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  • 1
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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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  • 2
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by The PLOS ONE Editors
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 3
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Jeremy Smedley, Rhonda Macalister, Solomon Wangari, Mercy Gathuka, Joel Ahrens, Naoto Iwayama, Drew May, Debbie Bratt, Megan O’Connor, Paul Munson, Michael Koday, Lifson, Deborah Heydenburg Fuller
    Electronic ISSN: 1932-6203
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  • 4
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Laura J. Kraft, James Kopco, Jason P. Harmon, Kerry M. Oliver
    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 The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Yann Dujardin, Iadine Chadès Managing the biodiversity extinction crisis requires wise decision-making processes able to account for the limited resources available. In most decision problems in conservation biology, several conflicting objectives have to be taken into account. Most methods used in conservation either provide suboptimal solutions or use strong assumptions about the decision-maker’s preferences. Our paper reviews some of the existing approaches to solve multi-objective decision problems and presents new multi-objective linear programming formulations of two multi-objective optimization problems in conservation, allowing the use of a reference point approach. Reference point approaches solve multi-objective optimization problems by interactively representing the preferences of the decision-maker with a point in the criteria (objectives) space, called the reference point. We modelled and solved the following two problems in conservation: a dynamic multi-species management problem under uncertainty and a spatial allocation resource management problem. Results show that the reference point method outperforms classic methods while illustrating the use of an interactive methodology for solving combinatorial problems with multiple objectives. The method is general and can be adapted to a wide range of ecological combinatorial problems.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 7
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    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
    Topics: Medicine
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  • 8
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    Publication Date: 2018-01-03
    Description: by Yingtian Deng, Jubin Wang, Jeffrey Tung, Dan Liu, Yingjia Zhou, Shuang He, Yunlian Du, Barbara Baker, Feng Li Plant genomes encode large numbers of nucleotide-binding (NB) leucine-rich repeat (LRR) immune receptors ( NLR ) that mediate effector triggered immunity (ETI) and play key roles in protecting crops from diseases caused by devastating pathogens. Fitness costs are associated with plant NLR genes and regulation of NLR genes by micro(mi)RNAs and phased small interfering RNAs (phasiRNA) is proposed as a mechanism for reducing these fitness costs. However, whether NLR expression and NLR -mediated immunity are regulated during plant growth is unclear. We conducted genome-wide transcriptome analysis and showed that NLR expression gradually increased while expression of their regulatory small RNAs (sRNA) gradually decreased as plants matured, indicating that sRNAs could play a role in regulating NLR expression during plant growth. We further tested the role of miRNA in the growth regulation of NLRs using the tobacco mosaic virus (TMV) resistance gene N , which was targeted by miR6019 and miR6020. We showed that N -mediated resistance to TMV effectively restricted this virus to the infected leaves of 6-week old plants, whereas TMV infection was lethal in 1- and 3-week old seedlings due to virus-induced systemic necrosis. We further found that N transcript levels gradually increased while miR6019 levels gradually decreased during seedling maturation that occurs in the weeks after germination. Analyses of reporter genes in transgenic plants showed that growth regulation of N expression was post-transcriptionally mediated by MIR6019/6020 whereas MIR6019/6020 was regulated at the transcriptional level during plant growth. TMV infection of MIR6019/6020 transgenic plants indicated a key role for miR6019-triggered phasiRNA production for regulation of N -mediated immunity. Together our results demonstrate a mechanistic role for miRNAs in regulating innate immunity during plant growth.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 9
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Nathalie Gayrard, Alain Ficheux, Flore Duranton, Caroline Guzman, Ilan Szwarc, Fernando Vetromile, Chantal Cazevieille, Philippe Brunet, Marie-Françoise Servel, Àngel Argilés, Moglie Le Quintrec
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Jasmine E. Burr-Hersey, Sacha J. Mooney, A. Glyn Bengough, Stefan Mairhofer, Karl Ritz
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Ashley L. Waldron, Sara Helms Cahan, Christopher S. Francklyn, Alicia M. Ebert
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Tsai-Ling Liu, A. Sidney Barritt 4th, Morris Weinberger, John E. Paul, Bruce Fried, Justin G. Trogdon
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Anna Martinez-Alvarez, Ferran Pons, Ruth de Diego-Balaguer
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 15
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Verónica García-Sanz, Vanessa Paredes-Gallardo, Omel Mendoza-Yero, Miguel Carbonell-Leal, Alberto Albaladejo, José María Montiel-Company, Carlos Bellot-Arcís Lasers have recently been introduced as an alternative means of conditioning dental ceramic surfaces in order to enhance their adhesive strength to cements and other materials. The present systematic review and meta-analysis aimed to review and quantitatively analyze the available literature in order to determine which bond protocols and laser types are the most effective. A search was conducted in the Pubmed, Embase and Scopus databases for papers published up to April 2017. PRISMA guidelines for systematic review and meta-analysis were followed. Fifty-two papers were eligible for inclusion in the review. Twenty-five studies were synthesized quantitatively. Lasers were found to increase bond strength of ceramic surfaces to resin cements and composites when compared with control specimens (p-value 〈 0.01), whereas no significant differences were found in comparison with air-particle abraded surfaces. High variability can be observed in adhesion values between different analyses, pointing to a need to standardize study protocols and to determine the optimal parameters for each laser type.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Robert B. Dudas, Chris Lovejoy, Sarah Cassidy, Carrie Allison, Paula Smith, Simon Baron-Cohen
    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: 2018-01-03
    Description: by Walace P. Kiffer Jr, Flavio Mendes, Cinthia G. Casotti, Larissa C. Costa, Marcelo S. Moretti We evaluated the effect of leaves of native and exotic tree species on the feeding activity and performance of the larvae of Triplectides gracilis , a typical caddisfly shredder in Atlantic Forest streams. Leaves of four native species that differ in chemistry and toughness ( Hoffmannia dusenii , Miconia chartacea , Myrcia lineata and Styrax pohlii ) and the exotic Eucalyptus globulus were used to determine food preferences and rates of consumption, production of fine particulate organic matter (FPOM), growth and survival of shredders. We hypothesized that the consumption rates of leaves of Eucalyptus and their effects on the growth and survival of shredders could be predicted by leaf chemistry and toughness. The larvae preferred to feed on soft leaves ( H . dusenii and M . chartacea ) independently of the content of nutrients (N and P) and secondary compounds (total phenolics). When such leaves were absent, they preferred E . globulus and did not consume the tough leaves ( M . lineata and S . pohlii ). In monodietary experiments, leaf consumption and FPOM production differed among the studied leaves, and the values observed for the E . globulus treatments were intermediate between the soft and tough leaves. The larvae that fed on H . dusenii and M . chartacea grew constantly over five weeks, while those that fed on E . globulus lost biomass. Larval survival was higher on leaves of H . dusenii , M . chartacea and S . pohlii than on E . globulus and M . lineata leaves. Although E . globulus was preferred over tougher leaves, long-term consumption of leaves of the exotic species may affect the abundance of T . gracilis in the studied stream. Additionally, our results suggest that leaf toughness can be a determining factor for the behavior of shredders where low-quality leaves are abundant, as in several tropical streams.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 18
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Sophie Cohen, Steve Innes, Sibyl P. M. Geelen, Jonathan C. K. Wells, Colette Smit, Tom F. W. Wolfs, Berthe L. F. van Eck-Smit, Taco W. Kuijpers, Peter Reiss, Henriette J. Scherpbier, Dasja Pajkrt, Madeleine J. Bunders
    Electronic ISSN: 1932-6203
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  • 19
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-03
    Description: by Julia Novotny, Sue Chandraratne, Tobias Weinberger, Vanessa Philippi, Konstantin Stark, Andreas Ehrlich, Joachim Pircher, Ildiko Konrad, Paul Oberdieck, Anna Titova, Qendresa Hoti, Irene Schubert, Kyle R. Legate, Nicole Urtz, Michael Lorenz, Jaroslav Pelisek, Steffen Massberg, Marie-Luise von Brühl, Christian Schulz Aims Medical treatment of arterial thrombosis is mainly directed against platelets and coagulation factors, and can lead to bleeding complications. Novel antithrombotic therapies targeting immune cells and neutrophil extracellular traps (NETs) are currently being investigated in animals. We addressed whether immune cell composition of arterial thrombi induced in mouse models of thrombosis resemble those of human patients with acute myocardial infarction (AMI). Methods and results In a prospective cohort study of patients suffering from AMI, 81 human arterial thrombi were harvested during percutaneous coronary intervention and subjected to detailed histological analysis. In mice, arterial thrombi were induced using two distinct experimental models, ferric chloride (FeCl 3 ) and wire injury of the carotid artery. We found that murine arterial thrombi induced by FeCl 3 were highly concordant with human coronary thrombi regarding their immune cell composition, with neutrophils being the most abundant cell type, as well as the presence of NETs and coagulation factors. Pharmacological treatment of mice with the protein arginine deiminase (PAD)-inhibitor Cl-amidine abrogated NET formation, reduced arterial thrombosis and limited injury in a model of myocardial infarction. Conclusions Neutrophils are a hallmark of arterial thrombi in patients suffering from acute myocardial infarction and in mouse models of arterial thrombosis. Inhibition of PAD could represent an interesting strategy for the treatment of arterial thrombosis to reduce neutrophil-associated tissue damage and improve functional outcome.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 20
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    Publication Date: 2018-01-03
    Description: by Megan E. Schmidt, Cory J. Knudson, Stacey M. Hartwig, Lecia L. Pewe, David K. Meyerholz, Ryan A. Langlois, John T. Harty, Steven M. Varga Memory CD8 T cells can provide protection from re-infection by respiratory viruses such as influenza and SARS. However, the relative contribution of memory CD8 T cells in providing protection against respiratory syncytial virus (RSV) infection is currently unclear. To address this knowledge gap, we utilized a prime-boost immunization approach to induce robust memory CD8 T cell responses in the absence of RSV-specific CD4 T cells and antibodies. Unexpectedly, RSV infection of mice with pre-existing CD8 T cell memory led to exacerbated weight loss, pulmonary disease, and lethal immunopathology. The exacerbated disease in immunized mice was not epitope-dependent and occurred despite a significant reduction in RSV viral titers. In addition, the lethal immunopathology was unique to the context of an RSV infection as mice were protected from a normally lethal challenge with a recombinant influenza virus expressing an RSV epitope. Memory CD8 T cells rapidly produced IFN-γ following RSV infection resulting in elevated protein levels in the lung and periphery. Neutralization of IFN-γ in the respiratory tract reduced morbidity and prevented mortality. These results demonstrate that in contrast to other respiratory viruses, RSV-specific memory CD8 T cells can induce lethal immunopathology despite mediating enhanced viral clearance.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 21
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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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  • 22
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by Maegen A. Ackermann, Marey Shriver, Nicole A. Perry, Li-Yen R. Hu, Aikaterini Kontrogianni-Konstantopoulos
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 23
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    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by David Siegel, Donna D. Dehn, Samantha S. Bokatzian, Kevin Quinn, Donald S. Backos, Andrea Di Francesco, Michel Bernier, Nichole Reisdorph, Rafael de Cabo, David Ross NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain. Under normal cellular conditions NQO1 is not immunoprecipitated by these antibodies, however, following treatment with β-lapachone which caused rapid oxidation of NAD(P)H NQO1 could be readily pulled-down. Similarly, immunostaining for NQO1 was significantly increased in cells following treatment with β-lapachone demonstrating that under non-denaturing conditions the immunoreactivity of NQO1 is reflective of the NAD(P) + /NAD(P)H ratio. In untreated human cells, regions with high intensity immunostaining for NQO1 co-localize with acetyl α-tubulin and the NAD + -dependent deacetylase Sirt2 on the centrosome(s), the mitotic spindle and midbody during cell division. These data provide evidence that during the centriole duplication cycle NQO1 may provide NAD + for Sirt2-mediated deacetylation of microtubules. Overall, NQO1 may act as a redox-dependent switch where the protein responds to the NAD(P) + /NAD(P)H redox environment by altering its structure promoting the binding or dissociation of NQO1 with target macromolecules.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 24
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    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by Tomoya Iida, Hiroyuki Kaneto, Kohei Wagatsuma, Hajime Sasaki, Yumiko Naganawa, Suguru Nakagaki, Shuji Satoh, Haruo Shimizu, Hiroshi Nakase The Endoscopic procedures for common bile duct (CBD) stones are reportedly safe in the elderly patients. However, the definition of the elderly is different in each report. If the elderly are defined as people aged 85 years or older, data on the effectiveness and safety of endoscopic retrograde cholangiopancreatography (ERCP) for CBD stones are limited. This study investigated the efficacy and safety of endoscopic procedures for CBD stones in patients aged 85 years or older. 1,016 consecutive ERCP procedures were performed at our institution from January 2009 to December 2014. Of these, 235 cases with CBD stones were finally analyzed. Group A patients were younger than 85 years and Group B patients were 85 years or older. Patient background, details of endoscopic therapy, complications, and related factors were retrospectively reviewed for 185 cases in Group A, and 50 cases in Group B. Patients in Group B showed high rates of dementia and cerebrovascular disorders and larger CBD stones and diameters, in comparison with patients in Group A. The complete removal rate of bile duct stones was slightly higher in Group A. However, there was no difference between the two groups in recurrence rate of CBD stones, complication and mortality rates, and length and cost of hospitalization. Despite some differences between the two groups, endoscopic procedures for CBD stones in patients aged 85 years or older can be performed effectively and safely without increasing medical costs.
