bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Capture of Viral and Plasmid DNA by Yeast Nuclear Chromosomes
Authors: Frank A. Carolin , Wolfe Kenneth H.
Published: August 2009

A 10-kb region of the nuclear genome of the yeastVanderwaltozyma polysporacontains an unusual cluster of five pseudogenes homologous to five different genes from yeast killer viruses, killer plasmids, the 2μm plasmid, and aPenicilliumvirus. By further database searches, we show that this phenomenon is not unique toV. polysporabut that about 40% of the sequenced genomes of Saccharomycotina species contain integrated copies of genes from DNA plasmids or RNA viruses. We propose the name NUPAVs (nuclear sequences of plasmid and viral origin) for these objects, by analogy to NUMTs (nuclear copies of mitochondrial DNA) and NUPTs (nuclear copies of plastid DNA, in plants) of organellar origin. Although most of the NUPAVs are pseudogenes, one intact and active gene that was formed in this way is theKHS1chromosomal killer locus ofSaccharomyces cerevisiae. We show thatKHS1is a NUPAV related to M2 killer virus double-stranded RNA. Many NUPAVs are located beside tRNA genes, and some contain sequences from a mixture of different extrachromosomal sources. We propose that NUPAVs are sequences that were captured by the nuclear genome during the repair of double-strand breaks that occurred during evolution and that some of their properties may be explained by repeated breakage at fragile chromosomal sites.
Tricarboxylic Acid Cycle-Dependent Attenuation of
Staphylococcus aureus
In Vivo Virulence by Selective Inhibition of Amino Acid Transport
Authors: Zhu Yefei , Xiong Yan Q. , Sadykov Marat R. , Fey Paul D. , Lei Mei G. , Lee Chia Y. , Bayer Arnold S. , Somerville Greg A.
Published: August 2009

Staphylococci are the leading causes of endovascular infections worldwide. Commonly, these infections involve the formation of biofilms on the surface of biomaterials. Biofilms are a complex aggregation of bacteria commonly encapsulated by an adhesive exopolysaccharide matrix. In staphylococci, this exopolysaccharide matrix is composed of polysaccharide intercellular adhesin (PIA). PIA is synthesized when the tricarboxylic acid (TCA) cycle is repressed. The inverse correlation between PIA synthesis and TCA cycle activity led us to hypothesize that increasing TCA cycle activity would decrease PIA synthesis and biofilm formation and reduce virulence in a rabbit catheter-induced model of biofilm infection. TCA cycle activity can be induced by preventing staphylococci from exogenously acquiring a TCA cycle-derived amino acid necessary for growth. To determine if TCA cycle induction would decrease PIA synthesis in
Staphylococcus aureus
, the glutamine permease gene (
glnP
) was inactivated and TCA cycle activity, PIA accumulation, biofilm forming ability, and virulence in an experimental catheter-induced endovascular biofilm (endocarditis) model were determined. Inactivation of this major glutamine transporter increased TCA cycle activity, transiently decreased PIA synthesis, and significantly reduced in vivo virulence in the endocarditis model in terms of achievable bacterial densities in biofilm-associated cardiac vegetations, kidneys, and spleen. These data confirm the close linkage of TCA cycle activity and virulence factor production and establish that this metabolic linkage can be manipulated to alter infectious outcomes.
Cytotoxicity and Secretion of Gamma Interferon Are Carried Out by Distinct CD8 T Cells duringMycobacterium tuberculosisInfection
Authors: Einarsdottir Thorbjorg , Lockhart Euan , Flynn JoAnne L.
Published: August 2009

The host immune response is generally sufficient to containMycobacterium tuberculosisinfection. It does not, however, efficiently prevent subsequent infection withM. tuberculosisor provide sterilizing immunity. While the understanding of the immune response generated against this pathogen is incomplete, improvements have been achieved due to advances in immunological tools. In this study, we analyzed the multifunctional nature of primary and memory CD8 T-cell responses generated during murineM. tuberculosisinfection. We generated a recombinantM. tuberculosisstrain expressing ovalbumin (OVA) epitopes in order to expand the peptides for the detection of CD8 T cells duringM. tuberculosisinfection and enable us to use OVA-specific reagents. Our results indicate that the majority ofM. tuberculosis-specific CD8 T cells are limited to either cytotoxicity or the secretion of gamma interferon (IFN-γ), with cytotoxicity being far more prevalent than IFN-γ secretion. Memory CD8 T cells responded earlier and reached higher levels in the lungs than naïve CD8 T cells, as was expected. They were, however, less cytotoxic and secreted less IFN-γ than newly primed CD8 T cells, suggesting that one factor contributing to bacterial persistence and lack of sterilizing immunity may be the low quality of memory cells that are generated.
RecombinantListeria monocytogenesExpressing a Cell Wall-Associated Listeriolysin O Is Weakly Virulent but Immunogenic
Authors: Carrero Javier A. , Calderon Boris , Vivanco-Cid Hector , Unanue Emil R.
Published: August 2009

