bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMC278, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI-Resistant HIV-1
Authors: Azijn Hilde , Tirry Ilse , Vingerhoets Johan , de Béthune Marie-Pierre , Kraus Guenter , Boven Katia , Jochmans Dirk , Van Craenenbroeck Elke , Picchio Gaston , Rimsky Laurence T. 
Published: November 2009

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) have proven efficacy against human immunodeficiency virus type 1 (HIV-1). However, in the setting of incomplete viral suppression, efavirenz and nevirapine select for resistant viruses. The diarylpyrimidine etravirine has demonstrated durable efficacy for patients infected with NNRTI-resistant HIV-1. A screening strategy used to test NNRTI candidates from the same series as etravirine identified TMC278 (rilpivirine). TMC278 is an NNRTI showing subnanomolar 50% effective concentrations (EC50values) against wild-type HIV-1 group M isolates (0.07 to 1.01 nM) and nanomolar EC50values against group O isolates (2.88 to 8.45 nM). Sensitivity to TMC278 was not affected by the presence of most single NNRTI resistance-associated mutations (RAMs), including those at positions 100, 103, 106, 138, 179, 188, 190, 221, 230, and 236. The HIV-1 site-directed mutant with Y181C was sensitive to TMC278, whereas that with K101P or Y181I/V was resistant.In vitro, considerable cross-resistance between TMC278 and etravirine was observed. Sensitivity to TMC278 was observed for 62% of efavirenz- and/or nevirapine-resistant HIV-1 recombinant clinical isolates. TMC278 inhibited viral replication at concentrations at which first-generation NNRTIs could not suppress replication. The rates of selection of TMC278-resistant strains were comparable among HIV-1 group M subtypes. NNRTI RAMs emerging in HIV-1 under selective pressure from TMC278 included combinations of V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L. E138R was identified as a new NNRTI RAM. Thesein vitroanalyses demonstrate that TMC278 is a potent next-generation NNRTI, with a high genetic barrier to resistance development.
Triclosan Resistance of
Pseudomonas aeruginosa
PAO1 Is Due to FabV, a Triclosan-Resistant Enoyl-Acyl Carrier Protein Reductase
Authors: Zhu Lei , Lin Jinshui , Ma Jincheng , Cronan John E. , Wang Haihong 
Published: November 2009

ABSTRACT

Triclosan, a very widely used biocide, specifically inhibits fatty acid synthesis by inhibition of enoyl-acyl carrier protein (ACP) reductase.
Escherichia coli
FabI is the prototypical triclosan-sensitive enoyl-ACP reductase, and
E. coli
is extremely sensitive to the biocide. However, other bacteria are resistant to triclosan, because they encode triclosan-resistant enoyl-ACP reductase isozymes. In contrast, the triclosan resistance of
Pseudomonas aeruginosa
PAO1 has been attributed to active efflux of the compound (R. Chuanchuen, R. R. Karkhoff-Schweizer, and H. P. Schweizer, Am. J. Infect. Control
31:
124-127, 2003). We report that
P. aeruginosa
contains two enoyl-ACP reductase isozymes, the previously characterized FabI homologue plus a homologue of FabV, a triclosan-resistant enoyl-ACP reductase recently demonstrated in
Vibrio cholerae
. By deletion of the genes encoding
P. aeruginosa
FabI and FabV, we demonstrated that FabV confers triclosan resistance on
P. aeruginosa
. Upon deletion of the
fabV
gene, the mutant strain became extremely sensitive to triclosan (>2,000-fold more sensitive than the wild-type strain), whereas the mutant strain lacking FabI remained completely resistant to the biocide.
Micafungin Concentrations from Brain Tissue and Pancreatic Pseudocyst Fluid
Authors: Lat Asma , Thompson George R. , Rinaldi Michael G. , Dorsey Sheryl A. , Pennick Gennethel , Lewis James S. 
Published: November 2009

ABSTRACT
We report the attainment of micafungin concentrations from brain tissue and pancreatic pseudocyst fluid from two patients with invasive candidiasis. Micafungin was present in low levels at both body sites, indicating limited penetration into central nervous system (CNS) tissue and pancreatic fluid. Further studies are needed to fully characterize its pharmacokinetics at these locations, as micafungin may potentially serve as an alternative antifungal therapy for CNS or pancreatic candidal infections for which the currently recommended first-line therapy fails.
The Virulence Transcriptional Activator AphA Enhances Biofilm Formation by
Vibrio cholerae
by Activating Expression of the Biofilm Regulator VpsT
Authors: Yang Menghua , Frey Erin M. , Liu Zhi , Bishar Rima , Zhu Jun 
Published: November 2009

