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  • 1
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    Public Library of Science (PLoS) | PubMed Central
    Online: 1.2009 –
    Publisher: Public Library of Science (PLoS) , PubMed Central
    Electronic ISSN: 2157-3999
    Topics: Medicine , Natural Sciences in General
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  • 2
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    Public Library of Science (PLoS)
    Online: 1.2010 –
    Publisher: Public Library of Science (PLoS)
    Topics: Biology
    Keywords: Biodiversität
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  • 3
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    Public Library of Science (PLoS)
    Online: 1.2003 –
    Publisher: Public Library of Science (PLoS)
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 4
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    Public Library of Science (PLoS)
    Online: 1.2005 –
    Publisher: Public Library of Science (PLoS)
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 5
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    Public Library of Science (PLoS)
    Online: 1.2005 –
    Publisher: Public Library of Science (PLoS)
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-22
    Description: by Bayazit Yunusbayev, Mait Metspalu, Ene Metspalu, Albert Valeev, Sergei Litvinov, Ruslan Valiev, Vita Akhmetova, Elena Balanovska, Oleg Balanovsky, Shahlo Turdikulova, Dilbar Dalimova, Pagbajabyn Nymadawa, Ardeshir Bahmanimehr, Hovhannes Sahakyan, Kristiina Tambets, Sardana Fedorova, Nikolay Barashkov, Irina Khidiyatova, Evelin Mihailov, Rita Khusainova, Larisa Damba, Miroslava Derenko, Boris Malyarchuk, Ludmila Osipova, Mikhail Voevoda, Levon Yepiskoposyan, Toomas Kivisild, Elza Khusnutdinova, Richard Villems The Turkic peoples represent a diverse collection of ethnic groups defined by the Turkic languages. These groups have dispersed across a vast area, including Siberia, Northwest China, Central Asia, East Europe, the Caucasus, Anatolia, the Middle East, and Afghanistan. The origin and early dispersal history of the Turkic peoples is disputed, with candidates for their ancient homeland ranging from the Transcaspian steppe to Manchuria in Northeast Asia. Previous genetic studies have not identified a clear-cut unifying genetic signal for the Turkic peoples, which lends support for language replacement rather than demic diffusion as the model for the Turkic language’s expansion. We addressed the genetic origin of 373 individuals from 22 Turkic-speaking populations, representing their current geographic range, by analyzing genome-wide high-density genotype data. In agreement with the elite dominance model of language expansion most of the Turkic peoples studied genetically resemble their geographic neighbors. However, western Turkic peoples sampled across West Eurasia shared an excess of long chromosomal tracts that are identical by descent (IBD) with populations from present-day South Siberia and Mongolia (SSM), an area where historians center a series of early Turkic and non-Turkic steppe polities. While SSM matching IBD tracts (〉 1cM) are also observed in non-Turkic populations, Turkic peoples demonstrate a higher percentage of such tracts ( p -values ≤ 0.01) compared to their non-Turkic neighbors. Finally, we used the ALDER method and inferred admixture dates (~9th–17th centuries) that overlap with the Turkic migrations of the 5th–16th centuries. Thus, our results indicate historical admixture among Turkic peoples, and the recent shared ancestry with modern populations in SSM supports one of the hypothesized homelands for their nomadic Turkic and related Mongolic ancestors.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 7
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-22
    Description: by Francesco De Cobelli, Giulio Pezzetti, Sergio Margari, Antonio Esposito, Francesco Giganti, Giulia Agostini, Alessandro Del Maschio Introduction Abdominal pain in PNH has never been investigated by in-vivo imaging studies. With MRI, we aimed to assess mesenteric vessels flow and small bowel wall perfusion to investigate the ischemic origin of abdominal pain. Materials and Methods Six PNH patients with (AP) and six without (NOP) abdominal pain underwent MRI. In a blinded fashion, mean flow (MF, quantity of blood moving through a vessel within a second, in mL·s -1 ) and stroke volume (SV, volume of blood pumped out at each heart contraction, in mL) of Superior Mesenteric Vein (SMV) and Artery (SMA), areas under the curve at 60 (AUC 60 ) and 90 seconds (AUC 90 ) and K trans were assessed by two operators. Results Mean total perfusion and flow parameters were lower in AP than in NOP group. AUC 60 : 84.81 ± 11.75 vs. 131.73 ± 18.89 ( P 〈 0.001); AUC 90 : 102.33 ± 14.16 vs. 152.58 ± 22.70 ( P 〈 0.001); K trans : 0.0346 min -1 ± 0.0019 vs. 0.0521 ± 0.0015 ( P = 0.093 duodenum, 0.009 jejunum/ileum). SMV: MF 4.67 ml/s ± 0.85 vs. 8.32 ± 2.14 ( P = 0.002); SV 3.85 ml ± 0.76 vs. 6.55 ± 1.57 ( P = 0.02). SMA: MF 6.95 ± 2.61 vs. 11.2 ± 2.32 (P = 0.07); SV 6.52 ± 2.19 vs. 8.78 ± 1.63 ( P = 0.07). We found a significant correlation between MF and SV of SMV and AUC 60 (MF: ρ = 0.88, P 〈 0.001; SV: ρ = 0.644, P = 0.024), AUC 90 (MF: ρ = 0.874, P 〈 0.001; SV: ρ = 0.774, P = 0.003) and K trans (MF: ρ = 0.734, P = 0.007; SV: ρ = 0.581, P = 0.047). Conclusions Perfusion and flow MRI findings suggest that the impairment of small bowel blood supply is significantly associated with abdominal pain in PNH.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 8
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-22
    Description: by Wen-Pin Cheng, Bao-Wei Wang, Huey-Ming Lo, Kou-Gi Shyu The expression of TRB3 (tribbles 3), an apoptosis regulated gene, increases during endoplasmic reticulum (ER) stress. How mechanical stress affects the regulation of TRB3 in cardiomyocytes during apoptosis is not fully understood. An in vivo model of aorta-caval shunt in adult rats demonstrated the increased TRB3 protein expression in the myocardium. The tumor necrosis factor-alpha (TNF-α) antagonist etanercept reversed the TRB3 protein expression and cardiomyocyte apoptosis induced by AV shunt. An in vitro model of cyclic stretch in neonatal rats was also used to investigate TRB3 expression. We hypothesized that cardiomyocyte apoptosis induced by cyclic stretch is TRB3 dependent. Neonatal rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. Cyclic stretch significantly increased TRB3 protein and mRNA expression. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, TNF-α antibody and etanercept 30 min before stretch reversed the induction of TRB3 protein induced by stretch. Cyclic stretch induced the DNA-binding activity of growth arrest and DNA damaged inducible gene-153 (GADD153) by electrophoretic mobility shift assay. SP600125, JNK siRNA, TNF-α antibody and etanercept abolished the binding activity induced by stretch. TRB3 promoter activity was enhanced by stretch and TRB3-mut plasmid, SP600125, TNF-α antibody and etanercept attenuated TRB3 promoter activity induced by stretch. Exogenous administration of TNF-α recombinant protein to the non-stretched cardiomyocytes increased TRB3 protein expression similar to that seen after stretch. Cyclic stretch induced cardiomyocyte apoptosis is inhibited by TRB3 siRNA and etanercept. The stretch-induced TRB3 is mediated by TNF-α、JNK and GADD153 pathway. These results indicate that TRB3 plays an important role in stretch-induced cardiomyocyte apoptosis.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
    Publication Date: 2015-04-22
    Description: by Yoon Hong Chun, Kyungdo Han, Yong-Gyu Park, Jong-seo Yoon, Hyun Hee Kim, Jin Tack Kim, Dae Chul Jeong Purpose Asthma during adolescence can induce social, psychological, and behavioral problems. We examined the impact of asthma and other allergic diseases on psychological symptoms and health risk behaviors among South Korean adolescents. Methods In this population-based cross-sectional study, 3192 adolescents (10–18 years of age) participating in the 2008–2011 Korean National Health and Nutrition Examination Survey were enrolled. Psychological problems associated with clinically diagnosed asthma, allergic rhinitis, and atopic dermatitis were assessed using questionnaires and surveys. Data was analyzed using logistic regression to determine the association of depression with allergic disease while controlling for age, sex, body mass index, smoking experience, and alcohol use. Results Asthma and atopic dermatitis were associated with a higher prevalence of depression (17.2% and 13%, respectively). After adjusting for the covariates, asthma patients were approximately two times as likely to have depression as non-allergic participants (odds ratio, 1.81; 95% confidence interval, 1.22–2.68). Psychosocial stress significantly increased in the following order: no allergy, any allergy without asthma, asthma only, and asthma with any allergy (p for linear trend = 0.01). The asthma without other allergies group showed the highest prevalence of cigarette smoking (p = 0.007). Conclusions In this study, asthma with or without other allergies was significantly related to increases in depression, psychosocial stress, and smoking experience. Thus, care should be taken to adjust treatment to account for the psychological symptoms and health risk behaviors common among asthmatic adolescents.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2015-04-22
    Description: by Melissa C. Smith, Richard Gomulkiewicz, Richard N. Mack We hypothesized that the ongoing naturalization of frost/shade tolerant Asian bamboos in North America could cause environmental consequences involving introduced bamboos, native rodents and ultimately humans. More specifically, we asked whether the eventual masting by an abundant leptomorphic (“running”) bamboo within Pacific Northwest coniferous forests could produce a temporary surfeit of food capable of driving a population irruption of a common native seed predator, the deer mouse ( Peromyscus maniculatus ), a hantavirus carrier. Single-choice and cafeteria-style feeding trials were conducted for deer mice with seeds of two bamboo species ( Bambusa distegia and Yushania brevipaniculata ), wheat, Pinus ponderosa , and native mixed diets compared to rodent laboratory feed. Adult deer mice consumed bamboo seeds as readily as they consumed native seeds. In the cafeteria-style feeding trials, Y . brevipaniculata seeds were consumed at the same rate as native seeds but more frequently than wheat seeds or rodent laboratory feed. Females produced a median litter of 4 pups on a bamboo diet. Given the ability of deer mice to reproduce frequently whenever food is abundant, we employed our feeding trial results in a modified Rosenzweig-MacArthur consumer-resource model to project the population-level response of deer mice to a suddenly available/rapidly depleted supply of bamboo seeds. The simulations predict rodent population irruptions and declines similar to reported cycles involving Asian and South American rodents but unprecedented in deer mice. Following depletion of a mast seed supply, the incidence of Sin Nombre Virus (SNV) transmission to humans could subsequently rise with dispersal of the peridomestic deer mice into nearby human settlements seeking food.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
    Publication Date: 2015-04-22
    Description: by Rui Chen, Jinchuan Yan, Peijing Liu, Zhongqun Wang Background Inflammation is a common feature in patients with type 2 diabetes mellitus (T 2 DM). This meta-analysis aimed to assess the influence of thiazolidinedione (TZD) therapy on the circulating levels of inflammatory markers in patients with T 2 DM. Methods and Results We searched the databases Medline, Embase, ScienceDirect, Web of Science, SpringerLink, and the Cochrane Library for randomized controlled trials (RCTs) that examined the effects of thiazolidinedione vs. a placebo on patients with T 2 DM. The main outcomes were absolute changes in levels of circulating inflammatory markers. Twenty-seven RCTs were included and data were analyzed using a fixed-effect model or a random-effect model based on heterogeneity. Pooled results indicated that circulating levels of high-sensitivity C reactive protein (hsCRP; SMD = –0.65, 95% CI = –0.98 to –0.32, p 〈 0.01), monocyte chemoattractant protein-1 (MCP-1; WMD = –54.19, 95% CI = –73.86 to –34.52, p 〈 0.01), von Willebrand factor% (vWF%; WMD = –8.18, 95% CI = –13.54 to –2.81, p 0.01), fibrinogen (SMD = –0.26, 95% CI = –0.41 to –0.11, p 〈 0.01) and E-selectin(WMD = –3.57, 95% CI = –5.59 to -1.54, p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
    Publication Date: 2015-04-22
    Description: by Byung Ha Chung, Yu Young Joo, Jaesin Lee, Hyung Duk Kim, Ji-Il Kim, In Sung Moon, Bum Soon Choi, Eun-Jee Oh, Cheol Whee Park, Yong-Soo Kim, Chul Woo Yang Whether the coexistence of anti-A/B antibody and donor specific anti-HLA antibody (HLA-DSA) has a synergistic impact on the development of acute antibody-mediated rejection (AAMR) in kidney transplant recipients (KTRs) is unclear. This study includes 92 KTRs who received a kidney from an ABO-incompatible (ABOi) donor or were presensitized to donor HLA (HLAs) and 292 controls (CONT). HLAs was defined as a crossmatch positivity or the presence of HLA-DSA. We compared the incidence of AAMR among ABOi (n = 58), ABOi+HLAs (n = 12), HLAs (n = 22), and CONT (n = 292) groups and evaluated the risk factors and antibody type (anti-A/B vs. HLA-DSA) responsible for AAMR. AAMR developed less frequently in ABOi and CONT than in the ABOi+HLAs or HLAs (P 〈 0.05 for all); however, there was no difference between the ABOi+HLAs and HLAs groups. AAMR developed more frequently with strong HLA-DSA at baseline; however, high baseline anti-A/B titer did not affect AAMR development. Strong baseline HLA-DSA was an independent predictor for AAMR, however the baseline anti-A/B titer was not. All four AAMR episodes in ABOi+HLAs were positive to HLA-DSA but not to anti-A/B. In conclusion, ABO incompatibility does not increase the risk for AAMR in HLAs KTRs.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-22
    Description: by Maria E. Vaquero, Laura I. de Eugenio, Maria J. Martínez, Jorge Barriuso The fungus Pseudozyma antarctica produces a lipase (CalB) with broad substrate specificity, stability, high regio- and enantio-selectivity. It is active in non-aqueous organic solvents and at elevated temperatures. Hence, CalB is a robust biocatalyst for chemical conversions on an industrial scale. Here we report the in silico mining of public metagenomes and fungal genomes to discover novel lipases with high homology to CalB. The candidates were selected taking into account homology and conserved motifs criteria, as well as, phylogeny and 3D model analyses. The most promising candidate (PlicB) presented interesting structural properties. PlicB was expressed in a heterologous host, purified and partially characterized. Further experiments will allow finding novel catalytic properties with biotechnological interest.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-24
    Description: by Anne-Laure Boulesteix
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 15
    Publication Date: 2015-04-24
    Description: by Jian Tian, Jaie C. Woodard, Anna Whitney, Eugene I. Shakhnovich Design of proteins with desired thermal properties is important for scientific and biotechnological applications. Here we developed a theoretical approach to predict the effect of mutations on protein stability from non-equilibrium unfolding simulations. We establish a relative measure based on apparent simulated melting temperatures that is independent of simulation length and, under certain assumptions, proportional to equilibrium stability, and we justify this theoretical development with extensive simulations and experimental data. Using our new method based on all-atom Monte-Carlo unfolding simulations, we carried out a saturating mutagenesis of Dihydrofolate Reductase (DHFR), a key target of antibiotics and chemotherapeutic drugs. The method predicted more than 500 stabilizing mutations, several of which were selected for detailed computational and experimental analysis. We find a highly significant correlation of r = 0.65–0.68 between predicted and experimentally determined melting temperatures and unfolding denaturant concentrations for WT DHFR and 42 mutants. The correlation between energy of the native state and experimental denaturation temperature was much weaker, indicating the important role of entropy in protein stability. The most stabilizing point mutation was D27F, which is located in the active site of the protein, rendering it inactive. However for the rest of mutations outside of the active site we observed a weak yet statistically significant positive correlation between thermal stability and catalytic activity indicating the lack of a stability-activity tradeoff for DHFR. By combining stabilizing mutations predicted by our method, we created a highly stable catalytically active E . coli DHFR mutant with measured denaturation temperature 7.2°C higher than WT. Prediction results for DHFR and several other proteins indicate that computational approaches based on unfolding simulations are useful as a general technique to discover stabilizing mutations.
