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  • 1
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Shayna Stein, Rui Zhao, Hiroshi Haeno, Igor Vivanco, Franziska Michor Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 2
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Berta Vidal, Ulkar Aghayeva, Haosheng Sun, Chen Wang, Lori Glenwinkel, Emily A. Bayer, Oliver Hobert One goal of modern day neuroscience is the establishment of molecular maps that assign unique features to individual neuron types. Such maps provide important starting points for neuron classification, for functional analysis, and for developmental studies aimed at defining the molecular mechanisms of neuron identity acquisition and neuron identity diversification. In this resource paper, we describe a nervous system-wide map of the potential expression sites of 244 members of the largest gene family in the C . elegans genome, rhodopsin-like (class A) G-protein-coupled receptor (GPCR) chemoreceptors, using classic gfp reporter gene technology. We cover representatives of all sequence families of chemoreceptor GPCRs, some of which were previously entirely uncharacterized. Most reporters are expressed in a very restricted number of cells, often just in single cells. We assign GPCR reporter expression to all but two of the 37 sensory neuron classes of the sex-shared, core nervous system. Some sensory neurons express a very small number of receptors, while others, particularly nociceptive neurons, coexpress several dozen GPCR reporter genes. GPCR reporters are also expressed in a wide range of inter- and motorneurons, as well as non-neuronal cells, suggesting that GPCRs may constitute receptors not just for environmental signals, but also for internal cues. We observe only one notable, frequent association of coexpression patterns, namely in one nociceptive amphid (ASH) and two nociceptive phasmid sensory neurons (PHA, PHB). We identified GPCRs with sexually dimorphic expression and several GPCR reporters that are expressed in a left/right asymmetric manner. We identified a substantial degree of GPCR expression plasticity; particularly in the context of the environmentally-induced dauer diapause stage when one third of all tested GPCRs alter the cellular specificity of their expression within and outside the nervous system. Intriguingly, in a number of cases, the dauer-specific alterations of GPCR reporter expression in specific neuron classes are maintained during postdauer life and in some case new patterns are induced post-dauer, demonstrating that GPCR gene expression may serve as traits of life history. Taken together, our resource provides an entry point for functional studies and also offers a host of molecular markers for studying molecular patterning and plasticity of the nervous system.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 3
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Christophe Menichelli, Olivier Gascuel, Laurent Bréhélin Comparing and aligning protein sequences is an essential task in bioinformatics. More specifically, local alignment tools like BLAST are widely used for identifying conserved protein sub-sequences, which likely correspond to protein domains or functional motifs. However, to limit the number of false positives, these tools are used with stringent sequence-similarity thresholds and hence can miss several hits, especially for species that are phylogenetically distant from reference organisms. A solution to this problem is then to integrate additional contextual information to the procedure. Here, we propose to use domain co-occurrence to increase the sensitivity of pairwise sequence comparisons. Domain co-occurrence is a strong feature of proteins, since most protein domains tend to appear with a limited number of other domains on the same protein. We propose a method to take this information into account in a typical BLAST analysis and to construct new domain families on the basis of these results. We used Plasmodium falciparum as a case study to evaluate our method. The experimental findings showed an increase of 14% of the number of significant BLAST hits and an increase of 25% of the proteome area that can be covered with a domain. Our method identified 2240 new domains for which, in most cases, no model of the Pfam database could be linked. Moreover, our study of the quality of the new domains in terms of alignment and physicochemical properties show that they are close to that of standard Pfam domains. Source code of the proposed approach and supplementary data are available at: https://gite.lirmm.fr/menichelli/pairwise-comparison-with-cooccurrence
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 4
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Sang Jae Lee, Byeong-Gu Han, Jea-Won Cho, Jang-Sik Choi, Jaekyoo Lee, Ho-Juhn Song, Jong Sung Koh, Byung Il Lee
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 5
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Soosan Hadjialirezaei, Gianfranco Picco, Richard Beatson, Joy Burchell, Bjørn Torger Stokke, Marit Sletmoen
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Igor Marín de Mas, Esther Aguilar, Erika Zodda, Cristina Balcells, Silvia Marin, Guido Dallmann, Timothy M. Thomson, Balázs Papp, Marta Cascante Epithelial-mesenchymal-transition promotes intra-tumoral heterogeneity, by enhancing tumor cell invasiveness and promoting drug resistance. We integrated transcriptomic data for two clonal subpopulations from a prostate cancer cell line (PC-3) into a genome-scale metabolic network model to explore their metabolic differences and potential vulnerabilities. In this dual cell model, PC-3/S cells express Epithelial-mesenchymal-transition markers and display high invasiveness and low metastatic potential, while PC-3/M cells present the opposite phenotype and higher proliferative rate. Model-driven analysis and experimental validations unveiled a marked metabolic reprogramming in long-chain fatty acids metabolism. While PC-3/M cells showed an enhanced entry of long-chain fatty acids into the mitochondria, PC-3/S cells used long-chain fatty acids as precursors of eicosanoid metabolism. We suggest that this metabolic reprogramming endows PC-3/M cells with augmented energy metabolism for fast proliferation and PC-3/S cells with increased eicosanoid production impacting angiogenesis, cell adhesion and invasion. PC-3/S metabolism also promotes the accumulation of docosahexaenoic acid, a long-chain fatty acid with antiproliferative effects. The potential therapeutic significance of our model was supported by a differential sensitivity of PC-3/M cells to etomoxir, an inhibitor of long-chain fatty acid transport to the mitochondria.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 7
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Jürgen Rehm, Charlotte Probst In a Perspective, Jürgen Rehm and Charlotte Probst examine the links between socioeconomic status, alcohol use, and cardiovascular mortality and discuss implications for policy.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 8
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Seoung Min Bong, Kka-bi Son, Seung-Won Yang, Jae-Won Park, Jea-Won Cho, Kyung-Tae Kim, Hackyoung Kim, Seung Jun Kim, Young Jun Kim, Byung Il Lee
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Bethan Davies, Katy M. E. Turner, Thomas Benfield, Maria Frølund, Berit Andersen, Henrik Westh, on behalf of the Danish Chlamydia Study , Helen Ward Background Nucleic Acid Amplification Tests (NAATs) are the recommended test type for diagnosing Chlamydia trachomatis (chlamydia). However, less sensitive diagnostic methods—including direct immunofluorescence (IF) and enzyme-linked immunoassay (ELISA)—remain in use in lower resourced settings. We estimate the risk of pelvic inflammatory disease (PID) following undiagnosed infection in women tested with non-NAATs and estimate the health gain from using accurate diagnostic tests. Methods and findings We used Denmark’s national Chlamydia Study dataset to extract all chlamydia tests performed in women aged 15–34 years (1998–2001). Tests were categorised as non-NAAT (IF/ELISA) or NAAT and limited to each woman’s first test in the study period. We linked test data to hospital presentations for PID within 12 months from the Danish National Patient Register. The study included 272,105 women with a chlamydia test, just under half (44.78%, n = 121,857) were tested using NAATs. Overall, 6.38% ( n = 17,353) tested positive for chlamydia and 0.64% ( n = 1,732) were diagnosed with PID within 12 months. The risk of PID following a positive chlamydia test did not differ by test type (NAAT 0.81% [95% CI 0.61–1.00], non-NAAT 0.78% [0.59–0.96]). The risk of PID following a negative test was significantly lower in women tested with NAATs compared to non-NAATs (0.55% [0.51–0.59] compared to 0.69% [0.64–0.73]; adjusted odds ratio (AOR) 0.83 [0.75–0.93]). We estimate that 18% of chlamydia infections in women tested with a non-NAAT were undiagnosed and that the risk of progression from undiagnosed chlamydia infection to PID within 12 months was 9.52% (9.30–9.68). Using non-NAATs could lead to an excess 120 cases of PID per 100,000 women tested compared to using NAATs. The key limitations of this study are under ascertainment of PID cases, misclassification bias in chlamydia and PID exposure status, bias to the association between clinical presentation and test type and the presence of unmeasured confounders (including other sexually transmitted infection [STI] diagnoses and clinical indication for chlamydia test). Conclusion This retrospective observational study estimates the positive impact on women’s reproductive health from using accurate chlamydia diagnostic tests and provides further evidence for restricting the use of inferior tests. Women with a negative chlamydia test have a 17% higher adjusted risk of PID by 12 months if they are tested using a non-NAAT compared to a NAAT.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 10
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Svetlana Pitts, Elizabeth Pelser, Julian Meeks, Dean Smith
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Dennis Pérez, Patrick Van der Stuyft, María Eugenia Toledo, Enrique Ceballos, Francisco Fabré, Pierre Lefèvre Background Within the context of a field trial conducted by the Cuban vector control program ( Aa CP), we assessed acceptability of insecticide-treated curtains (ITCs) and residual insecticide treatment (RIT) with deltamethrin by the community. We also assessed the potential influence of interviewees’ risk perceptions for getting dengue and disease severity. Methodology/principal findings We embedded a qualitative study using in-depth interviews in a cluster randomized trial (CRT) testing the effectiveness of ITCs and RIT in Santiago de Cuba. In-depth interviews (N = 38) were conducted four and twelve months after deployment of the tools with people who accepted the tools, who stopped using them and who did not accept the tools. Data analysis was deductive. Main reasons for accepting ITCs at the start of the trial were perceived efficacy and not being harmful to health. Constraints linked to manufacturer instructions were the main reason for not using ITCs. People stopped using the ITCs due to perceived allergy, toxicity and low efficacy. Few heads of households refused RIT despite the noting reasons for rejection, such as allergy, health hazard and toxicity. Positive opinions of the vector control program influenced acceptability of both tools. However, frequent insecticide fogging as part of routine Aa CP vector control actions diminished perceived efficacy of both tools and, therefore, acceptability. Fifty percent of interviewees did feel at risk for getting dengue and considered dengue a severe disease. However, this did not appear to influence acceptability of ITCs or RIT. Conclusion/significance Acceptability of ITCs and RIT was linked to acceptability of Aa CP routine vector control activities. However, uptake and use were not always an indication of acceptability. Factors leading to acceptability may be best identified using qualitative methods, but more research is needed on the concept of acceptability and its measurement.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 12
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Michele Pohlen, Nils H. Thoennissen, Jan Braess, Johannes Thudium, Christoph Schmid, Matthias Kochanek, Karl-Anton Kreuzer, Pia Lebiedz, Dennis Görlich, Hans U. Gerth, Christian Rohde, Torsten Kessler, Carsten Müller-Tidow, Matthias Stelljes, Carsten Hullerman, Thomas Büchner, Günter Schlimok, Michael Hallek, Johannes Waltenberger, Wolfgang Hiddemann, Wolfgang E. Berdel, Bernhard Heilmeier, Utz Krug
    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: 2018-01-03
    Description: by Yuzhen Mei, Xiuling Yang, Changjun Huang, Xiuren Zhang, Xueping Zhou The whitefly-transmitted geminiviruses induce severe developmental abnormalities in plants. Geminivirus-encoded C4 protein functions as one of viral symptom determinants that could induce abnormal cell division. However, the molecular mechanism by which C4 contributes to cell division induction remains unclear. Here we report that tomato leaf curl Yunnan virus (TLCYnV) C4 interacts with a glycogen synthase kinase 3 (GSK3)/SHAGGY-like kinase, designed NbSKη, in Nicotiana benthamiana . Pro32, Asn34 and Thr35 of TLCYnV C4 are critical for its interaction with NbSKη and required for C4-induced typical symptoms. Interestingly, TLCYnV C4 directs NbSKη to the membrane and reduces the nuclear-accumulation of NbSKη. The relocalization of NbSKη impairs phosphorylation dependent degradation on its substrate-Cyclin D1.1 (NbCycD1;1), thereby increasing the accumulation level of NbCycD1;1 and inducing the cell division. Moreover, NbSKη-RNAi , 35S :: NbCycD1;1 transgenic N . benthamiana plants have the similar phenotype as 35S :: C4 transgenic N . benthamiana plants on callus-like tissue formation resulted from abnormal cell division induction. Thus, this study provides new insights into mechanism of how a viral protein hijacks NbSKη to induce abnormal cell division in plants.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 14
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-03
    Description: by Natalia Cheshenko, Carl Pierce, Betsy C. Herold Herpes simplex virus (HSV) entry is associated with Akt translocation to the outer leaflet of the plasma membrane to promote a complex signaling cascade. We hypothesized that phospholipid scramblase-1 (PLSCR1), a calcium responsive enzyme that flips phosphatidylserines between membrane leaflets, might redistribute Akt to the outside during entry. Confocal imaging, biotinylation of membrane proteins and flow cytometric analysis demonstrated that HSV activates PLSCR1 and flips phosphatidylserines and Akt to the outside shortly following HSV-1 or HSV-2 exposure. Translocation was blocked by addition of a cell permeable calcium chelator, pharmacological scramblase antagonist, or transfection with small interfering RNA targeting PLSCR1. Co-immunoprecipitation and proximity ligation studies demonstrated that PLSCR1 associated with glycoprotein L at the outer leaflet and studies with gL deletion viruses indicate that this interaction facilitates subsequent restoration of the plasma membrane architecture. Ionomycin, a calcium ionophore, also induced PLSCR1 activation resulting in Akt externalization, suggesting a previously unrecognized biological phenomenon.