ABSTRACT

Vibrio cholerae
is the agent of the severe diarrheal disease cholera, and it perpetuates in aquatic reservoirs when not in the host. Within the host's intestines, the bacteria execute a complex regulatory pathway culminating with the production of virulence factors that allow colonization and cause disease. The ability of
V. cholerae
to form biofilms is thought to aid its persistence in the aquatic environment and passage through the gastric acid barrier of the stomach. The transcriptional activators VpsR and VpsT are part of the biofilm formation-regulatory network. In this study, we screened a
V. cholerae
genomic library in
Escherichia coli
cells containing a P

vpsT

-
luxCDBAE
transcriptional fusion reporter and found that a plasmid clone containing the
aphA
gene activates the expression of
vpsT
in
E. coli
. AphA is a master virulence regulator in
V. cholerae
that is required to activate the expression of
tcpP
, whose gene products in turn activate all virulence genes including those responsible for the synthesis of the toxin-coregulated pilus (TCP) and cholera toxin through the activation of
toxT
. AphA has a direct effect on the
vpsT
promoter, as gel shift experiments demonstrated that AphA binds to the
vpsT
promoter region. Furthermore,
V. cholerae aphA
mutants exhibit significantly lower levels of
vpsT
expression as well as reduced biofilm formation. AphA thus links the expression of virulence and biofilm synthesis genes.
Association of
Vibrio parahaemolyticus
Thermostable Direct Hemolysin with Lipid Rafts Is Essential for Cytotoxicity but Not Hemolytic Activity
Authors: Matsuda Shigeaki , Kodama Toshio , Okada Natsumi , Okayama Kanna , Honda Takeshi , Iida Tetsuya 
Published: November 2009

ABSTRACT

Thermostable direct hemolysin (TDH), a major virulence factor of
Vibrio parahaemolyticus
, induces cytotoxicity in cultured cells. However, the mechanism of TDH's cytotoxic effect including its target molecules on the plasma membrane of eukaryotic cells remains unclear. In this study, we identified the role of lipid rafts, cholesterol- and sphingolipid-enriched microdomains, in TDH cytotoxicity. Treatment of cells with methyl-β-cyclodextrin (MβCD), a raft-disrupting agent, inhibited TDH cytotoxicity. TDH was associated with detergent-resistant membranes (DRMs), and MβCD eliminated this association. In contrast, there was no such association between a nontoxic TDH mutant and DRMs. The disruption of lipid rafts neither affected hemolysis nor inhibited Ca
2+
influx into HeLa cells induced by TDH. These findings indicate that the cytotoxicity but not the hemolytic activity of TDH is dependent on lipid rafts. The exogenous and endogenous depletion of cellular sphingomyelin also prevented TDH cytotoxicity, but a direct interaction between TDH and sphingomyelin was not detected with either a lipid overlay assay or a liposome absorption test. Treatment with sphingomyelinase (SMase) at 100 mU/ml disrupted the association of TDH with DRMs but did not affect the localization of lipid raft marker proteins (caveolin-1 and flotillin-1) with DRMs. These results suggest that sphingomyelin is important for the association of TDH with lipid rafts but is not a molecular target of TDH. We hypothesize that TDH may target a certain group of rafts that are sensitive to SMase at a certain concentration, which does not affect other types of rafts.
Health-related behaviours and sickness absence from work
Authors: Laaksonen M , Piha K , Martikainen P , Rahkonen O , Lahelma E 
Published: November 2009

