bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activities of TMC207, Rifampin, and Pyrazinamide against
Mycobacterium tuberculosis
Infection in Guinea Pigs
Authors: Shang Shaobin , Shanley Crystal A. , Caraway Megan L. , Orme Eileen A. , Henao-Tamayo Marcela , Hascall-Dove Laurel , Ackart David , Lenaerts Anne J. , Basaraba Randall J. , Orme Ian M. , Ordway Diane J. 
Published: October 2010

ABSTRACT

The experimental compound TMC207 is showing promise against infections caused by
Mycobacterium tuberculosis
both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis.
Structural and Biochemical Analysis of the Pentapeptide Repeat Protein
Efs
Qnr, a Potent DNA Gyrase Inhibitor
Authors: Hegde Subray S. , Vetting Matthew W. , Mitchenall Lesley A. , Maxwell Anthony , Blanchard John S. 
Published: October 2010

ABSTRACT

The chromosomally encoded Qnr homolog protein from
Enterococcus faecalis
(
Efs
Qnr), when expressed, confers to its host a decreased susceptibility to quinolones and consists mainly of tandem repeats, which is consistent with belonging to the pentapeptide repeat family of proteins (PRPs).
Efs
Qnr was cloned with an N-terminal 6× His tag and purified to homogeneity.
Efs
Qnr partially protected DNA gyrase from fluoroquinolone inhibition at concentrations as low as 20 nM.
Efs
Qnr inhibited the ATP-dependent supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC
50
) of 1.2 μM, while no significant inhibition of ATP-independent relaxation activity was observed.
Efs
Qnr was cytotoxic when overexpressed in
Escherichia coli
, resulting in the clumping of cells and a loss of viability. The X-ray crystal structure of
Efs
Qnr was determined to 1.6-Å resolution.
Efs
Qnr exhibits the right-handed quadrilateral beta-helical fold typical of PRPs, with features more analogous to MfpA (mycobacterium fluoroquinolone resistance pentapeptide) than to the PRPs commonly found in cyanobacteria.
Domains of the
Shigella flexneri
Type III Secretion System IpaB Protein Involved in Secretion Regulation
Authors: Shen Da-Kang , Saurya Saroj , Wagner Carolin , Nishioka Hiroaki , Blocker Ariel J. 
Published: October 2010

ABSTRACT
Type III secretion systems (T3SSs) are key determinants of virulence in many Gram-negative bacterial pathogens. Upon cell contact, they inject effector proteins directly into eukaryotic cells through a needle protruding from the bacterial surface. Host cell sensing occurs through a distal needle “tip complex,” but how this occurs is not understood. The tip complex of quiescent needles is composed of IpaD, which is topped by IpaB. Physical contact with host cells initiates secretion and leads to assembly of a pore, formed by IpaB and IpaC, in the host cell membrane, through which other virulence effector proteins may be translocated. IpaB is required for regulation of secretion and may be the host cell sensor. It binds needles via its extreme C-terminal coiled coil, thereby likely positioning a large domain containing its hydrophobic regions at the distal tips of needles. In this study, we used short deletion mutants within this domain to search for regions of IpaB involved in secretion regulation. This identified two regions, amino acids 227 to 236 and 297 to 306, the presence of which are required for maintenance of IpaB at the needle tip, secretion regulation, and normal pore formation but not invasion. We therefore propose that removal of either of these regions leads to an inability to block secretion prior to reception of the activation signal and/or a defect in host cell sensing.
Human Airway Epithelial Cell Responses to
Neisseria lactamica
and Purified Porin via Toll-Like Receptor 2-Dependent Signaling
Authors: Liu Xiuping , Wetzler Lee M. , Oliveira Nascimento Laura , Massari Paola 
Published: October 2010

