bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Dengue Virus-Specific NS2B/NS3 Protease Inhibitor, BP2109, Discovered by a High-Throughput Screening Assay
Authors: Yang Chi-Chen , Hsieh Yi-Chen , Lee Shiow-Ju , Wu Szu-Huei , Liao Ching-Len , Tsao Chang-Huei , Chao Yu-Sheng , Chern Jyh-Haur , Wu Chung-Pu , Yueh Andrew 
Published: October 2010

ABSTRACTDengue virus (DENV) causes disease globally, with an estimated 25 to 100 million new infections per year. At present, no effective vaccine is available, and treatment is supportive. In this study, we identified BP2109, a potent and selective small-molecule inhibitor of the DENV NS2B/NS3 protease, by a high-throughput screening assay using a recombinant protease complex consisting of the central hydrophilic portion of NS2B and the N terminus of the protease domain. BP2109 inhibited DENV (serotypes 1 to 4), but not Japanese encephalitis virus (JEV), replication and viral RNA synthesis without detectable cytotoxicity. The compound inhibited recombinant DENV-2 NS2B/NS3 protease with a 50% inhibitory concentration (IC50) of 15.43 ± 2.12 μM and reduced the reporter expression of the DENV-2 replicon with a 50% effective concentration (EC50) of 0.17 ± 0.01 μM. Sequencing analyses of several individual clones derived from BP2109-resistant DENV-2 RNAs revealed that two amino acid substitutions (R55K and E80K) are found in the region of NS2B, a cofactor of the NS2B/NS3 protease complex. The introduction of R55K and E80K double mutations into the dengue virus NS2B/NS3 protease and a dengue virus replicon construct conferred 10.3- and 73.8-fold resistance to BP2109, respectively. The E80K mutation was further determined to be the key mutation conferring dengue virus replicon resistance (61.3-fold) to BP2109, whereas the R55K mutation alone did not affect resistance to BP2109. Both the R55K and E80K mutations are located in the central hydrophilic portion of the NS2B cofactor, where extensive interactions with the NS3pro domain exist. Thus, our data provide evidence that BP2109 likely inhibits DENV by a novel mechanism.
Investigation of the Mechanisms by WhichListeria monocytogenesGrows in Porcine Gallbladder Bile
Authors: Dowd Georgina C. , Joyce Susan A. , Hill Colin , Gahan Cormac G. M. 
Published: October 2010

ABSTRACTThe food-borne pathogenListeria monocytogenesis known to colonize the lumen of the gallbladder in infected mice and to grow rapidly in this environment (J. Hardy et al., Science 303:851-853, 2004). However, relatively little is known about the mechanisms utilized by the pathogen to survive and grow in this location. We utilized gallbladder bile (GB bile) isolated directly from porcine gallbladders as anex vivomodel of gallbladder growth. We demonstrate that GB bile is generally nontoxic for bacteria and can readily support growth of a variety of bacterial species includingL. monocytogenes,Lactococcus lactis,Salmonella entericaserovar Typhimurium, andEscherichia coli. Significantly,L. monocytogenesgrew at the same rate as the nonpathogenic speciesListeria innocua, indicating that the pathogen does not possess specialized mechanisms that enable growth in this environment. However, when we reduced the pH of GB bile to pH 5.5 in order to mimic the release of bile within the small intestine, the toxicity of GB bile increased significantly and specific resistance mechanisms (Sigma B, BSH, and BilE) were essential for survival of the pathogen under these conditions. In order to identify genetic loci that are necessary for growth ofL. monocytogenesin the gallbladder, a mariner transposon bank was created and screened for mutants unable to replicate in GB bile. This led to the identification of mutants in six loci, including genes encoding enzymes involved in purine metabolism, amino acid biosynthesis, and biotin uptake. Although GB bile does not represent a significant impediment to bacterial growth, specific metabolic processes are required byL. monocytogenesin order to grow in this environment.
The Early Secretory Pathway Contributes to the Growth of the
Coxiella
-Replicative Niche
Authors: Campoy Emanuel Martín , Zoppino Felipe Carlos Martín , Colombo María Isabel 
Published: October 2010