Objectives:To compare associations of health-related behaviours with self-certified and medically confirmed sickness absence, and to examine whether these associations can be explained by psychosocial and physical working conditions and occupational social class.Methods:The study included 5470 female and 1464 male employees of the City of Helsinki surveyed in 2000–2002. These data were linked to sickness absence records until the end of 2005, providing a mean follow-up time of 3.9 years. Poisson regression analysis was used to examine associations of smoking, alcohol use, physical activity, dietary habits and relative weight (body mass index) with self-certified (1–3 days) and medically confirmed (⩾4 days) absence spells. Population attributable fractions (PAFs) were calculated to quantify the sickness absence burden related to the behaviours.Results:Smoking and high relative weight were most strongly associated with sickness absence, while the associations of other studied health-related behaviours were weaker. The associations were stronger for medically confirmed sickness absence spells for which heavy smoking and obesity more than doubled the risk of sickness absence in men and nearly doubled it in women. Adjusting for psychosocial working conditions had little or no effect on the associations. Physical working conditions and social class somewhat attenuated the associations, especially for smoking and relative weight. In self-certified sickness absence the PAF for smoking (16.4 in men, 10.3 in women) was largest, while in medically confirmed absence relative weight had the largest PAF (23.5 in men, 15.0 in women).Conclusions:Health-related behaviours, smoking and high relative weight in particular, were associated with subsequent sickness absence independently of psychosocial and physical working conditions and social class. Decreasing smoking and relative weight is likely to provide important gains in work ability and reduce sickness absence.
Evaluation of anti-obesity activity of duloxetine in comparison with sibutramine along with its anti-depressant activity: an experimental study in obese rats
Authors: Chudasama H.P. , Bhatt P.A. 
Published: November 2009

5-HT and noradrenaline are important neurotransmitters that control increase in body mass and are involved in the pathophysiology of obesity and depression. Sibutramine, an established anti-obesity agent, and duloxetine, an anti-depressant agent, are serotonin noradrenaline reuptake inhibitors (SNRIs). The objective of the present study was to compare the anti-obesity effect of duloxetine with sibutramine along with its effect on blood pressure and depression in obese rats. The secondary objective of the study was to determine if a relationship exists between obesity and depression. Obesity was induced by high-fat diet (HFD) in healthy male Sprague–Dawley rats. After 5 weeks of feeding HFD, animals were overweight (17.57%) with high food intake (57.15%) in comparison with normal animals. These obese animals were treated with duloxetine (30 mg·kg–1, p.o.) and sibutramine (5 mg·kg–1, p.o.) for 4 weeks. Control animals were treated with duloxetine alone (30 mg·kg–1, p.o.). Our results depict that duloxetine was as effective as sibutramine in reducing food intake, body mass, and relative adiposity, and increasing rectal temperature with an added advantage of decreasing blood pressure, which sibutramine failed to do. Besides reduction in body mass, unlike sibutramine, duloxetine improved depressive state as evaluated by despair swimming test, tail suspension test, and open field test, speculating its use as an anti-obesity agent in obese-depressive animals. Since obese control animals reflected decreased locomotor activity, a positive relationship can be speculated to exist between obesity and depression. Further studies on various antidepressant models are required to confirm this relationship.
Hemodynamic and histomorphometric characteristics of heart failure induced by aortic stenosis in the guinea pig: comparison of two constriction sizes
Authors: Laviolle Bruno , Pape Danielle , Verdier Marie-Clémence , Lavenu Audrey , Bellissant Eric 
Published: November 2009

Heart failure induced by aortic stenosis in young guinea pigs could constitute an interesting model for pharmacology, but its natural history needs to be characterized. One hundred five guinea pigs (3–4 weeks old) underwent thoracic aortic banding with 12- (B12G) or 14-gauge (B14G) needles or similar sham operations (S12G, S14G). Animals alive at 7 d (S12G, n = 16; B12G, n = 28; S14G, n = 19; B14G, n = 27) were assessed at 60 or 120 d. At 60 d, compared with sham groups, left ventricular (LV) mass and wall thickness increased in operated groups, but LV systolic pressure and right ventricular (RV) wall thickness only increased in the B14G group. At 120 d, B12G animals still showed signs of compensated hypertrophy with LV and RV wall thickening (+8%, +21%) and LV dilation (+20%), whereas B14G animals showed signs of decompensation with LV end-diastolic pressure increase (+167%) and mean arterial pressure decrease (–28%) associated with LV and RV hypertrophy (+77%, + 51%) and greater increases of LV and RV wall thickening (+19%, + 57%), as well as LV dilation (+43%). A 12G stenosis results in compensated hypertrophy at 60 and 120 d; a 14G stenosis leads to compensated hypertrophy at 60 d and heart failure at 120 d.
Aqueous extracts ofCimicifuga racemosaand phenolcarboxylic constituents inhibit production of proinflammatory cytokines in LPS-stimulated human whole blood
Authors: Schmid Diethart , Woehs Florian , Svoboda Martin , Thalhammer Theresia , Chiba Peter , Moeslinger Thomas 
Published: November 2009

