type.
Width and flow of hypersurfaces by curvature functions
Authors: Calle Maria , Kleene Stephen , Kramer Joel
Published: November 2010

In this paper, we generalize a well-known estimate of Colding-Minicozzi for the extinction time of convex hypersurfaces in Euclidean space evolving by their mean curvature to a much broader class of parabolic curvature flows.
The 𝐿^{𝑝} regularity problem on Lipschitz domains
Authors: Kilty Joel , Shen Zhongwei
Published: November 2010

This paper contains two results on the

L
p

L^p

regularity problem on Lipschitz domains. For second order elliptic systems and

1
>
p
>
∞

1>p>\infty

, we prove that the solvability of the

L
p

L^p

regularity problem is equivalent to that of the

L

p
′

L^{p^\prime }

Dirichlet problem. For higher order elliptic equations and systems, we show that if

p
>
2

p>2

, the solvability of the

L
p

L^p

regularity problem is equivalent to a weak reverse Hölder condition with exponent

p
p

.
The moduli of curves of genus six and K3 surfaces
Authors: Artebani Michela , Kondō Shigeyuki
Published: November 2010

We prove that the coarse moduli space of curves of genus six is birational to an arithmetic quotient of a bounded symmetric domain of type IV by giving a period map to the moduli space of some lattice-polarized K3 surfaces.
Generalized manifolds in products of curves
Authors: Koyama Akira , Krasinkiewicz Józef , Spież Stanisław
Published: November 2010

The intent of this article is to distinguish and study some

n
n

-dimensional compacta (such as weak

n
n

-manifolds) with respect to embeddability into products of

n
n

curves. We show that if

X
X

is a locally connected weak

n
n

-manifold lying in a product of

n
n

curves, then

rank
⁡

H

1

(
X
)
≥
n

\operatorname {rank} H^{1}(X)\ge n

. If

rank
⁡

H

1

(
X
)
=
n

\operatorname {rank} H^{1}(X)=n

, then

X
X

is an

n
n

-torus. Moreover, if

rank
⁡

H

1

(
X
)
>
2
n

\operatorname {rank} H^{1}(X)>2n

, then

X
X

can be presented as a product of an

m
m

-torus and a weak

(
n
−
m
)

(n-m)

-manifold, where

m
≥
2
n
−
rank
⁡

H

1

(
X
)

m\ge 2n-\operatorname {rank} H^{1}(X)

. If

rank
⁡

H

1

(
X
)
>
∞

\operatorname {rank} H^{1}(X)>\infty

, then

X
X

is a polyhedron. It follows that certain 2-dimensional compact contractible polyhedra are not embeddable in products of two curves. On the other hand, we show that any collapsible 2-dimensional polyhedron embeds in a product of two trees. We answer a question of Cauty proving that closed surfaces embeddable in a product of two curves embed in a product of two graphs. We construct a 2-dimensional polyhedron that embeds in a product of two curves but does not embed in a product of two graphs. This solves in the negative another problem of Cauty. We also construct a weak

2
2

-manifold

X
X

lying in a product of two graphs such that

H

2

(
X
)
=
0

H^{2}(X)=0

.
Schur functors and dominant dimension
Authors: Fang Ming , Koenig Steffen
Published: November 2010

The dominant dimension of an algebra

A
A

provides information about the connection between

A

-mod

A\textrm {-mod}

and

B

-mod

B\textrm {-mod}

for

B
=
e
A
e

B=eAe

, a certain centralizer subalgebra of

A
A

. Well-known examples of such a situation are the connection (given by Schur-Weyl duality) between Schur algebras and group algebras of symmetric groups, and the connection (given by Soergel’s ’Struktursatz’) between blocks of the category

O

\mathcal O

of a complex semisimple Lie algebra and the coinvariant algebra. We study cohomological aspects of such connections, in the framework of highest weight categories. In this setup we characterize the dominant dimension of

A
A

by the vanishing of certain extension groups over

A
A

, we determine the range of degrees, for which certain cohomology groups over

A
A

and over

e
A
e

eAe

get identified, we show that Ringel duality does not change dominant dimensions and we determine the dominant dimension of Schur algebras.
Bispectral commuting difference operators for multivariable Askey-Wilson polynomials
Authors: Iliev Plamen
Published: November 2010

We construct a commutative algebra

A

z

\mathcal A_{z}

, generated by

d
d

algebraically independent

q
q

-difference operators acting on variables

z
1

,

z
2

,
…
,

z
d

z_1,z_2,\dots ,z_d

, which is diagonalized by the multivariable Askey-Wilson polynomials

P
n

(
z
)

P_n(z)

considered by Gasper and Rahman (2005). Iterating Sears’

4

ϕ
3

{}_4\phi _3

transformation formula, we show that the polynomials

P
n

(
z
)