Listeriolysin O (LLO) is an essential virulence factor for the gram-positive bacteriumListeria monocytogenes. Our goal was to determine if altering the topology of LLO would alter the virulence and toxicity ofL. monocytogenesin vivo. A recombinant strain was generated that expressed a surface-associated LLO (sLLO) variant secreted at 40-fold-lower levels than the wild type. In culture, the sLLO strain grew in macrophages, translocated to the cytosol, and induced cell death. However, the sLLO strain showed decreased infectivity, reduced lymphocyte apoptosis, and decreased virulence despite a normal in vitro phenotype. Thus, the topology of LLO inL. monocytogeneswas a factor in the pathogenesis of the infection and points to a role of LLO secretion during in vivo infection. The sLLO strain was cleared by severe combined immunodeficient (SCID) mice. Despite the attenuation of virulence, the sLLO strain was immunogenic and capable of eliciting protective T-cell responses.
A Comparative Genomics, Network-Based Approach to Understanding Virulence in
Vibrio cholerae
Authors: Gu Jianying , Wang Yufeng , Lilburn Timothy
Published: August 2009

Our views of the genes that drive phenotypes have generally been built up one locus or operon at a time. However, a given phenotype, such as virulence, is a multilocus phenomenon. To gain a more comprehensive view of the genes and interactions underlying a phenotype, we propose an approach that incorporates information from comparative genomics and network biology and illustrate it by examining the virulence phenotype of
Vibrio cholerae
O1 El Tor N16961. We assessed the associations among the virulence-associated proteins from
Vibrio cholerae
and all the other proteins from this bacterium using a functional-association network map. In the context of this map, we were able to identify 262 proteins that are functionally linked to the virulence-associated genes more closely than is typical of the proteins in this strain and 240 proteins that are functionally linked to the virulence-associated proteins with a confidence score greater than 0.9. The roles of these genes were investigated using functional information from online data sources, comparative genomics, and the relationships shown by the protein association map. We also incorporated core proteome data from the family
Vibrionaceae
; 35% of the virulence-associated proteins have orthologs among the 1,822 orthologous groups of proteins in the core proteome, indicating that they may be dual-role virulence genes or encode functions that have value outside the human host. This approach is a valuable tool in searching for novel functional associations and in investigating the relationship between genotype and phenotype.
The Structure and Assembly Dynamics of Plasmid Actin AlfA Imply a Novel Mechanism of DNA Segregation
Authors: Polka Jessica K. , Kollman Justin M. , Agard David A. , Mullins R. Dyche
Published: August 2009

Bacterial cytoskeletal proteins participate in a variety of processes, including cell division and DNA segregation. Polymerization of one plasmid-encoded, actin-like protein, ParM, segregates DNA by pushing two plasmids in opposite directions and forms the current paradigm for understanding active plasmid segregation. An essential feature of ParM assembly is its dynamically instability, the stochastic switching between growth and disassembly. It is unclear whether dynamic instability is an essential feature of all actin-like protein-based segregation mechanisms or whether bacterial filaments can segregate plasmids by different mechanisms. We expressed and purified AlfA, a plasmid-segregating actin-like protein from
Bacillus subtilis
, and found that it forms filaments with a unique structure and biochemistry; AlfA nucleates rapidly, polymerizes in the presence of ATP or GTP, and forms highly twisted, ribbon-like, helical filaments with a left-handed pitch and protomer nucleotide binding pockets rotated away from the filament axis. Intriguingly, AlfA filaments spontaneously associate to form uniformly sized, mixed-polarity bundles. Most surprisingly, our biochemical characterization revealed that AlfA does not display dynamic instability and is relatively stable in the presence of diphosphate nucleotides. These results (i) show that there is remarkable structural diversity among bacterial actin filaments and (ii) indicate that AlfA filaments partition DNA by a novel mechanism.
A CLASS OF STATIONARY NONLINEAR MAXWELL SYSTEMS
Authors: MIRANDA FERNANDO , RODRIGUES JOSÉ-FRANCISCO , SANTOS LISA
Published: August 2009

We study a new class of electromagnetostatic problems in the variational framework of the subspace of W1,p(Ω) of vector functions with zero divergence and zero normal trace, for [Formula: see text], in smooth, bounded and simply connected domains Ω of ℝ3. We prove a Poincaré–Friedrichs type inequality and we obtain the existence of steady-state solutions for an electromagnetic induction heating problem and for a quasi-variational inequality modelling a critical state generalized problem for type-II superconductors.
Context semantics, linear logic, and computational complexity
Authors: Lago Ugo Dal
Published: August 2009

We show that context semantics can be fruitfully applied to the quantitative analysis of proof normalization in linear logic. In particular, context semantics lets us define the
weight
of a proof-net as a measure of its inherent complexity: it is both an upper bound to normalization time (modulo a polynomial overhead, independently on the reduction strategy) and a lower bound to the amount of resources needed to compute the normal form. Weights are then exploited in proving strong soundness theorems for various subsystems of linear logic, namely elementary linear logic, soft linear logic, and light linear logic.
Sup-interpretations, a semantic method for static analysis of program resources
Authors: Marion Jean-Yves , Péchoux Romain
Published: August 2009