Cimicifuga racemosa (black cohosh) is commonly used in traditional medicines as treatment for menopausal symptoms and as an antiinflammatory remedy. To clarify the mechanism of action and active principle for the antiinflammatory action, the effects of aqueous C. racemosa root extracts (CRE) and its major constituents on the release of the proinflammatory cytokines IL-6, TNF-α, IFN-γ, and the chemokine IL-8 were investigated in lipopolysaccharide (LPS)-stimulated whole blood of healthy volunteers. CRE (3 µg/µL and 6 µg/µL) reduced LPS-induced release of IL-6 and TNF-α in a concentration- and time-dependent manner and almost completely blocked release of IFN-γ into the plasma supernatant. Except for IFN-γ, these effects were attenuated at longer incubation periods. IL-8 secretion was stimulated by CRE. As shown by quantitative real-time RT-PCR, effects on cytokines were based on preceding changes in mRNA levels except for IL-8. According to their content in CRE, the phenolcarboxylic compounds caffeic acid, ferulic acid, and isoferulic acid, as well as the triterpene glycosides 23-epi-26-deoxyactein and cimigenol-3-O-xyloside, were tested at representative concentrations. Among these, isoferulic acid was the prominent active principle in CRE, responsible for the observed inhibition of IL-6, TNF-α, and IFN-γ, but not for IL-8 stimulation. The effect of this compound may explain the antiinflammatory activities of CRE and its beneficial actions in rheumatism and other inflammatory diseases.
CS woes
Authors: Wing Jeannette M. , Guzdial Mark 
Published: November 2009

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish excerpts from selected posts.

Follow us on Twitter at http://twitter.com/blogCACM
Jeannette M. Wing writes about the negative effects of deadline-driven research and Mark Guzdial discusses the role of computer science faculty in fostering inequality.
Assessing open source software as a scholarly contribution
Authors: Hafer Lou , Kirkpatrick Arthur E. 
Published: November 2009

Introduction

Academic computer science has an odd relationship with software: Publishing papers about software is considered a distinctly stronger contribution than publishing the software. The historical reasons for this paradox no longer apply, but their legacy remains. This limits researchers who see the open-source software movement as an opportunity to make a scholarly contribution. Expanded definitions of scholarship acknowledge both application and discovery as important components.
1
One obstacle remains: evaluation. To raise software to the status of a first-class contribution, we propose "best practices" for the evaluation of the scholarly contribution of open-source software.

Typically, scholars who develop software do not include it as a primary contribution for performance reviews. Instead, they write articles about the software and present the articles as contributions. This conflation of articles and software serves neither medium well. An article describes an original intellectual contribution consisting of an idea, the argument for its importance and correctness, and supporting data. In contrast, software is more often an implementation of prior ideas in a usable form. It bridges the often considerable gap between an idea and the practical application of that idea. The original idea and its implementation represent distinct kinds of contribution.
The critical gap is the perceived incomparability of these two contributions. Lacking a concise description adapted to the traditional practices of performance review committees, software is difficult to evaluate as a scholarly contribution and is often relegated to second-class status. We propose a framework for common assessment based on widely accepted definitions of scholarship. Within this general framework, we consider the material and procedures that a performance review committee uses to evaluate a publication. We then describe how software can be summarized in a compatible form of bibliographic citation and supplementary material.
Syntagmatische Phonemtypologie
Authors: Kempgen Sebastian 
Published: November 2009

Abstract
Based on the recent developments of the distributional calculus of Harary and Paper, a method is proposed to discover the constructional mechanism underlying the phonemic distribution of a language. The phonemes are classified hierarchically and the mutual interdependence of their distributional characteristics is studied. To this end, the technics of correlation and regression are being used. In this way, a ‘typology’ of phonemes in the sense of Hempel and Oppenheim is arrived at.
A Relationship between Coarticulation and Compensatory Shortening
Authors: Fowler Carol A. 
Published: November 2009