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  • 15
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-04
    Description: by Chenxi Qiu, Olivia C. Erinne, Jui M. Dave, Ping Cui, Huiyan Jin, Nandhini Muthukrishnan, Leung K. Tang, Sabareesh Ganesh Babu, Kenny C. Lam, Paul J. Vandeventer, Ralf Strohner, Jan Van den Brulle, Sing-Hoi Sze, Craig D. Kaplan
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 16
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by Martin Grundy, Claire Seedhouse, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents–notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors–sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by Takeo Tatsuta, Toshiyuki Satoh, Shigeki Sugawara, Akiyoshi Hara, Masahiro Hosono Malignant mesothelioma is an aggressive cancer that results from exposure to asbestos. The therapeutic options for this type of cancer are limited; therefore, the development of novel therapeutic agents is urgently required. Sialic acid-binding lectin isolated from Rana catesbeiana oocytes (cSBL) is a novel therapeutic candidate for cancer, which exhibits antitumor activity mediated through RNA degradation. In the present study, we evaluated the effect of cSBL in vitro and in vivo . Xenograft-competent H2452 and MSTO human mesothelioma cell lines were treated with cSBL, and the pathway by which cSBL induces apoptosis was analyzed. In vivo studies were performed using nude mice inoculated with one of the two cell lines, and the effects of cSBL and pemetrexed were monitored simultaneously. Furthermore, the pharmacological interactions between the three agents (pemetrexed, cisplatin and cSBL) were statistically assessed. It was demonstrated that cSBL treatments caused morphological and biochemical apoptotic changes in both cell lines. Caspase cascade analysis revealed that an intrinsic pathway mediated cSBL-induced apoptosis. The administration of cSBL significantly inhibited tumor growth in two xenograft models, without any adverse effects. Furthermore, the combination index and dose reduction index values indicated that the cSBL + pemetrexed combination showed the highest synergism, and thus potential for reducing dosage of each drug, compared with the other combinations, including the existing pemetrexed + cisplatin regimen. cSBL exerted prominent antitumor effects on malignant mesothelioma cells in vitro and in vivo , and showed favorable effects when combined with pemetrexed. These results suggest that cSBL has potential as a novel drug for the treatment of malignant mesothelioma.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 18
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-05
    Description: by Marilena P. Etna, Alessandro Sinigaglia, Angela Grassi, Elena Giacomini, Alessandra Romagnoli, Manuela Pardini, Martina Severa, Melania Cruciani, Fabiana Rizzo, Eleni Ananstasiadou, Barbara Di Camillo, Luisa Barzon, Gian Maria Fimia, Riccardo Manganelli, Eliana M. Coccia Autophagy is a primordial eukaryotic pathway, which provides the immune system with multiple mechanisms for the elimination of invading pathogens including Mycobacterium tuberculosis (Mtb). As a consequence, Mtb has evolved different strategies to hijack the autophagy process. Given the crucial role of human primary dendritic cells (DC) in host immunity control, we characterized Mtb-DC interplay by studying the contribution of cellular microRNAs (miRNAs) in the post-transcriptional regulation of autophagy related genes. From the expression profile of de-regulated microRNAs obtained in Mtb-infected human DC, we identified 7 miRNAs whose expression was previously found to be altered in specimens of TB patients. Among them, gene ontology analysis showed that miR-155, miR-155* and miR-146a target mRNAs with a significant enrichment in biological processes linked to autophagy. Interestingly, miR-155 was significantly stimulated by live and virulent Mtb and enriched in polysome-associated RNA fraction, where actively translated mRNAs reside. The putative pair interaction among the E2 conjugating enzyme involved in LC3-lipidation and autophagosome formation—ATG3—and miR-155 arose by target prediction analysis, was confirmed by both luciferase reporter assay and Atg3 immunoblotting analysis of miR-155-transfected DC, which showed also a consistent Atg3 protein and LC3 lipidated form reduction. Late in infection, when miR-155 expression peaked, both the level of Atg3 and the number of LC3 puncta per cell (autophagosomes) decreased dramatically. In accordance, miR-155 silencing rescued autophagosome number in Mtb infected DC and enhanced autolysosome fusion, thereby supporting a previously unidentified role of the miR-155 as inhibitor of ATG3 expression. Taken together, our findings suggest how Mtb can manipulate cellular miRNA expression to regulate Atg3 for its own survival, and highlight the importance to develop novel therapeutic strategies against tuberculosis that would boost autophagy.
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  • 19
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    Publication Date: 2018-01-05
    Description: by Zoe Patterson Ross, Jennifer Klunk, Gino Fornaciari, Valentina Giuffra, Sebastian Duchêne, Ana T. Duggan, Debi Poinar, Mark W. Douglas, John-Sebastian Eden, Edward C. Holmes, Hendrik N. Poinar Hepatitis B virus (HBV) is a ubiquitous viral pathogen associated with large-scale morbidity and mortality in humans. However, there is considerable uncertainty over the time-scale of its origin and evolution. Initial shotgun data from a mid-16 th century Italian child mummy, that was previously paleopathologically identified as having been infected with Variola virus (VARV, the agent of smallpox), showed no DNA reads for VARV yet did for hepatitis B virus (HBV). Previously, electron microscopy provided evidence for the presence of VARV in this sample, although similar analyses conducted here did not reveal any VARV particles. We attempted to enrich and sequence for both VARV and HBV DNA. Although we did not recover any reads identified as VARV, we were successful in reconstructing an HBV genome at 163.8X coverage. Strikingly, both the HBV sequence and that of the associated host mitochondrial DNA displayed a nearly identical cytosine deamination pattern near the termini of DNA fragments, characteristic of an ancient origin. In contrast, phylogenetic analyses revealed a close relationship between the putative ancient virus and contemporary HBV strains (of genotype D), at first suggesting contamination. In addressing this paradox we demonstrate that HBV evolution is characterized by a marked lack of temporal structure. This confounds attempts to use molecular clock-based methods to date the origin of this virus over the time-frame sampled so far, and means that phylogenetic measures alone cannot yet be used to determine HBV sequence authenticity. If genuine, this phylogenetic pattern indicates that the genotypes of HBV diversified long before the 16 th century, and enables comparison of potential pathogenic similarities between modern and ancient HBV. These results have important implications for our understanding of the emergence and evolution of this common viral pathogen.
    Print ISSN: 1553-7366
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  • 20
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    Publication Date: 2018-01-05
    Description: by Ulrike Theisen, Christian Hennig, Tobias Ring, Ralf Schnabel, Reinhard W. Köster Neuronal migration during embryonic development contributes to functional brain circuitry. Many neurons migrate in morphologically distinct stages that coincide with differentiation, requiring tight spatial regulation. It had been proposed that neurotransmitter-mediated activity could exert this control. Here, we demonstrate that intracellular calcium transients occur in cerebellar neurons of zebrafish embryos during migration. We show that depolarization increases and hyperpolarization reduces the speed of tegmental hindbrain neurons using optogenetic tools and advanced track analysis optimized for in vivo migration. Finally, we introduce a compound screening assay to identify acetylcholine (ACh), glutamate, and glycine as regulators of migration, which act regionally along the neurons’ route. We summarize our findings in a model describing how different neurotransmitters spatially interact to control neuronal migration. The high evolutionary conservation of the cerebellum and hindbrain makes it likely that polarization state-driven motility constitutes an important principle in building a functional brain.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 21
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-05
    Description: by Rosa Ana Risques, Scott R. Kennedy DNA mutations are inevitable. Despite proficient DNA repair mechanisms, somatic cells accumulate mutations during development and aging, generating cells with different genotypes within the same individual, a phenomenon known as somatic mosaicism. While the existence of somatic mosaicism has long been recognized, in the last five years, advances in sequencing have provided unprecedented resolution to characterize the extent and nature of somatic genetic variation. Collectively, these new studies are revealing a previously uncharacterized aging phenotype: the accumulation of clones with cancer driver mutations. Here, we summarize the most recent findings, which converge in the novel notion that cancer-associated mutations are prevalent in normal tissue and accumulate with aging.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 22
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-05
    Description: by Anuj Tiwari, Pramilesh Suryawanshi, Akash Raikwar, Mohammad Arif, Jan Hendrik Richardus Background Leprosy is a major public health problem in many low and middle income countries, especially in India, and contributes considerably to the global burden of the disease. Leprosy and poverty are closely associated, and therefore the economic burden of leprosy is a concern. However, evidence on patient’s expenditure is scarce. In this study, we estimate the expenditure in primary care (outpatient) by leprosy households in two different public health settings. Methodology / principal findings We performed a cross-sectional study, comparing the Union Territory of Dadra and Nagar Haveli with the Umbergaon block of Valsad, Gujrat, India. A household (HH) survey was conducted between May and October, 2016. We calculated direct and indirect expenditure by zero inflated negative binomial and negative binomial regression. The sampled households were comparable on socioeconomic indicators. The mean direct expenditure was USD 6.5 (95% CI: 2.4–17.9) in Dadra and Nagar Haveli and USD 5.4 (95% CI: 3.8–7.9) per visit in Umbergaon. The mean indirect expenditure was USD 8.7 (95% CI: 7.2–10.6) in Dadra and Nagar Haveli and USD 12.4 (95% CI: 7.0–21.9) in Umbergaon. The age of the leprosy patients and type of health facilities were the major predictors of total expenditure on leprosy primary care. The higher the age, the higher the expenditure at both sites. The private facilities are more expensive than the government facilities at both sites. If the public health system is enhanced, government facilities are the first preference for patients. Conclusions/significance An enhanced public health system reduces the patient’s expenditure and improves the health seeking behaviour. We recommend investing in health system strengthening to reduce the economic burden of leprosy.