    Electronic ISSN: 1932-6203
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  • 25
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    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
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  • 26
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    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by Yoo Jin Choi, Seong-Joon Park, You-Soo Park, Hee Sung Park, Kwang Mo Yang, Kyu Heo Cancer stem-like cells (CSCs) may play a key role in tumor initiation, self-renewal, differentiation, and resistance to current treatments. Dendritic cells (DCs) play a vital role in host immune reactions as well as antigen presentation. In this study, we explored the suitability of using CSC peptides as antigen sources for DC vaccination against human breast cancer and hepatocellular carcinoma (HCC) with the aim of achieving CSC targeting and enhancing anti-tumor immunity. CD44 is used as a CSC marker for breast cancer and EpCAM is used as a CSC marker for HCC. We selected CD44 and EpCAM peptides that bind to HLA-A2 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Our data showed that CSCs express high levels of tumor-associated antigens (TAAs) as well as major histocompatibility complex (MHC) molecules. Pulsing DCs with CD44 and EpCAM peptides resulted in the efficient generation of mature DCs (mDCs), thus enhancing T cell stimulation and generating potent cytotoxic T lymphocytes (CTLs). The activation of CSC peptide-specific immune responses by the DC vaccine in combination with standard chemotherapy may provide better clinical outcomes in advanced carcinomas.
    Electronic ISSN: 1932-6203
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  • 27
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    In: PLoS ONE
    Publication Date: 2018-01-04
    Description: by Joanna Gerszon, Eligiusz Serafin, Adam Buczkowski, Sylwia Michlewska, Jakub Antoni Bielnicki, Aleksandra Rodacka Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is one of the key redox-sensitive proteins whose activity is largely affected by oxidative modifications at its highly reactive cysteine residue in the enzyme’s active site (Cys149). Prolonged exposure to oxidative stress may cause, inter alia , the formation of intermolecular disulfide bonds leading to accumulation of GAPDH aggregates and ultimately to cell death. Recently these anomalies have been linked with the pathogenesis of Alzheimer’s disease. Novel evidences indicate that low molecular compounds may be effective inhibitors potentially preventing the GAPDH translocation to the nucleus, and inhibiting or slowing down its aggregation and oligomerization. Therefore, we decided to establish the ability of naturally occurring compound, piceatannol, to interact with GAPDH and to reveal its effect on functional properties and selected parameters of the dehydrogenase structure. The obtained data revealed that piceatannol binds to GAPDH. The ITC analysis indicated that one molecule of the tetrameric enzyme may bind up to 8 molecules of polyphenol (7.3 ± 0.9). Potential binding sites of piceatannol to the GAPDH molecule were analyzed using the Ligand Fit algorithm. Conducted analysis detected 11 ligand binding positions. We indicated that piceatannol decreases GAPDH activity. Detailed analysis allowed us to presume that this effect is due to piceatannol ability to assemble a covalent binding with nucleophilic cysteine residue (Cys149) which is directly involved in the catalytic reaction. Consequently, our studies strongly indicate that piceatannol would be an exceptional inhibitor thanks to its ability to break the aforementioned pathologic disulfide linkage, and therefore to inhibit GAPDH aggregation. We demonstrated that by binding with GAPDH piceatannol blocks cysteine residue and counteracts its oxidative modifications, that induce oligomerization and GAPDH aggregation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 28
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Renato Kawahisa Levin, Marcelo Katz, Paulo H. N. Saldiva, Adriano Caixeta, Marcelo Franken, Carolina Pereira, Salo V. Coslovsky, Antonio E. Pesaro Background In high-income temperate countries, the number of hospitalizations for heart failure (HF) and acute myocardial infarction (AMI) increases during the winter. This finding has not been fully investigated in low- and middle-income countries with tropical and subtropical climates. We investigated the seasonality of hospitalizations for HF and AMI in Sao Paulo (Brazil), the largest city in Latin America. Methods This was a retrospective study using data for 76,474 hospitalizations for HF and 54,561 hospitalizations for AMI obtained from public hospitals, from January 2008 to April 2015. The average number of hospitalizations for HF and AMI per month during winter was compared to each of the other seasons. The autoregressive integrated moving average (ARIMA) model was used to test the association between temperature and hospitalization rates. Findings The highest average number of hospital admissions for HF and AMI per month occurred during winter, with an increase of up to 30% for HF and 16% for AMI when compared to summer, the season with lowest figures for both diseases (respectively, HF: 996 vs . 767 per month, p
    Electronic ISSN: 1932-6203
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  • 29
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Damir Vetrini, Christine A. Kiire, Philip I. Burgess, Simon P. Harding, Petros C. Kayange, Khumbo Kalua, Gerald Msukwa, Nicholas A. V. Beare, Jason Madan Objective To investigate the economic impact of introducing targeted screening and laser photocoagulation treatment for sight-threatening diabetic retinopathy and macular edema in a setting with no previous screening or laser treatment for diabetic retinopathy in sub-Saharan Africa. Materials and methods A cohort Markov model was built to compare combined targeted screening and laser treatment for patients with sight-threatening diabetic retinopathy and macular edema against no intervention. Primary outcomes were incremental cost per quality-adjusted life year (QALY) gained and per disability-adjusted life year (DALY) averted. Primary data were collected on 357 participants from the Malawi Diabetic Retinopathy Study, a prospective, observational cohort study. Multiple scenarios were explored and a probabilistic sensitivity analysis was performed. Results In the base case (age: 50 years, service utilization rate: 80%), the cost of the intervention and the years of severe visual impairment averted per patient screened were $209 and 2.2 years respectively. Applying the World Health Organization threshold of cost-effectiveness for Malawi ($679), the base case was cost-effective when QALYs were used ($400 per QALY gained) but not when DALYs were used ($766 per DALY averted). The intervention was more cost-effective when it targeted younger patients (age: 30 years) and less cost-effective when the utilization rate was lowered to 50%. Conclusions Annual photographic screening of diabetic patients attending medical diabetes clinics in Malawi, with the provision of laser treatment for those with sight-threatening diabetic retinopathy and macular edema, appears to be cost-effective in terms of QALYs gained, in our base case scenario. Cost-effectiveness improves if services are utilized more intensively and extended to younger patients.
    Electronic ISSN: 1932-6203
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Seonggyun Han, Dongwook Kim, Manu Shivakumar, Young-Ji Lee, Tullika Garg, Jason E. Miller, Ju Han Kim, Dokyoon Kim, Younghee Lee Eukaryotic organisms have developed a variety of mechanisms to regulate translation post-transcriptionally, including but not limited to the use of miRNA silencing in many species. One method of post-transcriptional regulation is through miRNAs that bind to the 3′ UTRs to regulate mRNA abundance and influence protein expression. Therefore, the diversity of mRNA 3′ UTRs mediating miRNA binding sites influence miRNA-mediated regulation. Alternative polyadenylation, by shortening mRNA isoforms, increases the diversity of 3′ UTRs; moreover, short mRNA isoforms elude miRNA-medicated repression. Because no current prediction methods for putative miRNA target sites consider whether or not 1) splicing-informed miRNA binding sites and/or 2) the use of 3′ UTRs provide higher resolution or functionality, we sought to identify not only the genome-wide impact of using exons in mRNA 3′ UTRs but also their functional connection to miRNA regulation and clinical outcomes in cancer. With a genome-wide expression of mRNA and miRNA quantified by 395 bladder cancer cases from The Cancer Genome Atlas (TCGA), we 1) demonstrate the diversity of 3′ UTRs affecting miRNA efficiency and 2) identify a set of genes clinically associated with mRNA expression in bladder cancer. Knowledge of 3′ UTR diversity will not only be a useful addition to current miRNA target prediction algorithms but also enhance the clinical utility of mRNA isoforms in the expression of mRNA in cancer. Thus, variability among cancer patient’s variability in molecular signatures based on these exon usage events in 3′ UTR along with miRNAs in bladder cancer may lead to better prognostic/treatment strategies for improved precision medicine.