P_n(z)

possess a certain duality between

z
z

and

n
n

. Analytic continuation allows us to obtain another commutative algebra

A

n

\mathcal A_{n}

, generated by

d
d

algebraically independent difference operators acting on the discrete variables

n
1

,

n
2

,
…
,

n
d

n_1,n_2,\dots ,n_d

, which is also diagonalized by

P
n

(
z
)

P_n(z)

. This leads to a multivariable

q
q

-Askey-scheme of bispectral orthogonal polynomials which parallels the theory of symmetric functions.
The number of cliques in graphs of given order and size
Authors: Nikiforov V.
Published: November 2010

Let

k

r

(
n
,
m
)

k_{r}\left (n,m\right )

denote the minimum number of

r
r

-cliques in graphs with

n
n

vertices and

m
m

edges. For

r
=
3
,
4

r=3,4

we give a lower bound on

k

r

(
n
,
m
)

k_{r}\left (n,m\right )

that approximates

k

r

(
n
,
m
)

k_{r}\left (n,m\right )

with an error smaller than

n

r

/

(

n

2

−
2
m
)

.

n^{r}/\left (n^{2}-2m\right ).

The solution is based on a constraint minimization of certain multilinear forms. Our proof combines a combinatorial strategy with extensive analytical arguments.
Localized Hardy spaces 𝐻¹ related to admissible functions on RD-spaces and applications to Schrödinger operators
Authors: Yang Dachun , Zhou Yuan
Published: November 2010

Let

X

{\mathcal X}

be an RD-space, which means that

X

{\mathcal X}

is a space of homogenous type in the sense of Coifman and Weiss with the additional property that a reverse doubling property holds in

X

{\mathcal X}

. In this paper, the authors first introduce the notion of admissible functions

ρ
\rho

and then develop a theory of localized Hardy spaces

H
ρ
1

(

X

)

H^1_\rho ({\mathcal X})

associated with

ρ
\rho

, which includes several maximal function characterizations of

H
ρ
1

(

X

)

H^1_\rho ({\mathcal X})

, the relations between

H
ρ
1

(

X

)

H^1_\rho ({\mathcal X})

and the classical Hardy space

H
1

(

X

)

H^1({\mathcal X})

via constructing a kernel function related to

ρ
\rho

, the atomic decomposition characterization of

H
ρ
1

(

X

)

H^1_\rho ({\mathcal X})

, and the boundedness of certain localized singular integrals on

H
ρ
1

(

X

)

H^1_\rho ({\mathcal X})

via a finite atomic decomposition characterization of some dense subspace of

H
ρ
1

(

X

)

H^1_\rho ({\mathcal X})

. This theory has a wide range of applications. Even when this theory is applied, respectively, to the Schrödinger operator or the degenerate Schrödinger operator on

R

n

\mathbb {R}^n

, or to the sub-Laplace Schrödinger operator on Heisenberg groups or connected and simply connected nilpotent Lie groups, some new results are also obtained. The Schrödinger operators considered here are associated with nonnegative potentials satisfying the reverse Hölder inequality.
A reduction of the target of the Johnson homomorphisms of the automorphism group of a free group
Authors: Satoh Takao
Published: November 2010

LetFnF_nbe a free group of ranknnandFnNF_n^Nthe quotient group ofFnF_nby a subgroup<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="left-bracket normal upper Gamma Subscript n Baseline left-parenthesis 3 right-parenthesis comma normal upper Gamma Subscript n Baseline left-parenthesis 3 right-parenthesis right-bracket left-bracket left-bracket normal upper Gamma Subscript n Baseline left-parenthesis 2 right-parenthesis comma normal upper Gamma Subscript n Baseline left-parenthesis 2 right-parenthesis right-bracket comma normal upper Gamma Subscript n Baseline left-parenthesis 2 right-parenthesis right-bracket">[Γn(3),Γn(3)][[Γn(2),Γn(2)],Γn(2)][\Gamma _n(3), \Gamma _n(3)][[\Gamma _n(2),\Gamma _n(2)],\Gamma _n(2)], whereΓn(k)\Gamma _n(k)denotes thekk-th subgroup of the lower central series of the free groupFnF_n. In this paper, we determine the group structure of the graded quotients of the lower central series of the groupFnNF_n^Nby using a generalized Chen’s integration in free groups. Then we apply it to the study of the Johnson homomorphisms of the automorphism group ofFnF_n. In particular, under taking a reduction of the target of the Johnson homomorphism induced from a quotient mapFn→FnNF_n \rightarrow F_n^N, we see that there appear only two irreducible components, the Morita obstructionSkHQS^k H_{\mathbf {Q}}and the Schur-Weyl module of typeHQ[k−2,12]H_{\mathbf {Q}}^{[k-2, 1^2]}, in the cokernel of the rational Johnson homomorphismτk,Q′=τk′⊗idQ\tau _{k, \mathbf {Q}}’=\tau _k’ \otimes \mathrm {id}_{\mathbf {Q}}fork≥5k \geq 5andn≥k+2n \geq k+2.
Diophantine properties for 𝑞-analogues of Dirichlet’s beta function at positive integers
Authors: Jouhet Frédéric , Mosaki Elie
Published: November 2010