ABSTRACT

Coxiella burnetii
is a Gram-negative obligate intracellular bacterium. After internalization, this bacterium replicates in a large parasitophorous vacuole that has features of both phagolysosomes and autophagosomal compartments. We have previously demonstrated that early after internalization
Coxiella
phagosomes interact with both the endocytic and the autophagic pathways. In this report, we present evidence that the
Coxiella
-replicative vacuoles (CRVs) also interact with the secretory pathway. Rab1b is a small GTPase responsible for the anterograde transport between the endoplasmic reticulum and the Golgi apparatus. We present evidence that Rab1b is recruited to the CRV at later infection times (i.e., after 6 h of infection). Interestingly, knockdown of Rab1b altered vacuole growth, indicating that this protein was required for the proper biogenesis of the CRV. In addition, overexpression of the active GTPase-defective mutant (GFP-Rab1b Q67L) affected the development of the
Coxiella
-replicative compartment inhibiting bacterial growth. On the other hand, disruption of the secretory pathway by brefeldin A treatment or by overexpression of Sar1 T39N, a defective dominant-negative mutant of Sar1, affected the typical spaciousness of the CRVs. Taken together, our results show for the first time that the
Coxiella
-replicative niche also intercepts the early secretory pathway.
Characterization of aStaphylococcus aureusSurface Virulence Factor That Promotes Resistance to Oxidative Killing and Infectious Endocarditis
Authors: Malachowa Natalia , Kohler Petra L. , Schlievert Patrick M. , Chuang Olivia N. , Dunny Gary M. , Kobayashi Scott D. , Miedzobrodzki Jacek , Bohach Gregory A. , Seo Keun Seok 
Published: October 2010

ABSTRACTStaphylococcus aureusis a prominent human pathogen and a leading cause of community- and hospital-acquired bacterial infections worldwide. Herein, we describe the identification and characterization of theS. aureus67.6-kDa hypothetical protein, named for thesurface factor promoting resistance tooxidativekilling (SOK) in this study. Sequence analysis showed that the SOK gene is conserved in all sequencedS. aureusstrains and homologous to the myosin cross-reactive antigen ofStreptococcus pyogenes.Immunoblotting and immunofluorescence analysis showed that SOK was copurified with membrane fractions and was exposed on the surface ofS. aureusNewman and RN4220. Comparative analysis of wild-typeS. aureusand an isogenic deletion strain indicated that SOK contributes to both resistance to killing by human neutrophils and to oxidative stress. In addition, theS. aureus sokdeletion strain showed dramatically reduced aortic valve vegetation and bacterial cell number in a rabbit endocarditis model. These results, plus the suspected role of the streptococcal homologue in certain diseases such as acute rheumatic fever, suggest that SOK plays an important role in cardiovascular and other staphylococcal infections.
Conjunctival Transcriptome in Scarring Trachoma
Authors: Burton Matthew J. , Rajak Saul N. , Bauer Julien , Weiss Helen A. , Tolbert Sonda B. , Shoo Alice , Habtamu Esmail , Manjurano Alphaxard , Emerson Paul M. , Mabey David C. W. , Holland Martin J. , Bailey Robin L. 
Published: October 2010

ABSTRACTTrachoma is a poorly understood immunofibrogenic disease process, initiated byChlamydia trachomatis. Differences in conjunctival gene expression profiles between Ethiopians with trachomatous trichiasis (with [TTI] or without [TT] inflammation) and controls (C) were investigated to identify relevant host responses. Tarsal conjunctival swab samples were collected for RNA isolation andC. trachomatisPCR. Transcriptome-wide microarray experiments were conducted on 42 samples (TTI,n= 13; TT,n= 15; C,n=14). Specific results were confirmed by using multiplex quantitative reverse transcription-PCR for 16 mRNA targets in an independent collection of case-control samples: 386 case-control pairs (TTI,n= 244; TT,n= 142; C,n= 386). The gene expression profiles of cases were consistent with squamous metaplasia (keratins, SPRR), proinflammatory cytokine production (IL1β,CXCL5, andS100A7), and tissue remodeling (MMP7,MMP9,MMP12, andHAS3). There was no difference in the level ofIFNγ between cases and controls. However, cases had increasedINDO,NOS2A, andIL13RA2and reducedIL13.C. trachomatiswas detected in 1/772. Cases show evidence of ongoing inflammation and tissue remodeling, which were more marked where clinical inflammation was also present. Significantly, these processes appear to be active in the absence of currentC. trachomatisinfection. There was limited evidence of a TH1 response (INDOandNOS2A) and no association between a TH2 response and cases. The epithelium appears to be actively involved in late cicatricial stages of trachoma through the production of proinflammatory factors (IL1β,CXCL5, andS100A7). Longitudinal studies are needed to investigate which etiological factors and pathways are associated with progressive scarring and whether simply controlling chlamydial infection will halt progression in people with established cicatricial disease.
ALGEBRAIC QUANTUM HYPERGROUPS II: CONSTRUCTIONS AND EXAMPLES
Authors: DELVAUX L. , VAN DAELE A. 
Published: October 2010