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  • 16
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-24
    Description: by Daniel K. Wells, Yishan Chuang, Louis M. Knapp, Dirk Brockmann, William L. Kath, Joshua N. Leonard Tumor growth involves a dynamic interplay between cancer cells and host cells, which collectively form a tumor microenvironmental network that either suppresses or promotes tumor growth under different conditions. The transition from tumor suppression to tumor promotion is mediated by a tumor-induced shift in the local immune state, and despite the clinical challenge this shift poses, little is known about how such dysfunctional immune states are initiated. Clinical and experimental observations have indicated that differences in both the composition and spatial distribution of different cell types and/or signaling molecules within the tumor microenvironment can strongly impact tumor pathogenesis and ultimately patient prognosis. How such “functional” and “spatial” heterogeneities confer such effects, however, is not known. To investigate these phenomena at a level currently inaccessible by direct observation, we developed a computational model of a nascent metastatic tumor capturing salient features of known tumor-immune interactions that faithfully recapitulates key features of existing experimental observations. Surprisingly, over a wide range of model formulations, we observed that heterogeneity in both spatial organization and cell phenotype drove the emergence of immunosuppressive network states. We determined that this observation is general and robust to parameter choice by developing a systems-level sensitivity analysis technique, and we extended this analysis to generate other parameter-independent, experimentally testable hypotheses. Lastly, we leveraged this model as an in silico test bed to evaluate potential strategies for engineering cell-based therapies to overcome tumor associated immune dysfunction and thereby identified modes of immune modulation predicted to be most effective. Collectively, this work establishes a new integrated framework for investigating and modulating tumor-immune networks and provides insights into how such interactions may shape early stages of tumor formation.
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  • 17
    Publication Date: 2015-04-24
    Description: by Manoj Gambhir, Thomas A. Clark, Simon Cauchemez, Sara Y. Tartof, David L. Swerdlow, Neil M. Ferguson Over the past ten years the incidence of pertussis in the United States (U.S.) has risen steadily, with 2012 seeing the highest case number since 1955. There has also been a shift over the same time period in the age group reporting the largest number of cases (aside from infants), from adolescents to 7–11 year olds. We use epidemiological modelling and a large case incidence dataset to explain the upsurge. We investigate several hypotheses for the upsurge in pertussis cases by fitting a suite of dynamic epidemiological models to incidence data from the National Notifiable Disease Surveillance System (NNDSS) between 1990–2009, as well as incidence data from a variety of sources from 1950–1989. We find that: the best-fitting model is one in which vaccine efficacy and duration of protection of the acellular pertussis (aP) vaccine is lower than that of the whole-cell (wP) vaccine, (efficacy of the first three doses 80% [95% CI: 78%, 82%] versus 90% [95% CI: 87%, 94%]), increasing the rate at which disease is reported to NNDSS is not sufficient to explain the upsurge and 3) 2010–2012 disease incidence is predicted well. In this study, we use all available U.S. surveillance data to: 1) fit a set of mathematical models and determine which best explains these data and 2) determine the epidemiological and vaccine-related parameter values of this model. We find evidence of a difference in efficacy and duration of protection between the two vaccine types, wP and aP (aP efficacy and duration lower than wP). Future refinement of the model presented here will allow for an exploration of alternative vaccination strategies such as different age-spacings, further booster doses, and cocooning.
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  • 18
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-24
    Description: by Xiaoquan Wen, Francesca Luca, Roger Pique-Regi Mapping expression quantitative trait loci (eQTLs) has been shown as a powerful tool to uncover the genetic underpinnings of many complex traits at molecular level. In this paper, we present an integrative analysis approach that leverages eQTL data collected from multiple population groups. In particular, our approach effectively identifies multiple independent cis-eQTL signals that are consistent across populations, accounting for population heterogeneity in allele frequencies and linkage disequilibrium patterns. Furthermore, by integrating genomic annotations, our analysis framework enables high-resolution functional analysis of eQTLs. We applied our statistical approach to analyze the GEUVADIS data consisting of samples from five population groups. From this analysis, we concluded that i) jointly analysis across population groups greatly improves the power of eQTL discovery and the resolution of fine mapping of causal eQTL ii) many genes harbor multiple independent eQTLs in their cis regions iii) genetic variants that disrupt transcription factor binding are significantly enriched in eQTLs (p-value = 4.93 × 10 -22 ).
    Print ISSN: 1553-7390
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  • 19
    Publication Date: 2015-04-24
    Description: by Wencheng Li, Bei You, Mainul Hoque, Dinghai Zheng, Wenting Luo, Zhe Ji, Ji Yeon Park, Samuel I. Gunderson, Auinash Kalsotra, James L. Manley, Bin Tian Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3’ untranslated regions (3’UTRs) and/or coding sequences. How core cleavage/polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3’UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1 and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI-25/68 or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly inhibiting C/P events in introns near the 5’ end of gene and U2 suppressing those in introns with features for efficient splicing. Furthermore, PABPN1 inhibits expression of transcripts with pAs near the transcription start site (TSS), a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results support an APA code where an APA event in a given cellular context is regulated by a number of parameters, including relative location to the TSS, splicing context, distance between competing pAs, surrounding cis elements and concentrations of core C/P factors.
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  • 20
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-24
    Description: by Cathy I. Ramos, Oghomwen Igiesuorobo, Qi Wang, Mihaela Serpe The molecular mechanisms controlling the subunit composition of glutamate receptors are crucial for the formation of neural circuits and for the long-term plasticity underlying learning and memory. Here we use the Drosophila neuromuscular junction (NMJ) to examine how specific receptor subtypes are recruited and stabilized at synaptic locations. In flies, clustering of ionotropic glutamate receptors (iGluRs) requires Neto (Neuropillin and Tolloid-like), a highly conserved auxiliary subunit that is essential for NMJ assembly and development. Drosophila neto encodes two isoforms, Neto-α and Neto-β, with common extracellular parts and distinct cytoplasmic domains. Mutations that specifically eliminate Neto-β or its intracellular domain were generated. When Neto-β is missing or is truncated, the larval NMJs show profound changes in the subtype composition of iGluRs due to reduced synaptic accumulation of the GluRIIA subunit. Furthermore, neto-β mutant NMJs fail to accumulate p21-activated kinase (PAK), a critical postsynaptic component implicated in the synaptic stabilization of GluRIIA. Muscle expression of either Neto-α or Neto-β rescued the synaptic transmission at neto null NMJs, indicating that Neto conserved domains mediate iGluRs clustering. However, only Neto-β restored PAK synaptic accumulation at neto null NMJs. Thus, Neto engages in intracellular interactions that regulate the iGluR subtype composition by preferentially recruiting and/or stabilizing selective receptor subtypes.
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  • 21
    Publication Date: 2015-04-24
    Description: by Jay S. Schneider, Stephanie Sendek, Chengwu Yang Background Although Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily by motor symptoms, PD patients, at all stages of the disease, can experience cognitive dysfunction. However, the relationships between cognitive and motor symptoms and specific demographic characteristics are not well defined, particularly for patients who have progressed to requiring dopaminergic medication. Objective To examine relationships between motor and cognitive symptoms and various demographic factors in mild to moderate, PD patients requiring anti-PD medication. Methods Cognitive function was assessed in 94 subjects with a variety of neuropsychological tests during baseline evaluations as part of an experimental treatment study. Data were analyzed in relation to Unified Parkinson’s Disease Rating Scale motor scores and demographic variables. Results Of the UPDRS subscores analyzed, posture/balance/gait was associated with the highest number of adverse cognitive outcomes followed by speech/facial expression, bradykinesia, and rigidity. No associations were detected between any of the cognitive performance measures and tremor. Motor functioning assessed in the “off” condition correlated primarily with disease duration; neuropsychological performance in general was primarily related to age. Conclusion In PD patients who have advanced to requiring anti-PD therapies, there are salient associations between axial signs and cognitive performance and in particular, with different aspects of visuospatial function suggesting involvement of similar circuits in these functions. Associations between executive functions and bradykinesia also suggest involvement similar circuits in these functions.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 22
    Publication Date: 2015-04-24
    Description: by Haihua Yang, Feng Long, Youzhi Zhang, Ronghuan Yu, Peng Zhang, Wenjing Li, Shuijun Li, Xianqiao Jin, Jingwen Xia, Liang Dong, Ning Zhu, Ying Huang, Yi Gong, Xiaodong Chen Background Reduced neutrophil apoptosis plays an important role in the pathogenesis of acute exacerbation chronic obstructive pulmonary disease (AECOPD). The p38 mitogen-activated protein kinase (MAPK) signaling pathway is involved in neutrophil apoptosis. 1α,25-Dihydroxyvitamin D3 (1α,25VitD3) can induce tumor cell apoptosis. The aim of this study was to assess the effects of 1α,25VitD3 on peripheral blood neutrophil apoptosis in AECOPD and examine the role of the p38 MAPK signaling pathway. Methods The study enrolled 36 AECOPD patients and 36 healthy volunteers. Venous blood samples were obtained from both groups. Serum 25-hydroxyvitamin D (25-(OH) D) levels in peripheral venous blood were assayed using liquid chromatography-tandem mass spectrometry (LC-MS/MS); the neutrophils were separated and cultured with SB203580 (a p38 inhibitor) and 1α,25VitD3. Neutrophil apoptosis was measured using flow cytometry, and phospho-p38 MAPK protein expression was detected by Western blot. Statistical analysis was performed using analysis of variance. Student's t-test and Pearson's correlation coefficient were used for the between-group differences and correlation analysis, respectively. Results The 25-(OH) D levels were lower in AECOPD patients than in healthy controls, and the peripheral blood neutrophil apoptosis results were similar. 1α,25VitD3 increased the apoptosis rate and the level of phospho-p38 MAPK in peripheral blood neutrophils of AECOPD patients. SB203580 partly inhibited 1α,25VitD3-induced peripheral blood neutrophil apoptosis and phospho-p38 MAPK overexpression. The 25-(OH) D levels were positively correlated with increased peripheral blood neutrophil apoptosis and phospho-p38 MAPK levels. In addition, expression of the phospho-p38 MAPK protein was also positively correlated with peripheral blood neutrophil apoptosis. Conclusion Our results suggest that 1α,25VitD3 induces peripheral blood neutrophil apoptosis through the p38 MAPK signaling pathway in AECOPD patients.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 23
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    Publication Date: 2015-04-24
    Description: by Kinna Thakarar, Jake R. Morgan, Jessie M. Gaeta, Carole Hohl, Mari-Lynn Drainoni Background Homelessness, HIV, and substance use are interwoven problems. Furthermore, homeless individuals are frequent users of emergency services. The main purpose of this study was to identify risk factors for frequent emergency room (ER) visits and to examine the effects of housing status and HIV serostatus on ER utilization. The second purpose was to identify risk factors for frequent ER visits in patients with a history of illicit drug use. Methods A retrospective analysis was performed on 412 patients enrolled in a Boston-based health care for the homeless program (HCH). This study population was selected as a 2:1 HIV seronegative versus HIV seropositive match based on age, sex, and housing status. A subgroup analysis was performed on 287 patients with history of illicit drug use. Chart data were analyzed to compare demographics, health characteristics, and health service utilization. Results were stratified by housing status. Logistic models using generalized estimating equations were used to predict frequent ER visits. Results In homeless patients, hepatitis C was the only predictor of frequent ER visits (OR 4.49, p
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  • 24
    Publication Date: 2015-04-24
    Description: by Domenico Cozzolino, Anna Grandone, Antonio Cittadini, Giuseppe Palmiero, Giovanni Esposito, Annamaria De Bellis, Raffaello Furlan, Silverio Perrotta, Laura Perrone, Daniele Torella, Emanuele Miraglia del Giudice Background The prevalence of obesity is increasing among children/adolescents. Subtle cardiovascular abnormalities, responsible for a higher mortality later in life, have been reported in obese children/adolescents. The aims of the study were to evaluate cardiovascular autonomic regulation, by means of spectrum analysis of R-R interval variability, and myocardial function, by means of standard and tissue Doppler echocardiography, in a group of non-hypertensive asymptomatic obese children and adolescents; furthermore, the influence of insulin resistance was tested. Subjects and Methods R-R interval variability was analyzed during both the 70° head-up tilt and 24-hour electrocardiographic holter monitoring. Spectrum analysis of R-R interval variability provided the indices of sympathetic (low frequency [LF RR ]) and vagal (high frequency [HF RR ]) modulation of the sinoatrial node. Homeostasis model assessment of insulin resistance (HOMA-IR) was used to classify obese children/adolescents (n=72) as insulin resistant (n=37) and non-insulin resistant (n=35). Results In obese subjects: a) left ventricular mass was significantly (p
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  • 25
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    Publication Date: 2015-04-24
    Description: by Tracy Stokol, Wee Ming Yeo, Deborah Burnett, Nicole DeAngelis, Teng Huang, Nikolaus Osterrieder, James Catalfamo Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in clinically infected horses and provides a new mechanism by which viruses activate hemostasis.