In this paper, we define

q
q

-analogues of Dirichlet’s beta function at positive integers, which can be written as
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="beta Subscript q Baseline left-parenthesis s right-parenthesis equals sigma-summation Underscript k greater-than-or-equal-to 1 Endscripts sigma-summation Underscript d vertical-bar k Endscripts chi left-parenthesis k slash d right-parenthesis d Superscript s minus 1 Baseline q Superscript k">

β
q

(
s
)
=

∑

k
≥
1

∑

d

|

k

χ
(
k

/

d
)

d

s
−
1

q
k

\beta _q(s)=\sum _{k\geq 1}\sum _{d|k}\chi (k/d)d^{s-1}q^k

for

s
∈

N

∗

s\in \mathbb {N}^*

, where

q
q

is a complex number such that

|

q

|

>
1

|q|>1

and

χ
\chi

is the nontrivial Dirichlet character modulo

4
4

. For odd

s
s

, these expressions are connected with the automorphic world, in particular with Eisenstein series of level

4
4

. From this, we derive through Nesterenko’s work the transcendance of the numbers

β
q

(
2
s
+
1
)

\beta _q(2s+1)

for

q
q

algebraic such that

0
>

|

q

|

>
1

0>|q|>1

. Our main result concerns the nature of the numbers

β
q

(
2
s
)

\beta _q(2s)

: we give a lower bound for the dimension of the vector space over

Q

\mathbb {Q}

spanned by

1
,

β
q

(
2
)
,

β
q

(
4
)
,
…
,

β
q

(
A
)

1,\beta _q(2),\beta _q(4),\dots ,\beta _q(A)

, where

1

/

q
∈

Z

∖
{
−
1
;
1
}

1/q\in \mathbb {Z}\setminus \{-1;1\}

and

A
A

is an even integer. As consequences for

1

/

q
∈

Z

∖
{
−
1
;
1
}

1/q\in \mathbb {Z}\setminus \{-1;1\}

, on the one hand there is an infinity of irrational numbers among

β
q

(
2
)
,

β
q

(
4
)
,
…

\beta _q(2),\beta _q(4),\dots

, and on the other hand at least one of the numbers

β
q

(
2
)
,

β
q

(
4
)
,
…
,

β
q

(
20
)

\beta _q(2),\beta _q(4),\dots , \beta _q(20)

is irrational.
On nonpositively curved compact Riemannian manifolds with degenerate Ricci tensor
Authors: Guler Dincer , Zheng Fangyang
Published: November 2010

In this article, we prove that if the Ricci tensor of a compact nonpositively curved manifold

M
n

M^n

is nowhere negative definite, then it admits local flat factors. To be more precise, let

U
⊆
M

U\subseteq M

be the open subset where the Ricci tensor has maximum rank

r
r

. Then for any connected component

U
a

U_a

of

U
U

, its universal cover

U
a

~

\widetilde {U_a}

is isometric to

R

n

−

r

×

N
a
r

\textbf {R}^{n\! -\! r} \! \times \! N^r_a

, where

N
a
r

N^r_a

is a nonpositively curved manifold with negative Ricci curvature.

In particular, if

M
n

M^n

is compact, nonpositively curved without Euclidean de Rham factor, and both the manifold and the metric are real analytic, then its Ricci tensor must be negative definite somewhere.
Germinating Spore Exudates from Arbuscular Mycorrhizal Fungi: Molecular and Developmental Responses in Plants and Their Regulation by Ethylene
Authors: Mukherjee Arijit , Ané Jean-Michel
Published: November 2010

Arbuscular mycorrhizal (AM) fungi stimulate root development and induce expression of mycorrhization-specific genes in both eudicots and monocots. Diffusible factors released by AM fungi have been shown to elicit similar responses in Medicago truncatula. Colonization of roots by AM fungi is inhibited by ethylene. We compared the effects of germinating spore exudates (GSE) from Glomus intraradices in monocots and in eudicots, their genetic control, and their regulation by ethylene. GSE modify root architecture and induce symbiotic gene expression in both monocots and eudicots. The genetic regulation of root architecture and gene expression was analyzed using M. truncatula and rice symbiotic mutants. These responses are dependent on the common symbiotic pathway as well as another uncharacterized pathway. Significant differences between monocots and eudicots were observed in the genetic control of plant responses to GSE. However, ethylene inhibits GSE-induced symbiotic gene expression and root development in both groups. Our results indicate that GSE signaling shares similarities and differences in monocots versus eudicots, that only a subset of AM signaling pathways has been co-opted in legumes for the establishment of root nodulation with rhizobia, and that regulation of these pathways by ethylene is a feature conserved across higher land plants.
The Role of Catalase-Peroxidase Secreted by Magnaporthe oryzae During Early Infection of Rice Cells
Authors: Tanabe Shigeru , Ishii-Minami Naoko , Saitoh Ken-Ichiro , Otake Yuko , Kaku Hanae , Shibuya Naoto , Nishizawa Yoko , Minami Eiichi
Published: November 2010

