bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Hormone Influence on Hepatitis in Young Male A/JCr Mice Infected withHelicobacter hepaticus
Authors: Theve Elizabeth J. , Feng Yan , Taghizadeh Koli , Cormier Kathleen S. , Bell David R. , Fox James G. , Rogers Arlin B. 
Published: June 2008

ABSTRACTHepatitis B virus (HBV), the leading cause of human hepatocellular carcinoma, is especially virulent in males infected at an early age. Likewise, the murine liver carcinogenHelicobacter hepaticusis most pathogenic in male mice infected before puberty. We used this model to investigate the influence of male sex hormone signaling on infectious hepatitis. Male A/JCr mice were infected withH. hepaticusor vehicle at 4 weeks and randomized into surgical and pharmacologic treatment groups. Interruption of androgen pathways was confirmed by hormone measurements, histopathology, and liver gene and Cyp4a protein expression. Castrated males and those receiving the competitive androgen receptor antagonist flutamide had significantly less severe hepatitis as determined by histologic activity index than intact controls at 4 months. Importantly, the powerful androgen receptor agonist dihydrotestosterone did not promote hepatitis. No effect on hepatitis was evident in males treated with the 5α-reductase inhibitor dutasteride, the peroxisome proliferator-activated receptor-α agonist bezafibrate, or the nonsteroidal anti-inflammatory drug flufenamic acid. Consistent with previous observations of hepatitis-associated liver-gender disruption, transcriptional alterations involved both feminine (cytochrome P450 4a14) and masculine (cytochrome P450 4a12 and trefoil factor 3) genes, as well gender-neutral (H19 fetal liver mRNA, lipocalin 2, and ubiquitin D) genes. Hepatitis was associated with increased unsaturated C18long-chain fatty acids (oleic acid and linoleic acid) relative to saturated stearic acid. Our results indicate that certain forms of androgen interruption can inhibitH. hepaticus-induced hepatitis in young male mice, whereas androgen receptor agonism does not worsen disease. This raises the possibility of targeted hormonal therapy in young male patients with childhood-acquired HBV.
Escherichia coliDraE Adhesin-Associated Bacterial Internalization by Epithelial Cells Is Promoted Independently by Decay-Accelerating Factor and Carcinoembryonic Antigen-Related Cell Adhesion Molecule Binding and Does Not Require the DraD Invasin
Authors: Korotkova Natalia , Yarova-Yarovaya Yuliya , Tchesnokova Veronika , Yazvenko Nina , Carl Mike A. , Stapleton Ann E. , Moseley Steve L. 
Published: June 2008

ABSTRACTThe Dr family ofEscherichia coliadhesins are virulence factors associated with diarrhea and urinary tract infections. Dr fimbriae are comprised of two subunits. DraE/AfaE represents the major structural, antigenic, and adhesive subunit, which recognizes decay-accelerating factor (DAF) and carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) CEA, CEACAM1, CEACAM3, and CEACAM6 as binding receptors. The DraD/AfaD subunit caps fimbriae and has been implicated in the entry of Dr-fimbriatedE. coliinto host cells. In this study, we demonstrate that DAF or CEACAM receptors independently promote DraE-mediated internalization ofE. coliby CHO cell transfectants expressing these receptors. We also found that DraE-positive recombinant bacteria adhere to and are internalized by primary human bladder epithelial cells which express DAF and CEACAMs. DraE-mediated bacterial internalization by bladder cells was inhibited by agents which disrupt lipid rafts, microtubules, and phosphatidylinositol 3-kinase (PI3K) activity. Immunofluorescence confocal microscopic examination of epithelial cells detected considerable recruitment of caveolin, β1integrin, phosphorylated ezrin, phosphorylated PI3K, and tubulin, but not F-actin, by cell-associated bacteria. Finally, we demonstrate that the DraD subunit, previously implicated as an “invasin,” is not required for β1integrin recruitment or bacterial internalization.
Identification of
fevR
, a Novel Regulator of Virulence Gene Expression in
Francisella novicida
Authors: Brotcke Anna , Monack Denise M. 
Published: June 2008