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  • 26
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    Publication Date: 2015-04-24
    Description: by The PLOS ONE Staff
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  • 27
    Publication Date: 2015-04-24
    Description: by Rita Ribeiro, Anthony J. Wilson, Telmo Nunes, David W. Ramilo, Rita Amador, Sara Madeira, Filipa M. Baptista, Lara E. Harrup, Javier Lucientes, Fernando Boinas Bluetongue virus (BTV) is transmitted by Culicoides biting midges and causes an infectious, non-contagious disease of ruminants. It has been rapidly emerging in southern Europe since 1998. In mainland Portugal, strains of BTV belonging to three serotypes have been detected: BTV-10 (1956-1960), BTV-4 (2004-2006 and 2013) and BTV-1 (2007-2012). This paper describes the design, implementation and results of the Entomological Surveillance Programme covering mainland Portugal, between 2005 and 2010, including 5,650 caches. Culicoides imicola Kieffer was mostly found in central and southern regions of Portugal, although it was sporadically detected in northern latitudes. Its peak activity occurred in the autumn and it was active during the winter months in limited areas of the country. Obsoletus group was present at the highest densities in the north although they were found throughout the country in substantial numbers. Culicoides activity occurred all year round but peaked in the spring. A generalized linear mixed model was developed for the analysis of the environmental factors associated with activity of the species of Culicoides suspected vectors of BTV in the country. For C . imicola Kieffer, the most important variables were month, diurnal temperature range (DTR), the number of frost days (FRS) and median monthly temperature (TMP). For the Obsoletus group, the most important factors were month, diurnal temperature range (DTR), and linear and quadratic terms for median monthly temperature (TMP). The results reported can improve our understanding of climatic factors in Culicoides activity influencing their distribution and seasonal pattern.
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  • 28
    Publication Date: 2015-04-24
    Description: by Birgitte Lindegaard, Thine Hvid, Thomas Grøndahl, Christian Frosig, Jan Gerstoft, Pernille Hojman, Bente Klarlund Pedersen
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  • 29
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    Publication Date: 2015-04-24
    Description: by Paulo De Marco Júnior, Joana Darc Batista, Helena Soares Ramos Cabette Community assembly theory is founded on the premise that the relative importance of local environmental processes and dispersal shapes the compositional structure of metacommunities. The species sorting model predicts that assemblages are dominated by the environmental filtering of species that are readily able to disperse to suitable sites. We propose an ecophysiological hypothesis (EH) for the mechanism underlying the organization of species-sorting odonate metacommunities based on the interplay of thermoregulation, body size and the degree of sunlight availability in small-to-medium tropical streams. Due to thermoregulatory restrictions, the EH predicts (i) that larger species are disfavored in small streams and (ii) that streams exhibit a nested compositional pattern characterized by species’ size distribution. To test the EH, we evaluate the longitudinal distribution of adult Odonata at 19 sites in 1 st - to 6 th -order streams in the Tropical Cerrado of Brazil. With increasing channel width, the total abundance and species richness of Anisoptera increased, while the abundance of Zygoptera decreased. The first axis of an ordination analysis of the species abundance data was directly related to channel width. Mean and maximum thorax size are positively correlated to channel width, but no relationship was found for the minimum thorax size, suggesting that there is no lower size constraint on the occurrence of these species. Additionally, a nested compositional pattern related to body size was observed. Our results support the EH and its use as an ecological assembly rule based on abiotic factors. Forest cover functions as a filter to determine which species successfully colonize a given site within a metacommunity. As a consequence, the EH also indicates higher treats for small-bodied zygopterans in relation to the loss of riparian forests in tropical streams.
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  • 30
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    Publication Date: 2015-04-24
    Description: by José P. Leite, Márcia Duarte, Ana M. Paiva, Frederico Ferreira-da-Silva, Pedro M. Matias, Olga C. Nunes, Luís Gales Molinate is a recalcitrant thiocarbamate used to control grass weeds in rice fields. The recently described molinate hydrolase, from Gulosibacter molinativorax ON4 T , plays a key role in the only known molinate degradation pathway ending in the formation of innocuous compounds. Here we report the crystal structure of recombinant molinate hydrolase at 2.27 Å. The structure reveals a homotetramer with a single mononuclear metal-dependent active site per monomer. The active site architecture shows similarities with other amidohydrolases and enables us to propose a general acid-base catalysis mechanism for molinate hydrolysis. Molinate hydrolase is unable to degrade bulkier thiocarbamate pesticides such as thiobencarb which is used mostly in rice crops. Using a structural-based approach, we were able to generate a mutant (Arg187Ala) that efficiently degrades thiobencarb. The engineered enzyme is suitable for the development of a broader thiocarbamate bioremediation system.
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  • 31
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    Publication Date: 2015-04-24
    Description: by John A. Marwick, Corina Tudor, Nadia Khorasani, Charalambos Michaeloudes, Pankaj K. Bhavsar, Kian F. Chung Oxidative stress enhances inflammation and reduces the effectiveness of corticosteroids, but the inflammatory signalling pathways induced by oxidants remain ill-defined. Phosphorylation of histone 3 at serine 10 (H3-Pser10) marks out a subset of inflammatory genes for transcription, several of which are induced in oxidant-associated inflammation. However, the influence of oxidants or of corticosteroids on this modification remains unknown. We assessed the regulation of H3-Pser10 by oxidants and lipopolysaccharide (LPS) in human blood monocytes and lung macrophages and the effectiveness of its abolition in controlling inflammatory gene expression in cells from asthmatic subjects compared to corticosteroids alone. Both oxidants and LPS promoted the induction of H3-Pser10 which was unaffected by corticosteroids. The induction of H3-Pser10 was mediated through p38α mitogen-activated protein kinase (MAPK) and IκB kinase 2 (IKK-2) signalling. Consequently, inhibitors of p38α MAPK or IKK-2 used in combination with dexamethasone were more effective at controlling inflammatory gene expression from monocytes and lung macrophages from asthmatic patients than the corticosteroid alone. Therefore, reduction of H3-Pser10 by inhibition of p38α MAPK or of IKK-2 may provide greater anti-inflammatory control than corticosteroids alone in oxidant-associated inflammation such as severe asthma.
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  • 32
    Publication Date: 2015-04-24
    Description: by Jong Hwa Ahn, June-Sik Kim, Seungill Kim, Hye Yeon Soh, Hosub Shin, Hosung Jang, Ju Hyun Ryu, Ahyeong Kim, Kil-Young Yun, Shinje Kim, Ki Sun Kim, Doil Choi, Jin Hoe Huh Zoysiagrass ( Zoysia japonica Steud.) is commonly found in temperate climate regions and widely used for lawns, in part, owing to its uniform green color. However, some zoysiagrass cultivars accumulate red to purple pigments in their spike and stolon tissues, thereby decreasing the aesthetic value. Here we analyzed the anthocyanin contents of two zoysiagrass cultivars ‘Anyang-jungji’ (AJ) and ‘Greenzoa’ (GZ) that produce spikes and stolons with purple and green colors, respectively, and revealed that cyanidin and petunidin were primarily accumulated in the pigmented tissues. In parallel, we performed a de novo transcriptome assembly and identified differentially expressed genes between the two cultivars. We found that two anthocyanin biosynthesis genes encoding anthocyanidin synthase (ANS) and dihydroflavonol 4-reductase (DFR) were preferentially upregulated in the purple AJ spike upon pigmentation. Both ANS and DFR genes were also highly expressed in other zoysiagrass cultivars with purple spikes and stolons, but their expression levels were significantly low in the cultivars with green tissues. We observed that recombinant ZjDFR1 and ZjANS1 proteins successfully catalyze the conversions of dihydroflavonols into leucoanthocyanidins and leucoanthocyanidins into anthocyanidins, respectively. These findings strongly suggest that upregulation of ANS and DFR is responsible for tissue-specific anthocyanin biosynthesis and differential pigmentation in zoysiagrass. The present study also demonstrates the feasibility of a de novo transcriptome analysis to identify the key genes associated with specific traits, even in the absence of reference genome information.
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  • 33
    Publication Date: 2015-04-24
    Description: by Lidia Lasecka, Abdelghani Bin-Tarif, Anne Bridgen, Nicholas Juleff, Ryan A. Waters, Michael D. Baron Nairobi sheep disease virus (NSDV; also called Ganjam virus in India) is a bunyavirus of the genus Nairovirus . It causes a haemorrhagic gastroenteritis in sheep and goats with mortality up to 90%. The virus is closely related to the human pathogen Crimean-Congo haemorrhagic fever virus (CCHFV). Little is currently known about the biology of NSDV. We have generated specific antibodies against the virus nucleocapsid protein (N) and polymerase (L) and used these to characterise NSDV in infected cells and to study its distribution during infection in a natural host. Due to its large size and the presence of a papain-like protease (the OTU-like domain) it has been suggested that the L protein of nairoviruses undergoes an autoproteolytic cleavage into polymerase and one or more accessory proteins. Specific antibodies which recognise either the N-terminus or the C-terminus of the NSDV L protein showed no evidence of L protein cleavage in NSDV-infected cells. Using the specific anti-N and anti-L antibodies, it was found that these viral proteins do not fully colocalise in infected cells; the N protein accumulated near the Golgi at early stages of infection while the L protein was distributed throughout the cytoplasm, further supporting the multifunctional nature of the L protein. These antibodies also allowed us to gain information about the organs and cell types targeted by the virus in vivo . We could detect NSDV in cryosections prepared from various tissues collected post-mortem from experimentally inoculated animals; the virus was found in the mucosal lining of the small and large intestine, in the lungs, and in mesenteric lymph nodes (MLN), where NSDV appeared to target monocytes and/or macrophages.
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  • 34
    Publication Date: 2015-04-24
    Description: by Julien Tripette, Linh-Chi Nguyen, Louise Allard, Pierre Robillard, Gilles Soulez, Guy Cloutier Background Diabetic patients present higher level of red blood cell (RBC) aggregation contributing to the development of vascular complications. While it has been suggested that this hematology/rheology parameter could bring additional prognostic information for the management of those patients, RBC aggregation screening is not included as a clinical practice. Most medical centers are not equipped to measure properly this parameter, although sedimentation tests can bring some indication. Here, we aimed at evaluating the feasibility of using ultrasound to assess in-vivo hyper-aggregation in type 2 diabetic patients. Research design and methods Seventeen diabetic patients and 15 control subjects underwent ultrasound measurements of RBC aggregation in both cephalic and great saphenous veins. Non-invasive in-vivo ultrasound measurements were performed using a newly developed cellular imaging technique, the structure factor size and attenuation estimator (SFSAE). Comparisons with an ex-vivo gold standard rheometry technique were done, along with measurements of pro-aggregating plasma molecule concentrations. Results In-vivo RBC aggregation was significantly higher in diabetic patients compared with controls for cephalic vein measurements, while a trend ( p = 0.055) was noticed in the great saphenous vein. SFSAE measurements were correlated with gold standard in-vitro measures, fibrinogen and C-reactive protein plasma concentrations. Conclusion RBC aggregation can be measured in-vivo in diabetic patients using ultrasound. Prospective studies are needed to determine whether the SFSAE method could help clinicians in the early management of vascular complications in this patient population.