The biological role of a secretory catalase of the rice blast fungus Magnaporthe oryzae was studied. The internal amino acid sequences of the partially purified catalase in the culture filtrate enabled us to identify its encoding gene as a catalase-peroxidase gene, CPXB, among four putative genes for catalase or catalase-peroxidase in M. oryzae. Knockout of the gene drastically reduced the level of catalase activity in the culture filtrate and supernatant of conidial suspension (SCS), and increased the sensitivity to exogenously added H2O2 compared with control strains, suggesting that CPXB is the major gene encoding the secretory catalase and confers resistance to H2O2 in hyphae. In the mutant, the rate of appressoria that induced accumulation of H2O2 in epidermal cells of the leaf sheath increased and infection at early stages was delayed; however, the formation of lesions in the leaf blade was not affected compared with the control strain. These phenotypes were complimented by reintroducing the putative coding regions of CPXB driven by a constitutive promoter. These results suggest that CPXB plays a role in fungal defense against H2O2 accumulated in epidermal cells of rice at the early stage of infection but not in pathogenicity of M. oryzae.
Identification of Weed Hosts of Tomato yellow leaf curl virus in Cyprus
Authors: Papayiannis L. C. , Katis N. I. , Idris A. M. , Brown J. K.
Published: November 2010

An extensive study was conducted during 2007 and 2008 in three major tomato production areas of Cyprus, where Tomato yellow leaf curl virus (TYLCV) is commonly found, to assess the incidence and prevalence of naturally infected weed species that could serve as TYLCV reservoirs. Approximately 4,000 of the most common dicotyledonous plants belonging to 122 species from 25 families were collected, identified, and tested for TYLCV presence using serological and molecular methods. The tests included a previously reported conventional polymerase chain reaction (PCR) assay and a real-time TaqMan PCR assay developed and optimized in this study. Real-time PCR was found to be the most sensitive technique, and enabled the detection of TYLCV in 461 samples of 49 different species belonging to the families Amaranthaceae, Chenopodiaceae, Compositae, Convolvulaceae, Cruciferae, Euphorbiaceae, Geraniaceae, Leguminosae, Malvaceae, Orobanchaceae, Plantaginaceae, Primulaceae, Solanaceae, Umbelliferae, and Urticaceae. The results further indicated that the host range of TYLCV in Cyprus is far more extensive than previously documented and, therefore, new management strategies are required. These should focus on the control of alternative virus hosts during the growing season and in crop-free periods.
The Effects of NMDA and GABAAPharmacological Manipulations on Acute and Rapid Tolerance to Ethanol During Ontogeny
Authors: Silveri M. M. , Spear L. P.
Published: November 2010

Background:Sensitivity to several ethanol effects increases during ontogeny, perhaps in part because of a notable decline in acute tolerance. In contrast, rapid tolerance to ethanol‐induced sedation emerges slowly during ontogeny. This study tested the hypothesis that ontogenetic differences in glutamate and/or γ‐aminobutyric acid systems influence tolerance expression.

Methods:Sprague‐Dawley rats at postnatal day (P)26 or P70 received (+)MK‐801, muscimol, or saline before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2. Loss of and time to regain the righting reflex and blood alcohol levels at recovery were recorded. The presence of acute tolerance was indicated as a positive slope of the linear regression of blood alcohol levels at recovery versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals given ethanol only on day 2 with those given ethanol on both days.

Results:Acute tolerance on day 1 only was observed at P26; this was disrupted by (+)MK‐801 but not muscimol. Evidence for acute tolerance also emerged in adults on day 2. Whereas both drugs increased ethanol sedation at both ages, they did not facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not evident at P26 regardless of pretreatment when indexed in terms of recovery time.

Conclusions:These data provide further evidence for an ontogenetic dissociation in the expression of acute and rapid tolerance to ethanol‐induced sedation. Pharmacological attenuation of the expression of acute tolerance was sufficient but not necessary to delay recovery of righting after ethanol. The greater propensity of young animals to develop acute tolerance, seemingly modulated in part by NMDA receptors, may contribute to their relative resistance to ethanol, although other factors, including pharmacokinetic factors, also contribute to their more rapid recovery from ethanol sedation.
Discriminative Stimulus Effects of Ethanol in Mice Lacking the γ‐Aminobutyric Acid Type A Receptor δ Subunit
Authors: Shannon Erin E. , Shelton Keith L. , Vivian Jeffrey A. , Yount Ingrid , Morgan Ashley R. , Homanics Gregg E. , Grant Kathleen A.
Published: November 2010

Background:Genetically altered mice have been used to examine gene contributions to ethanol phenotypes. Recently, mice with a targeted deletion of the δ subunit of the γ‐aminobutyric acid (GABA)Areceptor have been generated. These mice display decreased sensitivity to neuroactive steroids and altered responses to some behavioral effects of ethanol. Given the application of drug discrimination to characterize receptor‐mediated stimulus effects of ethanol and given the data showing altered ethanol responses in mice lacking the δ subunit of the GABAAreceptor, these mice were characterized in an ethanol‐discrimination procedure. It has been shown that neurosteroids will substitute for the discriminative stimulus effects of ethanol, and this study aimed to determine whether the substitution patterns of neuroactive steroids or other GABAA‐positive modulators would be altered in these mice.

