bluuebunny/crossref_metadata_2025 huggingface dataset:
A calpain unique to alveolates is essential in
Plasmodium falciparum
and its knockdown reveals an involvement in pre-S-phase development
Authors: Russo Ilaria , Oksman Anna , Vaupel Barbara , Goldberg Daniel E.
Published: January 2009

Plasmodium falciparum
encodes a single calpain that has a distinct domain composition restricted to alveolates. To evaluate the potential of this protein as a drug target, we assessed its essentiality. Both gene disruption by double cross-over and gene truncation by single cross-over recombination failed. We were also unable to achieve allelic replacement by using a missense mutation at the catalytic cysteine codon, although we could obtain synonymous allelic replacement parasites. These results suggested that the calpain gene and its proteolytic activity are important for optimal parasite growth. To gain further insight into its biological role, we used the FKBP degradation domain system to generate a fusion protein whose stability in transfected parasites could be modulated by a small FKBP ligand, Shield1 (Shld1). We made a calpain-GFP-FKBP fusion through single cross-over integration at the endogenous calpain locus. Calpain levels were knocked down and parasite growth was greatly impaired in the absence of Shld1. Parasites were delayed in their ability to transition out of the ring stage and in their ability to progress to the S phase. Calpain is required for cell cycle progression in
Plasmodium
parasites and appears to be an attractive drug target. We have shown that regulated knockdowns are possible in
P. falciparum
and can be useful for evaluating essentiality and function.
Quantifying environmental adaptation of metabolic pathways in metagenomics
Authors: Gianoulis Tara A. , Raes Jeroen , Patel Prianka V. , Bjornson Robert , Korbel Jan O. , Letunic Ivica , Yamada Takuji , Paccanaro Alberto , Jensen Lars J. , Snyder Michael , Bork Peer , Gerstein Mark B.
Published: January 2009

Recently, approaches have been developed to sample the genetic content of heterogeneous environments (metagenomics). However, by what means these sequences link distinct environmental conditions with specific biological processes is not well understood. Thus, a major challenge is how the usage of particular pathways and subnetworks reflects the adaptation of microbial communities across environments and habitats—i.e., how network dynamics relates to environmental features. Previous research has treated environments as discrete, somewhat simplified classes (e.g., terrestrial vs. marine), and searched for obvious metabolic differences among them (i.e., treating the analysis as a typical classification problem). However, environmental differences result from combinations of many factors, which often vary only slightly. Therefore, we introduce an approach that employs correlation and regression to relate multiple, continuously varying factors defining an environment to the extent of particular microbial pathways present in a geographic site. Moreover, rather than looking only at individual correlations (one-to-one), we adapted canonical correlation analysis and related techniques to define an ensemble of weighted pathways that maximally covaries with a combination of environmental variables (many-to-many), which we term a metabolic footprint. Applied to available aquatic datasets, we identified footprints predictive of their environment that can potentially be used as biosensors. For example, we show a strong multivariate correlation between the energy-conversion strategies of a community and multiple environmental gradients (e.g., temperature). Moreover, we identified covariation in amino acid transport and cofactor synthesis, suggesting that limiting amounts of cofactor can (partially) explain increased import of amino acids in nutrient-limited conditions.
Emergence of species in evolutionary “simulated annealing”
Authors: Heo Muyoung , Kang Louis , Shakhnovich Eugene I.
Published: January 2009

Which factors govern the evolution of mutation rates and emergence of species? Here, we address this question by using a first principles model of life where population dynamics of asexual organisms is coupled to molecular properties and interactions of proteins encoded in their genomes. Simulating evolution of populations, we found that fitness increases in punctuated steps via epistatic events, leading to formation of stable and functionally interacting proteins. At low mutation rates, species form populations of organisms tightly localized in sequence space, whereas at higher mutation rates, species are lost without an apparent loss of fitness. However, when mutation rate was a selectable trait, the population initially maintained high mutation rate until a high fitness level was reached, after which organisms with low mutation rates are gradually selected, with the population eventually reaching mutation rates comparable with those of modern DNA-based organisms. This study shows that the fitness landscape of a biophysically realistic system is extremely complex, with huge number of local peaks rendering adaptation dynamics to be a glass-like process. On a more practical level, our results provide a rationale to experimental observations of the effect of mutation rate on fitness of populations of asexual organisms.
A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore
Authors: Miller J. Richard , Dunham Steve , Mochalkin Igor , Banotai Craig , Bowman Matthew , Buist Susan , Dunkle Bill , Hanna Debra , Harwood H. James , Huband Michael D. , Karnovsky Alla , Kuhn Michael , Limberakis Chris , Liu Jia Y. , Mehrens Shawn , Mueller W. Thomas , Narasimhan Lakshmi , Ogden Adam , Ohren Jeff , Prasad J. V. N. Vara , Shelly John A. , Skerlos Laura , Sulavik Mark , Thomas V. Hayden , VanderRoest Steve , Wang LiAnn , Wang Zhigang , Whitton Amy , Zhu Tong , Stover C. Kendall
Published: January 2009

As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens includingHaemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.
Identification of small-molecule inducers of pancreatic β-cell expansion
Authors: Wang Weidong , Walker John R. , Wang Xia , Tremblay Matthew S. , Lee Jae Wook , Wu Xu , Schultz Peter G.
Published: January 2009