Let G be a group and let A be the algebra of complex functions on G with finite support. The product in G gives rise to a coproduct Δ on A making the pair (A,Δ) a multiplier Hopf algebra. In fact, because there exist integrals, we get an algebraic quantum group as introduced and studied in [A. Van Daele, Adv. Math.140 (1998) 323]. Now let H be a finite subgroup of G and consider the subalgebra A1 of functions in A that are constant on double cosets of H. The coproduct in general will not leave this algebra invariant but we can modify Δ and define Δ1 as [Formula: see text] where f ∈ A1, p,q ∈ G and where n is the number of elements in the subgroup H. Then Δ1 will leave the subalgebra invariant (in the sense that the image is in the multiplier algebra M(A1 ⊗ A1) of the tensor product). However, it will no longer be an algebra map. So, in general we do not have an algebraic quantum group but a so-called algebraic quantum hypergroup as introduced and studied in [L. Delvaux and A. Van Daele, Adv. Math.226 (2011) 1134–1167]. Group-like projections in a *-algebraic quantum group A (as defined and studied in [M. B. Landstad and A. Van Daele, arXiv:math.OA/0702458v1]) give rise, in a natural way, to *-algebraic quantum hypergroups, very much like subgroups do as above for a *-algebraic quantum group associated to a group (again see [M. B. Landstad and A. Van Daele, arXiv:math.OA/0702458v1]). In this paper we push these results further. On the one hand, we no longer assume the *-structure as in [M. B. Landstad and A. Van Daele, arXiv:math.OA/0702458v1] while on the other hand, we allow the group-like projection to belong to the multiplier algebra M(A) of A and not only to A itself. Doing so, we not only get some well-known earlier examples of algebraic quantum hypergroups but also some interesting new ones.
Asia-Pacific Thrombosis Advisory Board consensus paper on prevention of venous thromboembolism after major orthopaedic surgery
Authors: Cohen Alexander ,   the Asia-Pacific Thrombosis Advisory Board
Published: October 2010

SummaryThe incidence of postoperative venous thromboembolism (VTE) in Asian populations is generally thought to be lower than in Western populations, and the use of thromboprophylaxis after surgery is not routine. This paper is authored by the Asia-Pacific Thrombosis Advisory Board. To provide guidance on the most effective postoperative thrombo prophylaxis management, this paper reviews the available data on the incidence of VTE in Asian populations, considers current clinical guidelines for the prevention of VTE to determine whether these guidelines are applicable to Asian populations, and evaluates the potential of new thromboprophylactic agents. Based on the available evidence, it was agreed that VTE represents a genuine problem in Asian patients, although the exact incidence in local populations requires confirmation in large, well-designed clinical trials. Furthermore, there was consensus that current guideline recommendations for the routine use of postoperative thromboprophylaxis should be implemented in Asia, and that new oral agents now available represent an effective and potentially more convenient therapeutic option. In conclusion, we call for recognition that VTE is an issue in Asian patients, and that effective thromboprophylaxis is the most important strategy.
Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation
Authors: Jarai Rudolf , Farhan Serdar , Brozovic Ivan , Smetana Peter , Geppert Alexander , Wojta Johann , Siller-Matula Jolanta , Huber Kurt , Tentzeris Ioannis 
Published: October 2010

SummaryThe aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual anti-platelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for reACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean follow-up period of 7.8 (± 3.63) months (range 1–12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome.
Apixaban decreases coagulation activity in patients with acute deep-vein thrombosis
Authors: Wang Jessie , Knabb Robert , Mohan Puneet , Barrett Yu Chen 
Published: October 2010

SummaryIn patients with acute deep-vein thrombosis (DVT), apixaban, a direct oral factor Xa inhibitor, showed efficacy and safety similar to low-molecular-weight heparin followed by vitamin K antagonist (LMWH/VKA). We evaluated biomarkers of coagulation activity in relation to treatment dose, duration and clinical outcome. Patients (N = 520) with symptomatic DVT were randomised to receive apixaban (5 mg bid, 10 mg bid or 20 mg qd) or LMWH/VKA for 12 weeks. Plasma D-dimer, prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) levels were measured at baseline, and weeks 3 and 12 after treatment. Median plasma levels of D-dimer, F1+2 and TAT were elevated at baseline. At weeks 3 and 12, biomarker levels were normalised in most patients in all treatment groups, consistent with the low rate of venous thromboembolism (VTE) observed. Median reduction in D-dimer was similar in all treatment groups; percentage of patients with D-dimer above upper limit of normal decreased from 95% to 24–40% at week 12. F1+2 decline was greater with LMWH/VKA than apixaban. F1+2 in the apixaban groups changed to a similar extent (>84% of patients had F1+2 within reference range at week 12). Magnitude of TAT reduction was not quantifiable. In conclusion, levels of coagulation biomarkers decreased over 12 weeks of treatment with apixaban or LMWH/VKA in most patients with acute VTE. Baseline D-dimer and F1+2 were higher in patients with recurrent symptomatic VTE than in those without. Plasma levels of coagulation biomarkers did not appear to correlate with total bleeding events.
Mode of action of P2Y12 antagonists as inhibitors of platelet function
Authors: Glenn Jackie , White Ann , Fox Sue , van Giezen Hans , Nylander Sven , Heptinstall Stan , Iyú David 
Published: October 2010

