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Search Results: 1 - 10 of 232005 matches for " Victor C. Gan equal contributor "
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Utilities and Limitations of the World Health Organization 2009 Warning Signs for Adult Dengue Severity
Tun-Linn Thein equal contributor ,Victor C. Gan equal contributor,David C. Lye,Chee-Fu Yung,Yee-Sin Leo
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002023
Abstract: Background In 2009, the World Health Organization (WHO) proposed seven warning signs (WS) as criteria for hospitalization and predictors of severe dengue (SD). We assessed their performance for predicting dengue hemorrhagic fever (DHF) and SD in adult dengue. Method DHF, WS and SD were defined according to the WHO 1997 and 2009 dengue guidelines. We analyzed the prevalence, sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of WS before DHF and SD onset. Results Of 1507 cases, median age was 35 years (5th–95th percentile, 17–60), illness duration on admission 4 days (5th–95th percentile, 2–6) and length of hospitalization 5 days (5th–95th percentile, 3–7). DHF occurred in 298 (19.5%) and SD in 248 (16.5%). Of these, WS occurred before DHF in 124 and SD in 65 at median of two days before DHF or SD. Three commonest warning signs were lethargy, abdominal pain/tenderness and mucosal bleeding. No single WS alone or combined had Sn >64% in predicting severe disease. Specificity was >90% for both DHF and SD with persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, clinical fluid accumulation, and any 3 or 4 WS. Any one of seven WS had 96% Sn but only 18% Sp for SD. Conclusions No WS was highly sensitive in predicting subsequent DHF or SD in our confirmed adult dengue cohort. Persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, and clinical fluid accumulation, as well as any 3 or 4 WS were highly specific for DHF or SD.
Predictive Value of Proteinuria in Adult Dengue Severity
Farhad F. Vasanwala equal contributor,Tun-Linn Thein equal contributor,Yee-Sin Leo ,Victor C. Gan,Ying Hao,Linda K. Lee,David C. Lye
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0002712
Abstract: Background Dengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool. Methodology and principal findings Adult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF. Conclusions Proteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.
Peptidoglycan-Modifying Enzyme Pgp1 Is Required for Helical Cell Shape and Pathogenicity Traits in Campylobacter jejuni
Emilisa Frirdich,Jacob Biboy equal contributor,Calvin Adams equal contributor,Jooeun Lee,Jeremy Ellermeier,Lindsay Davis Gielda,Victor J. DiRita,Stephen E. Girardin,Waldemar Vollmer,Erin C. Gaynor
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002602
Abstract: The impact of bacterial morphology on virulence and transmission attributes of pathogens is poorly understood. The prevalent enteric pathogen Campylobacter jejuni displays a helical shape postulated as important for colonization and host interactions. However, this had not previously been demonstrated experimentally. C. jejuni is thus a good organism for exploring the role of factors modulating helical morphology on pathogenesis. We identified an uncharacterized gene, designated pgp1 (peptidoglycan peptidase 1), in a calcofluor white-based screen to explore cell envelope properties important for C. jejuni virulence and stress survival. Bioinformatics showed that Pgp1 is conserved primarily in curved and helical bacteria. Deletion of pgp1 resulted in a striking, rod-shaped morphology, making pgp1 the first C. jejuni gene shown to be involved in maintenance of C. jejuni cell shape. Pgp1 contributes to key pathogenic and cell envelope phenotypes. In comparison to wild type, the rod-shaped pgp1 mutant was deficient in chick colonization by over three orders of magnitude and elicited enhanced secretion of the chemokine IL-8 in epithelial cell infections. Both the pgp1 mutant and a pgp1 overexpressing strain – which similarly produced straight or kinked cells – exhibited biofilm and motility defects. Detailed peptidoglycan analyses via HPLC and mass spectrometry, as well as Pgp1 enzyme assays, confirmed Pgp1 as a novel peptidoglycan DL-carboxypeptidase cleaving monomeric tripeptides to dipeptides. Peptidoglycan from the pgp1 mutant activated the host cell receptor Nod1 to a greater extent than did that of wild type. This work provides the first link between a C. jejuni gene and morphology, peptidoglycan biosynthesis, and key host- and transmission-related characteristics.