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  • 35
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    Publication Date: 2015-04-25
    Description: by David C. Queller, Stephen Rong, Xiaoyun Liao
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 36
    Publication Date: 2015-04-25
    Description: by Mei Zhan, Matthew M. Crane, Eugeni V. Entchev, Antonio Caballero, Diana Andrea Fernandes de Abreu, QueeLim Ch’ng, Hang Lu Quantitative imaging has become a vital technique in biological discovery and clinical diagnostics; a plethora of tools have recently been developed to enable new and accelerated forms of biological investigation. Increasingly, the capacity for high-throughput experimentation provided by new imaging modalities, contrast techniques, microscopy tools, microfluidics and computer controlled systems shifts the experimental bottleneck from the level of physical manipulation and raw data collection to automated recognition and data processing. Yet, despite their broad importance, image analysis solutions to address these needs have been narrowly tailored. Here, we present a generalizable formulation for autonomous identification of specific biological structures that is applicable for many problems. The process flow architecture we present here utilizes standard image processing techniques and the multi-tiered application of classification models such as support vector machines (SVM). These low-level functions are readily available in a large array of image processing software packages and programming languages. Our framework is thus both easy to implement at the modular level and provides specific high-level architecture to guide the solution of more complicated image-processing problems. We demonstrate the utility of the classification routine by developing two specific classifiers as a toolset for automation and cell identification in the model organism Caenorhabditis elegans . To serve a common need for automated high-resolution imaging and behavior applications in the C . elegans research community, we contribute a ready-to-use classifier for the identification of the head of the animal under bright field imaging. Furthermore, we extend our framework to address the pervasive problem of cell-specific identification under fluorescent imaging, which is critical for biological investigation in multicellular organisms or tissues. Using these examples as a guide, we envision the broad utility of the framework for diverse problems across different length scales and imaging methods.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
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  • 37
    Publication Date: 2015-04-25
    Description: by Fernando R. Fernandez, Paola Malerba, John A. White The presence of voltage fluctuations arising from synaptic activity is a critical component in models of gain control, neuronal output gating, and spike rate coding. The degree to which individual neuronal input-output functions are modulated by voltage fluctuations, however, is not well established across different cortical areas. Additionally, the extent and mechanisms of input-output modulation through fluctuations have been explored largely in simplified models of spike generation, and with limited consideration for the role of non-linear and voltage-dependent membrane properties. To address these issues, we studied fluctuation-based modulation of input-output responses in medial entorhinal cortical (MEC) stellate cells of rats, which express strong sub-threshold non-linear membrane properties. Using in vitro recordings, dynamic clamp and modeling, we show that the modulation of input-output responses by random voltage fluctuations in stellate cells is significantly limited. In stellate cells, a voltage-dependent increase in membrane resistance at sub-threshold voltages mediated by Na + conductance activation limits the ability of fluctuations to elicit spikes. Similarly, in exponential leaky integrate-and-fire models using a shallow voltage-dependence for the exponential term that matches stellate cell membrane properties, a low degree of fluctuation-based modulation of input-output responses can be attained. These results demonstrate that fluctuation-based modulation of input-output responses is not a universal feature of neurons and can be significantly limited by subthreshold voltage-gated conductances.
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    Publication Date: 2015-04-25
    Description: by Naoki Hiratani, Tomoki Fukai The brain can learn and detect mixed input signals masked by various types of noise, and spike-timing-dependent plasticity (STDP) is the candidate synaptic level mechanism. Because sensory inputs typically have spike correlation, and local circuits have dense feedback connections, input spikes cause the propagation of spike correlation in lateral circuits; however, it is largely unknown how this secondary correlation generated by lateral circuits influences learning processes through STDP, or whether it is beneficial to achieve efficient spike-based learning from uncertain stimuli. To explore the answers to these questions, we construct models of feedforward networks with lateral inhibitory circuits and study how propagated correlation influences STDP learning, and what kind of learning algorithm such circuits achieve. We derive analytical conditions at which neurons detect minor signals with STDP, and show that depending on the origin of the noise, different correlation timescales are useful for learning. In particular, we show that non-precise spike correlation is beneficial for learning in the presence of cross-talk noise. We also show that by considering excitatory and inhibitory STDP at lateral connections, the circuit can acquire a lateral structure optimal for signal detection. In addition, we demonstrate that the model performs blind source separation in a manner similar to the sequential sampling approximation of the Bayesian independent component analysis algorithm. Our results provide a basic understanding of STDP learning in feedback circuits by integrating analyses from both dynamical systems and information theory.
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    Publication Date: 2015-04-25
    Description: by Kazuki Saito, Wataru Horikawa, Koichi Ito Incidental ribosome stalling during translation elongation is an aberrant phenomenon during protein synthesis and is subjected to quality control by surveillance systems, in which mRNA and a nascent protein are rapidly degraded. Their detailed molecular mechanisms as well as responsible factors for these processes are beginning to be understood. However, the initial processes for detecting stalled translation that result in degradation remain to be determined. Among the factors identified to date, two E3 ubiquitin ligases have been reported to function in distinct manners. Because ubiquitination is one of the most versatile of cellular signals, these distinct functions of E3 ligases suggested diverse ubiquitination pathways during surveillance for stalled translation. In this study, we report experimental evidences for a unique role of non-proteasomal K63 polyubiquitination during quality control for stalled translation. Inhibiting K63 polyubiquitination by expressing a K63R ubiquitin mutation in Saccharomyces cerevisiae cells markedly abolished the quality control responses for stalled translation. More detailed analyses indicated that the effects of K63R mutants were independent of the proteasome and that K63 polyubiquitination is dependent on Hel2, one of the E3 ligases. Moreover, a K63R ubiquitin mutant barely inhibited the quality control pathway for nonstop translation, indicating distinct mechanisms for these highly related quality control pathways. Our results suggest that non-proteasomal K63 polyubiquitination is included in the initial surveillance process of stalled translation and presumably triggers protein degradation steps upon translational stall. These findings provide crucial information regarding the detailed molecular mechanisms for the initial steps involved in quality control systems and their classification.
    Print ISSN: 1553-7390
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  • 40
    Publication Date: 2015-04-25
    Description: by Takuya Awata, Hisakuni Yamashita, Susumu Kurihara, Tomoko Morita-Ohkubo, Yumi Miyashita, Shigehiro Katayama, Keisuke Mori, Shin Yoneya, Masakazu Kohda, Yasushi Okazaki, Taro Maruyama, Akira Shimada, Kazuki Yasuda, Nao Nishida, Katsushi Tokunaga, Asako Koike
    Electronic ISSN: 1932-6203
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  • 41
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    Publication Date: 2015-04-25
    Description: by Naphavanh Nanthavong, Antony P. Black, Phonethipsavanh Nouanthong, Chanthasone Souvannaso, Keooudomphone Vilivong, Claude P. Muller, Sylvie Goossens, Fabrice Quet, Yves Buisson Background During late 2012 and early 2013 several outbreaks of diphthe-ria were notified in the North of the Lao People’s Democratic Republic. The aim of this study was to determine whether the re-emergence of this vaccine-preventable disease was due to insufficient vaccination coverage or reduction of vaccine effectiveness within the affected regions. Methods A serosurvey was conducted in the Huaphan Province on a cluster sampling of 132 children aged 12–59 months. Serum samples, socio-demographic data, nutri-tional status and vaccination history were collected when available. Anti-diphtheria and anti-tetanus IgG antibody levels were measured by ELISA. Results Overall, 63.6% of participants had detectable diphtheria antibodies and 71.2% tetanus antibodies. Factors independently associated with non-vaccination against diphtheria were the distance from the health centre (OR: 6.35 [95% CI: 1.4–28.8], p = 0.01), the Lao Theung ethnicity (OR: 12.2 [95% CI:1,74–85, 4], p = 0.01) and the lack of advice on vac-cination given at birth (OR: 9.8 [95% CI: 1.5–63.8], (p = 0.01) while the level of maternal edu-cation was a protective factor (OR: 0.08 [95% CI: 0.008–0.81], p = 0.03). Most respondents claimed financial difficulties as the main reason for non-vaccination. Out of 55 children whose vaccination certificates stated that they were given all 3 doses of diphtheria-containing vaccine, 83.6% had diphtheria antibodies and 92.7% had tetanus antibodies. Furthermore, despite a high prevalence of stunted and underweight children (53% and 25.8%, respectively), the low levels of anti-diphtheria antibodies were not correlated to the nutritional status. Conclusions Our data highlight a significant deficit in both the vaccination coverage and diphtheria vaccine effectiveness within the Huaphan Province. Technical defi-ciencies in the methods of storage and distribution of vaccines as well as unreliability of vac-cination cards are discussed. Several hypotheses are advanced to explain such a decline in immunity against diphtheria and recommendations are provided to prevent future outbreaks.
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  • 42
    Publication Date: 2015-04-25
    Description: by Susan G. Poole, J. Simon Bell, Natali Jokanovic, Carl M. Kirkpatrick, Michael J. Dooley Introduction It is not known to what extent medication use has been comprehensively assessed in prospective cohort studies of older Australians. Understanding the varying methods to assess medication use is necessary to establish comparability and to understand the opportunities for pharmacoepidemiological analysis. The objective of this review was to compare and contrast how medication-related data have been collected in prospective cohorts of community-dwelling older Australians. Methods MEDLINE and EMBASE (1990–2014) were systematically searched to identify prospective cohorts of ≥1000 older participants that commenced recruitment after 1990. The data collection tools used to assess medication use in each cohort were independently examined by two investigators using a structured approach. Results Thirteen eligible cohorts were included. Baseline medication use was assessed in participant self-completed surveys (n = 3), by an investigator inspecting medications brought to a clinic interview (n = 7), and by interviewing participants in their home (n = 3). Five cohorts sought participant consent to access administrative claims data. Six cohorts used multiple methods to assess medication use across one or more study waves. All cohorts assessed medication use at baseline and 12 cohorts in follow-up waves. Twelve cohorts recorded prescription medications by trade or generic name; 12 cohorts recorded medication strength; and 9 recorded the daily medication dose in at least one wave of the cohort. Seven cohorts asked participants about their “current” medication use without providing a definition of “current”; and nine cohorts asked participants to report medication use over recall periods ranging from 1-week to 3-months in at least one wave of the cohort. Sixty-five original publications, that reported the prevalence or outcomes of medication use, in the 13 cohorts were identified (median = 3, range 1–21). Conclusion There has been considerable variability in the assessment of medication use within and between cohorts. This may limit the comparability of medication data collected in these cohorts.
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  • 43
    Publication Date: 2015-04-25
    Description: by Jean Cyr Yombi, Pierre Emmanuel Schwab, Emmanuel Thienpont Minimally invasive total knee arthroplasty (MITKA) has been developed to reduce surgical trauma and facilitate rehabilitation after arthroplasty. A plausible hypothesis is that this reduced trauma results in lower concentrations of circulating inflammatory biomarkers, such as C-reactive protein (CRP). In this study, we compared CRP concentrations in patients undergoing MITKA to those undergoing conventional TKA (CTKA). Eight hundred and seven patients undergoing MITKA were prospectively recruited. CRP was measured before operation and on days 2, 4, 21, and 42 after operation. Two hundred and forty-seven patients who had CTKA were collected retrospectively, with the same inclusion and exclusion criteria as those who had MITKA. We found in both groups, that CRP values rose abruptly after operation, with peak values reached on day 2 or 4. Values then declined so that by days 21 and 42 they were only modestly above baseline values. Throughout the entire study period, mean CRP in MITKA patients did not differ significantly from those in CTKA patients. However, a significantly higher proportion of CTKA patients than of MITKA patients had peak CRP values at day 4 rather than at day 2 (76.8% vs 42.5%), a difference that was more pronounced in women. Also, by day 42, CRP values were still above baseline in 18.5% of MITKA patients and 28.8% of CTKA patients without known complications. In conclusion, CRP distribution pattern was similar in patients who received MITKA or CTKA,. CRP values remained slightly elevated in both MITKA and CTKA patients for as long 42 days after operation. These findings suggest that MITKA is no less traumatic than CTKA, as determined by CRP values, and the patterns of postoperative CRP may be useful in the management of TKA patients.