The sup-interpretation method is proposed as a new tool to control memory resources of first order functional programs with pattern matching by static analysis. It has been introduced in order to increase the intensionality, that is the number of captured algorithms, of a previous method, the quasi-interpretations. Basically, a sup-interpretation provides an upper bound on the size of function outputs. A criterion, which can be applied to terminating as well as nonterminating programs, is developed in order to bound the stack frame size polynomially. Since this work is related to quasi-interpretation, dependency pairs, and size-change principle methods, we compare these notions obtaining several results. The first result is that, given any program, we have heuristics for finding a sup-interpretation when we consider polynomials of bounded degree. Another result consists in the characterizations of the sets of functions computable in polynomial time and in polynomial space. A last result consists in applications of sup-interpretations to the dependency pair and the size-change principle methods.
Client-centered multimedia content adaptation
Authors: Wei Yong , Bhandarkar Suchendra M. , Li Kang
Published: August 2009

The design and implementation of a client-centered multimedia content adaptation system suitable for a mobile environment comprising of resource-constrained handheld devices or clients is described. The primary contributions of this work are: (1) the overall architecture of the client-centered content adaptation system, (2) a data-driven multi-level Hidden Markov model (HMM)-based approach to perform both video segmentation and video indexing in a single pass, and (3) the formulation and implementation of a Multiple-choice Multidimensional Knapsack Problem (MMKP)-based video personalization strategy. In order to segment and index video data, a video stream is modeled at both the semantic unit level and video program level. These models are learned entirely from training data and no domain-dependent knowledge about the structure of video programs is used. This makes the system capable of handling various kinds of videos without having to manually redefine the program model. The proposed MMKP-based personalization strategy is shown to include more relevant video content in response to the client's request than the existing 0/1 knapsack problem and fractional knapsack problem-based strategies, and is capable of satisfying multiple client-side constraints simultaneously. Experimental results on CNN news videos and Major League Soccer (MLS) videos are presented and analyzed.
Design of multimedia surveillance systems
Authors: Sivaram G. S. V. S. , Kankanhalli Mohan S. , Ramakrishnan K. R.
Published: August 2009

This article addresses the problem of how to select the optimal combination of sensors and how to determine their optimal placement in a surveillance region in order to meet the given performance requirements at a minimal cost for a multimedia surveillance system. We propose to solve this problem by obtaining a performance vector, with its elements representing the performances of subtasks, for a given input combination of sensors and their placement. Then we show that the optimal sensor selection problem can be converted into the form of Integer Linear Programming problem (ILP) by using a linear model for computing the optimal performance vector corresponding to a sensor combination. Optimal performance vector corresponding to a sensor combination refers to the performance vector corresponding to the optimal placement of a sensor combination. To demonstrate the utility of our technique, we design and build a surveillance system consisting of PTZ (Pan-Tilt-Zoom) cameras and active motion sensors for capturing faces. Finally, we show experimentally that optimal placement of sensors based on the design maximizes the system performance.
The New Legal Pluralism
Authors: Berman Paul Schiff
Published: August 2009

Scholars studying interactions among multiple communities have often used the term legal pluralism to describe the inevitable intermingling of normative systems that results from these interactions. In recent years, a new application of pluralist insights has emerged in the international and transnational realm. This review aims to survey and help define this emerging field of global legal pluralism. I begin by briefly describing sites for pluralism research, both old and new. Then I discuss how pluralism has come to be seen as an attractive analytical framework for those interested in studying law on the world stage. Finally, I identify advantages of a pluralist approach and respond to criticisms, and I suggest ways in which pluralism can help both in reframing old conceptual debates and in generating useful normative insights for designing procedural mechanisms, institutions, and discursive practices for managing hybrid legal/cultural spaces.
Recursivity of Global Normmaking: A Sociolegal Agenda
Authors: Halliday Terence C.
Published: August 2009

This review proposes that the recursivity of law offers a promising framework for sociolegal and interdisciplinary research on global norm-making. The recursivity approach is systematic, generates hypotheses and questions about global actors and mechanisms, takes seriously historical contingency, and is inherently comparative across issue areas and different levels of governance. In global lawmaking, recursivity proceeds principally through the intersection of three interacting cycles of global normmaking, national lawmaking, and the interaction between the two. With particular focus on genocide and war crimes, violence against women, trade law, and climate change, the review demonstrates how four mechanisms—actor mismatch, diagnostic struggles, contradictions, and indeterminacy—drive forward these cycles of reform until the inherent tensions within them are resolved and normmaking settles. A sociolegal approach to the recursivity of global normmaking emphasizes (a) the politics of the legal complex, (b) the constitutive power of legal concepts, (c) the structure and dynamics of global regulatory institutions, and (d) the formal properties of global law. The review concludes with generalizations about global normmaking and particularly promising topics for sociolegal scholarship.
Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD
Authors: Ahmad Mansoor , Zhao Xiangmin , Kelly Melissa R. , Kandhi Sharath , Perez Oscar , Abraham Nader G. , Wolin Michael S.
Published: August 2009