    Electronic ISSN: 1932-6203
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Anke Schultz, Anja Germann, Martina Fuss, Marcella Sarzotti-Kelsoe, Daniel A. Ozaki, David C. Montefiori, Heiko Zimmermann, Hagen von Briesen The standardized assessments of HIV-specific immune responses are of main interest in the preclinical and clinical stage of HIV-1 vaccine development. In this regard, HIV-1 Env-pseudotyped viruses play a central role for the evaluation of neutralizing antibody profiles and are produced according to Good Clinical Laboratory Practice- (GCLP-) compliant manual and automated procedures. To further improve and complete the automated production cycle an automated system for aliquoting HIV-1 pseudovirus stocks has been implemented. The automation platform consists of a modified Tecan-based system including a robot platform for handling racks containing 48 cryovials, a Decapper, a tubing pump and a safety device consisting of ultrasound sensors for online liquid level detection of each individual cryovial. With the aim to aliquot the HIV-1 pseudoviruses in an automated manner under GCLP-compliant conditions a validation plan was developed where the acceptance criteria—accuracy, precision as well as the specificity and robustness—were defined and summarized. By passing the validation experiments described in this article the automated system for aliquoting has been successfully validated. This allows the standardized and operator independent distribution of small-scale and bulk amounts of HIV-1 pseudovirus stocks with a precise and reproducible outcome to support upcoming clinical vaccine trials.
    Electronic ISSN: 1932-6203
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  • 32
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Sonja Stutz, Patrik Mráz, Hariet L. Hinz, Heinz Müller-Schärer, Urs Schaffner Species may become invasive after introduction to a new range because phenotypic traits pre-adapt them to spread and become dominant. In addition, adaptation to novel selection pressures in the introduced range may further increase their potential to become invasive. The diploid Leucanthemum vulgare and the tetraploid L . ircutianum are native to Eurasia and have been introduced to North America, but only L . vulgare has become invasive. To investigate whether phenotypic differences between the two species in Eurasia could explain the higher abundance of L . vulgare in North America and whether rapid evolution in the introduced range may have contributed to its invasion success, we grew 20 L . vulgare and 21 L . ircutianum populations from Eurasia and 21 L . vulgare populations from North America under standardized conditions and recorded performance and functional traits. In addition, we recorded morphological traits to investigate whether the two closely related species can be clearly distinguished by morphological means and to what extent morphological traits have changed in L . vulgare post-introduction. We found pronounced phenotypic differences between L . vulgare and L . ircutianum from the native range as well as between L . vulgare from the native and introduced ranges. The two species differed significantly in morphology but only moderately in functional or performance traits that could have explained the higher invasion success of L . vulgare in North America. In contrast, leaf morphology was similar between L . vulgare from the native and introduced range, but plants from North America flowered later, were larger and had more and larger flower heads than those from Eurasia. In summary, we found litte evidence that specific traits of L . vulgare may have pre-adapted this species to become more invasive than L . ircutianum , but our results indicate that rapid evolution in the introduced range likely contributed to the invasion success of L . vulgare .
    Electronic ISSN: 1932-6203
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  • 33
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Atsushi Kimura, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Tadasu Horai, Takeshi Izumi, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora Men have a higher rate of completed suicide than women, which suggests that sex chromosome abnormalities may be related to the pathophysiology of suicide. Recent studies have found an aberrant loss of chromosome Y (LOY) in various diseases; however, no study has investigated whether there is an association between LOY and suicide. The purpose of this study was to determine whether LOY occurs in men who completed suicide. Our study consisted of 286 male Japanese subjects comprised of 140 suicide completers without severe physical illness (130 post-mortem samples of peripheral blood and 10 brains) and 146 age-matched control subjects (130 peripheral blood samples from healthy individuals and 16 post-mortem brains). LOY was measured as the chromosome Y/chromosome X ratio of the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes ( AMELY and AMELX ). Regression analyses showed that LOY in the blood of suicide completers was significantly more frequent than that found in controls (odds ratio = 3.50, 95% confidence interval = 1.21–10.10), but not in the dorsolateral prefrontal cortex (DLPFC) region of brain. Normal age-dependent LOY in blood was found in healthy controls (r = -0.353, p 〈 0.001), which was not seen in suicide completers (r = -0.119, p = 0.177). DLPFC tissue had age-dependent LOY (B = -0.002, p = 0.015), which was independent of phenotype. To our knowledge, this is the first study demonstrating that LOY in blood is associated with suicide completion. In addition, our findings are the first to also indicate that age-dependent LOY may occur not only in blood, but also in specific brain regions.
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Fabrice B. R. Parmentier, Antonia P. Pacheco-Unguetti, Sara Valero Rare changes in a stream of otherwise repeated task-irrelevant sounds break through selective attention and disrupt performance in an unrelated visual task by triggering shifts of attention to and from the deviant sound (deviance distraction). Evidence indicates that the involuntary orientation of attention to unexpected sounds is followed by their semantic processing. However, past demonstrations relied on tasks in which the meaning of the deviant sounds overlapped with features of the primary task. Here we examine whether such processing is observed when no such overlap is present but sounds carry some relevance to the participants’ biological need to eat when hungry. We report the results of an experiment in which hungry and satiated participants partook in a cross-modal oddball task in which they categorized visual digits (odd/even) while ignoring task-irrelevant sounds. On most trials the irrelevant sound was a sinewave tone (standard sound). On the remaining trials, deviant sounds consisted of spoken words related to food (food deviants) or control words (control deviants). Questionnaire data confirmed state (but not trait) differences between the two groups with respect to food craving, as well as a greater desire to eat the food corresponding to the food-related words in the hungry relative to the satiated participants. The results of the oddball task revealed that food deviants produced greater distraction (longer response times) than control deviants in hungry participants while the reverse effect was observed in satiated participants. This effect was observed in the first block of trials but disappeared thereafter, reflecting semantic saturation. Our results suggest that (1) the semantic content of deviant sounds is involuntarily processed even when sharing no feature with the primary task; and that (2) distraction by deviant sounds can be modulated by the participants’ biological needs.
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  • 35
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Vinay Kansal, James J. Armstrong, Robert Pintwala, Cindy Hutnik Purpose Early detection, monitoring and understanding of changes in the retina are central to the diagnosis of glaucomatous optic neuropathy, and vital to reduce visual loss from this progressive condition. The main objective of this investigation was to compare glaucoma diagnostic accuracy of commercially available optical coherence tomography (OCT) devices (Zeiss Stratus, Zeiss Cirrus, Heidelberg Spectralis and Optovue RTVue, and Topcon 3D-OCT). Patients 16,104 glaucomatous and 11,543 normal eyes reported in 150 studies. Methods Between Jan. 2017 and Feb 2017, MEDLINE ® , EMBASE ® , CINAHL ® , Cochrane Library ® , Web of Science ® , and BIOSIS ® were searched for studies assessing glaucoma diagnostic accuracy of the aforementioned OCT devices. Meta-analysis was performed pooling area under the receiver operating characteristic curve (AUROC) estimates for all devices, stratified by OCT type (RNFL, macula), and area imaged. Results 150 studies with 16,104 glaucomatous and 11,543 normal control eyes were included. Key findings: AUROC of glaucoma diagnosis for RNFL average for all glaucoma patients was 0.897 (0.887–0.906, n = 16,782 patient eyes), for macula ganglion cell complex (GCC) was 0.885 (0.869–0.901, n = 4841 eyes), for macula ganglion cell inner plexiform layer (GCIPL) was 0.858 (0.835–0.880, n = 4211 eyes), and for total macular thickness was 0.795 (0.754–0.834, n = 1063 eyes). Conclusion The classification capability was similar across all 5 OCT devices. More diagnostically favorable AUROCs were demonstrated in patients with increased glaucoma severity. Diagnostic accuracy of RNFL and segmented macular regions (GCIPL, GCC) scans were similar and higher than total macular thickness. This study provides a synthesis of contemporary evidence with features of robust inclusion criteria and large sample size. These findings may provide guidance to clinicians when navigating this rapidly evolving diagnostic area characterized by numerous options.
    Electronic ISSN: 1932-6203
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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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    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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    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.
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  • 39
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Shefali Kumar, Megan Jones Bell, Jessie L. Juusola Background Generalized anxiety disorder (GAD) is a debilitating mental health illness that affects approximately 3.1% of U.S. adults and can be treated with cognitive behavioral therapy (CBT). With the emergence of digital health technologies, mobile CBT may be a cost-effective way to deliver care. We developed an analysis framework to quantify the cost-effectiveness of internet-based CBT for individuals with GAD. As a case study, we examined the potential value of a new mobile-delivered CBT program for GAD. Methods We developed a Markov model of GAD health states combined with a detailed economic analysis for a cohort of adults with GAD in the U.S. In our case study, we used pilot program efficacy data to evaluate a mobile CBT program as either prevention or treatment only and compared the strategies to traditional CBT and no CBT. Traditional CBT efficacy was estimated from clinical trial results. We calculated discounted incremental costs and quality-adjusted life-years (QALYs) over the cohort lifetime. Case study results In the base case, for a cohort of 100,000 persons with GAD, we found that mobile CBT is cost-saving. It leads to a gain of 34,108 QALYs and 81,492 QALYs and a cost reduction of $2.23 billion and $4.54 billion when compared to traditional CBT and no CBT respectively. Results were insensitive to most model inputs and mobile CBT remained cost-saving in almost all scenarios. Limitations The case study was conducted for illustrative purposes and used mobile CBT efficacy data from a small pilot program; the analysis should be re-conducted once robust efficacy data is available. The model was limited in its ability to measure the effectiveness of CBT in combination with pharmacotherapy. Conclusions Mobile CBT may lead to improved health outcomes at lower costs than traditional CBT or no intervention and may be effective as either prevention or treatment.