ABSTRACT

The human airway epithelium is constantly exposed to microbial products from colonizing organisms. Regulation of Toll-like receptor (TLR) expression and specific interactions with bacterial ligands is thought to mitigate exacerbation of inflammatory processes induced by the commensal flora in these cells. The genus
Neisseria
comprises pathogenic and commensal organisms that colonize the human nasopharynx.
Neisseria lactamica
is not associated with disease, but
N. meningitidis
occasionally invades the host, causing meningococcal disease and septicemia. Upon colonization of the airway epithelium, specific host cell receptors interact with numerous
Neisseria
components, including the PorB porin, at the immediate bacterial-host cell interface. This major outer membrane protein is expressed by all
Neisseria
strains, regardless of pathogenicity, but its amino acid sequence varies among strains, particularly in the surface-exposed regions. The interaction of
Neisseria
PorB with TLR2 is essential for driving TLR2/TLR1-dependent cellular responses and is thought to occur via the porin's surface-exposed loop regions. Our studies show that
N. lactamica
PorB is a TLR2 ligand but its binding specificity for TLR2 is different from that of meningococcal PorB. Furthermore,
N. lactamica
PorB is a poor inducer of proinflammatory mediators and of TLR2 expression in human airway epithelial cells. These effects are reproduced by whole
N. lactamica
organisms. Since the responsiveness of human airway epithelial cells to colonizing bacteria is in part regulated via TLR2 expression and signaling, commensal organisms such as
N. lactamica
would benefit from expressing a product that induces low TLR2-dependent local inflammation, likely delaying or avoiding clearance by the host.
Endovascular treatment of intracranial aneurysms: review of current practice
Authors: Currie Stuart , Mankad Kshitij , Goddard Anthony 
Published: October 2010

ABSTRACT
Subarachnoid haemorrhage remains a major cause of morbidity and mortality throughout the world. Of those suffering the condition, 15% are known to die before they reach hospital and half of all patients die within 1 month of presentation. Of those patients who survive the initial 30 days, just under half are believed to remain dependent for their normal activities of daily living. In the vast majority of cases, SAH results from the rupture of an intracranial aneurysm. After patient stabilisation, primary treatment is focused on the prevention of re-bleeding. Until recently, this exclusively involved the surgical clipping of the ruptured aneurysm via a craniotomy. The early 1990s, with the introduction of aneurysmal coiling via endovascular intervention, heralded the dawn of a new treatment option. Presently, endovascular therapy largely supersedes surgical intervention in the management of intracranial aneurysms in the developed world. Moreover, with the emergence of new technologies and approaches for the treatment of aneurysms, the field of neurovascular intervention is only likely to expand further. However, due to its relative infancy, unanswered questions regarding long term endovascular outcome remain. This is particularly pertinent to newer techniques of embolisation for which data on complete aneurysmal occlusion rates are limited. Thus, to understand fully the capability and limitations of this treatment, further well constructed randomised controlled trials are a necessity.
Partitioning techniques for partially protected caches in resource-constrained embedded systems
Authors: Lee Kyoungwoo , Shrivastava Aviral , Dutt Nikil , Venkatasubramanian Nalini 
Published: October 2010

Increasing exponentially with technology scaling, the soft error rate even in earth-bound embedded systems manufactured in deep subnanometer technology is projected to become a serious design consideration. Partially protected cache (PPC) is a promising microarchitectural feature to mitigate failures due to soft errors in power, performance, and cost sensitive embedded processors. A processor with PPC maintains two caches, one protected and the other unprotected, both at the same level of memory hierarchy. The intuition behind PPCs is that not all data in the application is equally prone to soft errors. By finding and mapping the data that is more prone to soft errors to the protected cache, and error-resilient data to the unprotected cache, failures induced by soft errors can be significantly reduced at a minimal power and performance penalty. Consequently, the effectiveness of PPCs critically hinges on the compiler's ability to partition application data into error-prone and error-resilient data. The effectiveness of PPCs has previously been demonstrated on multimedia applications—where an obvious partitioning of data exists, the multimedia data is inherently resilient to soft errors, and the rest of the data and the entire code is assumed to be error-prone. Since the amount of multimedia data is a quite significant component of the entire application data, this obvious partitioning is quite effective. However, no such obvious data and code partitioning exists for general applications. This severely restricts the applicability of PPCs to data caches and instruction caches in general. This article investigates vulnerability-based partitioning schemes that are applicable to applications in general and effectively reduce failures due to soft errors at minimal power and performance overheads.Our experimental results on an HP iPAQ-like processor enhanced with PPC architecture, running benchmarks from the MiBench suite demonstrate that our partitioning heuristic efficiently finds page partitions for data PPCs that can reduce the failure rate by 48% at only 2% performance and 7% energy overhead, and finds page partitions for instruction PPCs that reduce the failure rate by 50% at only 2% performance and 8% energy overhead, on average.
Integrative Genomics Analyses Reveal Molecularly Distinct Subgroups of B-Cell Chronic Lymphocytic Leukemia Patients with 13q14 Deletion
Authors: Mosca Laura , Fabris Sonia , Lionetti Marta , Todoerti Katia , Agnelli Luca , Morabito Fortunato , Cutrona Giovanna , Andronache Adrian , Matis Serena , Ferrari Francesco , Gentile Massimo , Spriano Mauro , Callea Vincenzo , Festini Gianluca , Molica Stefano , Deliliers Giorgio Lambertenghi , Bicciato Silvio , Ferrarini Manlio , Neri Antonino 
Published: October 2010