Endothelium-denuded bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving removing a superoxide-derived hydrogen peroxide-mediated relaxation. BPA organ cultured for 24 h with 0.1 mM cobalt chloride (CoCl2) to increase the expression and activity of heme oxygenase-1 (HO-1) is accompanied by a decrease in 5 μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to KCl in BPA was not affected by increases in HO-1, but the hypoxic pulmonary vasoconstriction (HPV) response was decreased. Organ culture with a HO-1 inhibitor (10 μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Treatment of HO-1-induced BPA with extracellular catalase resulted in reversal of the attenuation of HPV without affecting the force development to KCl. Increasing intracellular peroxide scavenging with 0.1 mM ebselen increased force development to KCl and partially reversed the decrease in HPV seen on induction of HO-1. HO-1 induction increases extracellular (ec) superoxide dismutase (SOD) expression without changing Cu,Zn-SOD and Mn-SOD levels. HO-1-induced BPA rings treated with the copper chelator 10 mM diethyldithiocarbamate to inactivate ecSOD and Cu,Zn-SOD showed increased superoxide and decreased peroxide to levels equal to non-HO-1-induced rings, whereas the addition of SOD to freshly isolated BPA rings attenuated HPV similar to HO-1 induction with CoCl2. Therefore, HO-1 induction in BPA increases ecSOD expression associated with enhanced generation of peroxide in amounts that may not be adequately removed during hypoxia, leading to an attenuation of HPV.
Sex-dependent differences in Rho activation contribute to contractile dysfunction in type 2 diabetic mice
Authors: Nuno Daniel W. , Harrod Jeremy S. , Lamping Kathryn G.
Published: August 2009

The objective of this study was to determine if mechanisms involved in vascular dysfunction in type 2 diabetes differ with sex. Vascular reactivity, expression, and activation of rhoA and rho kinase were measured in aorta from male and female nondiabetic C57BLKS/J and diabetic BKS.Cg- m+/+ Leprdb/J (db/db) mice, a model of type 2 diabetes. Relaxation to acetylcholine and nitroprusside was similar in aorta from nondiabetic male and female mice. Relaxation to acetylcholine was reduced ∼50% in both male and female diabetic mice. Although inhibition of rho kinase with H-1152 increased relaxation to acetylcholine and nitroprusside in nondiabetic males, it had no effect on the response in either nondiabetic or diabetic females or diabetic males. Contraction to serotonin was increased similarly in male and female diabetic mice compared with nondiabetic mice and was reduced following inhibition of rho kinase with either fasudil or H-1152. Activation of rhoA and its downstream effector, rho kinase, was greater in aorta from diabetic males compared with nondiabetic males. In contrast, there were no differences in vascular activation of rhoA or rho kinase in diabetic females. The increased activity of rhoA and rho kinase in diabetic mice was not due to a change in protein expression of rhoA or rho kinase (ROCK1 and ROCK2) in vessels from either males or females. Although contractile dysfunction in vessels occurs in both male and female diabetic mice, the dysfunction in diabetic males is dependent upon activation of rhoA and rho kinase. Alternative mechanisms affecting rho kinase activation may be involved in females.
PPAR-γ agonist rosiglitazone reverses increased cerebral venous hydraulic conductivity during hypertension
Authors: Roberts Tim J. M. , Chapman Abbie C. , Cipolla Marilyn J.
Published: August 2009

Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been shown to protect the cerebral vasculature, including the blood-brain barrier. In the present study, we investigated the effect of the PPAR-γ agonist rosiglitazone on changes in venous permeability during chronic hypertension induced by nitric oxide synthase inhibition. Female Sprague-Dawley rats were either treated with NG-nitro-l-arginine methyl ester (l-NAME; 0.5 g/l in drinking water) for 5 wk (HTN; n = 8), l-NAME for 5 wk plus the PPAR-γ agonist rosiglitazone (20 mg/kg in food) for the last 3 wk (HTN + Rosi; n = 5), l-NAME for 5 wk plus the superoxide dismutase mimetic Tempol (1 mmol/l in drinking water) for the last 3 wk (HTN + Tempol; n = 8), or were untreated controls ( n = 9). Fluid filtration ( Jv/ S) and hydraulic conductivity ( Lp) of cerebral veins were compared in vitro between groups after a step increase in pressure from 10 to 25 mmHg to mimic the change in hydrostatic pressure during acute hypertension. Hypertension increased Jv/ S by 2.2-fold and Lp by 3.2-fold. Rosiglitazone treatment after 2 wk of hypertension completely reversed the increased Jv/ S and Lp that occurred during hypertension, whereas Tempol had no effect. These results demonstrate that rosiglitazone was effective at reversing changes in venous permeability that occurred during chronic hypertension, an effect that does not appear to be related to its antioxidant properties. Our findings suggest that PPAR-γ may be a key regulator of blood-brain barrier permeability and a potential therapeutic target during hypertension.
An Iterative Decomposed Piecewise‐Linear Model Description
Authors: Jimenez-Fernandez Victor , Hernandez-Martinez Luis , Sarmiento-Reyes Arturo
Published: August 2009