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Yen-Te Liao, Irwin A. Quintela, Kimberly Nguyen, Alexandra Salvador, Michael B. Cooley, Vivian C. H. Wu Shiga toxin-producing E . coli (STEC) causes approximately 265,000 illnesses and 3,600 hospitalizations annually and is highly associated with animal contamination due to the natural reservoir of ruminant gastrointestinal tracts. Free STEC-specific bacteriophages against STEC strains are also commonly isolated from fecal-contaminated environment. Previous studies have evaluated the correlation between the prevalence of STEC-specific bacteriophages and STEC strains to improve animal-associated environment. However, the similar information regarding free STEC-specific bacteriophages prevalence in produce growing area is lacking. Thus, the objectives of this research were to determine the prevalence of STEC-specific phages, analyze potential effects of environmental factors on the prevalence of the phages, and study correlations between STEC-specific bacteriophages and the bacterial hosts in pre-harvest produce environment. Surface water from 20 samples sites was subjected to free bacteriophage isolation using host strains of both generic E . coli and STEC (O157, six non-O157 and one O179 strains) cocktails, and isolation of O157 and non-O157 STEC strains by use of culture methods combined with PCR-based confirmation. The weather data were obtained from weather station website. Free O145- and O179-specific bacteriophages were the two most frequently isolated bacteriophages among all (O45, O145, O157 and O179) in this study. The results showed June and July had relatively high prevalence of overall STEC-specific bacteriophages with minimum isolation of STEC strains. In addition, the bacteriophages were likely isolated in the area—around or within city—with predominant human impact, whereas the STEC bacterial isolates were commonly found in agriculture impact environment. Furthermore, there was a trend that the sample sites with positive of free STEC bacteriophage did not have the specific STEC bacterial hosts. The findings of the study enable us to understand the ecology between free STEC-specific phages and STEC bacteria for further pre-harvest food safety management in produce environment.
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Maria K. Mateyak, Justyna K. Pupek, Alexandra E. Garino, McCllelan C. Knapp, Sarah F. Colmer, Terri Goss Kinzy, Stephen Dunaway In most eukaryotic organisms, translation elongation requires two highly conserved elongation factors eEF1A and eEF2. Fungal systems are unique in requiring a third factor, the eukaryotic Elongation Factor 3 (eEF3). For decades, eEF3, a ribosome-dependent ATPase, was considered “fungal-specific”, however, recent bioinformatics analysis indicates it may be more widely distributed among other unicellular eukaryotes. In order to determine whether divergent eEF3-like proteins from other eukaryotic organisms can provide the essential functions of eEF3 in budding yeast, the eEF3-like proteins from Schizosaccharomyes pombe and an oomycete, Phytophthora infestans , were cloned and expressed in Saccharomyces cerevisiae . Plasmid shuffling experiments showed that both S . pombe and P . infestans eEF3 can support the growth of S . cerevisiae in the absence of endogenous budding yeast eEF3. Consistent with its ability to provide the essential functions of eEF3, P . infestans eEF3 possessed ribosome-dependent ATPase activity. Yeast cells expressing P . infestans eEF3 displayed reduced protein synthesis due to defects in translation elongation/termination. Identification of eEF3 in divergent species will advance understanding of its function and the ribosome specific determinants that lead to its requirement as well as contribute to the identification of functional domains of eEF3 for potential drug discovery.
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  • 42
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    In: PLoS ONE
    Publication Date: 2018-01-05
    Description: by Tjaša Lukan, Fabian Machens, Anna Coll, Špela Baebler, Katrin Messerschmidt, Kristina Gruden Cloning multiple DNA fragments for delivery of several genes of interest into the plant genome is one of the main technological challenges in plant synthetic biology. Despite several modular assembly methods developed in recent years, the plant biotechnology community has not widely adopted them yet, probably due to the lack of appropriate vectors and software tools. Here we present Plant X-tender, an extension of the highly efficient, scar-free and sequence-independent multigene assembly strategy AssemblX, based on overlap-depended cloning methods and rare-cutting restriction enzymes. Plant X-tender consists of a set of plant expression vectors and the protocols for most efficient cloning into the novel vector set needed for plant expression and thus introduces advantages of AssemblX into plant synthetic biology. The novel vector set covers different backbones and selection markers to allow full design flexibility. We have included ccd B counterselection, thereby allowing the transfer of multigene constructs into the novel vector set in a straightforward and highly efficient way. Vectors are available as empty backbones and are fully flexible regarding the orientation of expression cassettes and addition of linkers between them, if required. We optimised the assembly and subcloning protocol by testing different scar-less assembly approaches: the noncommercial SLiCE and TAR methods and the commercial Gibson assembly and NEBuilder HiFi DNA assembly kits. Plant X-tender was applicable even in combination with low efficient homemade chemically competent or electrocompetent Escherichia coli . We have further validated the developed procedure for plant protein expression by cloning two cassettes into the newly developed vectors and subsequently transferred them to Nicotiana benthamiana in a transient expression setup. Thereby we show that multigene constructs can be delivered into plant cells in a streamlined and highly efficient way. Our results will support faster introduction of synthetic biology into plant science.
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  • 43
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    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.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 44
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    Publication Date: 2018-01-05
    Description: by Andrea N. Killian, Justin K. Hines
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 45
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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
    Electronic ISSN: 1553-7374
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  • 46
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    Public Library of Science (PLoS)
    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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  • 47
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    Public Library of Science (PLoS)
    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.
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  • 48
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Katherine E. Gadek, Hong Wang, Monica N. Hall, Mitchell Sungello, Andrew Libby, Drew MacLaskey, Robert H. Eckel, Bradley B. Olwin Excessive circulating triglycerides due to reduction or loss of lipoprotein lipase activity contribute to hypertriglyceridemia and increased risk for pancreatitis. The only gene therapy treatment for lipoprotein lipase deficiency decreases pancreatitis but minimally reduces hypertriglyceridemia. Synthesized in multiple tissues including striated muscle and adipose tissue, lipoprotein lipase is trafficked to blood vessel endothelial cells where it is anchored at the plasma membrane and hydrolyzes triglycerides into free fatty acids. We conditionally knocked out lipoprotein lipase in differentiated striated muscle tissue lowering striated muscle lipoprotein lipase activity causing hypertriglyceridemia. We then crossed lipoprotein lipase striated muscle knockout mice with mice possessing a conditional avian retroviral receptor gene and injected mice with either a human lipoprotein lipase retrovirus or an mCherry control retrovirus. Post-heparin plasma lipoprotein lipase activity increased for three weeks following human lipoprotein lipase retroviral infection compared to mCherry infected mice. Human lipoprotein lipase infected mice had significantly lower blood triglycerides compared to mCherry controls and were comparable to wild-type blood triglyceride levels. Thus, targeted delivery of human lipoprotein lipase into striated muscle tissue identifies a potential therapeutic target for lipoprotein lipase deficiency.
    Electronic ISSN: 1932-6203
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  • 49
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Aoi Noda, Riku Yonesaka, Shinji Sasazaki, Hideyuki Mannen Background Aurochs ( Bos primigenius ) were distributed throughout large parts of Eurasia and Northern Africa during the late Pleistocene and the early Holocene, and all modern cattle are derived from the aurochs. Although the mtDNA haplogroups of most modern cattle belong to haplogroups T and I, several additional haplogroups (P, Q, R, C and E) have been identified in modern cattle and aurochs. Haplogroup P was the most common haplogroup in European aurochs, but so far, it has been identified in only three of 〉3,000 submitted haplotypes of modern Asian cattle. Methodology We sequenced the complete mtDNA D-loop region of 181 Japanese Shorthorn cattle and analyzed these together with representative bovine mtDNA sequences. The haplotype P of Japanese Shorthorn cattle was analyzed along with that of 36 previously published European aurochs and three modern Asian cattle sequences using the hypervariable 410 bp of the D-loop region. Conclusions We detected the mtDNA haplogroup P in Japanese Shorthorn cattle with an extremely high frequency (83/181). Phylogenetic networks revealed two main clusters, designated as Pa for haplogroup P in European aurochs and Pc in modern Asian cattle. We also report the genetic diversity of haplogroup P compared with the sequences of extinct aurochs. No shared haplotypes are observed between the European aurochs and the modern Asian cattle. This finding suggests the possibility of local and secondary introgression events of haplogroup P in northeast Asian cattle, and will contribute to a better understanding of its origin and genetic diversity.
    Electronic ISSN: 1932-6203
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  • 50
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Hironori Ozaki, Ran Inoue, Takako Matsushima, Masakiyo Sasahara, Atsushi Hayashi, Hisashi Mori Diabetic retinopathy (DR) is a leading cause of blindness. DR is recognized as a microvascular disease and inner retinal neurodegeneration. In the course of retinal neurodegeneration, N -methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity is involved. Full activation of NMDAR requires binding of agonist glutamate and coagonist glycine or D-serine. D-Serine is produced from L-serine by serine racemase (SRR) and contributes to retinal neurodegeneration in rodent models of DR. However, the involvement of SRR in both neurodegeneration and microvascular damage in DR remains unclear. Here, we established diabetic model of SRR knockout (SRR-KO) and control wild-type (WT) mice by streptozotocin injection. Six months after the onset of diabetes, the number of survived retinal ganglion cells was higher in SRR-KO mice than that of WT mice. The reduction of thickness of inner retinal layer (IRL) was attenuated in SRR-KO mice than that of WT mice. Moreover, the number of damaged acellular capillaries was lower in SRR-KO mice than that of WT mice. Our results suggest the suppression of SRR activity may have protective effects in DR.
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  • 51
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Junichi Saito, Utako Yokoyama, Naoki Nicho, Yun-Wen Zheng, Yasuhiro Ichikawa, Satoko Ito, Masanari Umemura, Takayuki Fujita, Shuichi Ito, Hideki Taniguchi, Toshihide Asou, Munetaka Masuda, Yoshihiro Ishikawa Aims The ductus arteriosus (DA) closes after birth to adapt to the robust changes in hemodynamics, which require intimal thickening (IT) to occur. The smooth muscle cells of the DA have been reported to play important roles in IT formation. However, the roles of the endothelial cells (ECs) have not been fully investigated. We herein focused on tissue-type plasminogen activator (t-PA), which is a DA EC dominant gene, and investigated its contribution to IT formation in the DA. Methods and results ECs from the DA and aorta were isolated from fetal rats using fluorescence-activated cell sorting. RT-PCR showed that the t-PA mRNA expression level was 2.7-fold higher in DA ECs than in aortic ECs from full-term rat fetuses (gestational day 21). A strong immunoreaction for t-PA was detected in pre-term and full-term rat DA ECs. t-PA-mediated plasminogen-plasmin conversion activates gelatinase matrix metalloproteinases (MMPs). Gelatin zymography revealed that plasminogen supplementation significantly promoted activation of the elastolytic enzyme MMP-2 in rat DA ECs. In situ zymography demonstrated that marked gelatinase activity was observed at the site of disruption in the internal elastic laminae (IEL) in full-term rat DA. In a three-dimensional vascular model, EC-mediated plasminogen-plasmin conversion augmented the IEL disruption. In vivo administration of plasminogen to pre-term rat fetuses (gestational day 19), in which IT is poorly formed, promoted IEL disruption accompanied by gelatinase activation and enhanced IT formation in the DA. Additionally, experiments using five human DA tissues demonstrated that the t-PA expression level was 3.7-fold higher in the IT area than in the tunica media. t-PA protein expression and gelatinase activity were also detected in the IT area of the human DAs. Conclusion t-PA expressed in ECs may help to form IT of the DA via activation of MMP-2 and disruption of IEL.