SummaryP2Y12 receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y12 receptors. However, some P2Y12 receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y12 antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y12 receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y12 antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y12 antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y12 antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y12 antagonists enhanced VASPphosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y12 receptors and not through another G-protein-coupled receptor.
Population genetics of venous thromboembolism
Authors: Grandone Elvira , Margaglione Maurizio 
Published: October 2010

SummaryResults from epidemological studies are consistent with the hypothesis that disparities in venous thromboembolism (VTE) burden are attributable to differences in genetic structure among populations from different genetic backgrounds. To that end, recent genetic studies have demonstrated not only potential associations between certain alleles and VTE but also clear differences in the distribution of these alleles in patients stratified by ancestry. There are a number of notable clinical and pathophysiological questions that arise from these findings. First at all is defining the precise variant(s) that alter disease susceptibility. The comparatively lower rates of VTE recorded among Asians would imply that risk profile is devoid of many risk factors on comparison to Caucasian or African counterparts or that a putative protective factor is advocated in the former population. Identification of these variants provided specific insight into VTE disease in selected populations and also shed lights on the biology of the disease. The association observed between ancestry and VTE is likely to be multifactorial, possibly reflecting, in addition to genetic variation, also socioeconomic differences. Acknowledgment of this may provide useful information in biomedical contexts and help to identify individual risk factors for VTE.
Unravelling the mechanism and significance of thrombin binding to platelet glycoprotein Ib
Authors: Zarpellon Alessandro , Roberts James , Mc Clintock Richard , Jing Hua , Mendolicchio G. Loredana , Ruggeri Zaverio 
Published: October 2010

SummaryThe main question concerning the mechanism of α-thrombin binding to platelet membrane glycoprotein (GP)Ib is whether it involves both thrombin exosite I and exosite II. The solution of two independent crystal structures suggests alternative explanations that may actually reflect different modes of binding with distinct pathophysiological significance. With respect to function, it is still unclear whether thrombin binding to GPIb promotes procoagulant and prothrombotic pathways of re-sponse to vascular injury or limits such responses by sequestering, at least temporarily, the active enzyme. We review here published information on these topics and touch upon ongoing studies aimed at finding definitive answers to outstanding questions relevant for a better understanding of thrombosis and haemostasis.
Fibrillatory Conduction in the Atrial Free Walls of Goats in Persistent and Permanent Atrial Fibrillation
Authors: Verheule Sander , Tuyls Els , van Hunnik Arne , Kuiper Marion , Schotten Ulrich , Allessie Maurits 
Published: October 2010

Background—
Over a time course of months, the stability of atrial fibrillation (AF) gradually increases and the efficacy of pharmacological cardioversion declines both in humans and in animal models. Changes in fibrillatory conduction over this period largely are unexplored.

Methods and Result—
Goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. AF was maintained for 3 weeks (short-term AF [ST], n=10) or 6 months (long-term AF [LT], n=7). AF could be cardioverted pharmacologically at the early time point (persistent AF), but not at the later time point (permanent AF). At follow-up, a high-resolution mapping electrode was used to record epicardial conduction patterns in the free walls of the right atrium (RA) and left atrium (LA). A new method for mapping of fibrillation waves was used to describe AF conduction patterns.
Wavefronts propagated uniformly during slow pacing in both groups, although conduction velocity was significantly lower in the LT group (LA, 93±14 versus 72±10 cm/s; RA, 94±8 versus 78±8 cm/s). Median AF cycle length (AFCL) was not significantly different between the groups. However, the LT group showed highly complex activation patterns during AF, with an increased number of simultaneously propagating waves (LT group RA, 8.4±3.0 waves/AFCL; LA, 12.8±2.4 waves/AFCL; versus ST group RA, 4.3±2.2 waves/AFCL; LA, 4.5±2.5 waves/AFCL). Fibrillation waves in the LT group showed pronounced dissociation with large activation time differences. The incidence of waves newly appearing within the recording area also was increased in both atria. These alterations in conduction were accompanied by myocyte hypertrophy and increased endomysial fibrosis.

Conclusions—
Long-term AF in goats leads to dissociated conduction in the atrial free walls that may contribute to increased AF stability.