A model description for the representation of one‐dimensional piecewise‐linear characteristics is
presented. The model can be denoted as a decomposed one, because the independent and dependent variables of
the PWL characteristic are treated separately. It is also called iterative, because the particular representation of
each segment of the PWL characteristic depends on the value of only one parameter included in the mathematical
formulation, it gives the possibility of modeling both, univalued and multivalued PWL characteristics.
Glucose Metabolism Is Required for Oxidized LDL–Induced Macrophage Survival
Authors: Elsegood Caryn L. , Chang Margaret , Jessup Wendy , Scholz Glen M. , Hamilton John A.
Published: August 2009

Objective—

Oxidized low-density lipoprotein (oxLDL) induces survival of colony stimulating factor-1 (CSF-1)-dependent macrophages in vitro. Because atherosclerotic lesion–associated macrophages take up large amounts of glucose, we investigated whether, and how, oxLDL promotes glucose uptake and how glucose metabolism regulates oxLDL-induced macrophage survival.

Methods and Results—

OxLDL-induced macrophage survival required glucose metabolism. OxLDL stimulated 2 phases of glucose uptake, namely acute and chronic, which required PI3K but not MEK1/2 activity. PI3K appeared to regulate glucose transport via glucose transporter affinity and/or mobilization. OxLDL also maintained levels of the prosurvival proteins, Bcl-2 and Bcl-x
L
, after CSF-1 had been removed through a combination of mechanisms including transcription, translation, and protein stabilization. Significantly, inhibition of glucose metabolism reduced Bcl-2 and Bcl-x
L
protein levels. MEK1/2 and PI3K activities were also required for oxLDL-induced Bcl-2 and Bcl-x
L
mRNA upregulation.

Conclusions—

These results suggest that oxLDL enhances macrophage survival in the absence of CSF-1 by inducing PI3K-dependent glucose uptake, which is metabolized to maintain Bcl-2 and Bcl-x
L
protein levels.
A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol
Authors: Tomaszewski Maciej , Charchar Fadi J. , Barnes Timothy , Gawron-Kiszka Magdalena , Sedkowska Agnieszka , Podolecka Ewa , Kowalczyk Jacek , Rathbone Wendy , Kalarus Zbigniew , Grzeszczak Wladyslaw , Goodall Alison H. , Samani Nilesh J. , Zukowska-Szczechowska Ewa
Published: August 2009

Objective—

A rare mutation in low-density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesized that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C).

Methods and Results—

Twelve common (minor allele frequency ≥0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (
P
=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex-, and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations − 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (
P
=0.0268,
P
=0.0476, and
P
=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex-, and BMI-adjusted LDL-C (SE=0.05,
P
=0.0038).

Conclusions—

Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation.
Identification of Genetic Variants Associated With Response to Statin Therapy
Authors: Mega Jessica L. , Morrow David A. , Brown Alison , Cannon Christopher P. , Sabatine Marc S.
Published: August 2009

Objective—

The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins.

Methods and Results—

49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the ε2, ε3, and ε4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (ε2 carriers 53.8%, ε3/ε3 48.1%, and ε4 carriers 46.4%, respectively,
P
=0.00039) and replicated in the pravastatin arm (ε2 carriers 22.1%, ε3/ε3 21.8%, and ε4 carriers 16.6%, respectively,
P
=0.00038). The proportion of subjects achieving an LDL-C ≤70 mg/dL at day 30 was higher for ε2 than ε4 carriers (
P
=1.3×10
−5
). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in
ABCB1
was associated with the percent reduction in LDL-C (GG 23.3%, non-G heterozygote 20.3%, and non-G homozygote 17.4%,
P
=0.042).

Conclusion—

Carriers of
APOE
ε2 versus ε4 had significantly greater LDL-C reduction with atorvastatin and with pravastatin, and more frequently achieved a guideline-recommended LDL-C ≤70 mg/dL. Polymorphisms in triallelic G2677T/A variant in
ABCB1
were associated with the degree of LDL-C lowering with pravastatin.
Inhibition of Platelet-Rich Arterial Thrombus In Vivo
Authors: Obi Chike , Wysokinski Waldemar , Karnicki Krzystof , Owen Whyte G. , McBane Robert D.
Published: August 2009

Objective—

To test the hypothesis that statins will acutely inhibit platelet thrombus formation, intravenous lovastatin was assessed in our well-characterized porcine carotid injury model.