To identify small molecules that can induce β-cell replication, a large chemical library was screened for proliferation of growth-arrested, reversibly immortalized mouse β cells by using an automated high-throughput screening platform. A number of structurally diverse, active compounds were identified, including phorbol esters, which likely act through protein kinase C, and a group of thiophene-pyrimidines that stimulate β-cell proliferation by activating the Wnt signaling pathway. A group of dihydropyridine (DHP) derivatives was also shown to reversibly induce β-cell replication in vitro by activating L-type calcium channels (LTCCs). Our data suggest that the LTCC agonist 2a affects the expression of genes involved in cell cycle progression and cellular proliferation. Furthermore, treatment of β cells with both LTCC agonist 2a and the Glp-1 receptor agonist Exendin-4 showed an additive effect on β-cell replication. The identification of small molecules that induce β-cell proliferation suggests that it may be possible to reversibly expand other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.
Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia
Authors: Agosta Federica , Vossel Keith A. , Miller Bruce L. , Migliaccio Raffaella , Bonasera Stephen J. , Filippi Massimo , Boxer Adam L. , Karydas Anna , Possin Katherine L. , Gorno-Tempini Maria Luisa
Published: January 2009

Apolipoprotein ε4 (apoE4) has been strongly linked with Alzheimer's disease (AD) and contributes to several other neurological disorders. We investigated the influence of ε4 allele carrier status on the pattern of gray matter atrophy and disease severity in 51 patients with probable AD and 31 patients with behavioral variant frontotemporal dementia (bvFTD), compared with 56 healthy controls. Voxel-based morphometry was performed by using statistical parametric mapping. The ε4 allele frequency was higher in the AD group (
P
< 0.001) than the controls but not in the bvFTD group. No differences in demographic or cognitive profiles were observed between ε4 allele carriers and noncarriers within any of the diagnostic groups. However, ε4 carrier status was associated with more severe brain atrophy in disease-specific regions compared with noncarriers in both AD and bvFTD. AD ε4 carriers showed greater atrophy in the bilateral parietal cortex and right hippocampus, and bvFTD ε4 carriers demonstrated greater atrophy in the bilateral medial, dorsolateral, and orbital frontal cortex, anterior insula, and cingulate cortex with right predominance. This regional ε4 effect is consistent with the hypothesis that apoE may affect the morphologic expression uniquely in different neurodegenerative diseases. The atrophy patterns in ε4 carriers may indicate that they are at greater risk for clinical progression.
Comparative sequence analysis of
MONOCULM1
-orthologous regions in 14
Oryza
genomes
Authors: Lu Fei , Ammiraju Jetty S. S. , Sanyal Abhijit , Zhang Shengli , Song Rentao , Chen Jinfeng , Li Guisheng , Sui Yi , Song Xiang , Cheng Zhukuan , de Oliveira Antonio Costa , Bennetzen Jeffrey L. , Jackson Scott A. , Wing Rod A. , Chen Mingsheng
Published: January 2009

Comparative genomics is a powerful tool to decipher gene and genome evolution. Placing multiple genome comparisons in a phylogenetic context improves the sensitivity of evolutionary inferences. In the genus
Oryza
, this comparative approach can be used to investigate gene function, genome evolution, domestication, polyploidy, and ecological adaptation. A large genomic region surrounding the
MONOCULM1
(
MOC1
) locus was chosen for study in 14
Oryza
species, including 10 diploids and 4 allotetraploids. Sequencing and annotation of 18 bacterial artificial chromosome clones for these species revealed highly conserved gene colinearity and structure in the
MOC1
region. Since the
Oryza
radiation about 14 Mya, differences in transposon amplification appear to be responsible for the different current sizes of the
Oryza
genomes. In the
MOC1
region, transposons were only conserved between genomes of the same type (e.g., AA or BB). In addition to the conserved gene content, several apparent genes have been generated de novo or uniquely retained in the AA lineage. Two different 3-gene segments have been inserted into the
MOC1
region of
O. coarctata
(KK) or
O. sativa
by unknown mechanism(s). Large and apparently noncoding sequences flanking the
MOC1
gene were observed to be under strong purifying selection. The allotetraploids
Oryza alta
and
Oryza minuta
were found to be products of recent polyploidization, less than 1.6 and 0.4 Mya, respectively. In allotetraploids, pseudogenization of duplicated genes was common, caused by large deletions, small frame-shifting insertions/deletions, or nonsense mutations.
Prognostic significance of the interaction between abnormal umbilical and middle cerebral artery Doppler velocimetry in pregnancies complicated by fetal growth restriction
Authors: SPINILLO ARSENIO , MONTANARI LAURA , ROCCIO MARIANNA , ZANCHI SILVIA , TZIALLA CHRYSSOULA , STRONATI MAURO
Published: January 2009