ABSTRACT

Francisella tularensis
infects wild animals and humans to cause tularemia. This pathogen targets the cytosol of macrophages, where it replicates using the genes in the
Francisella
pathogenicity island (FPI). Virulence gene regulation in
Francisella
is complex, but transcriptional regulators MglA and SspA have been shown to regulate the expression of approximately 100 genes, including the entire FPI. We utilized a
Francisella novicida
transposon mutant library to identify additional regulatory factors and identified five additional genes that are essential for virulence gene expression. One regulatory gene, FTN_0480 (
fevR
,
Francisella e
ffector of
v
irulence
r
egulation), present in all
Francisella
species, is required for expression of the FPI genes and other genes in the MglA/SspA regulon. The expression of
fevR
is positively regulated by MglA. However, constitutive expression of
fevR
in an
mglA
mutant strain did not restore expression of the MglA/SspA regulon, demonstrating that
mglA
and
fevR
act in parallel to positively regulate virulence gene expression. Virulence studies revealed that
fevR
is essential for bacterial replication in macrophages and in mice, where we additionally show that
fevR
is required for the expression of genes in the MglA/SspA regulon in vivo. Thus,
fevR
is a crucial virulence gene in
Francisella
, required for the expression of virulence factors known to be essential for this pathogen's subversion of host defenses and pathogenesis in vivo.
Characterization of
Klebsiella pneumoniae
Type 1 Fimbriae by Detection of Phase Variation during Colonization and Infection and Impact on Virulence
Authors: Struve Carsten , Bojer Martin , Krogfelt Karen Angeliki 
Published: June 2008

ABSTRACT

Klebsiella pneumoniae
is recognized as an important gram-negative opportunistic pathogen. The ability of bacteria to adhere to host structures is considered essential for the development of infections; however, few studies have examined the influence of adhesion factors on
K. pneumoniae
virulence. In this study, we cloned and characterized the type 1 fimbria gene cluster of a clinical
K. pneumoniae
isolate. Although this cluster was not identical to the
Escherichia coli
type 1 fimbria gene cluster, an overall high degree of structural resemblance was demonstrated. Unique to the
K. pneumoniae fim
gene cluster is the
fimK
gene, whose product contains an EAL domain, suggesting that it has a role in regulation of fimbrial expression. Like expression of type 1 fimbriae in
E. coli
, expression of type 1 fimbriae in
K. pneumoniae
was found to be phase variable, and an invertible DNA element (
fim
switch) was characterized. An isogenic type 1 fimbria mutant was constructed and used to evaluate the influence of type 1 fimbriae in different infection models. Type 1 fimbriae did not influence the ability of
K. pneumoniae
to colonize the intestine or infect the lungs, but they were determined to be a significant virulence factor in
K. pneumoniae
urinary tract infection. By use of a PCR-based assay, the orientation of the
fim
switch during colonization and infection was investigated and was found to be all “off” in the intestine and lungs but all “on” in the urinary tract. Our results suggest that during colonization and infection, there is pronounced selective pressure in different host environments for selection of either the type 1 fimbriated or nonfimbriated phenotype of
K. pneumoniae
.
Galactose Residues on the Lipooligosaccharide ofMoraxella catarrhalis26404 Form the Epitope Recognized by the Bactericidal Antiserum from Conjugate Vaccination
Authors: Yu Shengqing , Xie Hang , Datta Anup , Naidu Natasha , Gu Xin-Xing 
Published: June 2008