Abstract
Purpose: Chromosome 13q14 deletion occurs in a substantial number of chronic lymphocytic leukemia (CLL) patients and it is believed to play a pathogenetic role. The exact mechanisms involved in this lesion have not yet been fully elucidated because of its heterogeneity and the imprecise knowledge of the implicated genes. This study was addressed to further contribute to the molecular definition of this lesion in CLL.
Experimental Design: We applied single-nucleotide polymorphism (SNP)-array technology and gene expression profiling data to investigate the 13q14 deletion occurring in a panel of 100 untreated, early-stage (Binet A) patients representative of the major genetics, molecular, and biological features of the disease.
Results: Concordantly with FISH analysis, SNP arrays identified 44 patients with del(13)(q14) including 11 cases with a biallelic deletion. The shorter monoallelic deletion was 635-kb long. The loss of the miR-15a/16-1 cluster occurred in all del(13)(q14) cases except in 2 patients with a monoallelic deletion, who retained both copies. MiR-15a/16 expression was significantly downregulated only in patients with the biallelic loss of the miRNA cluster compared to 13q normal cases. Finally, the natural grouping of SNP profiles by nonnegative matrix factorization algorithm showed that patients could be classified into 2 separate clusters, mainly characterized by short/biallelic versus wide/monoallelic 13q14 deletions. Supervised analyses of expression data showed that specific transcriptional profiles are correlated with these 2 genomic subgroups.
Conclusions: Overall, our data highlight the presence of 2 distinct molecular types of 13q14 deletions, which may be of clinical relevance in CLL. Clin Cancer Res; 16(23); 5641–53. ©2010 AACR.
Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children
Authors: Frontroth Juan Pablo , Hepner Mirta , Sciuccati Gabriela , Torres Aurora Feliú , Pieroni Graciela , Bonduel Mariana 
Published: October 2010

SummaryType 2B von Willebrand disease (VWD2B) and platelet-type von Wille-brand disease (PT-VWD) are rare bleeding disorders characterised by an increased ristocetin-induced platelet aggregation (RIPA) at low dose of ristocetin. It was the objective of this study to detect children with VWD2B and PT-VWD using RIPA at low dose of ristocetin (0.5 mg/ml) in the screening evaluation of bleeding disorders, and to analyse the phenotypic data along with the molecular findings. Over a 14-year period, 641 children with personal and family bleeding symptoms or bleeding from birth with previously uncharacterised haemostatic disorders were prospectively studied. Six unrelated patients (0.93%) showed RIPA at low dose of ristocetin. RIPA-based mixing studies identified that the plasma of the six probands and at least one parent from five unrelated families induced aggregation of normal platelets with the addition of low-dose ristocetin. None of the probands’ platelets showed aggre-gation with cryoprecipitate. Low ristocetin cofactor activity/VWF antigen ratio with absent collagen binding activity or thrombocytopenia were detected respectively in only two patients. Molecular analysis of exon 28 of the VWF gene identified mutations in only three patients. No mutation in the GP1BA gene was found. In this large prospective paediatric study, the screening approach including RIPA at low dose of ristocetin permitted the detection of patients with VWD2B that would otherwise have been missed. No patient with phenotype or genotype of PT-VWD was identified. Heterogeneity of bleeding symptoms and phenotypic parameters were found among members of the same family.
Efficacy of prothrombin complex concentrate to reverse the anticoagulant effect of the pentasaccharide fondaparinux in a rabbit model
Authors: Durand Marion , Emmerich Joseph , Dizier Blandine , Lecompte Thomas , Samama Charles-Marc , Godier Anne 
Published: October 2010

SummaryAs a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg−1] and saline), PCC (fondaparinux and PCC [40 UI.kg−1]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelasto-metric parameters (ROTEM®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.
Increase in GLUT1 in Smooth Muscle Alters Vascular Contractility and Increases Inflammation in Response to Vascular Injury
Authors: Adhikari Neeta , Basi David L. , Carlson Marjorie , Mariash Ami , Hong Zhigang , Lehman Ute , Mullegama Sureni , Weir Edward K. , Hall Jennifer L. 
Published: October 2010

Objective—
The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease.