Objective. To evaluate the prognostic significance of the interaction between umbilical artery (UA) and middle cerebral artery (MCA) Doppler measurements in pregnancies complicated by fetal growth restriction (FGR). Design. Cohort study. Setting. Third‐level Perinatology Center in Northern Italy. Population. A study of 184 singleton pregnancies at 24–35 weeks’ gestational age complicated by FGR and abnormal UA Doppler measurements. Methods. FGR was diagnosed by serial ultrasonograms. Neonatal brain damage was defined as the presence of cystic leukomalacia or grade III‐IV intraventricular hemorrhage. Main outcome measures. Perinatal death and neonatal brain damage. Results. The prevalence of fetal/neonatal death or brain damage was 18.2% (16/88) in pregnancies with UA absent/reversed diastolic flow and 4.2% (4/96) in those with increased UA Doppler pulsatility. Stepwise logistic regression identified decreasing gestational age (OR = 1.75, 95% confidence interval, CI = 1.35–2.22) and absent/reversed UA blood flow (OR = 3.34, 95% CI = 1.1–10.9) as predictors of fetal/neonatal death or brain damage. A MCA pulsatility index below the 10th percentile was a risk factor for fetal/neonatal death or brain damage among women with absent/reversed UA diastolic flow (14/53 as compared to 2/35; OR = 5.9, CI =1.4–40.3) but not in pregnancies with forward velocity (1/33 as compared to 3/63; OR = 0.63, 95% CI = 0.02–6.13, Synergy index = 27.7, p = 0.007). Conclusions. In pregnancies complicated by FGR and absent/reversed UA end diastolic flow, vasodilatation of the MCA is a risk factor for neonatal death or brain damage.
Discontinuation of oxytocin in the active phase of labor
Authors: GIRARD BÉNÉDICTE , VARDON DELPHINE , CREVEUIL CHRISTIAN , HERLICOVIEZ MICHEL , DREYFUS MICHEL
Published: January 2009

Objective. To show that early discontinuation of oxytocin will not increase the mean duration of the active labor phase in a clinically significant way. Design. Controlled non‐inferiority study. Setting. Department of Obstetrics and Gynecology, University of Caen, Clémenceau Hospital, France. Population. A total of 138 women with singleton pregnancy and a vertex presentation of over 34 gestational weeks, presenting a medical indication of induction of labor or a dystocia at onset of labor, from May 2005 to June 2006. Methods. Two parallel groups were compared: continuation of oxytocin until delivery versus discontinuation of oxytocin at the onset of the active phase. The clinically acceptable increase in mean duration of the active phase of labor (non‐inferiority margin) was set at 60 minutes. Main outcome measures. Primary outcome measure was duration of the active labor phase. Secondary outcome measures included total duration of labor, parameters concerning oxytocin use, rates of uterine hyperstimulation and fetal heart rate (FHR) abnormalities, and mode of delivery. Some neonatal outcomes were also analyzed. Results. Equivalence of the two strategies (continuation vs. discontinuation of oxytocin) was not demonstrated (p = 0.97 testing for non‐inferiority), the active phase even being significantly longer by a mean of 113 minutes (p = 0.0001 testing for superiority). The rates of cesarean sections, alterations of FHR and delivery hemorrhage were higher when oxytocin was continued, but not significantly. There were significantly more infants hospitalized in neonatology when oxytocin was continued (p = 0.028). Conclusions. Discontinuation of oxytocin at the onset of the active phase prolongs labor. We found no argument for discontinuing the infusion of oxytocin at the onset of the active phase.
A quiet transfer: the Judaization of Jerusalem
Authors: Zink Valerie
Published: January 2009

Since its inception in 1948, Israel has sought to transform the physical and demographic landscape of Jerusalem to correspond with the Zionist vision of a united and fundamentally Jewish Jerusalem under Israeli sovereignty. While much of this has been accomplished through the violent expulsion of Arab residents during the wars of 1948 and 1967, the Judaization of Jerusalem has relied equally on measures taken during times of ‘peace’: the strategic extension of Jerusalem’s municipal boundaries, bureaucratic and legal restrictions on Palestinian land use, disenfranchisement of Jerusalem residents, the expansion of settlements in ‘Greater Jerusalem’, and the construction of the separation wall.
Vanishing point: the abatement of tradition and new architectural development in Baghdad’s historic centers over the past century
Authors: Al-Haidary Ali
Published: January 2009

This article gives an extensive, detailed historic overview of Baghdad’s unique architectural heritage from its ancient Sumerian roots in design through the Islamic and modern periods by an Iraqi professor of architecture. The functionally and aesthetically integrated residential architecture of the ancient Sumerians, its labyrinthine network of abutting houses with open innercourtyards, ingenious ventilation systems, and enclosed balconies (shanāshīl) that formed the warp and weft1 of the fabric of the urban society which it supported for millennia is disappearing. The ancient patterns which still survive in Baghdad are not only emblematic of Middle Eastern architecture but are the essential imprint of Babel (Babylon) – the mother of all cities. The author demonstrates how modernization and rapid changes brought on by economic growth and population explosions led to unregulated building projects that were often conceived and implemented by foreign firms in abject disregard of the unique and irreplaceable cultural heritage of Iraq. Landmarks of culture have already been lost, and there is much still to lose, but it is not too late if proper funds, urban planning and action at the level of the individual can be marshalled to preserve the living museum of Baghdad’s eternal architecture that is the most conspicuous physical expression of its social, cultural and historic identity.
Epidemiology of Healthcare-Associated Bloodstream Infection Caused by USA300 Strains of Methicillin-ResistantStaphylococcus aureusin 3 Affiliated Hospitals
Authors: Jenkins Timothy C. , McCollister Bruce D. , Sharma Rohini , McFann Kim K. , Madinger Nancy E. , Barron Michelle , Bessesen Mary , Price Connie S. , Burman William J.
Published: January 2009

Objective.