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  • 44
    Publication Date: 2015-04-25
    Description: by Priyamvada Paudyal, Carrie Llewellyn, Jason Lau, Mohammad Mahmud, Helen Smith Background Routine screening is key to sexually transmitted infection (STI) prevention and control. Previous studies suggest that clinic-based screening programmes capture only a small proportion of people with STIs. Self-sampling using non- or minimally invasive techniques may be beneficial for those reluctant to actively engage with conventional sampling methods. We systematically reviewed studies of patients’ experiences of obtaining self-samples to diagnose curable STIs. Methods We conducted an electronic search of MEDLINE, EMBASE, CINAHL, PsychINFO, BNI, and Cochrane Database of Systematic Reviews to identify relevant articles published in English between January 1980 and March 2014. Studies were included if participants self-sampled for the diagnosis of a curable STI and had specifically sought participants’ opinions of their experience, acceptability, preferences, or willingness to self-sample. Results The initial search yielded 558 references. Of these, 45 studies met the inclusion criteria. Thirty-six studies assessed patients’ acceptability and experiences of self-sampling. Pooled results from these studies shows that self-sampling is a highly acceptable method with 85% of patients reporting the method to be well received and acceptable. Twenty-eight studies reported on ease of self-sampling; the majority of patients (88%) in these studies found self-sampling an “easy” procedure. Self-sampling was favoured compared to clinician sampling, and home sampling was preferred to clinic-based sampling. Females and older participants were more accepting of self-sampling. Only a small minority of participants (13%) reported pain during self-sampling. Participants were willing to undergo self-sampling and recommend others. Privacy and safety were the most common concerns. Conclusion Self-sampling for diagnostic testing is well accepted with the majority having a positive experience and willingness to use again. Standardization of self-sampling procedures and rigorous validation of outcome measurement will lead to better comparability across studies. Future studies need to conduct rigorous economic evaluations of self-sampling to inform policy development for the management of STI.
    Electronic ISSN: 1932-6203
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  • 45
    Publication Date: 2015-04-25
    Description: by Antonio J. Osuna-Mascaró, Teresa Cruz-Bustos, Frédéric Marin, Antonio G. Checa The current model for the ultrastructure of the interlamellar membranes of molluscan nacre imply that they consist of a core of aligned chitin fibers surrounded on both sides by acidic proteins. This model was based on observations taken on previously demineralized shells, where the original structure had disappeared. Despite other earlier claims, no direct observations exist in which the different components can be unequivocally discriminated. We have applied different labeling protocols on non-demineralized nacreous shells of the bivalve Pteria . With this method, we have revealed the disposition and nature of the different fibers of the interlamellar membranes that can be observed on the surface of the nacreous shell of the bivalve Pteria hirundo by high resolution scanning electron microscopy (SEM). The minor chitin component consists of very thin fibers with a high aspect ratio and which are seemingly disoriented. Each fiber has a protein coat, which probably forms a complex with the chitin. The chitin-protein-complex fibers are embedded in an additional proteinaceous matrix. This is the first time in which the sizes, positions and distribution of the chitin fibers have been observed in situ.
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  • 46
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    Publication Date: 2015-04-25
    Description: by Nhung Nghiem, Tony Blakely, Linda J. Cobiac, Amber L. Pearson, Nick Wilson Background Given the high importance of dietary sodium (salt) as a global disease risk factor, our objective was to compare the impact of eight sodium reduction interventions, including feasible and more theoretical ones, to assist prioritisation. Methods Epidemiological modelling and cost-utility analysis were performed using a Markov macro-simulation model. The setting was New Zealand (NZ) (2.3 million citizens, aged 35+ years) which has detailed individual-level administrative cost data. Results Of the most feasible interventions, the largest health gains were from (in descending order): (i) mandatory 25% reduction in sodium levels in all processed foods; (ii) the package of interventions performed in the United Kingdom (UK); (iii) mandatory 25% reduction in sodium levels in bread, processed meats and sauces; (iv) media campaign (as per a previous UK one); (v) voluntary food labelling as currently used in NZ; (vi) dietary counselling as currently used in NZ. Even larger health gains came from the more theoretical options of a “sinking lid” on the amount of food salt released to the national market to achieve an average adult intake of 2300 mg sodium/day (211,000 QALYs gained, 95% uncertainty interval: 170,000 – 255,000), and from a salt tax. All the interventions produced net cost savings (except counselling – albeit still cost-effective). Cost savings were especially large with the sinking lid (NZ$ 1.1 billion, US$ 0.7 billion). Also the salt tax would raise revenue (up to NZ$ 452 million/year). Health gain per person was greater for Māori (indigenous population) men and women compared to non-Māori. Conclusions This study substantially expands on the range of previously modelled salt reduction interventions and suggests that some of these might achieve major health gains and major cost savings (particularly the regulatory interventions). They could also reduce ethnic inequalities in health.
    Electronic ISSN: 1932-6203
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  • 47
    Publication Date: 2015-04-25
    Description: by Philip K. Frykman, Agneta Nordenskjöld, Akemi Kawaguchi, Thomas T. Hui, Anna L. Granström, Zhi Cheng, Jie Tang, David M. Underhill, Iliyan Iliev, Vince A. Funari, Tomas Wester, HAEC Collaborative Research Group (HCRG) Development of potentially life-threatening enterocolitis is the most frequent complication in children with Hirschsprung disease (HSCR), even after definitive corrective surgery. Intestinal microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to compare the fecal bacterial and fungal communities of children who developed Hirschsprung-associated enterocolitis (HAEC) with HSCR patients who had never had enterocolitis. Eighteen Hirschsprung patients who had completed definitive surgery were enrolled: 9 had a history of HAEC and 9 did not. Fecal DNA was isolated and 16S and ITS-1 regions sequenced using Next Generation Sequencing and data analysis for species identification. The HAEC group bacterial composition showed a modest reduction in Firmicutes and Verrucomicrobia with increased Bacteroidetes and Proteobacteria compared with the HSCR group. In contrast, the fecal fungi composition of the HAEC group showed marked reduction in diversity with increased Candida sp ., and reduced Malassezia and Saccharomyces sp . compared with the HSCR group. The most striking finding within the HAEC group is that the Candida genus segregated into “high burden” patients with 97.8% C . albicans and 2.2% C . tropicalis compared with “low burden” patients 26.8% C . albicans and 73% C . tropicalis . Interestingly even the low burden HAEC group had altered Candida community structure with just two species compared to more diverse Candida populations in the HSCR patients. This is the first study to identify Candida sp . as potentially playing a role in HAEC either as expanded commensal species as a consequence of enterocolitis (or treatment), or possibly as pathobioants contributing to the pathogenesis of HAEC. These findings suggest a dysbiosis in the gut microbial ecosystem of HAEC patients, such that there may be dominance of fungi and bacteria predisposing patients to development of HAEC.
    Electronic ISSN: 1932-6203
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  • 48
    Publication Date: 2015-04-25
    Description: by Andrea Anzalone, Manuela Gabriel, Laura C. Estrada, Enrico Gratton Metallic nanoparticles (NPs) are able to modify the excitation and emission rates (plasmonic enhancement) of fluorescent molecules in their close proximity. In this work, we measured the emission spectra of 20 nm Gold Nanoparticles (AuNPs) fixed on a glass surface submerged in a solution of different fluorophores using a spectral camera and 2-photon excitation. While on the glass surface, we observed the presence in the emission at least 3 components: i) second harmonic signal (SHG), ii) a broad emission from AuNPS and iii) fluorescence arising from fluorophores nearby. When on the glass surface, we found that the 3 spectral components have different relative intensities when the incident direction of linear polarization was changed indicating different physical origins for these components. Then we measured by fluctuation correlation spectroscopy (FCS) the scattering and fluorescence signal of the particles alone and in a solution of 100 nM EGFP using the spectral camera or measuring the scattering and fluorescence from the particles. We observed occasional fluorescence bursts when in the suspension we added fluorescent proteins. The spectrum of these burst was devoid of the SHG and of the broad emission in contrast to the signal collected from the gold nanoparticles on the glass surface. Instead we found that the spectrum during the burst corresponded closely to the spectrum of the fluorescent protein. An additional control was obtained by measuring the cross-correlation between the reflection from the particles and the fluorescence arising from EGFP both excited at 488 nm. We found a very weak cross-correlation between the AuNPs and the fluorescence confirming that the burst originate from a few particles with a fluorescence signal.
    Electronic ISSN: 1932-6203
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  • 49
    Publication Date: 2015-04-25
    Description: by Nima Toosizadeh, Jane Mohler, Hong Lei, Saman Parvaneh, Scott Sherman, Bijan Najafi Advances in wearable technology allow for the objective assessment of motor performance in both in-home and in-clinic environments and were used to explore motor impairments in Parkinson’s disease (PD). The aims of this study were to: 1) assess differences between in-clinic and in-home gait speed, and sit-to-stand and stand-to-sit duration in PD patients (in comparison with healthy controls); and 2) determine the objective physical activity measures, including gait, postural balance, instrumented Timed-up-and-go (iTUG), and in-home spontaneous physical activity (SPA), with the highest correlation with subjective/semi-objective measures, including health survey, fall history (fallers vs. non-fallers), fear of falling, pain, Unified Parkinson's Disease Rating Scale, and PD stage (Hoehn and Yahr). Objective assessments of motor performance were made by measuring physical activities in the same sample of PD patients (n = 15, Age: 71.2±6.3 years) and age-matched healthy controls (n = 35, Age: 71.9±3.8 years). The association between in-clinic and in-home parameters, and between objective parameters and subjective/semi-objective evaluations in the PD group was assessed using linear regression-analysis of variance models and reported as Pearson correlations ( R ). Both in-home SPA and in-clinic assessments demonstrated strong discriminatory power in detecting impaired motor function in PD. However, mean effect size (0.94±0.37) for in-home measures was smaller compared to in-clinic assessments (1.30±0.34) for parameters that were significantly different between PD and healthy groups. No significant correlation was observed between identical in-clinic and in-home parameters in the PD group ( R = 0.10–0.25; p 〉0.40), while the healthy showed stronger correlation in gait speed, sit-to-stand duration, and stand-to-sit duration ( R = 0.36–0.56; p
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  • 50
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    Publication Date: 2015-04-25
    Description: by Teruhisa Takagishi, Masataka Oda, Michiko Kabura, Mie Kurosawa, Kaori Tominaga, Shiori Urano, Yoshibumi Ueda, Keiko Kobayashi, Toshihide Kobayashi, Jun Sakurai, Yutaka Terao, Masahiro Nagahama Clostridium perfringens alpha-toxin elicits various immune responses such as the release of cytokines, chemokines, and superoxide via the GM1a/TrkA complex. Alpha-toxin possesses phospholipase C (PLC) hydrolytic activity that contributes to signal transduction in the pathogenesis of gas gangrene. Little is known about the relationship between lipid metabolism and TrkA activation by alpha-toxin. Using live-cell fluorescence microscopy, we monitored transbilayer movement of diacylglycerol (DAG) with the yellow fluorescent protein-tagged C1AB domain of protein kinase C-γ (EYFP-C1AB). DAG accumulated at the marginal region of the plasma membrane in alpha toxin-treated A549 cells, which also exhibited GM1a clustering and TrkA phosphorylation. Annexin V binding assays showed that alpha-toxin induced the exposure of phosphatidylserine on the outer leaflet of the plasma membrane. However, H148G, a variant toxin which binds cell membrane and has no enzymatic activity, did not induce DAG translocation, GM1a clustering, or TrkA phosphorylation. Alpha-toxin also specifically activated endogenous phospholipase Cγ-1 (PLCγ-1), a TrkA adaptor protein, via phosphorylation. U73122, an endogenous PLC inhibitor, and siRNA for PLCγ-1 inhibited the formation of DAG and release of IL-8. GM1a accumulation and TrkA phosphorylation in A549 cells treated with alpha-toxin were also inhibited by U73122. These results suggest that the flip-flop motion of hydrophobic lipids such as DAG leads to the accumulation of GM1a and TrkA. We conclude that the formation of DAG by alpha-toxin itself (first step) and activation of endogenous PLCγ-1 (second step) leads to alterations in membrane dynamics, followed by strong phosphorylation of TrkA.