    Electronic ISSN: 1932-6203
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  • 52
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Rachel C. Anderson, Alastair K. H. MacGibbon, Neill Haggarty, Kelly M. Armstrong, Nicole C. Roy Appropriate intestinal barrier maturation is essential for absorbing nutrients and preventing pathogens and toxins from entering the body. Compared to breast-fed infants, formula-fed infants are more susceptible to barrier dysfunction-associated illnesses. In infant formula dairy lipids are usually replaced with plant lipids. We hypothesised that dairy complex lipids improve in vitro intestinal epithelial barrier integrity. We tested milkfat high in conjugated linoleic acid, beta serum (SureStart™Lipid100), beta serum concentrate (BSC) and a ganglioside-rich fraction (G600). Using Caco-2 cells as a model of the human small intestinal epithelium, we analysed the effects of the ingredients on trans-epithelial electrical resistance (TEER), mannitol flux, and tight junction protein co-localisation. BSC induced a dose-dependent improvement in TEER across unchallenged cell layers, maintained the co-localisation of tight junction proteins in TNFα-challenged cells with increased permeability, and mitigated the TEER-reducing effects of lipopolysaccharide (LPS). G600 also increased TEER across healthy and LPS-challenged cells, but it did not alter the co-location of tight junction proteins in TNFα-challenged cells. SureStart™Lipid100 had similar TEER-increasing effects to BSC when added at twice the concentration (similar lipid concentration). Ultimately, this research aims to contribute to the development of infant formulas supplemented with dairy complex lipids that support infant intestinal barrier maturation.
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  • 53
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Min-Ji Kang, Yong-Eun Lee, Jun-Sub Choi, Choun-Ki Joo In femtosecond laser-assisted cataract surgery, the parameter such as horizontal spot spacing and energy level can be adjusted. Although there have been several studies reported on various laser systems, showing the effects of varying energy levels and horizontal spot spacing on lens capsulotomy cut edges, none have been reported on the Catalys laser system (Abbott Medical Optics, Inc., Santa Ana, CA). The aim of this study is to evaluate, using scanning electron microscopy (SEM), the quality of the cut edges of the laser lens capsulotomy obtained using the Catalys Laser System, using different horizontal spot spacing and energy levels, and to determine the ideal parameters based on SEM results. Fifty rabbit capsulorhexis specimens from a femtosecond laser with different spot spacing and energy settings were divided into five groups randomly. Spot spacing was 3 um and laser pulse energy was 4 uJ in group 1. The respective values were 5 um and 2 uJ in group 2, 5 um and 4 uJ in group 3, 5 um and 6 uJ in group 4, and 7 um and 4 uJ in group 5. All samples were evaluated using SEM to compare the number of tags per capsulotomy and the laser emission time. Group 1 had a significantly lower tag formation than groups 3 and 5 ( P = 0.042 and 0.021, respectively). Although the laser emission time increased about 1.5 sec as the spot spacing increased from 3 to 7 um, the quality of the cut was smoother in group 1 because of overlapping effect of photodisruption cavities. There was no significant difference between groups 2, 3 and 4 at different laser energy settings. In an ex-vivo study, samples from an energy setting of 10 uJ showed increased irregularity and damage. The degree of irregularity was higher at increasing spot spacing and laser energy settings, with abundant tag formation. Dense spot spacing with low-energy settings provide a better cut quality, which is probably correlated with the reduction in anterior capsular tear complications.
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  • 54
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Kei Ando, Shiro Imagama, Kazuyoshi Kobayashi, Kenyu Ito, Mikito Tsushima, Masayoshi Morozumi, Satoshi Tanaka, Masaaki Machino, Kyotaro Ota, Koji Nishida, Yoshihiro Nishida, Naoki Ishiguro Spinal fusion and bone defect after injuries, removal of bone tumors, and infections need to be repaired by implantation. In an aging society, recovery from these procedures is often difficult. In this study, we found that injection of SPG-178 leads to expression of several bone marker genes and mineralization in vitro, and revealed a significantly higher degree of newly formed bone matrix with use of SPG-178 in vivo. MC3T3-E1 cells were used to evaluate osteoblast differentiation promoted by SPG-178. To analyze gene expression, total RNA was isolated from MC3T3-E1 cells cultured for 7 and 14 days with control medium or SPG-178 medium. Among the several bone marker genes examined, SPG-178 significantly increased the mRNA levels for ALP, BMP-2 and Osteocalcin, OPN, BSP and for the Osterix. Ten-week-old female Wistar rats were used for all transplantation procedures. A PEEK cage was implanted into a bony defect (5 mm) within the left femoral mid-shaft, and stability was maintained by an external fixator. The PEEK cages were filled with either a SPG-178 hydrogel plus allogeneic bone chips (n = 4) or only allogeneic bone chips (n = 4). The rats were then kept for 56 days. Newly formed bone matrix was revealed inside the PEEK cage and there was an increased bone volume per total volume with the cage filled with SPG-178, compared to the control group. SPG-178 has potential in clinical applications because it has several benefits. These include its favorable bone conduction properties its ability to act as a support for various different cells and growth factors, its lack of infection risk compared with materials of animal origin such as ECM, and the ease with which it can be used to fill defects with complex shapes and combined with a wide range of other materials.
    Electronic ISSN: 1932-6203
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  • 55
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Hsy-Yu Tzeng, Wei Wang, Yen-Hsueh Tseng, Ching-An Chiu, Chu-Chia Kuo, Shang-Te Tsai Global warming-induced extreme climatic changes have increased the frequency of severe typhoons bringing heavy rains; this has considerably affected the stability of the forest ecosystems. Since the Taiwan 921 earthquake occurred in 21 September 1999, the mountain geology of the Island of Taiwan has become unstable and typhoon-induced floods and mudslides have changed the topography and geomorphology of the area; this has further affected the stability and functions of the riparian ecosystem. In this study, the vegetation of the unique Aowanda Formosan gum forest in Central Taiwan was monitored for 3 years after the occurrence of floods and mudslides during 2009–2011. Tree growth and survival, effects of floods and mudslides, and factors influencing tree survival were investigated. We hypothesized that (1) the effects of floods on the survival are significantly different for each tree species; (2) tree diameter at breast height (DBH) affects tree survival–i.e., the larger the DBH, the higher the survival rate; and (3) the relative position of trees affects tree survival after disturbances by floods and mudslides–the farther trees are from the river, the higher is their survival rate. Our results showed that after floods and mudslides, the lifespans of the major tree species varied significantly. Liquidambar formosana displayed the highest flood tolerance, and the trunks of Lagerstoemia subcostata began rooting after disturbances. Multiple regression analysis indicated that factors such as species, DBH, distance from sampled tree to the above boundary of sample plot (far from the riverbank), and distance from the upstream of the river affected the lifespans of trees; the three factors affected each tree species to different degrees. Furthermore, we showed that insect infestation had a critical role in determining tree survival rate. Our 3-year monitoring investigation revealed that severe typhoon-induced floods and mudslides disturbed the riparian vegetation in the Formosan gum forest, replacing the original vegetation and beginning secondary succession. Moreover, flooding provided new habitats for various plants to establish their progeny. By using our results, lifecycles of trees (including death) can be understood in detail, facilitating riparian vegetation engineering in forests severely disturbed by typhoon-induced floods and mudslides.
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  • 56
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Rafael Gonçalves-Araujo, Benjamin Rabe, Ilka Peeken, Astrid Bracher As consequences of global warming sea-ice shrinking, permafrost thawing and changes in fresh water and terrestrial material export have already been reported in the Arctic environment. These processes impact light penetration and primary production. To reach a better understanding of the current status and to provide accurate forecasts Arctic biogeochemical and physical parameters need to be extensively monitored. In this sense, bio-optical properties are useful to be measured due to the applicability of optical instrumentation to autonomous platforms, including satellites. This study characterizes the non-water absorbers and their coupling to hydrographic conditions in the poorly sampled surface waters of the central and eastern Arctic Ocean. Over the entire sampled area colored dissolved organic matter (CDOM) dominates the light absorption in surface waters. The distribution of CDOM, phytoplankton and non-algal particles absorption reproduces the hydrographic variability in this region of the Arctic Ocean which suggests a subdivision into five major bio-optical provinces: Laptev Sea Shelf, Laptev Sea, Central Arctic/Transpolar Drift, Beaufort Gyre and Eurasian/Nansen Basin. Evaluating ocean color algorithms commonly applied in the Arctic Ocean shows that global and regionally tuned empirical algorithms provide poor chlorophyll- a (Chl- a ) estimates. The semi-analytical algorithms Generalized Inherent Optical Property model (GIOP) and Garver-Siegel-Maritorena (GSM), on the other hand, provide robust estimates of Chl- a and absorption of colored matter. Applying GSM with modifications proposed for the western Arctic Ocean produced reliable information on the absorption by colored matter, and specifically by CDOM. These findings highlight that only semi-analytical ocean color algorithms are able to identify with low uncertainty the distribution of the different optical water constituents in these high CDOM absorbing waters. In addition, a clustering of the Arctic Ocean into bio-optical provinces will help to develop and then select province-specific ocean color algorithms.
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  • 57
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Diana Caine, Akin Nihat, Philippa Crabb, Peter Rudge, Lisa Cipolotti, John Collinge, Simon Mead Background Akinetic mutism is a key diagnostic feature of prion diseases, however, their rapidly progressive nature makes detailed investigation of the language disorder in a large cohort extremely challenging. This study aims to position prion diseases in the nosology of language disorders and improve early clinical recognition. Methods A systematic, prospective investigation of language disorders in a large cohort of patients diagnosed with prion diseases. 568 patients were included as a sub-study of the National Prion Monitoring Cohort. All patients had at least one assessment with the MRC Scale, a milestone-based functional scale with language and non-language components. Forty patients, with early symptoms and able to travel to the study site, were also administered a comprehensive battery of language tests (spontaneous speech, semantics, syntax, repetition, naming, comprehension and lexical retrieval under different conditions). Results 5/568 (0.9%) patients presented with leading language symptoms. Those with repeated measurements deteriorated at a slower rate in language compared to non-language milestones. Amongst the subgroup of 40 patients who underwent detailed language testing, only three tasks–semantic and phonemic fluency and sentence comprehension–were particularly vulnerable early in the disease. These tasks were highly correlated with performance on non-verbal executive tests. Patients were also impaired on a test of dynamic aphasia. Conclusion These results provide evidence that the language disorder in prion disease is rarely an isolated clinical or cognitive feature. The language abnormality is indicative of a dynamic aphasia in the context of a prominent dysexecutive syndrome, similar to that seen in patients with the degenerative movement disorder progressive supranuclear palsy (PSP).