ABSTRACTLipooligosaccharide (LOS) fromMoraxella catarrhalishas the potential to elicit bactericidal antibodies against the pathogen. We generated LOS-based conjugate vaccines that elicited bactericidal antibodies in animal models. However, epitopes on the LOS recognized by the functional anti-LOS antibodies remain unidentified. In this study, a mutant strain, D4, which lost the recognition by a bactericidal anti-LOS rabbit serum in Western blotting was generated from a serotype C strain 26404 by random transposon mutagenesis. Sequence analysis revealed there was an insertion of a kanamycin resistance gene in thelgt2gene of D4, which encodes β(1-4)-galactosyltransferase. An isogeniclgt2mutant, 26404lgt2, was constructed. Structural analysis indicated that the mutant strain produced a truncated LOS lacking terminal galactoses from 4- and 6-linked oligosaccharide chains of strain 26404. Further studies showed that the antiserum lost the recognition of both mutant cells and LOSs in Western blotting, an enzyme-linked immunosorbent assay (ELISA), or a flow cytometry assay. The antiserum also lost the ability to kill the mutant strain in a bactericidal assay, whereas it showed a bactericidal titer of 1:80 to strain 26404. In an inhibition ELISA,d-(+)-galactose or 26404lgt2 LOS showed no inhibition. However, the 26404 LOS and a serotype A O35E LOS with terminal galactoses on its 6-linked oligosaccharide chain showed >90% inhibition, while a serotype B 26397 LOS showed >60% inhibition. These studies suggest that the terminal α-Gal-(1→4)-β-Gal on the 6-linked oligosaccharide chain of 26404 LOS plays a critical role in forming the epitope recognized by the bactericidal antiserum induced by immunization with our conjugate vaccine.
Caspase-1 Activation in Macrophages Infected with
Yersinia pestis
KIM Requires the Type III Secretion System Effector YopJ
Authors: Lilo Sarit , Zheng Ying , Bliska James B. 
Published: June 2008

ABSTRACT

Pathogenic
Yersinia
species utilize a type III secretion system (T3SS) to translocate effectors called
Yersinia
outer proteins (Yops) into infected host cells. Previous studies demonstrated a role for effector Yops in the inhibition of caspase-1-mediated cell death and secretion of interleukin-1β (IL-1β) in naïve macrophages infected with
Yersinia enterocolitica
. Naïve murine macrophages were infected with a panel of different
Yersinia pestis
and
Yersinia pseudotuberculosis
strains to determine whether Yops of these species inhibit caspase-1 activation. Cell death was measured by release of lactate dehydrogenase (LDH), and enzyme-linked immunosorbent assay for secreted IL-1β was used to measure caspase-1 activation. Surprisingly, isolates derived from the
Y. pestis
KIM strain (e.g., KIM5) displayed an unusual ability to activate caspase-1 and kill infected macrophages compared to other
Y. pestis
and
Y. pseudotuberculosis
strains tested. Secretion of IL-1β following KIM5 infection was reduced in caspase-1-deficient macrophages compared to wild-type macrophages. However, release of LDH was not reduced in caspase-1-deficient macrophages, indicating that cell death occurred independently of caspase-1. Analysis of KIM-derived strains defective for production of functional effector or translocator Yops indicated that translocation of catalytically active YopJ into macrophages was required for caspase-1 activation and cell death. Release of LDH and secretion of IL-1β were not reduced when actin polymerization was inhibited in KIM5-infected macrophages, indicating that extracellular bacteria translocating YopJ could trigger cell death and caspase-1 activation. This study uncovered a novel role for YopJ in the activation of caspase-1 in macrophages.
Pneumolysin Released duringStreptococcus pneumoniaeAutolysis Is a Potent Activator of Intracellular Oxygen Radical Production in Neutrophils
Authors: Martner Anna , Dahlgren Claes , Paton James C. , Wold Agnes E. 
Published: June 2008

ABSTRACTStreptococcus pneumoniaeis a major cause of otitis media, pneumonia, meningitis, and septicemia in humans. The host defense against this pathogen largely depends on bacterial killing by neutrophils. A peculiar property of pneumococci is their tendency to undergo autolysis, i.e., autoinduced disruption of the bacterial cell wall mediated by activation of the enzyme LytA, under stationary growth conditions. LytA is a virulence factor, but the molecular background for this has not been fully clarified. Here we examine how bacterial compounds released upon autolysis affect the production of reactive oxygen species (ROS) in neutrophils. We found that theS. pneumoniaestrains A17 and D39 induced activation of the NADPH oxidase and the production of ROS in human neutrophils and that this activation was blocked when LytA was inactivated. The ROS-inducing bacterial substance released from autolyzed bacteria was identified as the cytoplasmic toxin pneumolysin. Further screening of clinical pneumococcal strains of various sero- and genotypes revealed that selected strains expressing toxins with reduced pneumolysin-dependent hemolytic activity had decreased abilities to induce ROS in neutrophils. Furthermore, a mutated form of purified pneumolysin lacking hemolytic and complement binding functions (PdT) did not induce any oxygen radical production. The ROS produced in response to pneumolysin formed mainly intracellularly, which may explain why this production was not detected previously. ROS released intracellularly may function as signaling molecules, modifying the function of neutrophils in bacterial defense.
Evaluation of the new Canadian highway bridge design code shear provisions for concrete beams with fiber-reinforced polymer reinforcement
Authors: El-Sayed Ahmed K. , Benmokrane Brahim 
Published: June 2008