    Electronic ISSN: 1932-6203
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  • 51
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    Publication Date: 2015-04-28
    Description: by Elisabetta Marini, Roberto Buffa, Monica Contreras, Magda Magris, Glida Hidalgo, Wilmer Sanchez, Vanessa Ortiz, Maryluz Urbaez, Stefano Cabras, Martin J. Blaser, Maria G. Dominguez-Bello Background and Aims Bioelectrical impedance analysis (BIA) is a widely used technique to assess body composition and nutritional status. While bioelectrical values are affected by diverse variables, there has been little research on validation of BIA in acute illness, especially to understand prognostic significance. Here we report the use of BIA in acute febrile states induced by influenza. Methods Bioimpedance studies were conducted during an H1N1 influenza A outbreak in Venezuelan Amerindian villages from the Amazonas. Measurements were performed on 52 subjects between 1 and 40 years of age, and 7 children were re-examined after starting Oseltamivir treatment. Bioelectrical Impedance Vector Analysis (BIVA) and permutation tests were applied. Results For the entire sample, febrile individuals showed a tendency toward greater reactance (p=0.058) and phase angle (p=0.037) than afebrile individuals, while resistance and impedance were similar in the two groups. Individuals with repeated measurements showed significant differences in bioimpedance values associated with fever, including increased reactance (p
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  • 52
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    Publication Date: 2015-04-28
    Description: by Jianguo Liang, Li Liu, Mandy Cheung, Man-Po Lee, Haibo Wang, Chun-ho Li, Chun-Chung Chan, Kenji Nishiura, Xian Tang, Zhiwu Tan, Jie Peng, Ka-Wai Cheung, Wing-Cheong Yam, Zhiwei Chen The increasing prevalence of HIV-1 among men having sex with men (MSM) calls for an investigation of HIV-1 prevalence and incidence in MSM by early diagnosis to assist with early preventive interventions in Hong Kong. The participants were recruited randomly from MSM communities within a one-year period. Rapid HIV Test (RHT) and real-time dried blood spot (DBS)-based quantitative polymerase chain reaction (DBS-qPCR) were used for the early diagnosis of 474 participants. Risk behavior analysis was performed by studying information obtained from the participants during the study period. The HIV-1 prevalence and incident rates in the studied MSM population were 4.01% (19/474) and 1.47% (7/474), respectively. Three infected participants were found at the acute phase of infection by DBS-qPCR. Only 46.4% (220/474) MSM were using condoms regularly for anal sex. HIV infection significantly correlated with unprotected receptive anal sex and syphilis infection. An increased number of infections was found among foreign MSM in Hong Kong. This study is the first to use DBS-qPCR to identify acutely infected individuals in a community setting and to provide both the prevalence and incident rates of HIV-1 infection among MSM in Hong Kong. The risk analysis provided evidence that behavior intervention strengthening is necessary to fight against the increasing HIV-1 epidemic among MSM in Hong Kong and surrounding regions in Asia.
    Electronic ISSN: 1932-6203
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  • 53
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    Publication Date: 2015-04-28
    Description: by Guanzhong Ni, Jiaming Qin, Hongliang Li, Ziyi Chen, Yafang Zhou, Ziyan Fang, Yishu Chen, Jueqian Zhou, Min Huang, Liemin Zhou Purpose The aim of this study was to compare the serum levels of one-carbon metabolism (OCM) nutrients (e.g., folate, homocysteine and vitamin B12) and peripheral blood DNA methylation in epileptic patients under treatment with antiepileptic drugs (AEDs) and in healthy controls. Methods In this cross-sectional study, 60 patients with epilepsy who were receiving valproate (VPA) (n = 30) or lamotrigine (LTG) (n = 30) monotherapy were enrolled. Thirty age and sex matched healthy subjects served as the controls. Serum concentrations of OCM nutrients and peripheral blood DNA methylation status were measured. Results Compared to the control group, the VPA group had higher serum levels of homocysteine (p
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  • 54
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    Publication Date: 2015-04-28
    Description: by Tomoya Tachi, Hitomi Teramachi, Kazuhide Tanaka, Shoko Asano, Tomohiro Osawa, Azusa Kawashima, Masahiro Yasuda, Takashi Mizui, Takumi Nakada, Yoshihiro Noguchi, Teruo Tsuchiya, Chitoshi Goto The objective of our study was to clarify the impact of adverse events associated with the initial course of outpatient chemotherapy on the quality of life of breast cancer patients. We conducted a survey to assess the quality of life in 48 breast cancer patients before and after receiving their first course of outpatient chemotherapy at Gifu Municipal Hospital. Patients completed the European Quality of Life 5 Dimensions and Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs before and after 1 course of outpatient chemotherapy. European Quality of Life 5 Dimensions utility value and Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs total score decreased significantly after chemotherapy ( p
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  • 55
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    Publication Date: 2015-04-28
    Description: by Mohamed Abdo Rizk, Shimaa Abd El-Salam El-Sayed, Mohamed Alaa Terkawi, Mohamed Ahmed Youssef, El Said El Shirbini El Said, Gehad Elsayed, Sabry El-Khodery, Maged El-Ashker, Ahmed Elsify, Mosaab Omar, Akram Salama, Naoaki Yokoyama, Ikuo Igarashi A rapid and accurate assay for evaluating antibabesial drugs on a large scale is required for the discovery of novel chemotherapeutic agents against Babesia parasites. In the current study, we evaluated the usefulness of a fluorescence-based assay for determining the efficacies of antibabesial compounds against bovine and equine hemoparasites in in vitro cultures. Three different hematocrits (HCTs; 2.5%, 5%, and 10%) were used without daily replacement of the medium. The results of a high-throughput screening assay revealed that the best HCT was 2.5% for bovine Babesia parasites and 5% for equine Babesia and Theileria parasites. The IC 50 values of diminazene aceturate obtained by fluorescence and microscopy did not differ significantly. Likewise, the IC 50 values of luteolin, pyronaridine tetraphosphate, nimbolide, gedunin, and enoxacin did not differ between the two methods. In conclusion, our fluorescence-based assay uses low HCT and does not require daily replacement of culture medium, making it highly suitable for in vitro large-scale drug screening against Babesia and Theileria parasites that infect cattle and horses.
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  • 56
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    Publication Date: 2015-04-28
    Description: by Adam Bajgar, Katerina Kucerova, Lucie Jonatova, Ales Tomcala, Ivana Schneedorferova, Jan Okrouhlik, Tomas Dolezal Immune defense is energetically costly, and thus an effective response requires metabolic adaptation of the organism to reallocate energy from storage, growth, and development towards the immune system. We employ the natural infection of Drosophila with a parasitoid wasp to study energy regulation during immune response. To combat the invasion, the host must produce specialized immune cells (lamellocytes) that destroy the parasitoid egg. We show that a significant portion of nutrients are allocated to differentiating lamellocytes when they would otherwise be used for development. This systemic metabolic switch is mediated by extracellular adenosine released from immune cells. The switch is crucial for an effective immune response. Preventing adenosine transport from immune cells or blocking adenosine receptor precludes the metabolic switch and the deceleration of development, dramatically reducing host resistance. Adenosine thus serves as a signal that the “selfish” immune cells send during infection to secure more energy at the expense of other tissues.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 57
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    Publication Date: 2015-04-28
    Description: by Brian P. Lazzaro Life history theory predicts that trait evolution should be constrained by competing physiological demands on an organism. Immune defense provides a classic example in which immune responses are presumed to be costly and therefore come at the expense of other traits related to fitness. One strategy for mitigating the costs of expensive traits is to render them inducible, such that the cost is paid only when the trait is utilized. In the current issue of PLOS Biology , Bajgar and colleagues elegantly demonstrate the energetic and life history cost of the immune response that Drosophila melanogaster larvae induce after infection by the parasitoid wasp Leptopilina boulardi . These authors show that infection-induced proliferation of defensive blood cells commands a diversion of dietary carbon away from somatic growth and development, with simple sugars instead being shunted to the hematopoetic organ for rapid conversion into the raw energy required for cell proliferation. This metabolic shift results in a 15% delay in the development of the infected larva and is mediated by adenosine signaling between the hematopoietic organ and the central metabolic control organ of the host fly. The adenosine signal thus allows D . melanogaster to rapidly marshal the energy needed for effective defense and to pay the cost of immunity only when infected.
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  • 58
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    Publication Date: 2015-04-28
    Description: by The PLOS Genetics Staff
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 59
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    Publication Date: 2015-04-28
    Description: by Pedro Ramirez, Sherri Baker Mosley The increased demand for oil and gas places a burden on lands set aside for natural resource conservation. Oil and gas development alters the environment locally and on a much broader spatial scale depending on the intensity and extent of mineral resource extraction. The current increase in oil and gas exploration and production in the United States prompted an update of the number of pipelines and wells associated with oil and gas production on National Wildlife Refuge System (NWRS) lands. We obtained geospatial data on the location of oil and gas wells and pipelines within and close to the boundaries of NWRS lands (units) acquired as fee simple ( i . e . absolute title to the surface land) by the U.S. Fish and Wildlife Service. We found that 5,002 wells are located in 107 NWRS units and 595 pipelines transect 149 of the 599 NWRS units. Almost half of the wells (2,196) were inactive, one-third (1,665) were active, and the remainder of the wells were either plugged and abandoned or the status was unknown. Pipelines crossed a total of 2,155 kilometers (1,339 miles) of NWRS fee simple lands. The high level of oil and gas activity warrants follow up assessments for wells lacking information on production type or well status with emphasis on verifying the well status and identifying abandoned and unplugged wells. NWRS fee simple lands should also be assessed for impacts from brine, oil and other hydrocarbon spills, as well as habitat alteration associated with oil and gas, including the identification of abandoned oil and gas facilities requiring equipment removal and site restoration.
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  • 60
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    Publication Date: 2015-04-28
    Description: by Gerine M. A. Lodder, Ron H. J. Scholte, Ivar A. H. Clemens, Rutger C. M. E. Engels, Luc Goossens, Maaike Verhagen The goal of the present study was to examine whether lonely individuals differ from nonlonely individuals in their overt visual attention to social cues. Previous studies showed that loneliness was related to biased post-attentive processing of social cues (e.g., negative interpretation bias), but research on whether lonely and nonlonely individuals also show differences in an earlier information processing stage (gazing behavior) is very limited. A sample of 25 lonely and 25 nonlonely students took part in an eye-tracking study consisting of four tasks. We measured gazing (duration, number of fixations and first fixation) at the eyes, nose and mouth region of faces expressing emotions (Task 1), at emotion quadrants (anger, fear, happiness and neutral expression) (Task 2), at quadrants with positive and negative social and nonsocial images (Task 3), and at the facial area of actors in video clips with positive and negative content (Task 4). In general, participants tended to gaze most often and longest at areas that conveyed most social information, such as the eye region of the face (T1), and social images (T3). Participants gazed most often and longest at happy faces (T2) in still images, and more often and longer at the facial area in negative than in positive video clips (T4). No differences occurred between lonely and nonlonely participants in their gazing times and frequencies, nor at first fixations at social cues in the four different tasks. Based on this study, we found no evidence that overt visual attention to social cues differs between lonely and nonlonely individuals. This implies that biases in social information processing of lonely individuals may be limited to other phases of social information processing. Alternatively, biased overt attention to social cues may only occur under specific conditions, for specific stimuli or for specific lonely individuals.
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  • 61
    Publication Date: 2015-04-28
    Description: by Toshiya Osanai, Vinay Pasupuleti, Abhishek Deshpande, Priyaleela Thota, Yuani Roman, Adrian V. Hernandez, Ken Uchino Background Randomized controlled trials (RCTs) of endovascular therapy for acute ischemic stroke have had inconsistent results. We evaluated the efficacy and safety of endovascular therapy in published RCTs. Methods We performed a systematic review of RCTs of endovascular therapy with thrombolytic or mechanical reperfusion compared with interventions without endovascular therapy. Primary outcome was the frequency of good functional outcome (modified Rankin scale (mRS) of 0-2 at 90 days) and secondary outcomes were mortality at 90 days and symptomatic intracranial hemorrhage (sICH). Random-effects meta-analysis was performed and the Cochrane risk of bias assessment was used to evaluate quality of evidence. Results Ten studies involving 1,612 subjects were included. Endovascular therapy was not significantly associated with good functional outcome (Relative Risk [RR] =1.17; 95% CI, 0.97 to 1.42; p=0.10 and Absolute Risk Difference [ARD] =7%; 95%CI -0.1% to 14%; p=0.05); heterogeneity was moderate among studies (I 2 =30%). Mortality was unchanged with endovascular therapy (RR=0.92; 95 % CI, 0.75 to 1.13; p=0.45) and there was no difference in sICH (RR=1.20; 95 % CI, 0.79 to 1.82; p=0.39). The quality of evidence was low for all outcomes and the recommendation is weak for the use of endovascular therapy as per GRADE methodology. Conclusions Intra-arterial therapy did not show significant increase in good outcomes and no changes in either mortality or sICH in patients with acute ischemic stroke. We need further RCTs with better design and quality to evaluate the true efficacy of endovascular therapy.
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  • 62
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    Publication Date: 2015-04-28
    Description: by Oleg S. Matusovsky, Ulyana V. Shevchenko, Galina G. Matusovskaya, Apolinary Sobieszek, Anna V. Dobrzhanskaya, Nikolay S. Shelud’ko Myorod is expressed exclusively in molluscan catch muscle and localizes on the surface of thick filaments together with twitchin and myosin. Myorod is an alternatively spliced product of the myosin heavy-chain gene that contains the C-terminal rod part of myosin and a unique N-terminal domain. The unique domain is a target for phosphorylation by gizzard smooth myosin light chain kinase (smMLCK) and, perhaps, molluscan twitchin, which contains a MLCK-like domain. To elucidate the role of myorod and its phosphorylation in the catch muscle, the effect of chromatographically purified myorod on the actin-activated Mg 2+ -ATPase activity of myosin was studied. We found that phosphorylation at the N-terminus of myorod potentiated the actin-activated Mg 2+ -ATPase activity of mussel and rabbit myosins. This potentiation occurred only if myorod was phosphorylated and introduced into the ATPase assay as a co-filament with myosin. We suggest that myorod could be related to the catch state, a function specific to molluscan muscle.