To describe the epidemiology of bloodstream infection caused by USA300 strains of methicillin-resistantStaphylococcus aureus(MRSA), which are traditionally associated with cases of community-acquired infection, in the healthcare setting.

Design.

Retrospective cohort study.

Setting.

Three academically affiliated hospitals in Denver, Colorado.

Methods.

Review of cases of S.aureusbloodstream infection during the period from 2003 through 2007. Polymerase chain reaction was used to identify MRSA USA300 isolates.

Results.

A total of 330 cases of MRSA bloodstream infection occurred during the study period, of which 286 (87%) were healthcare-associated. The rates of methicillin resistance among theS. aureusisolates recovered did not vary during the study period and were similar among the 3 hospitals. However, the percentages of cases of healthcare-associated MRSA bloodstream infection due to USA300 strains varied substantially among the 3 hospitals: 62%, 19%, and 36% (P< .001) for community-onset cases and 33%, 3%, and 33% (P= .005) for hospital-onset cases, in hospitals A, B, and C, respectively. In addition, the number of cases of healthcare-associated MRSA bloodstream infection caused by USA300 strains increased during the study period at 2 of the 3 hospitals. At each hospital, USA300 strains were most common among cases of community-associated infection and were least common among cases of hospital-onset infection. Admission to hospital A (a safety-net hospital), injection drug use, and human immunodeficiency virus infection were independent risk factors for healthcare-associated MRSA bloodstream infection due to USA300 strains.

Conclusions.

The prevalence of USA300 strains among cases of healthcare-associated MRSA bloodstream infection varied dramatically among geographically clustered hospitals. USA300 strains are replacing traditional healthcare-related strains of MRSA in some healthcare settings. Our data suggest that the prevalence of USA300 strains in the community is the dominant factor affecting the prevalence of this strain type in the healthcare setting.
Subelliptic estimates for some systems of complex vector fields: Quasihomogeneous case
Authors: Derridj M. , Helffer B.
Published: January 2009

For about twenty five years it was a kind of folk theorem that complex vector-fields defined on

Ω
×

R

t

\Omega \times \mathbb R_t

(with

Ω
\Omega

open set in

R

n

\mathbb R^n

) by
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper L Subscript j Baseline equals StartFraction partial-differential Over partial-differential t Subscript j Baseline EndFraction plus i StartFraction partial-differential phi Over partial-differential t Subscript j Baseline EndFraction left-parenthesis bold t right-parenthesis StartFraction partial-differential Over partial-differential x EndFraction comma j equals 1 comma ellipsis comma n comma bold t element-of normal upper Omega comma x element-of double-struck upper R comma">

L
j

=

∂

∂

t
j

+
i

∂
φ

∂

t
j

(

t

)

∂

∂
x

,

j
=
1
,
…
,
n

,

t

∈
Ω
,
x
∈

R

,

L_j = \frac {\partial }{\partial t_j} + i \frac {\partial \varphi }{\partial t_j}(\mathbf {t})\, \frac {\partial }{\partial x}\;,\; j=1,\dots , n\;,\; \mathbf {t}\in \Omega , x\in \mathbb R,

\]
with

φ
\varphi

analytic, were subelliptic as soon as they were hypoelliptic. This was the case when

n
=
1

n=1

, but in the case

n
>
1

n>1

, an inaccurate reading of the proof given by Maire (see also Trèves) of the hypoellipticity of such systems, under the condition that

φ
\varphi

does not admit any local maximum or minimum (through a nonstandard subelliptic estimate), was supporting the belief for this folk theorem. Quite recently, J.L. Journé and J.M. Trépreau show by examples that there are very simple systems (with polynomial

φ
\varphi

’s) which are hypoelliptic but not subelliptic in the standard

L
2

L^2

-sense. So it is natural to analyze this problem of subellipticity which is in some sense intermediate (at least when

φ
\varphi

is

C
∞

C^\infty

) between the maximal hypoellipticity (which was analyzed by Helffer-Nourrigat and Nourrigat) and the simple local hypoellipticity (or local microhypoellipticity) and to start first with the easiest nontrivial examples. The analysis presented here is a continuation of a previous work by the first author and is devoted to the case of quasihomogeneous functions.
On estimates for the ratio of errors in best rational approximation of analytic functions
Authors: Kouchekian S. , Prokhorov V.
Published: January 2009

Let

E
E

be an arbitrary compact subset of the extended complex plane

C

¯

\overline {\mathbb C}

with nonempty interior. For a function

f
f

continuous on

E
E

and analytic in the interior of

E
E

denote by

ρ
n

(
f
;
E
)

\rho _n(f; E)

the least uniform deviation of

f
f

on

E
E

from the class of all rational functions of order at most

n
n

. In this paper we show that if

f
f

is not a rational function and if

K
K

is an arbitrary compact subset of the interior of

E
,

E,

then
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="product Underscript k equals 0 Overscript n Endscripts left-parenthesis rho Subscript k Baseline left-parenthesis f semicolon upper K right-parenthesis slash rho Subscript k Baseline left-parenthesis f semicolon upper E right-parenthesis right-parenthesis comma">