Methods and Results—

The first carotid artery was crush-injured and harvested after 30 minutes. Pigs then received intravenous lovastatin (100 μg/kg bolus+100 μg/kg/h infusion, n=6) or saline (n=11) before injury of the second carotid artery. Thrombus size was quantified by scintillation detection of autologous
111
In-platelets. Sequential carotid injury produced a thrombus more than 50% greater in volume in the second (3149±2053×10
6
/cm
2
) relative to the first injured artery (2081±1552×10
6
/cm
2
;
P
=0.04) in control pigs. This augmentation was inhibited by intravenous lovastatin which acutely reduced platelet deposition (944±246×10
6
/cm
2
) relative to saline control (
P
=0.02). Flow chamber closure times increased on average by 2.45-fold in response to whole blood lovastatin incubation. Lovastatin (
P
<0.05) and simvastatin (
P
<0.05) reduced platelet dense granule secretion in vitro.

Conclusions—

Sequential arterial injury augments the thrombotic response suggesting that the propensity for arterial thrombosis is at least partially acquired. This thrombotic augmentation can be acutely attenuated by intravenous lovastatin which may result from a pleiotropic impact on platelet function. These results appear to be a class effect of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors.
Nevirapine Increases High-Density Lipoprotein Cholesterol Concentration by Stimulation of Apolipoprotein A-I Production
Authors: Franssen Remco , Sankatsing Raaj R. , Hassink Elly , Hutten Barbara , Ackermans Mariette T. , Brinkman Kees , Oesterholt René , Arenas-Pinto Alejandro , Storfer Stephen P. , Kastelein John J. , Sauerwein Hans P. , Reiss Peter , Stroes Erik S.
Published: August 2009

Objective—

The purpose of this study was to investigate the mechanism by which the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) increases high-density lipoprotein cholesterol (HDLc) in treatment-experienced human immunodeficiency virus-1 (HIV-1)–infected patients.

Methods and Results—

Twelve HIV-1 infected patients, with stably suppressed HIV-1 viral load using AZT/3TC/abacavir for ≥6 months, added NVP to their current antiretroviral regimen. Patients received a primed bolus infusion of the stable isotope L-[1-
13
C]-valine for 12 hours before, as well as 6 and 24 weeks after, the addition of NVP to study apolipoprotein A-I (apoA-I) kinetics. Absolute production rate (APR) and fractional catabolic rate (FCR) of apoA-I were calculated using SAAM-II modeling. Major HDLc-modulating enzymes were assessed. Plasma apoA-I and HDLc levels increased significantly after 24 weeks of treatment by, respectively, 13±4% (
P
=0.01) and 16±6% (
P
=0.015). Concomitantly, apoA-I production rate at 24 weeks increased by 17±7% (
P
=0.04). ApoA-I catabolism did not change. A modest increase of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity was observed.

Conclusions—

NVP increases apoA-I production, which contributes to the HDLc increase after introduction of NVP-containing regimens. In view of the potent antiatherogenic effects of apoA-I, the observed increase may contribute to the favorable cardiovascular profile of NVP.
Inactivation of the LRP1 Intracellular NPxYxxL Motif in LDLR-Deficient Mice Enhances Postprandial Dyslipidemia and Atherosclerosis
Authors: Gordts Philip L.S.M. , Reekmans Sara , Lauwers Annick , Van Dongen Amber , Verbeek Leen , Roebroek Anton J.M.
Published: August 2009

Objective—

The purpose of this study was to determine the significance of the intracellular NPxYxxL motif of LRP1 for the atheroprotective role of this multifunctional receptor.

Methods and Results—

LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with LDLR-deficient mice, a model for atherosclerosis. In this LDLR
−/−
background the mutated mice showed a more atherogenic lipoprotein profile, which was associated with a decreased clearance of postprandial lipids because of a compromised endocytosis rate and reduced lipase activity. On an atherogenic diet LRP1 mutant mice revealed a 50% increased development of atherosclerosis. This aggravation was accompanied by an increase in smooth muscle cell (SMC) and collagen content and apoptotic cells in the lesions. The mutation showed, however, a limited impact on basal PDGFR-β expression and signaling and the antimigratory property of apoE on PDGF-BB–stimulated SMCs. Additionally, levels of LRP1 atherogenic ligands, like MMP2, t-PA, FVIII, and the inflammatory ligand TNF-α showed to be significantly elevated.