    Print ISSN: 1935-2727
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  • 23
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Fernando Antoneli, Fernando M. Passos, Luciano R. Lopes, Marcelo R. S. Briones Divergence date estimates are central to understand evolutionary processes and depend, in the case of molecular phylogenies, on tests of molecular clocks. Here we propose two non-parametric tests of strict and relaxed molecular clocks built upon a framework that uses the empirical cumulative distribution (ECD) of branch lengths obtained from an ensemble of Bayesian trees and well known non-parametric (one-sample and two-sample) Kolmogorov-Smirnov (KS) goodness-of-fit test. In the strict clock case, the method consists in using the one-sample Kolmogorov-Smirnov (KS) test to directly test if the phylogeny is clock-like, in other words, if it follows a Poisson law. The ECD is computed from the discretized branch lengths and the parameter λ of the expected Poisson distribution is calculated as the average branch length over the ensemble of trees. To compensate for the auto-correlation in the ensemble of trees and pseudo-replication we take advantage of thinning and effective sample size, two features provided by Bayesian inference MCMC samplers. Finally, it is observed that tree topologies with very long or very short branches lead to Poisson mixtures and in this case we propose the use of the two-sample KS test with samples from two continuous branch length distributions, one obtained from an ensemble of clock-constrained trees and the other from an ensemble of unconstrained trees. Moreover, in this second form the test can also be applied to test for relaxed clock models. The use of a statistically equivalent ensemble of phylogenies to obtain the branch lengths ECD, instead of one consensus tree, yields considerable reduction of the effects of small sample size and provides a gain of power.
    Electronic ISSN: 1932-6203
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  • 24
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Marcos A. González-López, Marina Lacalle, Cristina Mata, María López-Escobar, Alfonso Corrales, Raquel López-Mejías, Javier Rueda, M. Carmen González-Vela, Miguel A. González-Gay, Ricardo Blanco, José L. Hernández Introduction Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disease which has been associated with an increased risk of adverse cardiovascular (CV) outcomes. Adequate stratification of the CV risk is an issue of major importance in patients with HS. To analyze the usefulness of carotid ultrasound (US) assessment for the CV disease risk stratification compared with a traditional score, the Framingham risk score (FRS), in a series of patients with HS. Methods Cross-sectional study of 60 patients with HS without history of CV events, diabetes mellitus or chronic kidney disease. Information on CV risk factors was collected and the FRS was calculated. Thus, the patients were classified into low, intermediate and high-CV disease risk categories based on FRS. Carotid US was performed in all participants, and the presence of atherosclerotic plaques was considered as a marker of high CV risk. Results HS patients had a mean age of 45.1±10.2 years, and 55% were female. The median FRS was 5.7 (IQR: 3.1–14.7). Twenty-four (40%) of the patients were classified into the low risk group, 28 (46.7%) in the intermediate risk group, and 8 (13.3%) into the FRS-high risk category. Noteworthy, carotid US revealed that about one-third of the patients (17/52; 32.6%) in the FRS-based low and intermediate risk categories had carotid plaques, and, therefore, they were reclassified into a high-risk category. Conclusion CV risk in HS patients may be underestimated by using the FRS. Carotid US may be useful to improve the CV risk stratification of patients with HS.
    Electronic ISSN: 1932-6203
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  • 25
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Asnakew Achaw Ayele, Abebe Basazn Mekuria, Henok Getachew Tegegn, Begashaw Melaku Gebresillassie, Alemayehu Birhane Mekonnen, Daniel Asfaw Erku Community pharmacy professionals are being widely accepted as sources of treatment and advice for managing minor ailments, largely owing to their location at the heart of the community. The aim of the present study was, therefore, to document the involvement of community pharmacy professionals in the management of minor ailments and perceived barriers that limit their provision of such services. Simulated patient (SP) visits combined with a qualitative study using in-depth interviews was conducted among community pharmacy professionals in Gondar town, Northwest Ethiopia. Scenarios of three different minor ailments (uncomplicated upper respiratory tract infection, back pain and acute diarrhea) were selected and results were reported as percentages. Pharmacy professionals were also interviewed about the barriers in the management of minor ailments. Out of 66 simulated visits, 61 cases (92.4%) provided one or more medications to the SPs. Pharmacy professionals in 16 visits asked SPs information on details of symptoms and past medical and medication history. Ibuprofen alone or in combination with paracetamol was the most commonly dispensed analgesics for back pain. Oral rehydration fluid (ORS) with zinc was the most frequently dispensed medication (33.3%) for the management of acute diarrhea followed by mebendazole (23.9%). Moreover, amoxicillin-clavulanic acid capsule (35%) followed by Amoxicillin (25%) were the most commonly dispensed antibiotics for uncomplicated upper respiratory tract infection. Lack of clinical training and poor community awareness towards the role of community pharmacists in the management of minor ailments were the main barriers for the provision of minor ailment management by community pharmacy professionals. Overall, community pharmacists provided inadequate therapy for the simulated minor ailments. Lack of access to clinical training and poor community awareness were the most commonly cited barriers for providing such services. So as to improve community pharmacists’ involvement in managing minor ailments and optimize the contribution of pharmacists, interventions should focus on overcoming the identified barriers.
    Electronic ISSN: 1932-6203
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  • 26
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by David Boisclair, Yann Décarie, François Laliberté-Auger, Pierre-Carl Michaud, Carole Vincent Objectives We assess how different scenarios of cardiovascular disease (CVD) prevention, aimed at meeting targets set by the World Health Organization (WHO) for 2025), may impact healthcare spending in Quebec, Canada over the 2050 horizon. Methods We provide long-term forecasts of healthcare use and costs at the Quebec population level using a novel dynamic microsimulation model. Using both survey and administrative data, we simulate the evolution of the Quebec population’s health status until death, through a series of dynamic transitions that accounts for social and demographic characteristics associated with CVD risk factors. Results A 25% reduction in CVD mortality between 2012 and 2025 achieved through decreased incidence could contain the pace of healthcare cost growth towards 2050 by nearly 7 percentage points for consultations with a physician, and by almost 9 percentage points for hospitalizations. Over the 2012–2050 period, the present value of cost savings is projected to amount to C$13.1 billion in 2012 dollars. The years of life saved due to improved life expectancy could be worth another C$38.2 billion. Addressing CVD mortality directly instead would bring about higher healthcare costs, but would generate more value in terms of years of life saved, at C$69.6 billion. Conclusions Potential savings associated with plausible reductions in CVD, aimed at reaching a World Health Organization target over a 12-year period, are sizeable and may help address challenges associated with an aging population.
    Electronic ISSN: 1932-6203
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  • 27
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Mi Yoon Chung, Son Hai Vu, Jordi López-Pujol, Sonia Herrando-Moraira, Sungwon Son, Gang Uk Suh, Hoa Thi Quynh Le, Myong Gi Chung The so-called “Baekdudaegan” (BDDG), a mountain range that stretches along the Korean Peninsula, has been recently proposed as a major “southern” glacial refugium for boreal or temperate plant species based on palaeoecological and, especially, genetic data. Genetic studies comparing genetic variation between population occurring on the BDDG and more northern ones (i.e. in NE China and/or in Russian Far East) are, however, still too few to draw firm conclusions on the role of the BDDG as a refugium and a source for possible northward post-glacial recolonizations. In order to fill this gap, we selected a boreal/temperate herb, Lilium cernuum , and compared levels of allozyme-based genetic diversity of five populations from NE China with five populations from South Korea (home of its hypothesized refuge areas). As a complementary tool, we used the maximum entropy algorithm implemented in MaxEnt to infer the species’ potential distribution for the present time, which was projected to different past climate scenarios for the Last Glacial Maximum (LGM). Permutation tests revealed that Korean populations harbored significantly higher levels of within-population genetic variation than those from NE China (expected heterozygosity = 0.173 vs. 0.095, respectively). Our results suggest that the lowered levels of genetic diversity in NE Chinese populations might be due to founder effects associated with post-glacial migration from southern regions. Congruent with genetic data, past distribution models showed higher probability of occurrence in southern ranges than in northern ones during the LGM. In addition, a positive correlation was detected between the expected heterozygosity and environmental LGM suitability. From a conservation perspective, our results further suggest that the southern populations in South Korea may be particularly worthy of protection.
    Electronic ISSN: 1932-6203
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  • 28
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Yan Wu, Xiao Peng Guo, Soshi Kanemoto, Yujiro Maeoka, Atsushi Saito, Rie Asada, Koji Matsuhisa, Yosuke Ohtake, Kazunori Imaizumi, Masayuki Kaneko We identified 37 ubiquitin ligases containing RING-finger and transmembrane domains. Of these, we found that RNF183 is abundantly expressed in the kidney. RNF183 predominantly localizes to the endoplasmic reticulum (ER), Golgi, and lysosome. We identified Sec16A, which is involved in coat protein complex II vesicle formation, as an RNF183-interacting protein. RNF183 colocalized with Sec16A and interacted through the central conserved domain (CCD) of Sec16A. Although Sec16A is not a substrate for RNF183, RNF183 was more rapidly degraded by the ER-associated degradation (ERAD) in the absence of Sec16A. Sec16A also stabilized the interacting ubiquitin ligase RNF152, which localizes to the lysosome and has structural similarity with RNF183. These results suggest that Sec16A appears to regulate the protein stability and localization of lysosomal ubiquitin ligases.
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  • 29
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    Publication Date: 2018-01-05
    Description: by Derek Walsh
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 30
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    Publication Date: 2018-01-05
    Description: by Wenshuo Zhou, Michael Woodson, Biswas Neupane, Fengwei Bai, Michael B. Sherman, Kyung H. Choi, Girish Neelakanta, Hameeda Sultana Molecular determinants and mechanisms of arthropod-borne flavivirus transmission to the vertebrate host are poorly understood. In this study, we show for the first time that a cell line from medically important arthropods, such as ticks, secretes extracellular vesicles (EVs) including exosomes that mediate transmission of flavivirus RNA and proteins to the human cells. Our study shows that tick-borne Langat virus (LGTV), a model pathogen closely related to tick-borne encephalitis virus (TBEV), profusely uses arthropod exosomes for transmission of viral RNA and proteins to the human- skin keratinocytes and blood endothelial cells. Cryo-electron microscopy showed the presence of purified arthropod/neuronal exosomes with the size range of 30 to 200 nm in diameter. Both positive and negative strands of LGTV RNA and viral envelope-protein were detected inside exosomes derived from arthropod, murine and human cells. Detection of Nonstructural 1 (NS1) protein in arthropod and neuronal exosomes further suggested that exosomes contain viral proteins. Viral RNA and proteins in exosomes derived from tick and mammalian cells were secured, highly infectious and replicative in all tested evaluations. Treatment with GW4869, a selective inhibitor that blocks exosome release affected LGTV loads in both arthropod and mammalian cell-derived exosomes. Transwell-migration assays showed that exosomes derived from infected-brain-microvascular endothelial cells (that constitute the blood-brain barrier) facilitated LGTV RNA and protein transmission, crossing of the barriers and infection of neuronal cells. Neuronal infection showed abundant loads of both tick-borne LGTV and mosquito-borne West Nile virus RNA in exosomes. Our data also suggest that exosome-mediated LGTV viral transmission is clathrin-dependent. Collectively, our results suggest that flaviviruses uses arthropod-derived exosomes as a novel means for viral RNA and protein transmission from the vector, and the vertebrate exosomes for dissemination within the host that may subsequently allow neuroinvasion and neuropathogenesis.