Methods and Results—

A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non–insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3,
P
<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10,
P
<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4,
P
<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4,
P
<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4,
P
<0.003).

Conclusion—
In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-β activity.
p53 Impairs Endothelial Function by Transcriptionally Repressing Kruppel-Like Factor 2
Authors: Kumar Ajay , Kim Cuk-Seong , Hoffman Timothy A. , Naqvi Asma , DeRicco Jeremy , Jung Saet-Byel , Lin Zhiyong , Jain Mukesh K. , Irani Kaikobad 
Published: October 2010

Objective—
To evaluate if p53 decreases Kruppel-Like Factor 2 (KLF2) expression and determine whether p53-mediated suppression of KLF2 plays a role in p53-induced endothelial dysfunction.

Methods and Results—
Endothelial KLF2 mediates endothelium-dependent vascular homeostasis by differentially regulating endothelial genes, leading to an anti-inflammatory and antithrombotic endothelial surface with normal vasodilatory function. In contrast, the tumor suppressor p53 leads to inflammatory gene expression and impairs endothelium-dependent vasodilatation, thus promoting endothelial dysfunction. The effect of p53 on KLF2 expression was determined. p53 inhibited KLF2 transcription in a histone deacetylase–dependent and a histone acetyltransferase–independent fashion. KLF2 expression was suppressed by p53 via a conserved p53-binding repressor sequence in its promoter. p53 bound to, and stimulated, deacetylation of Histone H3 at the KLF2 promoter. The effect of p53 on endothelial KLF2 target genes was examined. Downregulation of p53 increased expression of endothelial NO synthase and thrombomodulin and inhibited expression of plasminogen activator inhibitor 1. Conversely, overexpression of p53 suppressed endothelial NO synthase and thrombomodulin expression and stimulated plasminogen activator inhibitor 1 and endothelin-1 expression. Knockdown of KLF2 abolished the p53-induced decrease in thrombomodulin and increase in endothelin-1. Both, overexpression of p53 and knockdown of KLF2 in endothelial cells increased blood coagulation on an endothelial cell monolayer. The p53-induced increase in coagulation was rescued by forced expression of KLF2. p53 also impaired endothelium-dependent vasodilatation and decreased bioavailable vascular NO, both of which were rescued by forced KLF2 expression.

Conclusion—
These findings illustrate a novel p53-dependent mechanism for the regulation of endothelial KLF2 expression. In addition, they show that downregulation of KLF2, in part, mediates a p53-stimulated dysfunctional endothelium.
Determinants of Postinfarction Ventricular Tachycardia
Authors: Crawford Thomas , Cowger Jennifer , Desjardins Benoit , Kim Hyungjin Myra , Good Eric , Jongnarangsin Krit , Oral Hakan , Chugh Aman , Pelosi Frank , Morady Fred , Bogun Frank 
Published: October 2010

Background—
Structural factors contributing to the development of postinfarction ventricular tachycardia (VT) are unclear. The purpose of this study was to analyze infarct architecture and electrogram characteristics in patients with and without inducible VT and to identify correlates of postinfarction VT.

Methods and Results—
Twenty-four postinfarction patients (median age, 64 [53, 70] years) were referred for radiofrequency catheter ablation of VT (n=12) or frequent symptomatic premature ventricular contractions (PVCs) (n=12). Delayed-enhanced (DE) MRI was obtained before ablation. Electroanatomical mapping was performed and scar area and electrogram characteristics of the scar tissue compared in patients with and without inducible VT.

The median ejection fraction in patients with and without inducible VT was 27% (22%, 43%) and 43% (40%, 47%), respectively (
P
=0.085). Subendocardial infarct area determined by DE-MRI was larger in patients with inducible VT (43 [38, 62] cm
2
) than in those with noninducible VT (8 [4, 11] cm
2
;
P
=0.002), and unipolar and bipolar voltages on electroanatomical maps were significantly lower in patients with inducible VT (both
P
<0.05). An infarct volume of >14% identified 11 of 12 patients with inducible VT (area under the curve, 0.94;
P
=0.007). On electroanatomical mapping, distinct sites with isolated potentials (IPs) were more prevalent in patients with inducible VT than in those without (13.2% versus 1.1% of points within scar;
P
<0.001). The number of inducible VTs correlated with the number of distinct sites with IPs (
R
=0.87;
P
<0.0001).

Conclusions—
Scar tissue in postinfarction patients with inducible VT shows quantitative and qualitative differences from scars in patients without inducible VT. Scar size and IPs are correlated with VT inducibility.