Conclusion—

These findings demonstrate that the NPxYxxL motif is essential for the atheroprotective role of LRP1. This motif is relevant for normal control of lipid metabolism and of atherogenic and inflammatory ligands, but has no pronounced effect on regulating PDGF-BB/PDGFR-β signaling in SMCs.
Is Primary Prevention of Rheumatic Fever the Missing Link in the Control of Rheumatic Heart Disease in Africa?
Authors: Karthikeyan Ganesan , Mayosi Bongani M.
Published: August 2009

Rheumatic fever and rheumatic heart disease continue to be major public health problems in the developing world, particularly in the countries of sub-Saharan Africa. Because of its cost effectiveness, secondary prophylaxis is advocated as the principal means of disease prevention and control. However, in developing countries, valvular damage, due to earlier, unrecognized episodes of rheumatic fever, has already occurred by the time secondary prophylaxis is instituted. Secondary prophylaxis cannot reduce the incidence of new cases of rheumatic fever and has not been shown to alter the natural history of rheumatic valvular disease. Experience from several regions of the world suggests that incorporation of a strategy of primary antibiotic prophylaxis into a comprehensive program for disease control can reduce the incidence of rheumatic fever and rheumatic heart disease. In this article, we argue that a strategy of primary antibiotic prophylaxis, with appropriate modifications, can be successfully implemented in resource-poor settings across the world and should be a key component of any rheumatic heart disease control program. This, we believe, is essential for reducing the global burden of rheumatic heart disease.
1,25(OH)
2
Vitamin D Inhibits Foam Cell Formation and Suppresses Macrophage Cholesterol Uptake in Patients With Type 2 Diabetes Mellitus
Authors: Oh Jisu , Weng Sherry , Felton Shaili K. , Bhandare Sweety , Riek Amy , Butler Boyd , Proctor Brandon M. , Petty Marvin , Chen Zhouji , Schechtman Kenneth B. , Bernal-Mizrachi Leon , Bernal-Mizrachi Carlos
Published: August 2009

Background—

Cardiovascular disease is the leading cause of death among those with diabetes mellitus. Vitamin D deficiency is associated with an increased risk of cardiovascular disease in this population. To determine the mechanism by which vitamin D deficiency mediates accelerated cardiovascular disease in patients with diabetes mellitus, we investigated the effects of active vitamin D on macrophage cholesterol deposition.

Methods and Results—

We obtained macrophages from 76 obese, diabetic, hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D <80 nmol/L; group A) and 4 control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B; n=15); obese, nondiabetic, hypertensive patients with vitamin D deficiency (group C; n=25); and nonobese, nondiabetic, nonhypertensive patients with vitamin D deficiency (group D; n=10) or sufficiency (group E; n=10). Macrophages from the same patients in all groups were cultured in vitamin D—deficient or 1,25-dihydroxyvitamin D
3
[1,25(OH)
2
D
3
] –supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)
2
D
3
suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetic subjects only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam cell formation induced by modified LDL. 1,25(OH)
2
D
3
downregulation of c-Jun N-terminal kinase activation reduced peroxisome proliferated–activated receptor-γ expression, suppressed CD36 expression, and prevented oxidized low-density lipoprotein–derived cholesterol uptake. In addition, 1,25(OH)
2
D
3
suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1 expression, and prevented oxidized and acetylated low-density lipoprotein–derived cholesterol uptake.

Conclusion—

These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.
Pharmacological Activation of Soluble Guanylate Cyclase Protects the Heart Against Ischemic Injury
Authors: Korkmaz Sevil , Radovits Tamás , Barnucz Enikő , Hirschberg Kristóf , Neugebauer Philipp , Loganathan Sivakkanan , Veres Gábor , Páli Szabolcs , Seidel Beatrice , Zöllner Stefan , Karck Matthias , Szabó Gábor
Published: August 2009

Background—

The role of the nitric oxide/cGMP/cGMP–dependent protein kinase G pathway in myocardial protection and preconditioning has been the object of intensive investigations. The novel soluble guanylate cyclase activator cinaciguat has been reported to elevate intracellular [cGMP] and activate the nitric oxide/cGMP/cGMP–dependent protein kinase G pathway in vivo. We investigated the effects of cinaciguat on myocardial infarction induced by isoproterenol in rats.

Methods and Results—

Rats were treated orally twice a day for 4 days with vehicle or cinaciguat (10 mg/kg). Isoproterenol (85 mg/kg) was injected subcutaneously 2 days after the first treatment at an interval of 24 hours for 2 days to produce myocardial infarction. After 17 hours, histopathological observations and left ventricular pressure-volume analysis to assess cardiac function with a Millar microtip pressure-volume conductance catheter were performed, and levels of biochemicals of the heart tissues were measured. Gene expression analysis was performed by quantitative real-time polymerase chain reaction. Isolated canine coronary arterial rings exposed to peroxynitrite were investigated for vasomotor function, and immunohistochemistry was performed for cGMP and nitrotyrosine. The present results show that cinaciguat treatment improves histopathological lesions, improves cardiac performance, improves impaired cardiac relaxation, reduces oxidative stress, ameliorates intracellular enzyme release, and decreases cyclooxygenase 2, transforming growth factor-β, and β-actin mRNA expression in experimentally induced myocardial infarction in rats. In vitro exposure of coronary arteries to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation, increased nitro-oxidative stress, and reduced intracellular cGMP levels, which were all improved by cinaciguat. A cardioprotective effect of postischemic cinaciguat treatment was shown in a canine model of global ischemia/reperfusion.