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-28
    Description: by Tao Zhou, Xiaofang Chen, Zhanzhan Li, Lezhi Li Background Prospective studies have found low bilirubin levels were an important predictive factor of cardiovascular events. However, few have yet investigated possible association between serum bilirubin level and LVH in essential hypertension. The aim of the present study was to evaluate the relationship between serum bilirubin levels with LVH in newly diagnosed hypertension patients. Methods The present study evaluated the relationship between serum total bilirubin level and left ventricle hypertrophy (LVH) in newly diagnosed hypertensive patients with a sample size of 344. We divided subjects into LVH group (n=138) and non-LVH group (n=206). Physical examination, laboratory tests and echocardiography were conducted. The multivariate logistic regression model was used to verify the independent association between RDW and LVH. Results Our results found that patients with LVH had lower bilirubin levels than non-LVH ones. Stepwise multiple linear regression analysis showed total bilirubin level (B=-0.017, P =0.008) was negatively associated with left ventricle mass index (LVMI) even adjusting for some confounders. The multiples logistic regression found total bilirubin level was independently related with of LVH, as a protective factors (OR=0.91, P =0.010). Conclusion As a routine and quick laboratory examination index, serum bilirubin may be treated as novel marker for evaluating LVH risk in hypertensive patients. Cohort study with larger sample size are needed.
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-28
    Description: by The PLOS Genetics Staff
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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    Publication Date: 2015-04-28
    Description: by Apiruck Watthanasurorot, Netnapa Saelee, Amornrat Phongdara, Sittiruk Roytrakul, Pikul Jiravanichpaisal, Kenneth Söderhäll, Irene Söderhäll
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 66
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    Publication Date: 2015-04-28
    Description: by Peihu Fan, Xiaojun Li, Weiheng Su, Wei Kong, Xianggui Kong, Zhenxin Wang, Youchun Wang, Chunlai Jiang, Feng Gao The relatively high detection limit of the Enzyme-linked immunosorbent assay (ELISA) prevents its application for detection of low concentrations of antigens. To increase the sensitivity for detection of HIV-1 p24 antigen, we developed a highly sensitive nuclease-linked fluorescence oligonucleotide assay (NLFOA). Two major improvements were incorporated in NLFOA to amplify antibody-antigen interaction signals and reduce the signal/noise ratio; a large number of nuclease molecules coupled to the gold nanoparticle/streptavidin complex and fluorescent signals generated from fluorescent-labeled oligonucleotides by the nuclease. The detection limit of p24 by NLFOA was 1 pg/mL, which was 10-fold more sensitive than the conventional ELISA (10 pg/mL). The specificity was 100% and the coefficient of variation (CV) was 7.8% at low p24 concentration (1.5 pg/mL) with various concentrations of spiked p24 in HIV-1 negative sera. Thus, NLFOA is highly sensitive, specific, reproducible and user-friendly. The more sensitive detection of low p24 concentrations in HIV-1-infected individuals by NLFOA could allow detection of HIV-1 infections that are missed by the conventional ELISA at the window period during acute infection to further reduce the risk for HIV-1 infection due to the undetected HIV-1 in the blood products. Moreover, NLFOA can be easily applied to more sensitive detection of other antigens.
    Electronic ISSN: 1932-6203
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    Public Library of Science (PLoS)
    Publication Date: 2015-04-28
    Description: by You-Xin Fang, Meng He, Jun-Yi Lin, Kai-Jun Ma, Hai Zhao, Zhen Hong, Bei-Xu Li Psychiatric disorders exhibited in 13% suicidal drownings in Southwestern Croatia and 63% in Milan, but in China is unknown. This study is committed to outline the feature of a suicidal drowning with psychiatric disorder, show mental status and reveal key factor to high incidence in China. Immersed corpses were handled by SPSBMPH in its jurisdiction range. Half of immersed corpses were suicidal, and nearly half of suicides had psychiatric disorders. 104 suicidal drownings with psychiatric disorders cases from 2010.1 to 2014.6 were reviewed (21.5% of all immersed corpses, 42.1% of suicides). Most victims clothed normally, and only 2 fastened attached weights. Male victims were more and younger than female. Psycho were prone to commit suicidal drowning in warm and hot season. Psycho were prone to choose familiar area to commit suicide, 45 decedents were found in their familiar areas. Suicidal drowings were occult without suicide attempts, suicide note or abnormal clothing, but showed abnormal mental or behavior changes prior to suicide. The three leading psychiatric disorders were depression (33.7%), depression status (30.8%) and schizophrenia (20.2%). Only 44.2% decedents had visited psychiatric disorder specialist, and merely less than 10% patients could adhere to regular medication. No regular medication on psychiatric disorder was the key factor contributing to high incidence of suicide in psycho. Professional psychiatric and psychological intervention should be taken as soon as possible when they had psychiatric symptoms or suffered misfortune. Guardians should be alert to patients’ abnormality to detect their suicidal ideation and intervene, especially in warm season.
    Electronic ISSN: 1932-6203
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    Publication Date: 2015-04-28
    Description: by Yaqi Tan, Yixuan Wang, Li Li, Jinyu Xia, Shiguang Peng, Yanling He Psoriasis is an inflammatory disease characterized by the abnormal proliferation of skin cells, including dermal microvascular endothelial cells. Recently, chemokine-like factor 1 (CKLF1) was found to participate in the local inflammation and cell proliferation. To explore its role in the pathogenesis of psoriasis, the expression of both CKLF1 and its receptor (CCR4) was determined in the psoriatic lesions. Also, the effect of the C-terminal peptides (C19 and C27) of CKLF1 on the proliferation of human umbilical vein endothelial cells was studied in vitro. By immunohistochemistry and immunofluorescence, the expression of both CKLF1 and CCR4 was determined in the psoriatic lesions. The effect of C-terminal peptides on human umbilical vein endothelial cells (HUVECs) was studied in vitro by the evaluation of cell proliferation and apoptosis. The in vivo assessment was performed accordingly through the subcutaneous injection peptides on BALB/c mice. The results showed that, by immunohistochemistry, both CKLF1 and CCR4 were increasingly expressed in psoriatic lesions as compared to normal skins. Moreover, the primary umbilical vein endothelial cells exhibited higher proliferation ratio under the C19 or C27 stimulation, which was even enhanced by the addition of psoriatic sera or TNF-α. Furthermore, the enhancement of peptide simulation was accompanied with the activation of ERK1/2-MAPKs pathway. In addition, such effect of C19 and C27 was mirrored by the hyperproliferation of cutaneous microvessels in BALB/c mice that were subcutaneously injected with the two peptides. Therefore, we concluded that CKLF1 plays a role in the pathogenesis of psoriasis by promoting the proliferation of microvascular endothelial cells that possibly correlates with ERK1/2-MAPKs activation.
    Electronic ISSN: 1932-6203
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    Publication Date: 2015-04-28
    Description: by Peng Chen, Weikang Yang, Yaping Tian, Shutao Sun, Guangyu Chen, ChunYan Zhang, Fuxin Ma, Yiping Xun, Lili Shi, Chunhe Yang, Lanqing Zhao, Yabin Zhou, Hongwu Du Behçet’s disease (BD) is a chronic inflammatory disease with multisystem involvement, and it is listed as a rare disease in the United States but is common in the Middle East, China, and Japan. The aim of this study was to identify novel autoantigens in Chinese patients with BD. First, the candidate autoantigens were screened by Western blotting, and the sequences of putative antigens were identified by LC-MALDI-TOF/TOF mass spectrometry. Next, the screened protein was cloned, expressed and purified. Then, an optimized ELISA was developed, and the serological criteria were evaluated using a large number of confirmed patients. One antigen with a molecular weight of approximately 28 kDa was identified as electron transfer flavoprotein subunit beta (ETFB). Positive reactivity was detected in recombinant human ETFB sera from 38 of 92 BD patients (41 %) and 1 of 90 healthy controls (1 %).
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  • 70
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    Publication Date: 2015-04-28
    Description: by Sílvia Fontenete, Marina Leite, Nuno Guimarães, Pedro Madureira, Rui Manuel Ferreira, Céu Figueiredo, Jesper Wengel, Nuno Filipe Azevedo In recent years, there have been several attempts to improve the diagnosis of infection caused by Helicobacter pylori . Fluorescence in situ hybridization (FISH) is a commonly used technique to detect H . pylori infection but it requires biopsies from the stomach. Thus, the development of an in vivo FISH-based method (FIVH) that directly detects and allows the visualization of the bacterium within the human body would significantly reduce the time of analysis, allowing the diagnosis to be performed during endoscopy. In a previous study we designed and synthesized a phosphorothioate locked nucleic acid (LNA)/ 2’ O-methyl RNA (2’OMe) probe using standard phosphoramidite chemistry and FISH hybridization was then successfully performed both on adhered and suspended bacteria at 37°C. In this work we simplified, shortened and adapted FISH to work at gastric pH values, meaning that the hybridization step now takes only 30 minutes and, in addition to the buffer, uses only urea and probe at non-toxic concentrations. Importantly, the sensitivity and specificity of the FISH method was maintained in the range of conditions tested, even at low stringency conditions (e.g., low pH). In conclusion, this methodology is a promising approach that might be used in vivo in the future in combination with a confocal laser endomicroscope for H . pylori visualization.
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    Publication Date: 2015-04-28
    Description: by Elizabeth Stansell, Maria Panico, Kevin Canis, Poh-Choo Pang, Laura Bouché, Daniel Binet, Michael-John O'Connor, Elena Chertova, Julian Bess, Jeffrey D. Lifson, Stuart M. Haslam, Howard R. Morris, Ronald C. Desrosiers, Anne Dell As HIV-1-encoded envelope protein traverses the secretory pathway, it may be modified with N- and O-linked carbohydrate. When the gp120s of HIV-1 NL4-3, HIV-1 YU2, HIV-1 Bal, HIV-1 JRFL, and HIV-1 JRCSF were expressed as secreted proteins, the threonine at consensus position 499 was found to be O-glycosylated. For SIVmac239, the corresponding threonine was also glycosylated when gp120 was recombinantly expressed. Similarly-positioned, highly-conserved threonines in the influenza A virus H1N1 HA1 and H5N1 HA1 envelope proteins were also found to carry O-glycans when expressed as secreted proteins. In all cases, the threonines were modified predominantly with disialylated core 1 glycans, together with related core 1 and core 2 structures. Secreted HIV-1 gp140 was modified to a lesser extent with mainly monosialylated core 1 O-glycans, suggesting that the ectodomain of the gp41 transmembrane component may limit the accessibility of Thr499 to glycosyltransferases. In striking contrast to these findings, gp120 on purified virions of HIV-1 Bal and SIV CP-MAC lacked any detectable O-glycosylation of the C-terminal threonine. Our results indicate the absence of O-linked carbohydrates on Thr499 as it exists on the surface of virions and suggest caution in the interpretation of analyses of post-translational modifications that utilize recombinant forms of envelope protein.
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  • 72
    Publication Date: 2015-04-28
    Description: by Jianshe Wang, Junnian Zheng, Tianyou Tang, Feng Zhu, Yuanhu Yao, Jing Xu, Andrew Z. Wang, Longzhen Zhang Background This pilot trial is designed to determine whether PET/CT-guided radiotherapy dose escalation can improve local control while minimizing toxicity for the treatment of locally advanced nasopharyngeal carcinoma. Methods 67 patients were randomized into the three treatment arms: conventional chemoradiotherapy (group A), CT-guided dose escalation chemoradiotherapy (group B) and PET/CT-guided dose escalation chemoradiotherapy (group C). Radiotherapy was delivered using the simultaneous modulated accelerated radiation therapy (SMART) technique in the dose-escalation treatment arms. Patients received concurrent and adjuvant chemotherapy. Results The use of PET/CT significantly changed the treatment volume delineation of the gross tumor volume. 3-year local progression-free (LPF) survival rates of three groups were 83.3%, 90.9% and 100%, respectively. The 3-year regional progression-free survival (RPFS) rates were 95.8%, 95.5% and 100%, respectively. The 3-year disease free survival (DFS) rates were 79.2%, 86.4% and 95.2%, respectively. The 3-year overall survival (OS) rates were 83.3%, 90.9% and 95.2%, respectively. The 3-year disease-free survival (DFS) rates were 79.2%, 86.4% and 95.2%, respectively. No patient had grade 4 late toxicity. Conclusions PET/CT-guided dose escalation radiotherapy is well-tolerated and appears to be superior to conventional chemoradiotherapy for locally advanced NPC. Trial Registration ClinicalTrials.gov NCT02089204
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  • 73
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    Publication Date: 2015-04-28
    Description: by Andrea Valigurová, Gita G. Paskerova, Andrei Diakin, Magdaléna Kováčiková, Timur G. Simdyanov This study focused on the attachment strategy, cell structure and the host-parasite interactions of the protococcidian Eleutheroschizon duboscqi , parasitising the polychaete Scoloplos armiger . The attached trophozoites and gamonts of E . duboscqi were detected at different development stages. The parasite develops epicellularly, covered by a host cell-derived, two-membrane parasitophorous sac forming a caudal tipped appendage. Staining with Evans blue suggests that this tail is protein-rich, supported by the presence of a fibrous substance in this area. Despite the ultrastructural evidence for long filaments in the tail, it stained only weakly for F-actin, while spectrin seemed to accumulate in this area. The attachment apparatus consists of lobes arranged in one (trophozoites) or two (gamonts) circles, crowned by a ring of filamentous fascicles. During trophozoite maturation, the internal space between the parasitophorous sac and parasite turns translucent, the parasite trilaminar pellicle seems to reorganise and is covered by a dense fibrous glycocalyx. The parasite surface is organised in broad folds with grooves in between. Micropores are situated at the bottom of the grooves. A layer of filaments organised in bands, underlying the folds and ending above the attachment fascicles, was detected just beneath the pellicle. Confocal microscopy, along with the application of cytoskeletal drugs (jasplakinolide, cytochalasin D, oryzalin) confirmed the presence of actin and tubulin polymerised forms in both the parasitophorous sac and the parasite, while myosin labelling was restricted to the sac. Despite positive tubulin labelling, no microtubules were detected in mature stages. The attachment strategy of E . duboscqi shares features with that of cryptosporidia and gregarines, i.e. the parasite itself conspicuously resembles an epicellularly located gregarine, while the parasitophorous sac develops in a similar manner to that in cryptosporidia. This study provides a re-evaluation of epicellular development in other apicomplexans and directly compares their niche with that of E . duboscqi .