∏

k
=
0

n

(

ρ
k

(
f
;
K
)

/

ρ
k

(
f
;
E
)
)
,

\prod _{k=0}^n (\rho _k(f; K) /\rho _k(f; E) ),

the ratio of the errors in best rational approximation, converges to zero geometrically as

n
→
∞

n \to \infty

and the rate of convergence is determined by the capacity of the condenser

(
∂
E
,
K
)

(\partial E, K)

. In addition, we obtain results regarding meromorphic approximation and sharp estimates of the Hadamard type determinants.
Existence of solutions of the hyperbolic Keller-Segel model
Authors: Perthame Benoît , Dalibard Anne-Laure
Published: January 2009

We are concerned with the hyperbolic Keller-Segel model with quorum sensing, a model describing the collective cell movement due to chemical signalling with a flux limitation for high cell densities.

This is a first order quasilinear equation, its flux depends on space and time via the solution to an elliptic PDE in which the right-hand side is the solution to the hyperbolic equation. This model lacks strong compactness or contraction properties. Our purpose is to prove the existence of an entropy solution obtained, as usual, in passing to the limit in a sequence of solutions to the parabolic approximation.

The method consists in the derivation of a kinetic formulation for the weak limit. The specific structure of the limiting kinetic equation allows for a ‘rigidity theorem’, which identifies some property of the solution (which might be nonunique) to this kinetic equation. This is enough to deduce a posteriori the strong convergence of a subsequence.
Nilmanifolds of dimension ≤8 admitting Anosov diffeomorphisms
Authors: Lauret Jorge , Will Cynthia
Published: January 2009

After more than thirty years, the only known examples of Anosov diffeomorphisms are topologically conjugated to hyperbolic automorphisms of infranilmanifolds, and even the existence of an Anosov automorphism is a really strong condition on an infranilmanifold. Any Anosov automorphism determines an automorphism of the rational Lie algebra determined by the lattice, which is hyperbolic and unimodular (and conversely ...). These two conditions together are strong enough to make of such rational nilpotent Lie algebras (called Anosov Lie algebras) very distinguished objects. In this paper, we classify Anosov Lie algebras of dimension less than or equal to 8.

As a corollary, we obtain that if an infranilmanifold of dimension

n
≤
8

n\leq 8

admits an Anosov diffeomorphism

f
f

and it is not a torus or a compact flat manifold (i.e. covered by a torus), then

n
=
6

n=6

or 8 and the signature of

f
f

necessarily equals

{
3
,
3
}

\{ 3,3\}

or

{
4
,
4
}

\{ 4,4\}

, respectively.
Poisson geometry of 𝑆𝐿(3,ℂ)-character varieties relative to a surface with boundary
Authors: Lawton Sean
Published: January 2009

TheSL(3,C)\mathrm {SL}(3,\mathbb {C})-representation varietyR\mathfrak {R}of a free groupFr\mathtt {F}_rarises naturally by considering surface group representations for a surface with boundary. There is anSL(3,C)\mathrm {SL}(3,\mathbb {C})-action on the coordinate ring ofR\mathfrak {R}by conjugation. The geometric points of the subring of invariants of this action is an affine varietyX\mathfrak {X}. The points ofX\mathfrak {X}parametrize isomorphism classes of completely reducible representations. We show the coordinate ringC[X]\mathbb {C}[\mathfrak {X}]is a complex Poisson algebra with respect to a presentation ofFr\mathtt {F}_rimposed by the surface. Lastly, we work out the bracket on all generators when the surface is a three-holed sphere or a one-holed torus.
Local well posedness, asymptotic behavior and asymptotic bootstrapping for a class of semilinear evolution equations of the second order in time
Authors: Carvalho A. , Cholewa J.
Published: January 2009

A class of semilinear evolution equations of the second order in time of the form

u

t
t

+
A
u
+
μ
A

u
t

+
A

u

t
t

=
f
(
u
)

u_{tt} + A u + \mu A u_t + A u_{tt}=f(u)

is considered, where

−
A

-A

is the Dirichlet Laplacian,

Ω
\Omega

is a smooth bounded domain in

R

N

\mathbb R^N

and

f
∈

C
1

(

R

,

R

)

f\in C^1(\mathbb R,\mathbb R)

. A local well posedness result is proved in the Banach spaces

W
0

1
,
p

(
Ω
)
×

W
0

1
,
p

(
Ω
)

W^{1,p}_0(\Omega )\times W^{1,p}_0(\Omega )

when

f
f

satisfies appropriate critical growth conditions. In the Hilbert setting, if

f
f

satisfies an additional dissipativeness condition, the nonlinear semigroup of global solutions is shown to possess a gradient-like attractor. Existence and regularity of the global attractor are also investigated following the unified semigroup approach, bootstrapping and the interpolation-extrapolation techniques.
Filtered modules with coefficients
Authors: Ghate Eknath , Mézard Ariane
Published: January 2009

We classify the filtered modules with coefficients corresponding to two-dimensional potentially semi-stable

p
p

-adic representations of the Galois group of

Q

p

\mathbf {Q}_p

under some assumptions (e.g.,

p
p

is odd). We focus on the new features that arise when the coefficients are not necessarily