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  • 58
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Eva Gravesen, Maria Lerche Mace, Anders Nordholm, Jacob Hofman-Bang, Keith Hruska, Carsten Haagen Nielsen, Andreas Kjær, Klaus Olgaard, Ewa Lewin Hyperphosphatemia and vascular calcification are frequent complications of chronic renal failure and bone morphogenetic protein 7 (BMP7) has been shown to protect against development of vascular calcification in uremia. The present investigation examined the potential reversibility of established uremic vascular calcification by treatment of uremic rats with BMP7. A control model of isogenic transplantation of a calcified aorta from uremic rats into healthy littermates examined whether normalization of the uremic environment reversed vascular calcification. Uremia and vascular calcification were induced in rats by 5/6 nephrectomy, high phosphate diet and alfacalcidol treatment. After 14 weeks severe vascular calcification was present and rats were allocated to BMP7, vehicle or aorta transplantation. BMP7 treatment caused a significant decrease of plasma phosphate to 1.56 ± 0.17 mmol/L vs 2.06 ± 0.34 mmol/L in the vehicle group even in the setting of uremia and high phosphate diet. Uremia and alfacalcidol resulted in an increase in aortic expression of genes related to fibrosis, osteogenic transformation and extracellular matrix calcification, and the BMP7 treatment resulted in a decrease in the expression of profibrotic genes. The total Ca-content of the aorta was however unchanged both in the abdominal aorta: 1.9 ± 0.6 μg/mg tissue in the vehicle group vs 2.2 ± 0.6 μg/mg tissue in the BMP7 group and in the thoracic aorta: 71 ± 27 μg/mg tissue in the vehicle group vs 54 ± 18 μg/mg tissue in the BMP7 group. Likewise, normalization of the uremic environment by aorta transplantation had no effect on the Ca-content of the calcified aorta: 16.3 ± 0.6 μg/mg tissue pre-transplantation vs 15.9 ± 2.3 μg/mg tissue post-transplantation. Aortic expression of genes directly linked to extracellular matrix calcification was not affected by BMP7 treatment, which hypothetically might explain persistent high Ca-content in established vascular calcification. The present results highlight the importance of preventing the development of vascular calcification in chronic kidney disease. Once established, vascular calcification persists even in the setting when hyperphosphatemia or the uremic milieu is abolished.
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  • 59
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    In: PLoS ONE
    Publication Date: 2018-01-06
    Description: by Georgina Guilera, Maite Barrios, Eva Penelo, Christopher Morin, Piers Steel, Juana Gómez-Benito The present study is centered in adapting and validating a Spanish version of the Irrational Procrastination Scale (IPS). The sample consists of 365 adults aged 18–77 years ( M = 37.70, SD = 12.64). Participants were administered two measures of procrastination, the IPS and the Decisional Procrastination Questionnaire, as well as the Big Five Inventory, and the Satisfaction With Life Scale. First, the factor and replication analysis revealed that the internal structure of the scale is clearly one-dimensional, supporting the idea that IPS seems to measure general procrastination as a single trait. Second, the internal consistency is satisfactory as is the temporal stability of the IPS scores. Third, the correlations encountered between the IPS scores and other measures of procrastination, personality traits and satisfaction with life are all in the expected direction and magnitude. Finally, consistent with previous research, procrastination is related to age, with the youngest being the most procrastinating group. This study represents the first attempt in adapting and validating the IPS measure of procrastination into Spanish. Results suggest that the Spanish version of the IPS offers valid and reliable scores when applied to adult population.
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  • 60
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    Publication Date: 2018-01-06
    Description: by Jennifer M. Binning, Amber M. Smith, Judd F. Hultquist, Charles S. Craik, Nathalie Caretta, Melody G. Campbell, Lily Burton, Florencia La Greca, Michael J. McGregor, Hai M. Ta, Koen Bartholomeeusen, B. Matija Peterlin, Nevan J. Krogan, Natalia Sevillano, Yifan Cheng, John D. Gross The lentiviral protein Viral Infectivity Factor (Vif) counteracts the antiviral effects of host APOBEC3 (A3) proteins and contributes to persistent HIV infection. Vif targets A3 restriction factors for ubiquitination and proteasomal degradation by recruiting them to a multi-protein ubiquitin E3 ligase complex. Here, we describe a degradation-independent mechanism of Vif-mediated antagonism that was revealed through detailed structure-function studies of antibody antigen-binding fragments (Fabs) to the Vif complex. Two Fabs were found to inhibit Vif-mediated A3 neutralization through distinct mechanisms: shielding A3 from ubiquitin transfer and blocking Vif E3 assembly. Combined biochemical, cell biological and structural studies reveal that disruption of Vif E3 assembly inhibited A3 ubiquitination but was not sufficient to restore its packaging into viral particles and antiviral activity. These observations establish that Vif can neutralize A3 family members in a degradation-independent manner. Additionally, this work highlights the potential of Fabs as functional probes, and illuminate how Vif uses a multi-pronged approach involving both degradation dependent and independent mechanisms to suppress A3 innate immunity.
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  • 61
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    Publication Date: 2018-01-06
    Description: by Katinka Döhner, Ana Ramos-Nascimento, Dagmara Bialy, Fenja Anderson, Ana Hickford-Martinez, Franziska Rother, Thalea Koithan, Kathrin Rudolph, Anna Buch, Ute Prank, Anne Binz, Stefanie Hügel, Robert Jan Lebbink, Rob C. Hoeben, Enno Hartmann, Michael Bader, Rudolf Bauerfeind, Beate Sodeik Herpesviruses are large DNA viruses which depend on many nuclear functions, and therefore on host transport factors to ensure specific nuclear import of viral and host components. While some import cargoes bind directly to certain transport factors, most recruit importin β1 via importin α. We identified importin α1 in a small targeted siRNA screen to be important for herpes simplex virus (HSV-1) gene expression. Production of infectious virions was delayed in the absence of importin α1, but not in cells lacking importin α3 or importin α4. While nuclear targeting of the incoming capsids, of the HSV-1 transcription activator VP16, and of the viral genomes were not affected, the nuclear import of the HSV-1 proteins ICP4 and ICP0, required for efficient viral transcription, and of ICP8 and pUL42, necessary for DNA replication, were reduced. Furthermore, quantitative electron microscopy showed that fibroblasts lacking importin α1 contained overall fewer nuclear capsids, but an increased proportion of mature nuclear capsids indicating that capsid formation and capsid egress into the cytoplasm were impaired. In neurons, importin α1 was also not required for nuclear targeting of incoming capsids, but for nuclear import of ICP4 and for the formation of nuclear capsid assembly compartments. Our data suggest that importin α1 is specifically required for the nuclear localization of several important HSV1 proteins, capsid assembly, and capsid egress into the cytoplasm, and may become rate limiting in situ upon infection at low multiplicity or in terminally differentiated cells such as neurons.
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-09
    Description: by Akira Nagamori, Christopher M. Laine, Francisco J. Valero-Cuevas Involuntary force variability below 15 Hz arises from, and is influenced by, many factors including descending neural drive, proprioceptive feedback, and mechanical properties of muscles and tendons. However, their potential interactions that give rise to the well-structured spectrum of involuntary force variability are not well understood due to a lack of experimental techniques. Here, we investigated the generation, modulation, and interactions among different sources of force variability using a physiologically-grounded closed-loop simulation of an afferented muscle model. The closed-loop simulation included a musculotendon model, muscle spindle, Golgi tendon organ (GTO), and a tracking controller which enabled target-guided force tracking. We demonstrate that closed-loop control of an afferented musculotendon suffices to replicate and explain surprisingly many cardinal features of involuntary force variability. Specifically, we present 1) a potential origin of low-frequency force variability associated with co-modulation of motor unit firing rates (i.e.,‘common drive’), 2) an in-depth characterization of how proprioceptive feedback pathways suffice to generate 5-12 Hz physiological tremor, and 3) evidence that modulation of those feedback pathways (i.e., presynaptic inhibition of Ia and Ib afferents, and spindle sensitivity via fusimotor drive) influence the full spectrum of force variability. These results highlight the previously underestimated importance of closed-loop neuromechanical interactions in explaining involuntary force variability during voluntary ‘isometric’ force control. Furthermore, these results provide the basis for a unifying theory that relates spinal circuitry to various manifestations of altered involuntary force variability in fatigue, aging and neurological disease.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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    Publication Date: 2018-01-09
    Description: by Mathias Engel, James Longden, Jesper Ferkinghoff-Borg, Xavier Robin, Gaye Sağınç, Rune Linding Cell migration is a central biological process that requires fine coordination of molecular events in time and space. A deregulation of the migratory phenotype is also associated with pathological conditions including cancer where cell motility has a causal role in tumor spreading and metastasis formation. Thus cell migration is of critical and strategic importance across the complex disease spectrum as well as for the basic understanding of cell phenotype. Experimental studies of the migration of cells in monolayers are often conducted with ‘wound healing’ assays. Analysis of these assays has traditionally relied on how the wound area changes over time. However this method does not take into account the shape of the wound. Given the many options for creating a wound healing assay and the fact that wound shape invariably changes as cells migrate this is a significant flaw. Here we present a novel software package for analyzing concerted cell velocity in wound healing assays. Our method encompasses a wound detection algorithm based on cell confluency thresholding and employs a Bayesian approach in order to estimate concerted cell velocity with an associated likelihood. We have applied this method to study the effect of siRNA knockdown on the migration of a breast cancer cell line and demonstrate that cell velocity can track wound healing independently of wound shape and provides a more robust quantification with significantly higher signal to noise ratios than conventional analyses of wound area. The software presented here will enable other researchers in any field of cell biology to quantitatively analyze and track live cell migratory processes and is therefore expected to have a significant impact on the study of cell migration, including cancer relevant processes. Installation instructions, documentation and source code can be found at http://bowhead.lindinglab.science licensed under GPLv3.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
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    Publication Date: 2018-01-09