The Canadian highway bridge design code (CHBDC) contains provisions for designing concrete members with fiber-reinforced polymer (FRP) reinforcement. In the second edition of the code, new shear design procedures for FRP-reinforced sections are provided. These procedures are consistent with those for steel-reinforced members in the code, in consideration of some modifications that account for the substantial differences between FRP and steel reinforcement. The shear approach adopted in the CHBDC follows the traditional approach of Vc + Vs for shear design. This paper presents an evaluation of this approach by comparing it with experimental shear strengths of available test data on beams longitudinally reinforced with FRP bars and with or without FRP stirrups. In addition, the CHBDC approach was compared with the FRP shear design provisions currently in effect in North America using the available test results. The comparison shows that the CHBDC method significantly underestimates the shear strength of FRP-reinforced concrete beams. A proposed modification to this method is presented and verified against available test results.
Conditional correlation analysis for safe region-based memory management
Authors: Wang Xi , Xu Zhilei , Liu Xuezheng , Guo Zhenyu , Wang Xiaoge , Zhang Zheng 
Published: June 2008

Region-based memory management is a popular scheme in systems software for better organization and performance. In the scheme, a developer constructs a hierarchy of regions of different lifetimes and allocates objects in regions. When the developer deletes a region, the runtime will recursively delete all its subregions and simultaneously reclaim objects in the regions. The developer must construct a
consistent
placement of objects in regions; otherwise, if a region that contains pointers to other regions is not always deleted
before
pointees, an inconsistency will surface and cause dangling pointers, which may lead to either crashes or leaks.

This paper presents a static analysis tool RegionWiz that can find such lifetime inconsistencies in large C programs using regions. The tool is based on an analysis framework that generalizes the relations and constraints over regions and objects as conditional correlations. This framework allows a succinct formalization of consistency rules for region lifetimes, preserving memory safety and avoiding dangling pointers. RegionWiz uses these consistency rules to implement an efficient static analysis to compute the conditional correlation and reason about region lifetime consistency; the analysis is based on a context-sensitive, field-sensitive pointer analysis with heap cloning.
Experiments with applying RegionWiz to six real-world software packages (including the RC compiler, Apache web server, and Subversion version control system) with two different region-based memory management interfaces show that RegionWiz can reason about region lifetime consistency in large C programs. The experiments also show that RegionWiz can find several previously unknown inconsistency bugs in these packages.
Iterative optimization in the polyhedral model
Authors: Pouchet Louis-Noël , Bastoul Cédric , Cohen Albert , Cavazos John 
Published: June 2008

High-level loop optimizations are necessary to achieve good performance over a wide variety of processors. Their performance impact can be significant because they involve in-depth program transformations that aim to sustain a balanced workload over the computational, storage, and communication resources of the target architecture. Therefore, it is mandatory that the compiler accurately models the target architecture as well as the effects of complex code restructuring.
However, because optimizing compilers (1) use simplistic performance models that abstract away many of the complexities of modern architectures, (2) rely on inaccurate dependence analysis, and (3) lack frameworks to express complex interactions of transformation sequences, they typically uncover only a fraction of the peak performance available on many applications. We propose a complete iterative framework to address these issues. We rely on the polyhedral model to construct and traverse a large and expressive search space. This space encompasses only legal, distinct versions resulting from the restructuring of any static control loop nest. We first propose a feedback-driven iterative heuristic tailored to the search space properties of the polyhedral model. Though, it quickly converges to good solutions for small kernels, larger benchmarks containing higher dimensional spaces are more challenging and our heuristic misses opportunities for significant performance improvement. Thus, we introduce the use of a genetic algorithm with specialized operators that leverage the polyhedral representation of program dependences. We provide experimental evidence that the genetic algorithm effectively traverses huge optimization spaces, achieving good performance improvements on large loop nests.
Deriving linearizable fine-grained concurrent objects
Authors: Vechev Martin , Yahav Eran 
Published: June 2008