Methods:Twelve adult δ+/+and δ−/−mice were trained to discriminate between ethanol 1.5 g/kg and saline in daily 15‐min food‐reinforced operant sessions. Once the discrimination was trained, substitution tests with ethanol, pentobarbital, midazolam, androsterone, alphaxalone, pregnanolone, morphine, zolpidem, and MK‐801 were conducted.

Results:Both δ+/+and δ−/−mice acquired ethanol discrimination in a similar number of days. Ethanol, midazolam, alphaxalone, pregnanolone, and MK‐801 fully substituted (>80%) for ethanol in both δ+/+and δ−/−mice. Pentobarbital fully substituted for ethanol in δ−/−mice but only partially substituted (74%) for ethanol in δ+/+mice. Androsterone, zolpidem, and morphine did not substitute for ethanol in either δ+/+or δ−/−mice. There were no significant differences in the response rate–suppressing effects of any of the compounds between δ+/+and δ−/−mice.

Conclusions:The training dose of ethanol resulted in substitution of five GABAAreceptor ligands, indicating a robust GABAAmediation of ethanol's discriminative stimulus effects. Deletion of the δ subunit of the GABAAreceptor does not alter the acquisition of an ethanol/saline discrimination or the substitution patterns of GABAA‐positive modulators. Therefore, the δ subunit is not necessary in the mediation of ethanol‐like effects of any of the GABAAligands tested, including sensitivity to ethanol, barbiturate, benzodiazepine, and neurosteroid discriminative stimulus effects.
Differential Effects of Alcohol Drinking Pattern on Liver Enzymes in Men and Women
Authors: Stranges Saverio , Freudenheim Jo L. , Muti Paola , Farinaro Eduardo , Russell Marcia , Nochajski Thomas H. , Trevisan Maurizio
Published: November 2010

Background: Increasing evidence suggests that drinking pattern may have powerful implications for health; however, very few studies have focused on the association between drinking pattern and risk of alcoholic liver damage. This study was aimed at examining the association of γ‐glutamyltransferase (GGT), aspartate aminotransferase, and alanine aminotransferase with current alcohol consumption and with some aspects of drinking pattern (e.g., drinking frequency during the week and in relation to food consumption).

Methods: A cross‐sectional analysis was conducted of a random sample of 2943 white residents of Erie and Niagara Counties in New York State who were 35 to 80 years of age and free from known hepatic disease.

Results: The most significant associations were found for GGT; in both sexes, average levels were significantly higher in current and former drinkers compared with lifetime abstainers. In analyses based on quartiles of alcohol consumption, only participants in the two top quartiles showed significantly elevated enzymes compared with both lifetime abstainers and participants in other quartiles. For drinking pattern, there was evidence of sex‐specific associations. In men, daily drinkers showed the highest levels of GGT, whereas in women, the highest level of GGT was observed in weekend drinkers. Women (but not men) who consumed alcohol without food exhibited higher levels of GGT compared with women who consumed alcoholic beverages in relation to food.

Conclusions: These findings support the hypothesis that, in addition to amount, drinking pattern may affect liver function and that differences exist between sexes with regard to the effect of drinking pattern on liver function and potential liver damage.
Alcohol Consumption and Problems: The Relevance of Drinking Patterns
Authors: Russell Marcia , Light John M. , Gruenewald Paul J.
Published: November 2010

Background: Data on risks and benefits associated with drinking patterns provide the scientific basis for moderate, low‐risk drinking guidelines. Illustrated are methods to investigate and adjust for heterogeneity in relations between three‐dimensional drinking patterns and 41 alcohol problems assessed among current regular drinkers in the 1988 National Health Interview Survey.

Methods: Three dimensions of mean drinking patterns, (i.e., usual quantities, heavy drinking rates (days of 5× drinks/drinking days x 100), and drinking frequencies) were estimated in overlapping subsets of the population reporting each of the 41 problems, and mean usual quantities and heavy drinking rates were plotted against frequencies. Respondents were categorized into drinking problem groups associated with comparable mean drinking patterns; and main and interactive effects of age and sex on drinking patterns were examined by conducting three regression analyses within each group, with quantity, frequency, and heavy drinking rates as dependent variables, respectively.