    Description: by Neeta Bala Tannan, Giovanna Collu, Ashley C. Humphries, Ekatherina Serysheva, Ursula Weber, Marek Mlodzik AKAP200 is a Drosophila melanogaster member of the “A Kinase Associated Protein” family of scaffolding proteins, known for their role in the spatial and temporal regulation of Protein Kinase A (PKA) in multiple signaling contexts. Here, we demonstrate an unexpected function of AKAP200 in promoting Notch protein stability. In Drosophila , AKAP200 loss-of-function (LOF) mutants show phenotypes that resemble Notch LOF defects, including eye patterning and sensory organ specification defects. Through genetic interactions, we demonstrate that AKAP200 interacts positively with Notch in both the eye and the thorax. We further show that AKAP200 is part of a physical complex with Notch. Biochemical studies reveal that AKAP200 stabilizes endogenous Notch protein, and that it limits ubiquitination of Notch. Specifically, our genetic and biochemical evidence indicates that AKAP200 protects Notch from the E3-ubiquitin ligase Cbl, which targets Notch to the lysosomal pathway. Indeed, we demonstrate that the effect of AKAP200 on Notch levels depends on the lysosome. Interestingly, this function of AKAP200 is fully independent of its role in PKA signaling and independent of its ability to bind PKA. Taken together, our data indicate that AKAP200 is a novel tissue specific posttranslational regulator of Notch, maintaining high Notch protein levels and thus promoting Notch signaling.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 65
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    Publication Date: 2018-01-09
    Description: by Moytrey Chatterjee, Sudeep Ballav, Ardhendu K. Maji, Nandita Basu, Biplab Chandra Sarkar, Pabitra Saha Background The control and prevention of dengue largely depends on vector control measures, environmental management, and personal protection. Dengue control programmes are facing great challenges due to development of insecticide resistance among vector mosquitoes. Information on susceptibility status to different insecticides is important for national programmes to formulate vector control strategies. Methods We have studied the larval susceptibility of Aedes albopictus to temephos and adult susceptibility to 4% DDT, 0.05% deltamethrin, and 5% malathion as per WHO protocols in the northern districts of West Bengal. Polymorphisms in the VGSC gene were studied by direct sequencing of PCR products. Results The Ae . albopictus larval population showed sensitive [Resistance Ratio (RR 99 ) 98%), except in Dhupguri where a low level of resistance to deltamethrin (CM = 96.25%) was recorded. None of the six important kdr mutations (S953P, I975M/V, L978, V980G, F1474C, D1703Y) were found in the VGSC of studied mosquitoes, but we identified 11 synonymous and 1 non-synonymous mutation in the VGSC gene. Conclusion The higher susceptibility level to deltamethrin and malathion, along with the absence of important kdr mutations indicates that these two insecticides are still effective against Ae . albopictus in the study areas. The susceptibility status of temephos should be monitored closely as low to moderate levels of resistance were observed in few sites. A similar study is recommended for monitoring and early detection of insecticide resistance in other parts of the country.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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    Publication Date: 2018-01-09
    Description: by Susanne Wiese, Lynne Elson, Hermann Feldmeier Background Tungiasis (sand flea disease) is a neglected tropical skin disease caused by female sand fleas ( Tunga spp .) embedded in the skin of the host. The disease is common in sub-Saharan Africa and predominantly affects children living in impoverished rural communities. In these settings tungiasis is associated with important morbidity. Whether tungiasis impairs life quality has never been studied. Methods The study was performed in 50 children with tungiasis, living in resource-poor communities in coastal Kenya. Based on the Dermatology Life Quality Index (DLQI) a tool was developed to determine life quality impairment associated with tungiasis in children, the tungiasis-related Dermatology of Life Quality Index (tungiasis-related-DLQI). Pain and itching were assessed using visual scales ranging from 0–3 points. The intensity of infection and the acute and chronic severity of tungiasis were determined using standard methods. Results Seventy eight percent of the patients reported a moderate to very large effect of tungiasis on life quality at the time of the diagnosis. The degree of impairment correlated with the number of viable sand fleas present in the skin (rho = 0.64, p 〈 0.001), the severity score of acute clinical pathology (rho = 0.74, p 〈 0.001), and the intensity of pain (rho = 0.82, p 〈 0.001). Disturbance of sleep and concentration difficulties were the most frequent restriction categories (86% and 84%, respectively). Four weeks after curative treatment, life quality had improved significantly. On the individual level the amelioration of life quality correlated closely with the regression of clinical pathology (rho = 0.61, p 〈 0.001). Conclusion The parasitic skin disease tungiasis considerably impairs life quality in children in rural Kenya. After effective treatment, life quality improves rapidly.
    Print ISSN: 1935-2727
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Christian Seegelke, Matthias Weigelt The present study explored the sensitivity towards bimanual end-state comfort in a task that required anticipating different final grips. Participants simultaneously reached and grasped two objects with either a whole-hand grip (WHG) or a precision grip (PG), and placed them at two target locations by transporting them either over or under an obstacle. The transport path was varied such that it could be either congruent (i.e., both objects over or under) or incongruent (i.e., one object over and the other object under). In the congruent conditions, participants satisfied bimanual end-state comfort (and identical initial grips) on the majority of trials. That is, participants adopted a PG for either hand when the objects were transported over the obstacle and a WHG for either hand when the objects were transported under the obstacle. In contrast, in the incongruent conditions, bimanual end-state comfort was significantly reduced, indicating the presence of intermanual inference. The results indicate that goal-related planning constraints (i.e., bimanual end-state comfort) do not strictly take precedence over means-related constraints (i.e., identical initial grips) if this requires anticipating different final grips. Thus, bimanual end-state comfort per se does not provide a predominant constraint in action selection, by which sensorimotor interference can be reduced. In line with the proposal that bimanual grip planning relies on a flexible constraint hierarchy, a simple formal model that considers bimanual grip posture planning as a tradeoff between goal-related and means-related planning processes can explain our results reasonably well.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 68
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Nadezhda M. Belonogova, Gulnara R. Svishcheva, James F. Wilson, Harry Campbell, Tatiana I. Axenovich Functional linear regression models are effectively used in gene-based association analysis of complex traits. These models combine information about individual genetic variants, taking into account their positions and reducing the influence of noise and/or observation errors. To increase the power of methods, where several differently informative components are combined, weights are introduced to give the advantage to more informative components. Allele-specific weights have been introduced to collapsing and kernel-based approaches to gene-based association analysis. Here we have for the first time introduced weights to functional linear regression models adapted for both independent and family samples. Using data simulated on the basis of GAW17 genotypes and weights defined by allele frequencies via the beta distribution, we demonstrated that type I errors correspond to declared values and that increasing the weights of causal variants allows the power of functional linear models to be increased. We applied the new method to real data on blood pressure from the ORCADES sample. Five of the six known genes with P 〈 0.1 in at least one analysis had lower P values with weighted models. Moreover, we found an association between diastolic blood pressure and the VMP1 gene ( P = 8.18×10 −6 ), when we used a weighted functional model. For this gene, the unweighted functional and weighted kernel-based models had P = 0.004 and 0.006, respectively. The new method has been implemented in the program package FREGAT, which is freely available at https://cran.r-project.org/web/packages/FREGAT/index.html.
    Electronic ISSN: 1932-6203
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  • 69
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Jennifer S. McDonald, Robert J. McDonald, Jacob B. Ekins, Anthony S. Tin, Sylvain Costes, Tamara M. Hudson, Dana J. Schroeder, Kevin Kallmes, Scott H. Kaufmann, Philip M. Young, Aiming Lu, Ramanathan Kadirvel, David F. Kallmes Magnetic resonance imaging is considered low risk, yet recent studies have raised a concern of potential damage to DNA in peripheral blood leukocytes. This prospective Institutional Review Board-approved study examined potential double-strand DNA damage by analyzing changes in the DNA damage and repair markers γH2AX and 53BP1 in patients who underwent a 1.5 T gadolinium-enhanced cardiac magnetic resonance (MR) exam. Sixty patients were enrolled (median age 55 years, 39 males). Patients with history of malignancy or who were receiving chemotherapy, radiation therapy, or steroids were excluded. MR sequence data were recorded and blood samples obtained immediately before and after MR exposure. An automated immunofluorescence assay quantified γH2AX or 53BP1 foci number in isolated peripheral blood mononuclear cells. Changes in foci number were analyzed using the Wilcoxon signed-rank test. Clinical and MR procedural characteristics were compared between patients who had a 〉10% increase in γH2AX or 53BP1 foci numbers and patients who did not. The number of γH2AX foci did not significantly change following cardiac MR (median foci per cell pre-MR = 0.11, post-MR = 0.11, p = .90), but the number of 53BP1 foci significantly increased following MR (median foci per cell pre-MR = 0.46, post-MR = 0.54, p = .0140). Clinical and MR characteristics did not differ significantly between patients who had at least a 10% increase in foci per cell and those who did not. We conclude that MR exposure leads to a small (median 25%) increase in 53BP1 foci, however the clinical relevance of this increase is unknown and may be attributable to normal variation instead of MR exposure.
    Electronic ISSN: 1932-6203
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Weiwei Ping, Wenjun Cao, Hongzhuan Tan, Chongzheng Guo, Zhiyong Dou, Jianzhou Yang Objective A healthy lifestyle includes health protective and health promoting behaviors. Health promoting lifestyle profiles have been developed, but measures of health protective behavior are still lacking. This study sought to develop a health protecting behavior scale. Methods An initial item pool for the Health Protective Behavior Scale (HPBS) was generated based on read and referred literature and a single-item open-ended survey. An expert group screened this initial item pool using an item-level content validity index. Pilot testing was conducted. The degree of variation, the response rate, the item-total correlation coefficient, and the factor loading in factor analysis and item analysis were used to screen items using data of pilot testing. 454 subjects were recruited evaluate the psychometric properties of the HPBS. Analyses included internal consistency, test-retest reliability, factor analysis, parallel analysis, correlation analysis and criterion validity analysis. Results The final iteration of the HPBS was developed with 32 items and five dimensions: interpersonal support, general behavior, self-knowledge, nutrition behavior and health care. Cronbach’s alpha coefficient, and test-retest reliability were 0.89 and 0.89 respectively. Correlation coefficients of the five dimensions ranged from 0.28 to 0.55. The Spearman correlation coefficient between the total scores on the WHOQOL-BREF and on the HPBS was 0.34. Conclusions HPBS has sufficient validity and reliability to measure health protective behaviors in adults.