Most Caenorhabditis elegans microRNAs Are Individually Not Essential for Development or Viability
Eric A Miska equal contributor,Ezequiel Alvarez-Saavedra equal contributor,Allison L Abbott equal contributor,Nelson C Lau,Andrew B Hellman,Shannon M McGonagle,David P Bartel,Victor R Ambros,H. Robert Horvitz
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030215
Abstract: MicroRNAs (miRNAs), a large class of short noncoding RNAs found in many plants and animals, often act to post-transcriptionally inhibit gene expression. We report the generation of deletion mutations in 87 miRNA genes in Caenorhabditis elegans, expanding the number of mutated miRNA genes to 95, or 83% of known C. elegans miRNAs. We find that the majority of miRNAs are not essential for the viability or development of C. elegans, and mutations in most miRNA genes do not result in grossly abnormal phenotypes. These observations are consistent with the hypothesis that there is significant functional redundancy among miRNAs or among gene pathways regulated by miRNAs. This study represents the first comprehensive genetic analysis of miRNA function in any organism and provides a unique, permanent resource for the systematic study of miRNAs.
Studies of a Ring-Cleaving Dioxygenase Illuminate the Role of Cholesterol Metabolism in the Pathogenesis of Mycobacterium tuberculosis
Katherine C. Yam equal contributor,Igor D'Angelo equal contributor,Rainer Kalscheuer equal contributor,Haizhong Zhu,Jian-Xin Wang,Victor Snieckus,Lan H. Ly,Paul J. Converse,William R. Jacobs Jr.,Natalie Strynadka,Lindsay D. Eltis
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000344
Abstract: Mycobacterium tuberculosis, the etiological agent of TB, possesses a cholesterol catabolic pathway implicated in pathogenesis. This pathway includes an iron-dependent extradiol dioxygenase, HsaC, that cleaves catechols. Immuno-compromised mice infected with a ΔhsaC mutant of M. tuberculosis H37Rv survived 50% longer than mice infected with the wild-type strain. In guinea pigs, the mutant disseminated more slowly to the spleen, persisted less successfully in the lung, and caused little pathology. These data establish that, while cholesterol metabolism by M. tuberculosis appears to be most important during the chronic stage of infection, it begins much earlier and may contribute to the pathogen's dissemination within the host. Purified HsaC efficiently cleaved the catecholic cholesterol metabolite, DHSA (3,4-dihydroxy-9,10-seconandrost-1,3,5(1?0)-triene-9,17-dione;kcat/Km = 14.4±0.5 μM?1 s?1), and was inactivated by a halogenated substrate analogue (partition coefficient<50). Remarkably, cholesterol caused loss of viability in the ΔhsaC mutant, consistent with catechol toxicity. Structures of HsaC:DHSA binary complexes at 2.1 ? revealed two catechol-binding modes: bidentate binding to the active site iron, as has been reported in similar enzymes, and, unexpectedly, monodentate binding. The position of the bicyclo-alkanone moiety of DHSA was very similar in the two binding modes, suggesting that this interaction is a determinant in the initial substrate-binding event. These data provide insights into the binding of catechols by extradiol dioxygenases and facilitate inhibitor design.
Regulation of ATG4B Stability by RNF5 Limits Basal Levels of Autophagy and Influences Susceptibility to Bacterial Infection
Ersheng Kuang,Cheryl Y. M. Okumura equal contributor,Sharon Sheffy-Levin equal contributor,Tal Varsano,Vincent Chih-Wen Shu,Jianfei Qi,Ingrid R. Niesman,Huei-Jiun Yang,Carlos López-Otín,Wei Yuan Yang,John C. Reed,Limor Broday ,Victor Nizet ,Ze'ev A. Ronai
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003007
Abstract: Autophagy is the mechanism by which cytoplasmic components and organelles are degraded by the lysosomal machinery in response to diverse stimuli including nutrient deprivation, intracellular pathogens, and multiple forms of cellular stress. Here, we show that the membrane-associated E3 ligase RNF5 regulates basal levels of autophagy by controlling the stability of a select pool of the cysteine protease ATG4B. RNF5 controls the membranal fraction of ATG4B and limits LC3 (ATG8) processing, which is required for phagophore and autophagosome formation. The association of ATG4B with—and regulation of its ubiquitination and stability by—RNF5 is seen primarily under normal growth conditions. Processing of LC3 forms, appearance of LC3-positive puncta, and p62 expression are higher in RNF5?/? MEF. RNF5 mutant, which retains its E3 ligase activity but does not associate with ATG4B, no longer affects LC3 puncta. Further, increased puncta seen in RNF5?/? using WT but not LC3 mutant, which bypasses ATG4B processing, substantiates the role of RNF5 in early phases of LC3 processing and autophagy. Similarly, RNF-5 inactivation in Caenorhabditis elegans increases the level of LGG-1/LC3::GFP puncta. RNF5?/? mice are more resistant to group A Streptococcus infection, associated with increased autophagosomes and more efficient bacterial clearance by RNF5?/? macrophages. Collectively, the RNF5-mediated control of membranalATG4B reveals a novel layer in the regulation of LC3 processing and autophagy.