Q

p

\mathbf {Q}_p

.
Generalized Stark formulae over function fields
Authors: Tan Ki-Seng
Published: January 2009

We establish formulae of Stark type for the Stickelberger elements in the function field setting. Our result generalizes work of Hayes and a conjecture of Gross. It is used to deduce app-adic version of the Rubin-Stark Conjecture and the Burns Conjecture.
New evaluation measures for multifactor dimensionality reduction classifiers in gene–gene interaction analysis
Authors: Namkung Junghyun , Kim Kyunga , Yi Sungon , Chung Wonil , Kwon Min-Seok , Park Taesung
Published: January 2009

Motivation: Gene–gene interactions are important contributors to complex biological traits. Multifactor dimensionality reduction (MDR) is a method to analyze gene–gene interactions and has been applied to many genetics studies of complex diseases. In order to identify the best interaction model associated with disease susceptibility, MDR classifiers corresponding to interaction models has been constructed and evaluated as a predictor of disease status via a certain measure such as balanced accuracy (BA). It has been shown that the performance of MDR tends to depend on the choice of the evaluation measures.

Results: In this article, we introduce two types of new evaluation measures. First, we develop weighted BA (wBA) that utilizes the quantitative information on the effect size of each multi-locus genotype on a trait. Second, we employ ordinal association measures to assess the performance of MDR classifiers. Simulation studies were conducted to compare the proposed measures with BA, a current measure. Our results showed that the wBA and τb improved the power of MDR in detecting gene–gene interactions. Noticeably, the power increment was higher when data contains the greater number of genetic markers. Finally, we applied the proposed evaluation measures to real data.

Contact:  tspark@stats.snu.ac.kr

Supplementary information:  Supplementary data are available at Bioinformatics online.
Beneficial effect of rosuvastatin on cardiac dysfunction is associated with alterations in calcium‐regulatory proteins
Authors: Yang Ying , Mou Yun , Hu Shen‐Jiang , Fu Michael
Published: January 2009

Aims

The normal expression of Ca2+‐regulatory protein is critical for efficient myocardial function. The present study tested the hypothesis that rosuvastatin treatment may attenuate left ventricular (LV) remodelling and dysfunction in the failing heart, which may be associated with alterations of Ca2+‐regulatory protein.

Methods and results

We investigated the change of LV remodelling and function in a rat model of cardiac dysfunction due to myocardial infarction (MI) with or without rosuvastatin (10 mg/kg/day) treatment for 10 weeks. The protein expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA)2a, phospholamban (PLB), and phospho‐PLB at serine‐16 (pSer16‐PLB), as well as SERCA activity, interleukin (IL)‐6, and IL‐10 levels were evaluated. After rosuvastatin treatment, LV remodelling and dysfunction were prevented. Rosuvastatin prevented the decrease of SERCA2a and pSer16‐PLB expression, increased SERCA activity, but showed no effect on PLB expression. Furthermore, rosuvastatin reduced the increased IL‐6 level and further elevated IL‐10 level in the peri‐infarct and remote zones of MI. Serum lipid levels remained unchanged.

Conclusion

Rosuvastatin is effective in preventing LV remodelling and dysfunction in the failing heart. The molecular mechanism may be related to normalization of SERCA2a expression, SERCA activity, and pSer16‐PLB levels, as well as through cytokine alterations independent of its lipid‐lowering effect.
Adequacy of diagnosis and treatment of chronic heart failure in primary health care in Sweden
Authors: Dahlstrom Ulf , Hakansson Jan , Swedberg Karl , Waldenstrom Anders
Published: January 2009

Aims

We performed an observational multicentre study to obtain information of the diagnostic tools and treatments currently used in patients with chronic heart failure (CHF) in primary health care (PHC) in Sweden. Data were collected from 2093 patients in 158 randomly selected PHC centres.

Methods and results

The mean age was 79 years. The dominating aetiology of HF was hypertension and/or ischaemic heart disease. Diagnosis was based on symptoms and/or ECG and/or chest X‐ray in 69% of the patients. Treatment with a renin–angiotensin system (RAS) blocker was ongoing in 74% of the patients, but only 37% had ≥50% of the recommended target dose. In 68%, treatment with a beta‐blocker (BB) was present, but only 31% had ≥50% of the recommended target dose. Only 42% of the patients were on treatment with an RAS blocker and a BB and only 20% had ≥50% of the recommended target dose.

Conclusion

The diagnostic criteria for CHF according to the European Society of Cardiology were fulfilled in only ~30% of the patients. In addition, evidenced‐based treatments to reduce morbidity and mortality were markedly underused, particularly regarding dosing. Our findings may reflect the patients’ high age and the presence of important co‐morbidities.
Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology
Authors: Hawkins Nathaniel Mark , Petrie Mark C. , Jhund Pardeep S. , Chalmers George W. , Dunn Francis G. , McMurray John J.V.
Published: January 2009