Results: Analyses revealed substantial heterogeneity in relations between drinking patterns and alcohol problems. Respondents having only minor problems drank on average two days a week, usually had 2.6 drinks, and drank heavily 12–13 days a year. Whereas, those having minor and severe problems drank an average of 3.5 days a week, usually had 4.7 drinks, and drank heavily 58 days a year. Within each problem group, usual quantity and frequency were higher among males than females, but the greatest gender differences were seen in heavy‐drinking rates. Age‐related differences in drinking patterns were striking. Usual quantity and heavy‐drinking rates associated with problems decreased with age, whereas drinking frequency increased.

Conclusions: Findings demonstrated the importance of assessing and adjusting for heterogeneity in relations between drinking patterns and alcohol problems when aggregating and interpreting such data, (e.g., when assessing alcohol dependence criteria or evaluating guidelines for moderate drinking), and illustrated new methods for doing so.
National Institute on Alcohol Abuse and Alcoholism Report on Moderate Drinking
Authors: Gunzerath Lorraine , Faden Vivian , Zakhari Samir , Warren Kenneth
Published: November 2010

In support of the 2005 update of the U.S. Department of Agriculture/U.S. Department of Health and Human Services Dietary Guidelines, the National Institute on Alcohol Abuse and Alcoholism was asked to assess the strength of the evidence related to health risks and potential benefits of moderate alcohol consumption, with particular focus on the areas of cardiovascular disease, breast cancer, obesity, birth defects, breastfeeding, and aging. The findings were reviewed by external researchers with extensive research backgrounds on the consequences and benefits of alcohol consumption. This report now serves as the National Institutes of Health's formal position paper on the health risks and potential benefits of moderate alcohol use.
Cytotoxicity of Acetaldehyde‐Derived Advanced Glycation End‐Products (AA‐AGE) in Alcoholic‐Induced Neuronal Degeneration
Authors: Takeuchi Masayoshi , Saito Toshikazu
Published: November 2010

Abstract: Background: The Maillard reaction that leads to the formation of advanced glycation end‐products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging and in neurodegenerative processes. We hypothesize that acetaldehyde (AA), one of the main metabolites of alcohol, may be involved in alcohol‐induced neurotoxicity in vivo by formation of AA‐derived AGEs (AA‐AGE) with brain proteins.

Methods: AA‐AGE‐bovine serum albumin (BSA) and AA‐AGE‐rabbit serum albumin (RSA) were prepared as described previously. Antibody specific for AA‐AGE was isolated from rabbit antiserum by affinity chromatography. Primary cortical neuronal cell cultures were prepared as described previously.

Results: Incubation of cortical neurons with AA‐AGE produced a dose‐dependent increase in neuronal cell‐death, and the neurotoxicity of AA‐AGE was neutralized by the addition of an anti‐AA‐AGE specific antibody, but not by anti‐N‐ethyllysine (NEL) antibody. The AA‐AGE epitope was detected in human brain of alcoholism.

Conclusions: We propose that the structural epitope AA‐AGE is an important toxic moiety for neuronal cells in alcoholism.
Use of Serum Carbohydrate‐Deficient Transferrin Values to Exclude Alcoholic Hepatitis from Non‐Alcoholic Steatohepatitis: A Pilot Study
Authors: Ohtsuka Toshimi , Tsutsumi Mikihiro , Fukumura Atsushi , Tsuchishima Mutsumi , Takase Shujiro
Published: November 2010

Abstract:Background:Since no clinical or biochemical parameters allow an accurate diagnosis of non‐alcoholic steatohepatitis (NASH), the diagnosis by exclusion of alcoholic hepatitis is necessary. However, it is difficult to get the accurate amount of alcohol consumed from the patients, especially from females. To differentiate between NASH and alcoholic hepatitis, we investigated whether serum biochemical markers of chronic alcohol abuse are useful or not.

Methods:Sera were obtained from 13 patients with NASH and 26 patients with alcoholic hepatitis. Diagnoses in these patients were confirmed histologically by needle biopsy of the liver. All patients with alcoholic hepatitis consumed more than 80 g of ethanol/day for more than 10 years. As markers of chronic alcohol abuse, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma‐glutamyl transpeptidase (GGT), hyaluronate, mean corpuscular volume of red blood cells (MCV) and carbohydrate‐deficient transferrin (CDT) were measured.

Results:Among alcohol markers, serum values of AST, AST/ALT ratio, GGT, CDT and MCV in patients with alcoholic hepatitis were significantly higher than those in patients with NASH, respectively. However, serum values of these markers, except for CDT, were overlapped in many cases of NASH and alcoholic hepatitis. Serum CDT values of all patients with NASH were lower than the cutoff value, 2.66%, and those of all patients with alcoholic hepatitis were higher than the cutoff value.