Abstract
A comparison of the literatures on coarticulatory influences of a stressed vowel on consonants and unstressed vowels and on ‘compensatory shortening’ of stressed vowels in the contexts of consonants and unstressed vowels suggests that the two timing effects may be related. An experiment was conducted to provide an explicit comparison and to test a hypothesis that compensatory shortening aand coarticulation are not separate timing phenomena. The two timing effects were found to pattern very similarly and both to be predicted by Lindblom and Rapp’s compensatory shortening formula. 5 of 6 subjects showed significant correlations between coarticulation and shortening.
Prosodic Aspects of American English Speech Rhythm
Authors: Nakatani Lloyd H. , O’Connor Kathleen D. , Aston Carletta H. 
Published: November 2009

Abstract
We studied American English speech rhythm using reiterant speech with the prosody of normal speech but without its segmental variations. Syllable duration was strongly influenced by stress and by final positions in words and phrases, but negligibly by nonfinal positions within words and phrases. Word duration increased linearly with word size, and varied with stress pattern for words of constant size. Metrical foot duration increased approximately linearly with foot size. Feet of the same type and size were of constant duration.
Segmental and Temporal Aspects of Utterance-Final Lengthening
Authors: Cooper William E. , Danly Martha 
Published: November 2009

Abstract
Two experiments were conducted to examine the manner in which utterance-final lengthening is exhibited by the durations of words containing various fricatives and vowels in different phonetic environments. In experiment 1, utterance-final lengthening was measured for words containing the fricatives /f/, /v/, /s/, and /z/ in word-initial, word-medial, and word-final positions in both phrase-final and utterance-final locations. The results showed small amounts of utterance-final lengthening for words containing fricatives in word-initial and word-medial positions, with much greater elongation when fricatives appeared in word-final position. In experiment 2, utterance-final lengthening was measured for words containing a word-medial long versus short vowel followed by a word-final voiced versus voiceless stop consonant. The results showed a greater amount of utterance-final lengthening for words containing a terminal voiced versus voiceless stop. The findings are discussed in terms of constraints on the speaker’s programming of segment durations in sentence contexts.
Durations and Contexts as Cues to Word-Final Cognate Opposition in English
Authors: Raphael Lawrence J. 
Published: November 2009

Abstract
Many perceptual and acoustic studies of word-final cognate opposition have relied mainly on isolated synthetic utterances and have usually concluded that one or another of the potential cues is primary. Recent studies of natural speech segment durations in samples of connected discourse have raised questions about the efficacy of such cues. In the experiments reported here, naturally produced tokens of the word peg were excised from two different contexts and acoustically analyzed. One representative token from each context was then edited in several ways in order to ascertain the cue values of a number of variables. The stimuli were tested in isolation, in their original contexts and in contexts from which the word peck had been deleted. The results of the experiments indicate that a number of variables can be sufficient cues to cognate opposition, and that the efficacy of a particular cue depends in a large measure both on the context from which it was extracted and on the context in which it is heard. The potentially large number of cues, their temporal distribution and their variable effectiveness suggest that future research should be focussed on discovering and describing a general articulatory strategy underlying both the production and perception of cognate oppositions.
Mechanisms in the Control of Speech Rate
Authors: Gay Thomas 
Published: November 2009

Abstract
Mechanisms of speech rate control are discussed from the point of view that unidimensional models are inadequate to explain the extensive physiological and acoustical effects observed during changes in speech rate. Evidence is presented to demonstrate that changes in speech rate can result in changes in segmental duration, articulatory displacement, atriculatory velocity, and intrasyllabic coarticulation, and that these changes represent nonlinear transformations produced by a reorganization of speech motor strategies.
Speech Timing as a Tool in Phonology
Authors: Ohala John J. 
Published: November 2009

Abstract
Phonological questions of the sort ‘Is segment or feature [x] a surface-phonetic event or a property of the underlying mental representation?’ may be answered in some cases by considering the durations of the speech sounds in the word in which [x] appears. Here the status of the epenthetic stop [p] in words such as teamster [––t<sup>h</sup>impstÉš] was clarified by measurement of the duration of the preceding vowel + nasal (VN) sequence: a shortened VN implies the [p] is underlying; a long VN implies that it is a surface-phonetic event.