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are global epidemics incurring significant morbidity and mortality. The combination presents many diagnostic challenges. Clinical symptoms and signs frequently overlap. Evaluation of cardiac and pulmonary function is often problematic and occasionally misleading. Echocardiography and pulmonary function tests should be performed in every patient. Careful interpretation is required to avoid misdiagnosis and inappropriate treatment. Airflow obstruction, in particular, must be demonstrated when clinically euvolaemic. Very high and very low concentrations of natriuretic peptides have high positive and negative predictive values for diagnosing HF in those with both conditions. Intermediate values are less informative. Both conditions are systemic disorders with overlapping pathophysiological processes. In patients with HF, COPD is consistently an independent predictor of death and hospitalization. However, the impact on ischaemic and arrhythmic events is unknown. Greater collaboration is required between cardiologists and pulmonologists to better identify and manage concurrent HF and COPD. The resulting symptomatic and prognostic benefits outweigh those attainable by treating either condition alone.
Right ventricular cardiomyopathy: timing of heart transplantation in Uhl's anomaly and arrythmogenic right ventricular cardiomyopathy
Authors: Gilljam Thomas , Bergh Claes‐Håkan
Published: January 2009

Transplant indications for right ventricular (RV) cardiomyopathy have not been defined. We report on two boys, aged 18 and 17 years, one with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one with Uhl's anomaly. Both had implantable cardioverter defibrillator (ICD) for the prevention of sudden death (SD), but were not considered urgent heart transplant candidates due to the absence of heart failure symptoms. A ventricular tachycardia‐induced cardiac collapse occurred at school in the Uhl patient and in hospital in the ARVC patient. In both patients, ICD shocks intermittently restored sinus rhythm but with inadequate circulation. Only the ARVC patient received early chest compressions and was saved to heart transplantation. Due to RV failure, both patients had evidence of Fontan‐type physiology, in whom pulmonary blood flow is passive and propelled by the transpulmonary pressure gradient and intrathoracic pressure alterations produced by breathing. In these cases, at resuscitation, systemic circulation is not established until after pulmonary blood flow is restored by breathing or chest compressions. An ICD alone is therefore not sufficient for the prevention of SD. When invasive data show evidence of Fontan‐type circulation, the patient may be considered for heart transplantation.
A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study
Authors: Jarnert Christina , Landstedt‐Hallin Lena , Malmberg Klas , Melcher Anders , Ohrvik John , Persson Hans , Rydén Lars
Published: January 2009

Aims

Myocardial diastolic dysfunction (MDD) and impaired coronary flow reserve (CFR) are early signs of myocardial involvement in patients with diabetes. The important question of whether this may be reversed by glucose normalization has not been tested in a controlled clinical trial. We hypothesized that strict glycaemic control, particularly if insulin based, will improve MDD and CFR.

Methods and results

Thirty‐nine type 2 diabetes patients (mean age 61.0 ± 7 years) with signs of diastolic dysfunction were randomly assigned to strict metabolic control by insulin (I‐group; n = 21) or oral glucose lowering agents (O‐group; n = 18). MDD and CFR were studied with Doppler‐echocardiography including Tissue Doppler Imaging and myocardial contrast enhanced echocardiography. Fasting glucose (I‐group = −2.2 ± 2.1; O‐group −1.5 ± 0.8 mmol/L) and HbA1c were normalized (−0.6 ± 0.4 and −0.7 ± 0.4%, respectively) in both groups, but this did not significantly improve MDD in either of the groups (P = 0.65). There was no difference in CFR before and after improved glycaemic control.

Conclusion

The hypothesis that strict glycaemic control would reverse early signs of MDD and improve CFR in patients with type 2 diabetes could not be confirmed, despite achieved normalization. Whether it is possible to influence a more pronounced diastolic dysfunction, particularly in less well‐controlled diabetic patients, remains to be established.
Prevalence and prognostic significance of adrenergic escape during chronic β‐blocker therapy in chronic heart failure
Authors: Frankenstein Lutz , Zugck Christian , Schellberg Dieter , Nelles Manfred , Froehlich Hanna , Katus Hugo , Remppis Andrew
Published: January 2009

Aims

Like aldosterone escape to ACE‐inhibitors, adrenergic escape (AE) to β‐blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different β‐blocker agents and doses.

Methods and results

This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable β‐blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual β‐blocker agents used and the dose equivalent taken, the prevalence of AE was 31–39%. Norepinephrine levels neither correlated with heart rate (r = 0.02; 95% CI: −0.08–0.11; P = 0.74) nor were they related to underlying rhythm (P = 0.09) or the individual β‐blocker agent used (P = 0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387–2.645; χ2: 15.60).

Conclusion

We verified the presence of AE in CHF patients on chronic stable β‐blocker therapy, irrespective of the individual β‐blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape.
Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover
Authors: Martos Ramón , Baugh John , Ledwidge Mark , O'Loughlin Christina , Murphy Niamh F. , Conlon Carmel , Patle Anil , Donnelly Seamas C. , McDonald Kenneth
Published: January 2009

Aims

Heart failure with preserved ejection fraction (HF‐PEF) can be difficult to diagnose in clinical practice. Myocardial fibrosis is a major determinant of diastolic dysfunction (DD), potentially contributing to the progression of HF‐PEF. The aim of this study was to analyse whether serological markers of collagen turnover may predict HF‐PEF and DD.