Conclusion:The results of the present study suggest that serum CDT level could be used to differentiate between NASH and alcoholic hepatitis.
AICAR, an AMPK Activator, Has Protective Effects on Alcohol‐Induced Fatty Liver in Rats
Authors: Tomita Kengo , Tamiya Gen , Ando Satoshi , Kitamura Naoto , Koizumi Haruna , Kato Shinzo , Horie Yoshinori , Kaneko Takehiko , Azuma Toshifumi , Nagata Hiroshi , Ishii Hiromasa , Hibi Toshifumi
Published: November 2010

Abstract: Background: Previous work with metformin has shown that this antidiabetic agent improves nonalcoholic fatty liver in ob/ob mice. AMP‐activated protein kinase (AMPK) is one of the major cellular regulators of lipid and glucose metabolism, and reportedly mediates the beneficial metabolic effects of metformin. In this study, we examined the effects of 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside (AICAR), an AMPK activator, on an experimental model of ethanol‐induced hepatic steatosis.

Methods: Rats were randomly divided into three groups: (A) rats fed ethanol‐containing liquid diet for six weeks; (B) rats pair‐fed ethanol‐containing liquid diet for six weeks, during the last three weeks of which they were subcutaneously injected with 0.5 mg AICAR/g body weight per day; (C) rats pair‐fed isocaloric liquid diet without ethanol for six weeks. At the end of the six‐week period, the animals were sacrificed. Serum and liver specimens were analyzed using biochemical and histologic methods, as well as real‐time PCR.

Results: Chronic ethanol feeding resulted in fatty liver both histologically and biochemically, whereas AICAR administration attenuated the degree of change in the liver. AICAR also decreased the hepatic sterol regulatory factor binding protein‐1c (SREBP‐1c) and reduced fatty acid synthase (FAS) expression; these changes led to reduced triglyceride synthesis in rat livers. Furthermore, detection of 4‐hydroxy‐2‐nonenal (4‐HNE)‐protein adducts showed that the AICAR treatment also decreased the products of lipid peroxidation.

Conclusion: In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol‐induced fatty liver.
Effects of Acute Ethanol Administration on LPS‐Induced Expression of Cyclooxygenase‐2 and Inducible Nitric Oxide Synthase in Rat Alveolar Macrophages
Authors: Kato Hirohisa , Negoro Munetaka , Wakabayashi Ichiro
Published: November 2010

Abstract:Background:Activation of alveolar macrophages acts as a primary defense mechanism of lung with immunologic and inflammatory processes. Incidence of respiratory distress syndrome (ARDS) has been reported to be higher in alcoholics than that in nonalcoholics. Both cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS) are induced by inflammatory stimuli such as LPS and cytokines and are involved in host defense. COX‐2 and iNOS have been reported to play important roles in pathophysiology of ARDS. The aim of the present study was to elucidate whether acute ethanol administration to rats affects on COX‐2 and iNOS expression in isolated alveolar macrophages.

Methods:Ethanol (4.5 g per kg body weight as a 20% solution) was intraperitoneally injected to male Wistar rats. At 2.5 hrs after the injection, alveolar macrophages were collected from rats by bronchoalveolar lavage and were stimulated with lipopolysaccharide (LPS, 1 μg/ml). Expression of COX‐2 and iNOS and activation of MAPKs was evaluated by Western blotting.

Results:In alveolar macrophages isolated from ethanol‐treated rats, LPS‐stimulated production of both prostaglandin E2and nitrite was significantly lower than that in macrophages isolated from vehicle‐treated control rats. LPS‐induced expression of both COX‐2 and iNOS was significantly lower in macrophages from ethanol‐treated rats than that in macrophages from the control rats, while expression of β‐actin was not different in these groups. LPS increased phosphorylation of both extracellular signal‐regulated protein kinase (ERK) and p38 mitogen‐activated protein kinase (MAPK). The levels of phosphorylated ERK and p38 were significantly lower in macrophages from ethanol‐treated rats compared with those from the control rats. Treatment of macrophages with ethanol (100 – 400 mM)in vitrosignificantly inhibited expression of COX‐2 in a concentration‐dependent manner, while only a high concentration (400 mM) of ethanol significantly inhibited expression of iNOS. Ethanol also inhibited COX‐2 expression in the presence of Tiron. Expression of COX‐2 and iNOS was significantly inhibited by U0126 but not by SB203580.