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  • 31
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    Publication Date: 2018-01-05
    Description: by Andrea N. Killian, Justin K. Hines
    Print ISSN: 1553-7366
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  • 32
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Katelyn Truong, Suzanne Bradley, Bryana Baginski, Joseph R. Wilson, Donald Medlin, Leon Zheng, R. Kevin Wilson, Matthew Rusin, Endre Takacs, Delphine Dean The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar ® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G 0 /G 1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial “pause” in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.
    Electronic ISSN: 1932-6203
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  • 33
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    Publication Date: 2018-01-05
    Description: by Darius Armstrong-James, Leon de Boer, Amelia Bercusson, Anand Shah
    Print ISSN: 1553-7366
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  • 34
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    In: PLoS ONE
    Publication Date: 2018-02-22
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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  • 35
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Shubhada Hooli, Tim Colbourn, Norman Lufesi, Anthony Costello, Bejoy Nambiar, Satid Thammasitboon, Charles Makwenda, Charles Mwansambo, Eric D. McCollum, Carina King
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  • 36
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    Publication Date: 2018-02-23
    Description: by Elizabeth J. Mateer, Cheng Huang, Nathan Y. Shehu, Slobodan Paessler Although an association between Lassa fever (LF) and sudden-onset sensorineural hearing loss (SNHL) was confirmed clinically in 1990, the prevalence of LF-induced SNHL in endemic countries is still underestimated. LF, a viral hemorrhagic fever disease caused by Lassa virus (LASV), is endemic in West Africa, causing an estimated 500,000 cases and 5,000 deaths per year. Sudden-onset SNHL, one complication of LF, occurs in approximately one-third of survivors and constitutes a neglected public health and social burden. In the endemic countries, where access to hearing aids is limited, SNHL results in a decline of the quality of life for those affected. In addition, hearing loss costs Nigeria approximately 43 million dollars per year. The epidemiology of LF-induced SNHL has not been characterized well. The complication of LF induced by SNHL is also an important consideration for vaccine development and treatments. However, research into the mechanism has been hindered by the lack of autopsy samples and relevant small animal models. Recently, the first animal model that mimics the symptoms of SNHL associated with LF was developed. Preliminary data from the new animal model as well as the clinical case studies support the mechanism of immune-mediated injury that causes SNHL in LF patients. This article summarizes clinical findings of hearing loss in LF patients highlighting the association between LASV infection and SNHL as well as the potential mechanism(s) for LF-induced SNHL. Further research is necessary to identify the mechanism and the epidemiology of LF-induced SNHL.
    Print ISSN: 1935-2727
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  • 37
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Jaynee R. Kim, Kenneth A. Hayes, Norine W. Yeung, Robert H. Cowie
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  • 38
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Rodrigo Z. Megale, Allan Pollack, Helena Britt, Jane Latimer, Vasi Naganathan, Andrew J. McLachlan, Manuela L. Ferreira
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  • 39
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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  • 40
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    Publication Date: 2018-02-23
    Description: by Warllem Junio Oliveira, Fernanda do Carmo Magalhães, Andressa Mariana Saldanha Elias, Vanessa Normandio de Castro, Vivian Favero, Catieli Gobetti Lindholz, Áureo Almeida Oliveira, Fernando Sergio Barbosa, Frederico Gil, Maria Aparecida Gomes, Carlos Graeff-Teixeira, Martin Johannes Enk, Paulo Marcos Zech Coelho, Mariângela Carneiro, Deborah Aparecida Negrão-Corrêa, Stefan Michael Geiger Background In some tropical countries, such as Brazil, schistosomiasis control programs have led to a significant reduction in the prevalence and parasite burden of endemic populations. In this setting, the Kato-Katz technique, as the standard diagnostic method for the diagnosis of Schistosoma mansoni infections, which involves the analysis of two slides from one fecal sample, loses its sensitivity. As a result, a significant number of infected individuals are not detected. The objective of this study was to perform extensive parasitological testing of up to three fecal samples and include a rapid urine test (POC-CCA) in a moderate prevalence area in Northern Minas Gerais, Brazil, and evaluate the performance of each test separately and in combination. Methods and findings A total of 254 individuals were examined with variants of the standard Kato-Katz technique (up to18 Kato-Katz slides prepared from three fecal samples), a modified Helmintex (30 g of feces), the saline gradient (500 mg of feces), and the POC-CCA methods. We established a reference standard taking into consideration all the positive results in any of the parasitological exams. Evaluation of the parasite burden by two Kato-Katz slides confirmed that most of the individuals harbored a light infection. When additional slides and different parasitological methods were included, the estimated prevalence rose 2.3 times, from 20.4% to 45.9%. The best sensitivity was obtained with the Helmintex method (84%). All parasitological methods readily detected a high or moderate intensity of infection; however, all lost their high sensitivity in the case of low or very low intensity infections. The overall sensitivity of POC-CCA (64.9%) was similar to the six Kato-Katz slides from three fecal samples. However, POC-CCA showed low concordance (κ = 0.34) when compared with the reference standard. Conclusions The recommended Kato-Katz method largely underestimated the prevalence of S . mansoni infection. Because the best performance was achieved with a modified Helmintex method, this technique might serve as a more precise reference standard. An extended number of Kato-Katz slides in combination with other parasitological methods or with POC-CCA was able to detect more than 80% of egg-positive individuals; however, the rapid urine test (POC-CCA) produced a considerable percentage of false positive results.
    Print ISSN: 1935-2727
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  • 41
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    Publication Date: 2018-02-23
    Description: by Nattawan Palavutitotai, Anupop Jitmuang, Sasima Tongsai, Pattarachai Kiratisin, Nasikarn Angkasekwinai Background The incidence of nosocomial infections from extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) has been increasing worldwide. We investigated the prevalence and factors associated with XDR-PA infections, including the factors that predict mortality. Methods We retrospectively studied a cohort of adult, hospitalized patients with P . aeruginosa (PA) infections between April and December 2014. Results Of the 255 patients with PA infections, 56 (22%) were due to XDR-PA, 32 (12.5%) to multidrug resistant Pseudomonas aeruginosa (MDR-PA), and 167 (65.5%) to non-MDR PA. Receiving total parenteral nutrition (adjusted OR [aOR] 6.21; 95% CI 1.05–36.70), prior carbapenem use (aOR 4.88; 95% CI 2.36–10.08), and prior fluoroquinolone use (aOR 3.38; 95% CI 1.44–7.97) were independently associated with the XDR-PA infections. All XDR-PA remained susceptible to colistin. Factors associated with mortality attributable to the infections were the presence of sepsis/septic shock (aOR 11.60; 95% CI 4.66–28.82), admission to a medical department (aOR 4.67; 95% CI 1.81–12.06), receiving a central venous catheter (aOR 3.78; 95% CI 1.50–9.57), and XDR-PA infection (aOR 2.73; 95% CI 1.05–7.08). Conclusion The prevalence of XDR-PA infections represented almost a quarter of Pseudomonas aeruginosa hospital-acquired infections and rendered a higher mortality. The prompt administration of an appropriate empirical antibiotic should be considered when an XDR-PA infection is suspected.
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  • 42
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Ying Huo, Yaohua Zhang, Huifen Guo, Yingjuan Liu, Qi Fang, Jianxu Zhang The central 5-hydroxytryptamine system impairs sociosexual behaviors and olfaction preferences in sexually naive mice. However, it remains unknown whether reproductive experiences impart an effect on the sexual olfactory preferences of female mice lacking central serotonin. Here, we aimed at examining such effects and the underlying mechanisms using Tph2 knockout female mice. Sexually naive Tph2 −/− female mice failed to recognize olfactory cues regarding sex, genetic relatedness, and social hierarchy despite exhibiting normal olfactory discrimination. However, reproduction-experienced Tph2 −/− female mice recovered sexual olfactory preferences, as did sexually naive Tph2 +/+ females. Meanwhile, both the estrogen receptor α and oxytocin receptor in the amygdala of reproduction-experienced Tph2 −/− females presented upregulated expression at the mRNA level and an upward tendency at the protein level vs. sexually naive Tph2 −/− females. Intracerebroventricular administration of a combination of estrogen receptor α and oxytocin receptor agonists, but not either agent alone, could restore the sexual olfactory preferences of sexually naive Tph2 −/− female mice to some degree. We speculate that estrogen receptor α and oxytocin receptor activation in the amygdala after reproductive experiences restores sexual olfactory recognition in Tph2 −/− female mice.
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  • 43
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Heng-Fu Lin, Ying-Da Chen, Shyr-Chyr Chen Laparoscopy has been used for the diagnosis and treatment for hemodynamically stable patients with penetrating abdominal trauma. This study evaluated whether diagnostic and therapeutic laparoscopy can be used as effectively in select patients with blunt abdominal trauma. All hemodynamically stable patients undergoing operations for blunt abdominal trauma over a 10-year period (2006–2015) at a tertiary medical center were included. Patients undergoing laparotomy were categorized as group A. Patients who underwent laparoscopy were categorized as group B. The clinical outcomes of the 2 groups were compared. There were 139 patients in group A and 126 patients in group B. Group A patients were more severely injured (mean injury severity score of 23.3 vs. 18.9, P 〈 .001) and had a higher frequency of traumatic brain injuries (25.2% vs. 14.3%, P = .039). The sensitivity and specificity of diagnostic laparoscopy for patients in group B was 99.1% and 100.0%, respectively. No non-therapeutic laparotomies were performed in group B, and the success rate of therapeutic laparoscopy was 92.0% (103/112) for patients with significant intra-abdominal injuries. Patients in the 2 groups had similar perioperative and postoperative outcomes in terms of operation times, blood loss, blood transfusion requirements, mortality, and complications (all, P 〉 .05). Laparoscopy is a feasible and safe tool for the diagnosis and treatment of hemodynamically stable patients with blunt abdominal trauma who require surgery.
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  • 44
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Robert Y. Fidler, Jessica Carroll, Kristen W. Rynerson, Danielle F. Matthews, Ralph G. Turingan Human fishing effort is size-selective, preferentially removing the largest individuals from harvested stocks. Intensive, size-specific fishing mortality induces directional shifts in phenotypic frequencies towards the predominance of smaller and earlier-maturing individuals, which are among the primary causes of declining fish biomass. Fish that reproduce at smaller size and younger age produce fewer, smaller, and less viable larvae, severely reducing the reproductive capacity of harvested populations. Marine protected areas (MPAs) are extensively utilized in coral reefs for fisheries management, and are thought to mitigate the impacts of size-selective fishing mortality and supplement fished stocks through larval export. However, empirical evidence of disparities in fitness-relevant phenotypes between MPAs and adjacent fished reefs is necessary to validate this assertion. Here, we compare key life-history traits in three coral-reef fishes ( Acanthurus nigrofuscus , Ctenochaetus striatus , and Parupeneus multifasciatus ) between MPAs and fished reefs in the Philippines. Results of our analyses support previous hypotheses regarding the impacts of MPAs on phenotypic traits. Asymptotic length (L inf ) and growth rates ( K ) differed between conspecifics in MPAs and fished reefs, with protected populations exhibiting phenotypes that are known to confer higher fecundity. Additionally, populations demonstrated increases in length at 50% maturity (L 50 ) inside MPAs compared to adjacent areas, although age at 50% maturity (A 50 ) did not appear to be impacted by MPA establishment. Shifts toward advantageous phenotypes were most common in the oldest and largest MPAs, but occurred in all of the MPAs examined. These results suggest that MPAs may provide protection against the impacts of size-selective harvest on life-history traits in coral-reef fishes.