Methods and results

We included 85 Caucasian treated hypertensive patients (DD n = 65; both DD and HF‐PEF n = 32). Serum carboxy (PICP), amino (PINP), and carboxytelo (CITP) peptides of procollagen type I, amino (PIIINP) peptide of procollagen type III, matrix metalloproteinases (MMP‐1, MMP‐2, and MMP‐9), and tissue inhibitor of MMP levels were assayed. Using receiver operating characteristic curve analysis, MMP‐2 (AUC = 0.91; 95% CI: 0.84, 0.98), CITP (0.83; 0.72, 0.92), PICP (0.82; 0.72, 0.92), B‐type natriuretic peptide (BNP) (0.82; 0.73, 0.91), MMP‐9 (0.79; 0.68, 0.89), and PIIINP (0.78; 0.66, 0.89) levels were significant predictors of HF‐PEF (P < 0.01 for all). Carboxytelo peptides of procollagen type I (AUC = 0.74; 95% CI: 0.62, 0.86), MMP‐2 (0.73; 0.62, 0.84), PIIINP (0.73; 0.60, 0.85), BNP (0.69; 0.55, 0.83) and PICP (0.66; 0.54, 0.78) levels were significant predictors of DD (P < 0.05 for all). A cutoff of 1585 ng/mL for MMP‐2 provided 91% sensitivity and 76% specificity for predicting HF‐PEF and combinations of biomarkers could be used to adjust either sensitivity or specificity.

Conclusion

Markers of collagen turnover identify patients with HF‐PEF and DD. Matrix metalloproteinase 2 may be more useful than BNP in the identification of HF‐PEF. This suggests that these new biochemical tools may assist in identifying patients with these diagnostically challenging conditions.
Environmental Control in Tea Fields to Reduce Infection by Pseudomonas syringae pv. theae
Authors: Tomihama T. , Nonaka T. , Nishi Y. , Arai K.
Published: January 2009

Bacterial shoot blight (BSB) disease, caused by Pseudomonas syringae pv. theae, is a major bacterial disease of tea plants in Japan. BSB mainly occurs in the low-temperature season, and lesion formation by P. syringae pv. theae is enhanced by both low temperature and the presence of ice nucleation-active Xanthomonas campestris (INAX), which catalyzes ice formation at –2 to –4°C and is frequently co-isolated with P. syringae pv. theae from tea plants. Low temperature is thus the most important environmental factor influencing the incidence of BSB; however, the effects of low temperature on infection of the host by P. syringae pv. theae and of environmental controls in fields on the occurrence of the disease are poorly understood. In this study, we show that ice formation on tea leaves by INAX enhanced P. syringae pv. theae invasion into leaf tissue. The natural incidence of BSB in the field was closely related to early autumn frost. Frost protection in late autumn, which prevented ice formation on tea plants, significantly decreased the incidence of BSB, and frost protection combined with bactericide application held the incidence under the economic threshold level. Our data indicate that environmental control in the field based on microbial interactions in the host offers a new strategy for plant disease control.
Diaphragm Training in Amyotrophic Lateral Sclerosis
Authors: Nardin Rachel , O'Donnell Carl , Loring Stephen H , Nie Rui , Hembre Kristi , Walsh Joy , Arboleda Barbara Wilson , Muzikansky Alona , Nguyen Dang , Raynor Elizabeth
Published: January 2009

There is a continued need for therapies to improve respiratory function and quality of life in patients with amyotrophic lateral sclerosis. In this pilot trial, we studied 8 subjects with amyotrophic lateral sclerosis and respiratory involvement. We measured respiratory function and quality of life at baseline. We then taught subjects diaphragm training, a method of breath control designed to improve respiratory muscle strength and efficiency. We repeated measures of respiratory function and quality of life 6 and 12 weeks later. There was no significant improvement in any outcome measure after instituting diaphragm training. There was a nonsignificant trend toward a slower rate of decline in respiratory function in those subjects who mastered the technique; however, only half the subjects were able to successfully change their pattern of breathing. A larger study of this technique is warranted; however, in determining the sample size for a larger study, the difficulty for patients in mastering the technique must be taken into consideration.
What's in the Literature?
Authors: Simmons Zachary
Published: January 2009

The term “therapy” always is welcome when dealing with neuromuscular diseases, and I am pleased to report that the literature this quarter contains articles on promising treatments for muscle diseases, including some very exciting work on gene therapy. Over the past several years, genetics have assumed increasing importance in the neuromuscular literature, and this is apparent not only from the gene therapy article but also from articles on the genetics of so-called “sporadic” amyotrophic lateral sclerosis. There are also important studies reminding us that neuromuscular diseases have manifestations beyond the nervous system. Studies on statins described below will undoubtedly lead clinicians to reassess the frequently asked questions about the use of these agents in patients with neuromuscular disorders. Finally, peripheral neuropathies and some natural history and classification studies round out this issue's review.
DAMMIF, a program for rapidab-initioshape determination in small-angle scattering
Authors: Franke Daniel , Svergun Dmitri I.
Published: January 2009

DAMMIF, a revised implementation of theab-initioshape-determination programDAMMINfor small-angle scattering data, is presented. The program was fully rewritten, and its algorithm was optimized for speed of execution and modified to avoid limitations due to the finite search volume. Symmetry and anisometry constraints can be imposed on the particle shape, similar toDAMMIN. In equivalent conditions,DAMMIFis 25–40 times faster thanDAMMINon a single CPU. The possibility to utilize multiple CPUs is added toDAMMIF. The application is available in binary form for major platforms.