Conclusion:In rat alveolar macrophages, LPS‐induced expression of COX‐2 and iNOS is mediated by ERK MAPK but not by p38 MAPK. Acute ethanol administration to rats attenuates induction of both COX‐2 and iNOS in alveolar macrophages by inhibiting phosphorylation of ERK.
Transgenerational epigenetic inheritance: More questions than answers
Authors: Daxinger Lucia , Whitelaw Emma
Published: November 2010

Epigenetic modifications are widely accepted as playing a critical role in the regulation of gene expression and thereby contributing to the determination of the phenotype of multicellular organisms. In general, these marks are cleared and re-established each generation, but there have been reports in a number of model organisms that at some loci in the genome this clearing is incomplete. This phenomenon is referred to as transgenerational epigenetic inheritance. Moreover, recent evidence shows that the environment can stably influence the establishment of the epigenome. Together, these findings suggest that an environmental event in one generation could affect the phenotype in subsequent generations, and these somewhat Lamarckian ideas are stimulating interest from a broad spectrum of biologists, from ecologists to health workers.
High-throughput discovery of rare insertions and deletions in large cohorts
Authors: Vallania Francesco L.M. , Druley Todd E. , Ramos Enrique , Wang Jue , Borecki Ingrid , Province Michael , Mitra Robi D.
Published: November 2010

Pooled-DNA sequencing strategies enable fast, accurate, and cost-effect detection of rare variants, but current approaches are not able to accurately identify short insertions and deletions (indels), despite their pivotal role in genetic disease. Furthermore, the sensitivity and specificity of these methods depend on arbitrary, user-selected significance thresholds, whose optimal values change from experiment to experiment. Here, we present a combined experimental and computational strategy that combines a synthetically engineered DNA library inserted in each run and a new computational approach named SPLINTER that detects and quantifies short indels and substitutions in large pools. SPLINTER integrates information from the synthetic library to select the optimal significance thresholds for every experiment. We show that SPLINTER detects indels (up to 4 bp) and substitutions in large pools with high sensitivity and specificity, accurately quantifies variant frequency (r = 0.999), and compares favorably with existing algorithms for the analysis of pooled sequencing data. We applied our approach to analyze a cohort of 1152 individuals, identifying 48 variants and validating 14 of 14 (100%) predictions by individual genotyping. Thus, our strategy provides a novel and sensitive method that will speed the discovery of novel disease-causing rare variants.
Allergic contact dermatitis due to diclofenac sodium in eye drops
Authors: MIYAZATO Hitona , YAMAGUCHI Sayaka , TAIRA Kiyohito , ASATO Yutaka , YAMAMOTO Yu‐Ichi , HAGIWARA Keisuke , UEZATO Hiroshi
Published: November 2010

Eyelid dermatitis and/or periocular dermatitis (ED/PD) is commonly seen in a variety of skin diseases such as seborrheic dermatitis, atopic dermatitis and psoriasis, but is most often associated with allergic contact dermatitis (ACD). Here, a case of ACD in an 82‐year‐old man is described; he used 0.1% diclofenac sodium eye drops and exhibited pruritic erythema on the eyelids. Patch test for diclofenac sodium eye drops was positive. Further patch tests revealed a positive reaction to diclofenac sodium (monosodium 2‐[2, 6‐dichlorophenylamino] phenylacetate), which was the main component in the eye drop medicine. Diclofenac sodium is a non‐steroidal anti‐inflammatory drug (NSAID), and is frequently used in everyday oral medications, topical ointments, gel agents and eye drops. Case reports on ACD caused by diclofenac sodium eye drops are extremely rare. Nevertheless, it is necessary to consider ACD due to diclofenac sodium when a patient with ED/PD has a history of use of diclofenac sodium eye drops.
Sorafenib‐associated hand–foot syndrome in Japanese patients
Authors: IIJIMA Masafumi , FUKINO Koichi , ADACHI Masatoshi , TSUKAMOTO Taiji , MURAI Masaru , NAITO Seiji , MINAMI Hironobu , FURUSE Junji , AKAZA Hideyuki
Published: November 2010

Sorafenib (Nexavar) is an oral multi‐kinase inhibitor that targets tumor growth and angiogenesis, having encouraging efficacy and tolerability in patients with metastatic renal cell carcinoma (RCC) and other tumors. However, hand–foot syndrome (HFS), a frequently reported adverse event under sorafenib treatment, sometimes causes interruption of the treatment or dose reduction. This study was conducted to review sorafenib‐associated HSF in Japanese patients, to facilitate improvement of the management of HFS in clinical practice. We reviewed the combined results on HFS in three sorafenib studies in Japanese patients: (A) a phase II study of metastatic renal cell carcinoma; (B) a phase I study of solid tumor; and (C), phase I study of hepatocellular carcinoma. Severity of HFS was graded as 1–3 based on the modified grading scale of National Cancer Institute – Common Toxicity Criteria version 2.0 and Common Terminology Criteria for Adverse Events version 3.0. A total of 189 patients were included for analyses. The incidence of all‐grade HFS was 51% (55% in A, 39% in B and 44% in C), and the incidence of grade 3 HFS was 7% (9% in A, 0% in B and 7% in C). Incidence of HFS seemed dose‐dependent. These events were observed within 3–9 weeks after initiation of sorafenib treatment. The majority of HFS was manageable with symptomatic treatment and HFS caused permanent discontinuation of sorafenib in only one patient (in study A). The incidence of sorafenib‐associated HFS is high compared to other adverse events. However, the present analyses showed that HFS under sorafenib treatment is well manageable in Japanese patients.