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Paige M. Chorner, Roger A. Moorehead AKT is a serine-threonine kinase implicated in tumorigenesis as a central regulator of cellular growth, proliferation, survival, and metabolism. Activated AKT is commonly overexpressed in non-small cell lung cancer (NSCLC) and accordingly AKT inhibitors are under clinical investigation for NSCLC treatment. Thus far, the AKT inhibitors being evaluated broadly target all three (1–3) AKT isoforms but recent evidence suggests opposing roles in lung tumorigenesis where loss of Akt1 inhibits while the loss of Akt2 enhances lung tumor development. Based on these findings, we hypothesized that selective inhibition of AKT-1 would be a more effective therapeutic strategy than pan-AKT inhibition for NSCLC treatment. Using six NSCLC cell lines, we found that the AKT-1 inhibitor, A-674563, was significantly more effective at reducing NSCLC cell survival relative to the pan-AKT inhibitor MK-2206. Comparison of the downstream effects of the inhibitors suggests that altered cell cycle progression and off-target CDK2 inhibition are likely vital to the improved efficacy of A-674563 over MK-2206.
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  • 46
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Wanxue Wang, Zhenni Yue, Zhengping Tian, Yiran Xie, Jiamiao Zhang, Yuanping She, Bing Yang, Yuan Ye, Yihua Yang The molecular mechanisms of normal cervical squamous epithelium advancing to cervical intraepithelial neoplasia (CIN) and eventually to cervical squamous cell carcinoma (CSCC) are largely unknown. This study explored abnormal expression of Yin Yang 1 (YY1) in cervical cancer and its correlation with the expression of E-cadherin and human papillomavirus (HPV) 16 E6. YY1, E-cadherin and HPV16 E6 expression were detected by immunohistochemistry in 90 cervical tissue specimens collected from 30 patients with hysteromyoma, 15 patients with CIN I, 15 patients with CIN II-III, and 30 patients with CSCC. The H-score method was employed to measure the expression of YY1, E-cadherin and HPV16 E6. Increased expression of YY1 and HPV16 E6, and the decreased expression levels of E-cadherin were strongly associated with malignant transformation of the cervical epithelium and the histological progression of CSCC. The expression of YY1 in cervical tissues was inversely correlated with E-cadherin expression, and positively correlated with HPV16 E6 expression. Expression of YY1 in CSCC tissues was not significantly correlated with tumor differentiation, but was significantly correlated with an advanced clinical stage of CSCC. These results suggest that up-regulation of YY1 is closely associated with the progression of CSCC, and YY1 may play an important role in the pathogenesis of cervical cancer by modulating the expression of E-cadherin and HPV16 E6.
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  • 47
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Hyo Jung Sim, Sang-Hyun Kim, Kyung-Jae Myung, Taejoon Kwon, Hyun-Shik Lee, Tae Joo Park The airway epithelium in human plays a central role as the first line of defense against environmental contaminants. Most respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and respiratory infections, disturb normal muco-ciliary functions by stimulating the hypersecretion of mucus. Several muco-active agents have been used to treat hypersecretion symptoms in patients. Current muco-active reagents control mucus secretion by modulating either airway inflammation, cholinergic parasympathetic nerve activities or by reducing the viscosity by cleaving crosslinking in mucin and digesting DNAs in mucus. However, none of the current medication regulates mucus secretion by directly targeting airway goblet cells. The major hurdle for screening potential muco-active agents that directly affect the goblet cells, is the unavailability of in vivo model systems suitable for high-throughput screening. In this study, we developed a high-throughput in vivo model system for identifying muco-active reagents using Xenopus laevis embryos. We tested mucus secretion under various conditions and developed a screening strategy to identify potential muco-regulators. Using this novel screening technique, we identified narasin as a potential muco-regulator. Narasin treatment of developing Xenopus embryos significantly reduced mucus secretion. Furthermore, the human lung epithelial cell line, Calu-3, responded similarly to narasin treatment, validating our technique for discovering muco-active reagents.
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  • 48
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Ksenia S. Onufrieva, Alexey V. Onufriev An accurate quantitative relationship between key characteristics of an insect population, such as season-long and peak abundances, can be very useful in pest management programs. To the best of our knowledge, no such relationship has yet been established. Here we establish a predictive linear relationship between insect catch M pw during the week of peak abundance, the length of seasonal flight period, F (number of weeks) and season-long cumulative catch (abundance) A = 0.41 M pw F . The derivation of the equation is based on several general assumptions and does not involve fitting to experimental data, which implies generality of the result. A quantitative criterion for the validity of the model is presented. The equation was tested using extensive data collected on captures of male gypsy moths Lymantria dispar (L.) (Lepidoptera: Erebidae) in pheromone-baited traps during 15 years. The model was also tested using trap catch data for two species of mosquitoes, Culex pipiens (L.) (Diptera: Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae), in Gravid and BG-sentinel mosquito traps, respectively. The simple, parameter-free equation approximates experimental data points with relative error of 13% and R 2 = 0.997, across all of the species tested. For gypsy moth, we also related season-long and weekly trap catches to the daily trap catches during peak flight. We describe several usage scenarios, in which the derived relationships are employed to help link results of small-scale field studies to the operational pest management programs.
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  • 49
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Alexandra A. Portnova, Gaurav Mukherjee, Keshia M. Peters, Ann Yamane, Katherine M. Steele Assistive technology, such as wrist-driven orthoses (WDOs), can be used by individuals with spinal cord injury to improve hand function. A lack of innovation and challenges in obtaining WDOs have limited their use. These orthoses can be heavy and uncomfortable for users and also time-consuming for orthotists to fabricate. The goal of this research was to design a WDO with user (N = 3) and orthotist (N = 6) feedback to improve the accessibility, customizability, and function of WDOs by harnessing advancements in 3D-printing. The 3D-printed WDO reduced hands-on assembly time to approximately 1.5 hours and the material costs to $15 compared to current fabrication methods. Varying improvements in users' hand function were observed during functional tests, such as the Jebsen Taylor Hand Function Test. For example, one participant's ability on the small object task improved by 29 seconds with the WDO, while another participant took 25 seconds longer to complete this task with the WDO. Two users had a significant increase in grasp strength with the WDO (13–122% increase), while the other participant was able to perform a pinching grasp for the first time. The WDO designs are available open-source to increase accessibility and encourage future innovation.
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  • 50
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Dayse Távora-Vieira, Andre Wedekind, Roberta Marino, Suzanne C. Purdy, Gunesh P. Rajan Objectives To assess the use of cortical auditory evoked potentials (CAEPs) to verify, and if necessary, optimize the cochlear implant (CI) fitting of adult CI users with postlingual single-sided deafness (SSD). Methods Sound field cortical responses to the speech tokens /m/, /g/, /t/, and /s/ were recorded from input to the CI while the normal hearing ear was masked. Responses were evaluated by visual inspection and classified as presence or absence of the CAEPs components P1, N1, P2. In case of an absence fitting was adjusted accordingly. After fitting, subjects were asked to use their new setting for 2–3 weeks for acclimatization purposes and then return for retesting. At retesting, new CAEP recordings were performed to objectively ensure that the new fitting maps effectively activated the auditory cortex. Results In 14/19 subjects, as per visual inspection, clear CAEPs were recorded by each speech token and were, therefore, not refit. In the other 5 subjects, CAEPs could not be evoked for at least one speech token. The fitting maps in these subjects were adjusted until clear CAEPs were evoked for all 4 speech tokens. Conclusions CAEP can be used to quickly and objectively verify the suitability of CI fitting in experienced adult CI users with SSD. If used in the early post-implantation stage, this method could help CI users derive greater benefit for CI use and, therefore, be more committed to auditory training.
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  • 51
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    Publication Date: 2018-02-23
    Description: by Thamir Alandijany, Ashley P. E. Roberts, Kristen L. Conn, Colin Loney, Steven McFarlane, Anne Orr, Chris Boutell
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  • 52
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    Publication Date: 2018-02-23
    Description: by Kyle Burrows, Frann Antignano, Alistair Chenery, Michael Bramhall, Vladimir Korinek, T. Michael Underhill, Colby Zaph The intestinal immune system must be able to respond to a wide variety of infectious organisms while maintaining tolerance to non-pathogenic microbes and food antigens. The Vitamin A metabolite all- trans -retinoic acid (atRA) has been implicated in the regulation of this balance, partially by regulating innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of atRA-dependent intestinal immunity and homeostasis remain elusive. Here we define a role for the transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) in the regulation of ILC responses in the intestine. Intestinal ILCs express HIC1 in a vitamin A-dependent manner. In the absence of HIC1, group 3 ILCs (ILC3s) that produce IL-22 are lost, resulting in increased susceptibility to infection with the bacterial pathogen Citrobacter rodentium . Thus, atRA-dependent expression of HIC1 in ILC3s regulates intestinal homeostasis and protective immunity.
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  • 53
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Ji Hee Yu, Kyungdo Han, Nam Hoon Kim, Hye Jin Yoo, Ji A. Seo, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Nan Hee Kim Although sleep duration has been extensively studied in metabolic diseases, few studies have investigated the impact of sleep duration on chronic kidney disease. The aim of this study was to examine the relationship between sleep duration and albuminuria in the general population. Among 24,948 adults who participated in the 2011–2014 KNHANES, a total of 19,994 subjects were included in this analysis. Subjects were categorized into the following five groups according to self-reported sleep duration: less than 5 h, 6 h, 7 h, 8 h, and more than 9 h. The association between sleep duration and urinary albumin-creatinine ratio (UACR) was examined cross-sectionally. Subjects with both short and long sleep durations were significantly associated with higher UACR levels and higher proportions of patients with microalbuminuria (30–299 mg/g) and macroalbuminuria (≥300 mg/g) compared to those with a sleep duration of 7 hours. The U-shaped association between sleep duration and UACR remained significant even after adjustment for potential confounders, including age, sex, body mass index, smoking, alcohol, education, income, exercise, estimated glomerular filtration rate, diabetes mellitus, hypertension and hypercholesterolemia. The U-shaped association is more evident in the subgroup aged 65 or older, or in female subjects. Our findings suggest that both short and long sleep durations have a U-shaped association with UACR levels in the general population, independent of potential confounders.