    Electronic ISSN: 1932-6203
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    Publication Date: 2015-04-29
    Description: by Javier Quinteiro, Pablo Manent, Lois Pérez-Diéguez, José A. González, Corrine Almeida, Evandro Lopes, Ricardo Araújo, Gilberto P. Carreira, Manuel Rey-Méndez, Nieves González-Henríquez The Azorean barnacle, Megabalanus azoricus (Pilsbry, 1916), is a Macaronesian endemic whose obscure taxonomy and the unknown relationships among forms inhabiting isolated Northern Atlantic oceanic islands is investigated by means of molecular analysis herein. Mitochondrial data from the 16S rRNA and COX1 genes support its current species status, tropical ancestry, and the taxonomic homogeneity throughout its distribution range. In contrast, at the intraspecific level and based on control region sequences, we detected an overall low level of genetic diversity and three divergent lineages. The haplogroups α and γ were sampled in the Azores, Madeira, Canary, and Cabo Verde archipelagos; whereas haplogroup β was absent from Cabo Verde. Consequently, population analysis suggested a differentiation of the Cabo Verde population with respect to the genetically homogenous northern archipelagos generated by current oceanographic barriers. Furthermore, haplogroup α, β, and γ demographic expansions occurred during the interglacial periods MIS5 (130 Kya - thousands years ago -), MIS3 (60 Kya), and MIS7 (240 Kya), respectively. The evolutionary origin of these lineages is related to its survival in the stable southern refugia and its demographic expansion dynamics are associated with the glacial-interglacial cycles. This phylogeographic pattern suggests the occurrence of genetic discontinuity informative to the delimitation of an informally defined biogeographic entity, Macaronesia, and its generation by processes that delineate genetic diversity of marine taxa in this area.
    Electronic ISSN: 1932-6203
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    Publication Date: 2015-04-29
    Description: by Kristen M. Little, Madhukar Pai, David W. Dowdy Background There is growing concern that interferon-γ release assays (IGRAs) are being used off-label for the diagnosis of active tuberculosis (TB) disease in many high-burden settings, including India, where the background prevalence of latent TB infection is high. We analyzed the costs and consequences of using IGRAs for the diagnosis of active TB in India from the perspective of the Indian TB control sector. Methods and Findings We constructed a decision analytic model to estimate the incremental cost and effectiveness of IGRAs for the diagnosis of active TB in India. We compared a reference scenario of clinical examination and non-microbiological tests against scenarios in which clinical diagnosis was augmented by the addition of either sputum smear microscopy, IGRA, or Xpert MTB/RIF. We examined costs (in 2013 US dollars) and consequences from the perspective of the Indian healthcare sector. Relative to sputum smear microscopy, use of IGRA for active TB resulted in 23,700 (95% uncertainty range, UR: 3,800 – 38,300) additional true-positive diagnoses, but at the expense of 315,700 (95% UR: 118,300 – 388,400) additional false-positive diagnoses and an incremental cost of US$49.3 million (95% UR: $34.9 – $58.0 million) (2.9 billion Indian Rupees). Relative to Xpert MTB/RIF (including the cost of treatment for drug resistant TB), use of IGRA led to 400 additional TB cases treated (95% UR: [-8,000] – 16,200), 370,600 (95% UR: 252,200 – 441,700) more false-positive diagnoses, 70,400 (95% UR: [-7,900] – 247,200) fewer disability-adjusted life years averted, and US$14.6 million (95%UR: [-$7.2] – $28.7 million) (854 million Indian Rupees) in additional costs. Conclusion Using IGRAs for diagnosis of active TB in a setting like India results in tremendous overtreatment of people without TB, and substantial incremental cost with little gain in health. These results support the policies by WHO and Standards for TB Care in India, which discourage the use of IGRAs for the diagnosis of active TB in India and similar settings.
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    Publication Date: 2015-04-29
    Description: by David S. Lopez, Run Wang, Konstantinos K. Tsilidis, Huirong Zhu, Carrie R. Daniel, Arup Sinha, Steven Canfield Objectives Caffeine is consumed by more than 85% of adults and little is known about its role on erectile dysfunction (ED) in population-based studies. We investigated the association of caffeine intake and caffeinated beverages with ED, and whether these associations vary among comorbidities for ED. Material and Method Data were analyzed for 3724 men (≥20 years old) who participated in the National Health and Nutrition Examination Survey (NHANES). ED was assessed by a single question during a self-paced, computer-assisted self-interview. We analyzed 24-h dietary recall data to estimate caffeine intake (mg/day). Multivariable logistic regression analyses using appropriate sampling weights were conducted. Results We found that men in the 3 rd (85-170 mg/day) and 4 th (171-303 mg/day) quintiles of caffeine intake were less likely to report ED compared to men in the lowest 1 st quintile (0-7 mg/day) [OR: 0.58; 95% CI, 0.37–0.89; and OR: 0.61; 95% CI, 0.38–0.97, respectively], but no evidence for a trend. Similarly, among overweight/obese and hypertensive men, there was an inverse association between higher quintiles of caffeine intake and ED compared to men in the lowest 1 st quintile, P≤0 . 05 for each quintile. However, only among men without diabetes we found a similar inverse association ( Ptrend = 0.01). Conclusion Caffeine intake reduced the odds of prevalent ED, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive, but not among diabetic men. Yet, these associations are warranted to be investigated in prospective studies.
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    Publication Date: 2015-04-29
    Description: by Wei Zhu, Yan Wu, Ming Xu, Jin-Yu Wang, Yi-Fang Meng, Zheng Gu, Jiong Lu Background Retinal vein occlusion (RVO) is a common retinal vascular disease and it is one of the most frequently reported causes of visual damage and blindness in the elderly. The current study investigated the potential association between antiphospholipid antibodies (APLA) and RVO risk by conducting a meta-analysis of case–control studies. Methods A systematic literature search of Pubmed and Embase databases was conducted in August 1 st , 2014. Odds ratios (ORs) were used to evaluate the associations between APLA and the incidence of RVO. A random-effects model was obtained for the quantitative synthesis. Results A total of 11 studies were included in this meta-analysis. A meta-analysis of all studies assessing the risk of RVO revealed that APLA was associated with a statistically increased risk of RVO incidence (OR = 5.18, 95% CI = [3.37, 7.95]). The association between anticardiolipin antibodies (ACA) and the risk of RVO was significant (n =8, OR = 4.59, 95% CI = [2.75, 7.66]). However, the association between lupus anticoagulants (LA) and risk of RVO was non-significant (n = 5, OR = 3.90, 95% CI = [0.99, 15.37]). No significant publication bias was found in the 11 selected studies. Conclusion APLA was significantly associated with the risk of RVO. Advanced analyses showed that ACA rather than LA affected the risk of RVO. Additional well-designed and well-conducted epidemiological studies are required to further our understanding of the relationship between APLA and RVO risk.
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    Publication Date: 2015-04-29
    Description: by Saeed Soleyman-Jahi, Saharnaz Nedjat, Afshin Abdirad, Niloofar Hoorshad, Reza Heidari, Kazem Zendehdel The prognostic role of matrix metalloproteinase-7 in gastric cancer survival has been widely evaluated. However, the results are controversial. We aimed to set up a meta-analysis to reach a conclusion on the prognostic significance of metalloproteinase-7 in gastric cancer survival as well as its association with clinicopathological parameters. We searched popular databases from 1988 until October 2014 to gather eligible peer-reviewed papers addressing the prognostic effect of matrix metalloproteinase-7 in gastric cancer patients' survival. The CASP check list was used for quality appraisal. Pooled hazard ratio (HR) for survival and odds ratio (OR) for association with their 95% confidence interval (CI) were considered as summary measurements. Finally, 1208 gastric cancer patients from nine studies were included in the meta-analysis. Pooled HR estimate for survival was 2.01 (95% CI = 1.62 – 2.50, P 〈 0.001), which indicated a significant poor prognostic effect for matrix metalloproteinase-7. Sensitivity analysis detected no dominancy for any study. No publication bias was detected according to Egger’s and Begg’s tests. Clinicopathological assessment revealed that higher matrix metalloproteinase-7 expression is associated with deeper invasion (pooled OR = 3.20; 95% CI = 1.14 – 8.96; P = 0.026), higher TNM stage (pooled OR = 3.67; 95% CI = 2.281-5.99; P
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  • 79
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    Publication Date: 2015-04-29
    Description: by Huimin Xu, Huasheng Wang, Qianqian Xu, Le Lv, Chunhua Yin, Xiaolu Liu, Hongwu Du, Hai Yan Harmful cyanobacterial blooms in waters have become a global environmental problem, this mainly due to the production and release of various microalgal toxins, in which microcystins (MCs) are distributed widely. Here, we focused on the study of a typical form of microcystins called microcystin-YR (MC-YR). It was found that initial 14.8 mg/L of MC-YR could be completely eliminated within 10 hr by the crude enzymes (CEs) of Sphingopyxis sp. USTB-05, a promising bacterial strain we isolated and identified in our previous study. During the enzymatic biodegradation of MC-YR with time course, the peaks of two intermediate and two final products were observed on the profiles of HPLC at the wavelengths of 238 nm and 230 nm, respectively. Based on the analysis of m/z ratios of MC-YR and its four products by LC-MS/MS, we suggested that at least four enzymes were involved in the biodegradation of MC-YR by Sphingopyxis sp. USTB-05. The first enzyme microcystinase converted cyclic MC-YR to linear MC-YR as the first product. Then the second enzyme serine protease was found to cleave the target peptide bond between alanine (Ala) and tyrosine (Tyr) of linearized MC-YR, producing a tetrapeptide and a tripeptide as second products, which were Adda-Glu-Mdha-Ala and Tyr-Masp-Arg, respectively. Next, the third enzyme peptidase converted the tetrapeptide of Adda-Glu-Mdha-Ala to Adda. And the fourth enzyme cleaved the tripeptide of Tyr-Masp-Arg to produce Tyr and dipeptide (Masp-Arg), which has never been reported. These findings will help us better understand the biodegradation pathway of MC-YR by Sphingopyxis sp. USTB-05.
    Electronic ISSN: 1932-6203
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  • 80
    Publication Date: 2015-04-29
    Description: by Susan E. Steck, Lenore Arab, Hongmei Zhang, Jeannette T. Bensen, Elizabeth T. H. Fontham, Candace S. Johnson, James L. Mohler, Gary J. Smith, Joseph L. Su, Donald L. Trump, Anna Woloszynska-Read Background African Americans (AAs) have lower circulating 25-hydroxyvitamin D3 [25(OH)D3] concentrations and higher prostate cancer (CaP) aggressiveness than other racial/ethnic groups. The purpose of the current study was to examine the relationship between plasma 25(OH)D3, African ancestry and CaP aggressiveness among AAs and European Americans (EAs). Methods Plasma 25(OH)D3 was measured using LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in 537 AA and 663 EA newly-diagnosed CaP patients from the North Carolina-Louisiana Prostate Cancer Project (PCaP) classified as having either ‘high’ or ‘low’ aggressive disease based on clinical stage, Gleason grade and prostate specific antigen at diagnosis. Mean plasma 25(OH)D3 concentrations were compared by proportion of African ancestry. Logistic regression was used to calculate multivariable adjusted odds ratios (OR) and 95% confidence intervals (95%CI) for high aggressive CaP by tertile of plasma 25(OH)D3. Results AAs with highest percent African ancestry (〉95%) had the lowest mean plasma 25(OH)D3 concentrations. Overall, plasma 25(OH)D3 was associated positively with aggressiveness among AA men, an association that was modified by calcium intake (OR T3vs.T1 : 2.23, 95%CI: 1.26–3.95 among men with low calcium intake, and OR T3vs.T1 : 0.19, 95%CI: 0.05–0.70 among men with high calcium intake). Among EAs, the point estimates of the ORs were
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    Publication Date: 2015-04-29
    Description: by Janelle Weaver