Practical and efficient algorithms for concurrent data structures are difficult to construct and modify. Algorithms in the literature are often optimized for a specific setting, making it hard to separate the algorithmic insights from implementation details. The goal of this work is to systematically construct algorithms for a concurrent data structure starting from its sequential implementation. Towards that goal, we follow a construction process that combines manual steps corresponding to high-level insights with automatic exploration of implementation details. To assist us in this process, we built a new tool called Paraglider. The tool quickly explores large spaces of algorithms and uses bounded model checking to check linearizability of algorithms.
Starting from a sequential implementation and assisted by the tool, we present the steps that we used to derive various highly-concurrent algorithms. Among these algorithms is a new fine-grained set data structure that provides a wait-free contains operation, and uses only the compare-and-swap (CAS) primitive for synchronization.
Sketching concurrent data structures
Authors: Solar-Lezama Armando , Jones Christopher Grant , Bodik Rastislav 
Published: June 2008

We describe PSketch, a program synthesizer that helps programmers implement concurrent data structures. The system is based on the concept of sketching, a form of synthesis that allows programmers to express their insight about an implementation as a partial program: a sketch. The synthesizer automatically completes the sketch to produce an implementation that matches a given correctness criteria.
PSketch is based on a new counterexample-guided inductive synthesis algorithm (CEGIS) that generalizes the original sketch synthesis algorithm from Solar-Lezama et.al. to cope efficiently with concurrent programs. The new algorithm produces a correct implementation by iteratively generating candidate implementations, running them through a verifier, and if they fail, learning from the counterexample traces to produce a better candidate; converging to a solution in a handful of iterations.

PSketch also extends Sketch with higher-level sketching constructs that allow the programmer to express her insight as a "soup" of ingredients from which complicated code fragments must be assembled. Such sketches can be viewed as syntactic descriptions of huge spaces of candidate programs (over 10
8
candidates for some sketches we resolved).

We have used the PSketch system to implement several classes of concurrent data structures, including lock-free queues and concurrent sets with fine-grained locking. We have also sketched some other concurrent objects including a sense-reversing barrier and a protocol for the dining philosophers problem; all these sketches resolved in under an hour.
SharC
Authors: Anderson Zachary , Gay David , Ennals Rob , Brewer Eric 
Published: June 2008

Unintended or unmediated data sharing is a frequent cause of insidious bugs in multithreaded programs. We present a tool called SharC (short for
Sharing Checker
) that allows a user to write lightweight annotations to declare how they believe objects are being shared between threads in their program. SharC uses a combination of static and dynamic analyses to check that the program conforms to this specification.

SharC allows any type to have one of five "sharing modes" -- private to the current thread, read-only, shared under the control of a specified lock, intentionally racy, or checked dynamically. The dynamic mode uses run-time checking to verify that objects are either read-only, or only accessed by one thread. This allows us to check programs that would be difficult to check with a purely static system. If the user does not give a type an explicit annotation, then SharC uses a static type-qualifier analysis to infer that it is either private or should be checked dynamically.
SharC allows objects to move between different sharing modes at runtime by using reference counting to check that there are no other references to the objects when they change mode.
SharC's baseline dynamic analysis can check any C program, but is slow, and will generate false warnings about intentional data sharing. As the user adds more annotations, false warnings are reduced, and performance improves.We have found in practice that very few annotations are needed to describe all sharing and give reasonable performance. We ran SharC on 6 legacy C programs, summing to over 600k lines of code, and found that a total of only 60 simple annotations were needed to remove all false positives and to reduce performance overhead to only 2-14%.