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  • 54
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    Publication Date: 2018-02-23
    Description: by Jennifer Claire Hoving
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  • 55
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    Publication Date: 2018-02-23
    Description: by Ying Wang, Craig L. Zirbel, Neocles B. Leontis, Biao Ding
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  • 56
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    Publication Date: 2018-02-23
    Description: by Louise E. Hogan, Joshua Vasquez, Kristen S. Hobbs, Emily Hanhauser, Brandon Aguilar-Rodriguez, Rajaa Hussien, Cassandra Thanh, Erica A. Gibson, Alexander B. Carvidi, Louis C. B. Smith, Shahzada Khan, Martin Trapecar, Shomyseh Sanjabi, Ma Somsouk, Cheryl A. Stoddart, Daniel R. Kuritzkes, Steven G. Deeks, Timothy J. Henrich HIV-1-infected cells persist indefinitely despite the use of combination antiretroviral therapy (ART), and novel therapeutic strategies to target and purge residual infected cells in individuals on ART are urgently needed. Here, we demonstrate that CD4 + T cell-associated HIV-1 RNA is often highly enriched in cells expressing CD30, and that cells expressing this marker considerably contribute to the total pool of transcriptionally active CD4 + lymphocytes in individuals on suppressive ART. Using in situ RNA hybridization studies, we show co-localization of CD30 with HIV-1 transcriptional activity in gut-associated lymphoid tissues. We also demonstrate that ex vivo treatment with brentuximab vedotin, an antibody-drug conjugate (ADC) that targets CD30, significantly reduces the total amount of HIV-1 DNA in peripheral blood mononuclear cells obtained from infected, ART-suppressed individuals. Finally, we observed that an HIV-1-infected individual, who received repeated brentuximab vedotin infusions for lymphoma, had no detectable virus in peripheral blood mononuclear cells. Overall, CD30 may be a marker of residual, transcriptionally active HIV-1 infected cells in the setting of suppressive ART. Given that CD30 is only expressed on a small number of total mononuclear cells, it is a potential therapeutic target of persistent HIV-1 infection.
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  • 57
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    Publication Date: 2018-02-23
    Description: by Jarrod J. Mousa, Elad Binshtein, Stacey Human, Rachel H. Fong, Gabriela Alvarado, Benjamin J. Doranz, Martin L. Moore, Melanie D. Ohi, James E. Crowe Jr. Respiratory syncytial virus (RSV) is a major human pathogen that infects the majority of children by two years of age. The RSV fusion (F) protein is a primary target of human antibodies, and it has several antigenic regions capable of inducing neutralizing antibodies. Antigenic site IV is preserved in both the pre-fusion and post-fusion conformations of RSV F. Antibodies to antigenic site IV have been described that bind and neutralize both RSV and human metapneumovirus (hMPV). To explore the diversity of binding modes at antigenic site IV, we generated a panel of four new human monoclonal antibodies (mAbs) and competition-binding suggested the mAbs bind at antigenic site IV. Mutagenesis experiments revealed that binding and neutralization of two mAbs (3M3 and 6F18) depended on arginine (R) residue R429. We discovered two R429-independent mAbs (17E10 and 2N6) at this site that neutralized an RSV R429A mutant strain, and one of these mAbs (17E10) neutralized both RSV and hMPV. To determine the mechanism of cross-reactivity, we performed competition-binding, recombinant protein mutagenesis, peptide binding, and electron microscopy experiments. It was determined that the human cross-reactive mAb 17E10 binds to RSV F with a binding pose similar to 101F, which may be indicative of cross-reactivity with hMPV F. The data presented provide new concepts in RSV immune recognition and vaccine design, as we describe the novel idea that binding pose may influence mAb cross-reactivity between RSV and hMPV. Characterization of the site IV epitope bound by human antibodies may inform the design of a pan-Pneumovirus vaccine.
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  • 58
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    Publication Date: 2018-02-23
    Description: by Marco Biddau, Anne Bouchut, Jack Major, Tracy Saveria, Julie Tottey, Ojore Oka, Marcel van-Lith, Katherine Elizabeth Jennings, Jana Ovciarikova, Amy DeRocher, Boris Striepen, Ross Frederick Waller, Marilyn Parsons, Lilach Sheiner Apicomplexan parasites are global killers, being the causative agents of diseases like toxoplasmosis and malaria. These parasites are known to be hypersensitive to redox imbalance, yet little is understood about the cellular roles of their various redox regulators. The apicoplast, an essential plastid organelle, is a verified apicomplexan drug target. Nuclear-encoded apicoplast proteins traffic through the ER and multiple apicoplast sub-compartments to their place of function. We propose that thioredoxins contribute to the control of protein trafficking and of protein function within these apicoplast compartments. We studied the role of two Toxoplasma gondii apicoplast thioredoxins ( Tg ATrx), both essential for parasite survival. By describing the cellular phenotypes of the conditional depletion of either of these redox regulated enzymes we show that each of them contributes to a different apicoplast biogenesis pathway. We provide evidence for Tg ATrx1’s involvement in ER to apicoplast trafficking and Tg ATrx2 in the control of apicoplast gene expression components. Substrate pull-down further recognizes gene expression factors that interact with Tg ATrx2. We use genetic complementation to demonstrate that the function of both Tg ATrxs is dependent on their disulphide exchange activity. Finally, Tg ATrx2 is divergent from human thioredoxins. We demonstrate its activity in vitro thus providing scope for drug screening. Our study represents the first functional characterization of thioredoxins in Toxoplasma , highlights the importance of redox regulation of apicoplast functions and provides new tools to study redox biology in these parasites.
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  • 59
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Chonticha Saisawang, Atichat Kuadkitkan, Prasert Auewarakul, Duncan R. Smith, Albert J. Ketterman It has been estimated for dengue infection that the global population at risk is 3.5 billion people, which makes dengue an important public health problem. The causative agents of dengue are dengue viruses. For dengue virus replication, the dengue virus NS5 protein is of special importance as it has several enzyme activities important for viral replication. Previous reports of phosphorylation and SUMOylation of dengue NS5 have shown these protein modifications have important consequences for NS5 functions. In this report we identify glutathionylation, another reversible post translation modification that impacts on NS5 enzyme activity. Using dengue virus infected cells we employed specific antibodies and mass spectrometry to identify 3 cysteine residues of NS5 protein as being glutathionylated. Glutathionylation is a post translational protein modification where glutathione is covalently attached to a cysteine residue. We showed glutathionylation occurs on 3 conserved cysteine residues of dengue NS5. Then we generated two flavivirus recombinant full length proteins, dengue NS5 and Zika NS5, to characterize two of the NS5 enzyme activities, namely, guanylyltransferase and RNA-dependent RNA polymerase activities. We show glutathionylation of dengue and Zika NS5 affects enzyme activities of the two flavivirus proteins. The data suggests that glutathionylation is a general feature of the flavivirus NS5 protein and the modification has the potential to modulate several of the NS5 enzyme functions.
    Electronic ISSN: 1932-6203
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  • 60
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Meha Bhatt, Stefan Perera, Laura Zielinski, Rebecca B. Eisen, Sharon Yeung, Wala El-Sheikh, Jane DeJesus, Sumathy Rangarajan, Heather Sholer, Elizabeth Iordan, Pam Mackie, Shofiqul Islam, Mahshid Dehghan, Lehana Thabane, Zainab Samaan Background Suicidal behaviour remains challenging for clinicians to predict, with few established risk factors and warning signs among psychiatric patients. Aim We aimed to describe characteristics and identify risk factors for suicide attempts among patients with psychiatric disorders. Methods Multivariable logistic regression analysis, adjusted for clinically important confounders, was employed to determine risk factors for suicide attempts within a psychiatric patient population. Results The case (n = 146) and control groups (n = 104) did not differ significantly with regards to sociodemographic characteristics. The majority of the participants who had attempted suicide did so with high intent to die, and expected to die without medical intervention. The primary method of attempt was pharmaceutical overdose among the case participants (73.3%). Results showed impulsivity (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.03–1.30) and borderline personality symptoms (OR = 1.07, 95% CI = 1.01–1.13) were significantly associated with attempted suicide. Conclusions Our findings indicate that known sociodemographic risk factors for suicide may not apply within psychiatric populations. Prevention strategies for suicidal behaviour in psychiatric patients may be effective, including limited access to means for suicide attempts (i.e. excess pharmaceutical drugs) and target screening for high-risk personality and impulsivity traits.
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  • 61
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    In: PLoS ONE
    Publication Date: 2018-02-23
    Description: by Peter C. van den Akker, Anna M. G. Pasmooij, Hans Joenje, Robert M. W. Hofstra, Gerard J. te Meerman, Marcel F. Jonkman Revertant mosaicism, or “natural gene therapy”, is the phenomenon in which germline mutations are corrected by somatic events. In recent years, revertant mosaicism has been identified in all major types of epidermolysis bullosa, the group of heritable blistering disorders caused by mutations in the genes encoding epidermal adhesion proteins. Moreover, revertant mosaicism appears to be present in all patients with a specific subtype of recessive epidermolysis bullosa. We therefore hypothesized that revertant mosaicism should be expected at least in all patients with recessive forms of epidermolysis bullosa. Naturally corrected, patient-own cells are of extreme interest for their promising therapeutic potential, and their presence in all patients would open exciting, new treatment perspectives to those patients. To test our hypothesis, we determined the probability that single nucleotide reversions occur in patients’ skin using a mathematical developmental model. According to our model, reverse mutations are expected to occur frequently (estimated 216x) in each patient’s skin. Reverse mutations should, however, occur early in embryogenesis to be able to drive the emergence of recognizable revertant patches, which is expected to occur in only one per ~10,000 patients. This underestimate, compared to our clinical observations, can be explained by the “late-but-fitter revertant cell” hypothesis: reverse mutations arise at later stages of development, but provide revertant cells with a selective growth advantage in vivo that drives the development of recognizable healthy skin patches. Our results can be extrapolated to any other organ with stem cell division numbers comparable to skin, which may offer novel future therapeutic options for other genetic conditions if these revertant cells can be identified and isolated.
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  • 62
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    Publication Date: 2018-02-24
    Description: by Yan Huo, Yuanling Yu, Liying Chen, Qiong Li, Mengting Zhang, Zhiyu Song, Xiaoying Chen, Rongxiang Fang, Lili Zhang Insect vitellogenin (Vg) has been considered to be synthesized in the fat body. Here, we found that abundant Vg protein is synthesized in Laodelphax striatellus hemocytes as well. We also determined that only the hemocyte-produced Vg binds to Rice stripe virus (RSV) in vivo . Examination of the subunit composition of L . striatellus Vg (LsVg) revealed that LsVg was processed differently after its expression in different tissues. The LsVg subunit able to bind to RSV exist stably only in hemocytes, while fat body-produced LsVg lacks the RSV-interacting subunit. Nymph and male L . striatellus individuals also synthesize Vg but only in hemocytes, and the proteins co-localize with RSV. We observed that knockdown of LsVg transcripts by RNA interference decreased the RSV titer in the hemolymph, and thus interfered with systemic virus infection. Our results reveal the sex-independent expression and tissue-specific processing of LsVg and also unprecedentedly connect the function of this protein in mediating virus transmission to its particular molecular forms existing in tissues previously known as non-Vg producing.
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  • 63
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    Publication Date: 2018-02-27
    Description: by Chloe Spalding, Emma Keen, David J Smith, Anne-Marie Krachler, Sara Jabbari Here we formulate a mechanistic mathematical model to describe the growth dynamics of P. aeruginosa in the presence of the β -lactam antibiotic meropenem. The model is mechanistic in the sense that carrying capacity is taken into account through the dynamics of nutrient availability rather than via logistic growth. In accordance with our experimental results we incorporate a sub-population of cells, differing in morphology from the normal bacillary shape of P. aeruginosa bacteria, which we assume have immunity from direct antibiotic action. By fitting this model to experimental data we obtain parameter values that give insight into the growth of a bacterial population that includes different cell morphologies. The analysis of two parameters sets, that produce different long term behaviour, allows us to manipulate the system theoretically in order to explore the advantages of a shape transition that may potentially be a mechanism that allows P. aeruginosa to withstand antibiotic effects. Our results suggest that inhibition of this shape transition may be detrimental to bacterial growth and thus suggest that the transition may be a defensive mechanism implemented by bacterial machinery. In addition to this we provide strong theoretical evidence for the potential therapeutic strategy of using antimicrobial peptides (AMPs) in combination with meropenem. This proposed combination therapy exploits the shape transition as AMPs induce cell lysis by forming pores in the cytoplasmic membrane, which becomes exposed in the spherical cells.