Conclusion—

Pharmacological soluble guanylate cyclase activation could be a novel approach for the prevention and treatment of ischemic heart disease.
Diet-Dependent Net Acid Load and Risk of Incident Hypertension in United States Women
Authors: Zhang Luxia , Curhan Gary C. , Forman John P.
Published: August 2009

Animal and human studies suggest a potential link between acid-base status and blood pressure. Contemporary Western diets yield a daily systemic acid load of varying amounts, yet the association with hypertension has never been explored. We prospectively examined the association between the diet-dependent net acid load (also known as the estimated net endogenous acid production) and the risk of incident hypertension among 87 293 women without a history of hypertension in the Nurses’ Health Study II. We also used the ratio of animal protein intake to potassium intake as an alternative evaluation of diet-dependent net acid load. We identified 15 385 incident cases of hypertension during 995 239 person-years of follow-up. After adjusting for potential confounders, women in the top decile of estimated diet-dependent net acid load had an increased risk of hypertension (relative risk: 1.14; 95% CI: 1.05 to 1.24;
P
for trend=0.01) compared with women in the bottom decile. To test whether the association between estimated diet-dependent net acid load and hypertension is independent of its individual components, an additional adjustment for intakes of protein and potassium was made and resulted in a relative risk of 1.23 (95% CI: 1.08 to 1.41;
P
for trend=0.003) for the top decile of estimated diet-dependent net acid load. Results of the ratio of animal protein intake to potassium intake were similar with those of estimated diet-depend net acid load. In conclusion, a high diet-dependent net acid load is independently associated with a higher risk of incident hypertension.
Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor–β–Dependent and –Independent Smad Pathways
Authors: Yang Fuye , Chung Arthur C.K. , Huang Xiao Ru , Lan Hui Yao
Published: August 2009

Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)–mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II–induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-β1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II–induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II–induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-β–dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-β gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal–regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-β–independent, Ang II type 1 receptor–mediated extracellular signal–regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II–mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II–induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II–mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-β–dependent and –independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.
Cyclogenesis Simulation of Typhoon Prapiroon (2000) Associated with Rossby Wave Energy Dispersion*
Authors: Ge Xuyang , Li Tim , Peng Melinda S.
Published: August 2009

The genesis of Typhoon Prapiroon (2000), in the western North Pacific, is simulated to understand the role of Rossby wave energy dispersion of a preexisting tropical cyclone (TC) in the subsequent genesis event. Two experiments are conducted. In the control experiment (CTL), the authors retain both the previous typhoon, Typhoon Bilis, and its wave train in the initial condition. In the sensitivity experiment (EXP), the circulation of Typhoon Bilis was removed based on a spatial filtering technique of Kurihara et al., while the wave train in the wake is kept. The comparison between these two numerical simulations demonstrates that the preexisting TC impacts the subsequent TC genesis through both a direct and an indirect process. The direct process is through the conventional barotropic Rossby wave energy dispersion, which enhances the low-level wave train, the boundary layer convergence, and the convection–circulation feedback. The indirect process is through the upper-level outflow jet. The asymmetric outflow jet induces a secondary circulation with a strong divergence tendency to the left-exit side of the outflow jet. The upper-level divergence boosts large-scale ascending motion and promotes favorable environmental conditions for a TC-scale vortex development. In addition, the outflow jet induces a well-organized cyclonic eddy angular momentum flux, which acts as a momentum forcing that enhances the upper-level outflow and low-level inflow and favors the growth of the new TC.
Evolutionary Influence on Human Landscape Preference
Authors: Falk John H. , Balling John D.
Published: August 2009

Individuals residing in the rainforest belt of Nigeria were shown photographs of five biomes: rain forest, deciduous forest, coniferous forest, savanna, and desert. Subjects overwhelmingly selected savanna scenes as representing the most desirable place to live. These results, coupled with extensive American data, support the hypothesis that humans possess an innate preference for savanna-like settings, which then is modified through experience and enculturation. Findings are discussed in relation to anthropological, biological, and psychological research.
A hybrid approach to design deadlock-free Petri net controller for discrete event systems
Authors: Zeng G.Q. , Wu W.M. , Mao W.J. , Su H.Y. , Chu J.
Published: August 2009

The issue of supervisory control of discrete event systems (DES) based on Petri nets (PN) has been investigated by using various methods. However, there exists a problem that the supervisor, introduced to enforce the given specification, causes a deadlock in the closed-loop system, especially when the deadlock occurs in the closed-loop system in which the original plant model is live. To address this problem, we propose a hybrid approach to design a deadlock-free PN controller for DES with given specification. The approach mainly consists of two stages. Firstly, a supervisor is designed to enforce the given specification using the reported place invariants method. Then, we regard the obtained closed-loop system with deadlock introduced by the supervisor as a new plant net and adopt the theory of regions to design a deadlock-free PN controller. The controller designed by our approach is guaranteed to be maximally permissive when the original plant PN is fully controllable and observable. Even for partially controllable and observable plant PN, it is possible to obtain a suboptimal solution.