High-Resolution Genome-Wide Dissection of the Two Rules of Speciation in Drosophila
John P Masly equal contributor ,Daven C Presgraves equal contributor
PLOS Biology , 2007, DOI: 10.1371/journal.pbio.0050243
Abstract: Postzygotic reproductive isolation is characterized by two striking empirical patterns. The first is Haldane's rule—the preferential inviability or sterility of species hybrids of the heterogametic (XY) sex. The second is the so-called large X effect—substitution of one species's X chromosome for another's has a disproportionately large effect on hybrid fitness compared to similar substitution of an autosome. Although the first rule has been well-established, the second rule remains controversial. Here, we dissect the genetic causes of these two rules using a genome-wide introgression analysis of Drosophila mauritiana chromosome segments in an otherwise D. sechellia genetic background. We find that recessive hybrid incompatibilities outnumber dominant ones and that hybrid male steriles outnumber all other types of incompatibility, consistent with the dominance and faster-male theories of Haldane's rule, respectively. We also find that, although X-linked and autosomal introgressions are of similar size, most X-linked introgressions cause hybrid male sterility (60%) whereas few autosomal introgressions do (18%). Our results thus confirm the large X effect and identify its proximate cause: incompatibilities causing hybrid male sterility have a higher density on the X chromosome than on the autosomes. We evaluate several hypotheses for the evolutionary cause of this excess of X-linked hybrid male sterility.
Shifting Baselines, Local Impacts, and Global Change on Coral Reefs
Nancy Knowlton equal contributor ,Jeremy B. C Jackson equal contributor
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060054
Abstract:
Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies
Danielle C. M. Belgrave equal contributor ,Raquel Granell equal contributor,Angela Simpson equal contributor,John Guiver equal contributor,Christopher Bishop equal contributor,Iain Buchan equal contributor,A. John Henderson equal contributor,Adnan Custovic equal contributor
PLOS Medicine , 2014, DOI: 10.1371/journal.pmed.1001748
Abstract: Background The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level. Methods and Findings Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time. Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts. Conclusions The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (~7% of those with symptoms) follow trajectory profiles resembling the atopic march. Please see later in the article for the Editors' Summary
Histone Methylation Restrains the Expression of Subtype-Specific Genes during Terminal Neuronal Differentiation in Caenorhabditis elegans
Chaogu Zheng equal contributor,Siavash Karimzadegan equal contributor,Victor Chiang,Martin Chalfie
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1004017
Abstract: Although epigenetic control of stem cell fate choice is well established, little is known about epigenetic regulation of terminal neuronal differentiation. We found that some differences among the subtypes of Caenorhabditis elegans VC neurons, particularly the expression of the transcription factor gene unc-4, require histone modification, most likely H3K9 methylation. An EGF signal from the vulva alleviated the epigenetic repression of unc-4 in vulval VC neurons but not the more distant nonvulval VC cells, which kept unc-4 silenced. Loss of the H3K9 methyltransferase MET-2 or H3K9me2/3 binding proteins HPL-2 and LIN-61 or a novel chromodomain protein CEC-3 caused ectopic unc-4 expression in all VC neurons. Downstream of the EGF signaling in vulval VC neurons, the transcription factor LIN-11 and histone demethylases removed the suppressive histone marks and derepressed unc-4. Behaviorally, expression of UNC-4 in all the VC neurons caused an imbalance in the egg-laying circuit. Thus, epigenetic mechanisms help establish subtype-specific gene expression, which are needed for optimal activity of a neural circuit.
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