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  • 64
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    Publication Date: 2018-02-27
    Description: by Huijing Du, Yangyang Wang, Daniel Haensel, Briana Lee, Xing Dai, Qing Nie The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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    In: PLoS ONE
    Publication Date: 2018-02-27
    Description: by Michael S. Marshall, Benas Jakubauskas, Wil Bogue, Monika Stoskute, Zane Hauck, Emily Rue, Matthew Nichols, Lisa L. DiAntonio, Richard B. van Breemen, Jeffrey H. Kordower, Carlos A. Saavedra-Matiz, Ernesto R. Bongarzone α-Synuclein aggregation has been linked to Gaucher’s disease (GD) and Krabbe’s disease (KD), lysosomal conditions affecting glycosphingolipid metabolism. α-Synuclein pathology has been directly attributed to the dysregulation of glycosphingolipids in both conditions, specifically to increased galactosylsphingosine (psychosine) content in the context of KD. Furthermore, the gene ( GALC ) coding for the psychosine degrading enzyme galactosylceramidase (GALC), has recently been identified as a risk loci for Parkinson’s disease. However, it is unknown if changes in psychosine metabolism and GALC activity in the context of the aging human brain correlate with Parkinson’s disease. We investigated psychosine accumulation and GALC activity in the aging brain using fresh frozen post-mortem tissue from Parkinson’s (PD, n = 10), Alzheimer’s (AD, n = 10), and healthy control patients (n = 9), along with tissue from neuropsychiatric patients (schizophrenia, bipolar disorder and depression, n = 15 each). An expanded mutational analysis of PD (n = 20), AD (n = 10), and healthy controls (n = 30) examined if PD was correlated with carriers for severe GALC mutations. Psychosine content within the cerebral cortex of PD patients was elevated above control patients. Within all patients, psychosine displayed a significant (p
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    In: PLoS ONE
    Publication Date: 2018-02-27
    Description: by Damien Ambrosetti, Maeva Dufies, Bérengère Dadone, Matthieu Durand, Delphine Borchiellini, Jean Amiel, Jacques Pouyssegur, Nathalie Rioux-Leclercq, Gilles Pages, Fanny Burel-Vandenbos, Nathalie M. Mazure Background Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau ( vhl ) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. Methods ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. Results A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF.We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. Conclusions This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets.
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    In: PLoS ONE
    Publication Date: 2018-02-27
    Description: by Sunil Rajpal, Abhishek Kumar, William Joe With the ongoing demographic and epidemiological transition, cancer is emerging as a major public health concern in India. This paper uses nationally representative household survey to examine the overall prevalence and economic burden of cancer in India. The age-standardized prevalence of cancer is estimated to be 97 per 100,000 persons with greater prevalence in urban areas. The evidence suggests that cancer prevalence is highest among the elderly and also among females in the reproductive age groups. Cancer displays a significant socioeconomic gradient even after adjusting for age-sex specifics and clustering in a multilevel regression framework. We find that out of pocket expenditure on cancer treatment is among the highest for any ailment. The average out of pocket spending on inpatient care in private facilities is about three-times that of public facilities. Furthermore, treatment for about 40 percent of cancer hospitalization cases is financed mainly through borrowings, sale of assets and contributions from friends and relatives. Also, over 60 percent of the households who seek care from the private sector incur out of pocket expenditure in excess of 20 percent of their annual per capita household expenditure. Given the catastrophic implications, this study calls for a disease-based approach towards financing such high-cost ailment. It is suggested that universal cancer care insurance should be envisaged and combined with existing accident and life insurance policies for the poorer sections in India. In concluding, we call for policies to improve cancer survivorship through effective prevention and early detection. In particular, greater public health investments in infrastructure, human resources and quality of care deserve priority attention.
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    In: PLoS ONE
    Publication Date: 2018-02-27
    Description: by Alexia Roux-Sibilon, Floriane Rutgé, Florent Aptel, Arnaud Attye, Nathalie Guyader, Muriel Boucart, Christophe Chiquet, Carole Peyrin Primary open-angle glaucoma (POAG) firstly mainly affects peripheral vision. Current behavioral studies support the idea that visual defects of patients with POAG extend into parts of the central visual field classified as normal by static automated perimetry analysis. This is particularly true for visual tasks involving processes of a higher level than mere detection. The purpose of this study was to assess visual abilities of POAG patients in central vision. Patients were assigned to two groups following a visual field examination (Humphrey 24–2 SITA-Standard test). Patients with both peripheral and central defects and patients with peripheral but no central defect, as well as age-matched controls, participated in the experiment. All participants had to perform two visual tasks where low-contrast stimuli were presented in the central 6° of the visual field. A categorization task of scene images and human face images assessed high-level visual recognition abilities. In contrast, a detection task using the same stimuli assessed low-level visual function. The difference in performance between detection and categorization revealed the cost of high-level visual processing. Compared to controls, patients with a central visual defect showed a deficit in both detection and categorization of all low-contrast images. This is consistent with the abnormal retinal sensitivity as assessed by perimetry. However, the deficit was greater for categorization than detection. Patients without a central defect showed similar performances to the controls concerning the detection and categorization of faces. However, while the detection of scene images was well-maintained, these patients showed a deficit in their categorization. This suggests that the simple loss of peripheral vision could be detrimental to scene recognition, even when the information is displayed in central vision. This study revealed subtle defects in the central visual field of POAG patients that cannot be predicted by static automated perimetry assessment using Humphrey 24–2 SITA-Standard test.
    Electronic ISSN: 1932-6203
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    In: PLoS ONE
    Publication Date: 2018-02-27
    Description: by Abu Hena M. Kamal, Michael B. Fessler, Saiful M. Chowdhury Macrophages are specialized phagocytes that play an essential role in inflammation, immunity, and tissue repair. Profiling the global proteomic response of macrophages to microbial molecules such as bacterial lipopolysaccharide is key to understanding fundamental mechanisms of inflammatory disease. Ethanol is a widely abused substance that has complex effects on inflammation. Reports have indicated that ethanol can activate or inhibit the lipopolysaccharide receptor, Toll-like Receptor 4, in different settings, with important consequences for liver and neurologic inflammation, but the underlying mechanisms are poorly understood. To profile the sequential effect of low dose ethanol and lipopolysaccharide on macrophages, a gel-free proteomic technique was applied to RAW 264.7 macrophages. Five hundred four differentially expressed proteins were identified and quantified with high confidence using ≥ 5 peptide spectral matches. Among these, 319 proteins were shared across all treatment conditions, and 69 proteins were exclusively identified in ethanol-treated or lipopolysaccharide-stimulated cells. The interactive impact of ethanol and lipopolysaccharide on the macrophage proteome was evaluated using bioinformatics tools, enabling identification of differentially responsive proteins, protein interaction networks, disease- and function-based networks, canonical pathways, and upstream regulators. Five candidate protein coding genes (PGM2, ISYNA1, PARP1, and PSAP) were further validated by qRT-PCR that mostly related to glucose metabolism and fatty acid synthesis pathways. Taken together, this study describes for the first time at a systems level the interaction between ethanol and lipopolysaccharide in the proteomic programming of macrophages, and offers new mechanistic insights into the biology that may underlie the impact of ethanol on infectious and inflammatory disease in humans.
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    In: PLoS ONE
    Publication Date: 2018-02-27
    Description: by Tauqeer Hussain Mallhi, Amer Hayat Khan, Azreen Syazril Adnan, Azmi Sarriff, Yusra Habib Khan, Siew Hua Gan Background Despite myriad improvements in the care of dengue patients, acute kidney injury (AKI) remained least appreciated intricacy of dengue infection. Exiting literature does not provide any information on renal outcomes among dengue patients surviving an episode of AKI. Methods Dengue patients who developed AKI were followed up for post-discharge period of three months and renal recovery was assessed by using recovery criteria based on different thresholds of serum creatinine (SCr) and estimated glomerular filtration rates (eGFR). Results Out of the 526 dengue participants, AKI was developed in 72 (13.7%) patients. Renal recovery was assessed among AKI survivors (n = 71). The use of less (±50% recovery to baseline) to more (±5% recovery to baseline) stringent definitions of renal recovery yielded recovery rates from 88.9% to 2.8% by SCr and 94.4% to 5.6% by eGFR, as renal function biomarkers. At the end of study, eight patients had AKI with AKIN-II (n = 7) and AKIN-III (n = 1). Approximately 50% patients (n = 36/71) with AKI had eGFR primitive to CKD stage 2, while 18.3% (n = 13/71) and 4.2% (n = 3/71) patients had eGFR corresponding to advanced stages of CKD (stage 3 & 4). Factors such as renal insufficiencies at hospital discharge, multiple organ involvements, advance age, female gender and diabetes mellitus were associated with poor renal outcomes. Conclusions We conclude that dengue patients with AKI portend unsatisfactory short-term renal outcomes and deserve a careful and longer follow-up, especially under nephrology care.
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    Publication Date: 2018-02-27
    Description: by Yu Zhan, Christophe H. Marchand, Alexandre Maes, Adeline Mauries, Yi Sun, James S. Dhaliwal, James Uniacke, Simon Arragain, Heng Jiang, Nicholas D. Gold, Vincent J. J. Martin, Stéphane D. Lemaire, William Zerges Organelles are intracellular compartments which are themselves compartmentalized. Biogenic and metabolic processes are localized to specialized domains or microcompartments to enhance their efficiency and suppress deleterious side reactions. An example of intra-organellar compartmentalization is the pyrenoid in the chloroplasts of algae and hornworts. This microcompartment enhances the photosynthetic CO 2 -fixing activity of the Calvin-Benson cycle enzyme Rubisco, suppresses an energetically wasteful oxygenase activity of Rubisco, and mitigates limiting CO 2 availability in aquatic environments. Hence, the pyrenoid is functionally analogous to the carboxysomes in cyanobacteria. However, a comprehensive analysis of pyrenoid functions based on its protein composition is lacking. Here we report a proteomic characterization of the pyrenoid in the green alga Chlamydomonas reinhardtii . Pyrenoid-enriched fractions were analyzed by quantitative mass spectrometry. Contaminant proteins were identified by parallel analyses of pyrenoid-deficient mutants. This pyrenoid proteome contains 190 proteins, many of which function in processes that are known or proposed to occur in pyrenoids: e . g . the carbon concentrating mechanism, starch metabolism or RNA metabolism and translation. Using radioisotope pulse labeling experiments, we show that pyrenoid-associated ribosomes could be engaged in the localized synthesis of the large subunit of Rubisco. New pyrenoid functions are supported by proteins in tetrapyrrole and chlorophyll synthesis, carotenoid metabolism or amino acid metabolism. Hence, our results support the long-standing hypothesis that the pyrenoid is a hub for metabolism. The 81 proteins of unknown function reveal candidates for new participants in these processes. Our results provide biochemical evidence of pyrenoid functions and a resource for future research on pyrenoids and their use to enhance agricultural plant productivity. Data are available via ProteomeXchange with identifier PXD004509.
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    Publication Date: 2018-02-28
    Description: by Björn Jobke, Thomas McBride, Linda Nevin, Larry Peiperl, Amy Ross, Clare Stone, Richard Turner, as the PLOS Medicine Editors In this month’s editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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    In: PLoS ONE
    Publication Date: 2018-02-28
    Description: by Yanjun Hua, Wei Qiu, Qiuyi Xiao, Qiang Wu Purpose To assess the precision (repeatability and reproducibility) of ocular parameters measured by the Tomey OA-2000 biometer, and to compare them with those measured by the IOLMaster. Methods In this prospective study, the right eyes of 108 healthy subjects were included. Three consecutive scans were obtained by 2 observers using the Tomey OA-2000, and in the same session one observer used the IOLMaster (version 5.4.4.0006) for the measurements. About 1 week later, 3 scans were obtained by one observer using the Tomey OA-2000. The axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), keratometer readings, pupil diameter (PD) and corneal diameter (CD) values measured by the Tomey OA-2000 and IOLMaster were analyzed. The coefficient of variation (CoV), intraclass correlation coefficient (ICC), within subject standard deviation (Sw) and 2.77Sw were calculated to assess the repeatability and reproducibility. The paired t test and Bland-Altman plots were used to analyze the differences and agreements of parameters measured by the two devices, respectively. Results Intraobserver repeatability, and interobserver and intersession reproducibility of the AL, CCT, ACD, LT, Kf, Ks, Km, PD and CD values measured by the Tomey OA-2000 biometer showed a CoV of less than 1% except that for PD, and an ICC of more than 0.97 except that for PD and CD. The AL, Kf, Ks, Km and CD values measured by the Tomey OA-2000 were 0.058 ± 0.094 mm, 0.088± 0.150 diopters (D), 0.163 ± 0.170 D, 0.127 ± 0.117 D and 0.171 ± 0.217 mm lower than those measured by the IOLMaster, respectively (all Ps 〈 0.05). However, the ACD values from the two devices were comparable (P = 0.169). The 95% linite of agreement (LoA) of the AL, ACD, CD and all keratometer readings were no more than 0.24 mm, 0.14 mm 0.60 mm and 0.5 D, respectively. Conclusion Except for the PD and CD, the ocular parameters measured by the Tomey OA-2000 were highly repeatable and reproducible. Except for the CD value, there was good agreement of ocular parameters measured by the Tomey OA-2000 and the IOLMaster in healthy eyes.
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    In: PLoS ONE
    Publication Date: 2018-02-28
    Description: by Daniel Schöttle, Benno G. Schimmelmann, Friederike Ruppelt, Alexandra Bussopulos, Marietta Frieling, Evangelia Nika, Luise Antonia Nawara, Dietmar Golks, Andrea Kerstan, Matthias Lange, Michael Schödlbauer, Anne Daubmann, Karl Wegscheider, Anja Rohenkohl, Gizem Sarikaya, Mary Sengutta, Daniel Luedecke, Linus Wittmann, Gunda Ohm, Christina Meigel-Schleiff, Jürgen Gallinat, Klaus Wiedemann, Thomas Bock, Anne Karow, Martin Lambert The ACCESS-model offers integrated care including assertive community treatment to patients with psychotic disorders. ACCESS proved more effective compared to standard care (ACCESS-I study) and was successfully implemented into clinical routine (ACCESS-II study). In this article, we report the 4-year outcomes of the ACCESS-II study. Between May 2007 and December 2013, 115 patients received continuous ACCESS-care. We hypothesized that the low 2-year disengagement and hospitalization rates and significant improvements in psychopathology, functioning, and quality of life could be sustained over 4 years. Over 4 years, only 10 patients disengaged from ACCESS. Another 23 left for practical reasons and were successfully transferred to other services. Hospitalization rates remained low (13.0% in year 3; 9.1% in year 4). Involuntary admissions decreased from 35% in the 2 years prior to ACCESS to 8% over 4 years in ACCESS. Outpatient contacts remained stably high at 2.0–2.4 per week. We detected significant improvements in psychopathology (effect size d = 0.79 ), illness severity ( d = 1.29 ), level of functioning ( d = 0.77 ), quality of life ( d = 0.47 ) and stably high client satisfaction ( d = 0.02 ) over 4 years. Most positive effects were observed within the first 2 years with the exception of illness severity, which further improved from year 2 to 4. Within continuous intensive 4-year ACCESS-care, sustained improvements in psychopathology, functioning, quality of life, low service disengagement and re-hospitalization rates, as well as low rates of involuntary treatment, were observed in contrast to other studies, which reported a decline in these parameters once a specific treatment model was stopped. Yet, stronger evidence to prove these results is required. Trial registration: Clinical Trial Registration Number: NCT01888627
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    In: PLoS ONE
    Publication Date: 2018-02-28
    Description: by María Carmen Saucedo Figueredo, Juan Carlos Morilla Herrera, Mercedes San Alberto Giraldos, Inmaculada López Leiva, Álvaro León Campos, Celia Martí García, Silvia García Mayor, Shakira Kaknani Uttumchandani, José Miguel Morales Asencio Aims To adapt the Edinburgh Feeding Evaluation in Dementia Scale (EdFED) for use in a Spanish-speaking population and to assess its validity and reliability in patients with dementia. Method A cross-sectional study was carried out in two stages: 1. Cross-cultural adaptation (translation, back-translation, review by committee of experts, pilot test and weighting of results); 2. Clinimetric validation comprising interobserver reliability assessment, test-retest reliability and internal consistency. To determine construct validity, confirmatory factorial analysis and principal components analysis were performed by oblique rotations. Criteria validity was analysed using the Pearson correlation (p
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    Publication Date: 2018-02-28
    Description: by Jason A. Bleedorn, Troy A. Hornberger, Craig A. Goodman, Zhengling Hao, Susannah J. Sample, Ermias Amene, Mark D. Markel, Mary Behan, Peter Muir Mechanical signals play an integral role in the regulation of bone mass and functional adaptation to bone loading. The osteocyte has long been considered the principle mechanosensory cell type in bone, although recent evidence suggests the sensory nervous system may play a role in mechanosensing. The specific signaling pathways responsible for functional adaptation of the skeleton through modeling and remodeling are not clearly defined. In vitro studies suggest involvement of intracellular signaling through mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and mammalian target of rapamycin (mTOR). However, anabolic signaling responses to bone loading using a whole animal in vivo model have not been studied in detail. Therefore, we examined mechanically-induced signaling events at five time points from 0 to 24 hours after loading using the rat in vivo ulna end-loading model. Western blot analysis of bone for MAPK’s, PI3K/Akt, and mTOR signaling, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to estimate gene expression of calcitonin gene-related protein alpha (CGRP-α), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), c-jun, and c-fos in dorsal root ganglion (DRG) of the brachial intumescence were performed. There was a significant increase in signaling through MAPK’s including extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) in loaded limbs at 15 minutes after mechanical loading. Ulna loading did not significantly influence expression of the genes of interest in DRG neurons. Bone signaling and DRG gene expression from the loaded and contralateral limbs was correlated (S R 〉0.40, P
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    In: PLoS ONE
    Publication Date: 2018-02-28
    Description: by Yuancheng Li, Rixuan Qiu, Sitong Jing Advanced Metering Infrastructure (AMI) realizes a two-way communication of electricity data through by interconnecting with a computer network as the core component of the smart grid. Meanwhile, it brings many new security threats and the traditional intrusion detection method can’t satisfy the security requirements of AMI. In this paper, an intrusion detection system based on Online Sequence Extreme Learning Machine (OS-ELM) is established, which is used to detecting the attack in AMI and carrying out the comparative analysis with other algorithms. Simulation results show that, compared with other intrusion detection methods, intrusion detection method based on OS-ELM is more superior in detection speed and accuracy.
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    In: PLoS ONE
    Publication Date: 2018-02-28
    Description: by Yun Li, Shengpei Wang, Chuxiong Pan, Fushan Xue, Junfang Xian, Yaqi Huang, Xiaoyi Wang, Tianzuo Li, Huiguang He Background The mechanism of general anesthesia (GA) has been explored for hundreds of years, but unclear. Previous studies indicated a possible correlation between NREM sleep and GA. The purpose of this study is to compare them by in vivo human brain function to probe the neuromechanism of consciousness, so as to find out a clue to GA mechanism. Methods 24 healthy participants were equally assigned to sleep or propofol sedation group by sleeping ability. EEG and Ramsay Sedation Scale were applied to determine sleep stage and sedation depth respectively. Resting-state functional magnetic resonance imaging (RS-fMRI) was acquired at each status. Regional homogeneity (ReHo) and seed-based whole brain functional connectivity maps (WB-FC maps) were compared. Results During sleep, ReHo primarily weakened on frontal lobe (especially preoptic area), but strengthened on brainstem. While during sedation, ReHo changed in various brain areas, including cingulate, precuneus, thalamus and cerebellum. Cingulate, fusiform and insula were concomitance of sleep and sedation. Comparing to sleep, FCs between the cortex and subcortical centers (centralized in cerebellum) were significantly attenuated under sedation. As sedation deepening, cerebellum-based FC maps were diminished, while thalamus- and brainstem-based FC maps were increased. Conclusion There’re huge distinctions in human brain function between sleep and GA. Sleep mainly rely on brainstem and frontal lobe function, while sedation is prone to affect widespread functional network. The most significant differences exist in the precuneus and cingulate, which may play important roles in mechanisms of inducing unconciousness by anesthetics. Trial registration Institutional Review Board (IRB) ChiCTR-IOC-15007454.
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    In: PLoS ONE
    Publication Date: 2018-02-28
    Description: by Akhilesh Kumar Kasyap, Shiv Kumar Sah, Sitaram Chaudhary Background Gastro esophageal reflux disease (GERD) is a chronic and recurrent disease, and it varies in regions. However, to date, there are no reports available on clinical features and the risk factors for the asymptomatic reflux esophagitis in Nepalese adults. Methods Data were gathered from 142 erosive patients who had undergone endoscopy at Bir Hospital, Kathmandu. Los Angeles classification was used to grade the severity of the disease. Patients were interviewed to find out the presence of various reflux symptoms. Results Based on the Los Angeles classification, the severity of the disease assessed was; grade A 31.8% (31/142), grade B 39.4% (56/142), grade C 33.8% (48/142), and grade D 4.9% (7/142). One hundred and twenty six (88.7%) subjects had reflux symptoms. Prevalence of asymptomatic esophagitis was 16(11.3%). Age was independently linked to asymptomatic esophagitis (P
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    Publication Date: 2018-02-28
    Description: by Rebecca Maria Hasler, Sandra Stucky, Heinz Bähler, Aristomenis K. Exadaktylos, Frank Neff Objective Most deaths occur in the pre-hospital setting, whereas mortality in the emergency department (ED) is low (
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    Publication Date: 2018-02-28
    Description: by Sachin Kumar, Ron E. Knox, Asheesh K. Singh, Ron M. DePauw, Heather L. Campbell, Julio Isidro-Sanchez, Fran R. Clarke, Curtis J. Pozniak, Amidou N’Daye, Brad Meyer, Andrew Sharpe, Yuefeng Ruan, Richard D. Cuthbert, Daryl Somers, George Fedak Loose smut, caused by Ustilago tritici (Pers.) Rostr., is a systemic disease of tetraploid durum wheat ( Triticum turgidum L.). Loose smut can be economically controlled by growing resistant varieties, making it important to find and deploy new sources of resistance. Blackbird, a variety of T . turgidum L. subsp. carthlicum (Nevski) A. Love & D. Love, carries a high level of resistance to loose smut. Blackbird was crossed with the loose smut susceptible durum cultivar Strongfi