    Electronic ISSN: 1932-6203
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Zhaowei Li, Fubiao Wang, Qian Zhao, Jianchao Liu, Fangmin Cheng In this study, the differences in reactive oxygen species (ROS) generation and abscisic acid (ABA) accumulation in senescing leaves were investigated by early-senescence-leaf ( esl ) mutant and its wild type, to clarify the relationship among ABA levels, ROS generation, and NADPH oxidase (Nox) in senescing leaves of rice ( Oryza sativa ). The temporal expression levels of OsNox isoforms in senescing leaves and their expression patterns in response to ABA treatment were determined through quantitative real-time reverse transcription PCR (qRT-PCR). Results showed that the flag leaf of the esl mutant generated more O 2- concentrations and accumulated higher ABA levels than the wild-type cultivar did in the grain-filling stage. Exogenous ABA treatment induced O 2- generation; however, it was depressed by diphenyleneiodonium chloride (DPI) pretreatment in the detached leaf segments. This finding suggested the involvement of NADPH oxidase in ABA-induced O 2- generation. The esl mutant exhibited significantly higher expression of OsNox2 , OsNox5 , OsNox6 , and OsNox7 in the initial of grain-filling stage, followed by sharply decrease. The transcriptional levels of OsNox1 , OsNox3 , and OsFR07 in the flag leaf of the esl mutant were significantly lower than those in the wild-type cultivar. The expression levels of OsNox2 , OsNox5 , OsNox6 , and OsNox7 were significantly enhanced by exogenous ABA treatments. The enhanced expression levels of OsNox2 and OsNox6 were dependent on the duration of ABA treatment. The inducible expression levels of OsNox5 and OsNox7 were dependent on ABA concentrations. By contrast, exogenous ABA treatment severely repressed the transcripts of OsNox1 , OsNox3 , and OsFR07 in the detached leaf segments. Therefore, OsNox2 , OsNox5 , OsNox6 , and OsNox7 were probably involved in the ABA-induced O 2- generation in the initial stage of leaf senescence. Subsequently, other oxidases activated in deteriorating cells were associated with ROS generation and accumulation in the senescing leaves of the esl mutant. Conversely, OsNox1 , OsNox3 , and OsFR07 were not associated with ABA-induced O 2- generation during leaf senescence.
    Electronic ISSN: 1932-6203
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  • 72
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Benjamin Ruttenberg, Jennifer E. Caselle, Andrew J. Estep, Ayana Elizabeth Johnson, Kristen L. Marhaver, Lee J. Richter, Stuart A. Sandin, Mark J. A. Vermeij, Jennifer E. Smith, David Grenda, Abigail Cannon To inform a community-based ocean zoning initiative, we conducted an intensive ecological assessment of the marine ecosystems of Barbuda, West Indies. We conducted 116 fish and 108 benthic surveys around the island, and measured the abundance and size structure of lobsters and conch at 52 and 35 sites, respectively. We found that both coral cover and fish biomass were similar to or lower than levels observed across the greater Caribbean; live coral cover and abundance of fishery target species, such as large snappers and groupers, was generally low. However, Barbuda lacks many of the high-relief forereef areas where similar work has been conducted in other Caribbean locations. The distribution of lobsters was patchy, making it difficult to quantify density at the island scale. However, the maximum size of lobsters was generally larger than in other locations in the Caribbean and similar to the maximum size reported 40 years ago. While the lobster population has clearly been heavily exploited, our data suggest that it is not as overexploited as in much of the rest of the Caribbean. Surveys of Barbuda’s Codrington Lagoon revealed many juvenile lobsters, but none of legal size (95 mm carapace length), suggesting that the lagoon functions primarily as nursery habitat. Conch abundance and size on Barbuda were similar to that of other Caribbean islands. Our data suggest that many of the regional threats observed on other Caribbean islands are present on Barbuda, but some resources—particularly lobster and conch—may be less overexploited than on other Caribbean islands. Local management has the potential to provide sustainability for at least some of the island’s marine resources. We show that a rapid, thorough ecological assessment can reveal clear conservation opportunities and facilitate rapid conservation action by providing the foundation for a community-driven policymaking process at the island scale.
    Electronic ISSN: 1932-6203
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  • 73
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Peng Dong, Carolyn Zhang, Bao-Tran Parker, Lingchong You, Bernard Mathey-Prevot The length of the G1 phase in the cell cycle shows significant variability in different cell types and tissue types. To gain insights into the control of G1 length, we generated an E2F activity reporter that captures free E2F activity after dissociation from Rb sequestration and followed its kinetics of activation at the single-cell level, in real time. Our results demonstrate that its activity is precisely coordinated with S phase progression. Quantitative analysis indicates that there is a pre-S phase delay between E2F transcriptional dynamic and activity dynamics. This delay is variable among different cell types and is strongly modulated by the cyclin D/CDK4/6 complex activity through Rb phosphorylation. Our findings suggest that the main function of this complex is to regulate the appropriate timing of G1 length.
    Electronic ISSN: 1932-6203
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  • 74
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Maria João Jacinto, João R. C. Trabuco, Binh V. Vu, Gavin Garvey, Mohammad Khodadady, Ana M. Azevedo, Maria Raquel Aires-Barros, Long Chang, Katerina Kourentzi, Dmitri Litvinov, Richard C. Willson Lateral flow assays (LFAs) are a widely-used point-of care diagnostic format, but suffer from limited analytical sensitivity, especially when read by eye. It has recently been reported that LFA performance can be improved by using magnetic reporter particles and an external magnetic field applied at the test line. The mechanism of sensitivity/performance enhancement was suggested to be concentration/retardation of reporter particles at the test line. Here we demonstrate an additional mechanism of particle relocation where reporter particles from the lower depths of the translucent LFA strip relocate to more-visible locations nearer to the top surface, producing a more visible signal. With a magnetic field we observed an improvement in sensitivity of human chorionic gonadotropin (hCG) detection from 1.25 ng/mL to 0.31 ng/mL. We also observed an increase of the color intensity per particle in test lines when the magnetic field was present.
    Electronic ISSN: 1932-6203
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    In: PLoS ONE
    Publication Date: 2018-01-09
    Description: by Lian-Kuang Lim, Seong-Ling Yap, D. A. Bradley The plasma focus device discussed herein is a Z-pinch pulsed-plasma arrangement. In this, the plasma is heated and compressed into a cylindrical column, producing a typical density of 〉 10 25 particles/m 3 and a temperature of (1–3) × 10 7 o C. The plasma focus has been widely investigated as a radiation source, including as ion-beams, electron-beams and as a source of x-ray and neutron production, providing considerable scope for use in a variety of technological situations. Thus said, the nature of the radiation emission depends on the dynamics of the plasma pinch. In this study of the characteristics of deuteron-beam emission, in terms of energy, fluence and angular distribution were analyzed. The 2.7 kJ plasma focus discharge has been made to operate at a pressure of less than 1 mbar rather than at its more conventional operating pressure of a few mbar. Faraday cup were used to determine deuteron-beam energy and deuteron-beam fluence per shot while CR-39 solid-state nuclear track detectors were employed in studying the angular distribution of deuteron emission. Beam energy and deuteron-beam fluence per shot have been found to be pressure dependent. The largest value of average deuteron energy measured for present conditions was found to be (52 ± 7) keV, while the deuteron-beam fluence per shot was of the order of 10 15 ions/m 2 when operated at a pressure of 0.2 mbar. The deuteron-beam emission is in the forward direction and is observed to be highly anisotropic.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-01-09
    Description: by Thamir Alandijany, Ashley P. E. Roberts, Kristen L. Conn, Colin Loney, Steven McFarlane, Anne Orr, Chris Boutell Detection of viral nucleic acids plays a critical role in the induction of intracellular host immune defences. However, the temporal recruitment of immune regulators to infecting viral genomes remains poorly defined due to the technical difficulties associated with low genome copy-number detection. Here we utilize 5-Ethynyl-2’-deoxyuridine (EdU) labelling of herpes simplex virus 1 (HSV-1) DNA in combination with click chemistry to examine the sequential recruitment of host immune regulators to infecting viral genomes under low multiplicity of infection conditions. Following viral genome entry into the nucleus, PML-nuclear bodies (PML-NBs) rapidly entrapped viral DNA (vDNA) leading to a block in viral replication in the absence of the viral PML-NB antagonist ICP0. This pre-existing intrinsic host defence to infection occurred independently of the vDNA pathogen sensor IFI16 (Interferon Gamma Inducible Protein 16) and the induction of interferon stimulated gene (ISG) expression, demonstrating that vDNA entry into the nucleus alone is not sufficient to induce a robust innate immune response. Saturation of this pre-existing intrinsic host defence during HSV-1 ICP0-null mutant infection led to the stable recruitment of PML and IFI16 into vDNA complexes associated with ICP4, and led to the induction of ISG expression. This induced innate immune response occurred in a PML-, IFI16-, and Janus-Associated Kinase (JAK)-dependent manner and was restricted by phosphonoacetic acid, demonstrating that vDNA polymerase activity is required for the robust induction of ISG expression during HSV-1 infection. Our data identifies dual roles for PML in the sequential regulation of intrinsic and innate immunity to HSV-1 infection that are dependent on viral genome delivery to the nucleus and the onset of vDNA replication, respectively. These intracellular host defences are counteracted by ICP0, which targets PML for degradation from the outset of nuclear infection to promote vDNA release from PML-NBs and the onset of HSV-1 lytic replication.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 77
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    Publication Date: 2018-01-10
    Description: by Torsten Günther, Helena Malmström, Emma M. Svensson, Ayça Omrak, Federico Sánchez-Quinto, Gülşah M. Kılınç, Maja Krzewińska, Gunilla Eriksson, Magdalena Fraser, Hanna Edlund, Arielle R. Munters, Alexandra Coutinho, Luciana G. Simões, Mário Vicente, Anders Sjölander, Berit Jansen Sellevold, Roger Jørgensen, Peter Claes, Mark D. Shriver, Cristina Valdiosera, Mihai G. Netea, Jan Apel, Kerstin Lidén, Birgitte Skar, Jan Storå, Anders Götherström, Mattias Jakobsson Scandinavia was one of the last geographic areas in Europe to become habitable for humans after the Last Glacial Maximum (LGM). However, the routes and genetic composition of these postglacial migrants remain unclear. We sequenced the genomes, up to 57× coverage, of seven hunter-gatherers excavated across Scandinavia and dated from 9,500–6,000 years before present (BP). Surprisingly, among the Scandinavian Mesolithic individuals, the genetic data display an east–west genetic gradient that opposes the pattern seen in other parts of Mesolithic Europe. Our results suggest two different early postglacial migrations into Scandinavia: initially from the south, and later, from the northeast. The latter followed the ice-free Norwegian north Atlantic coast, along which novel and advanced pressure-blade stone-tool techniques may have spread. These two groups met and mixed in Scandinavia, creating a genetically diverse population, which shows patterns of genetic adaptation to high latitude environments. These potential adaptations include high frequencies of low pigmentation variants and a gene region associated with physical performance, which shows strong continuity into modern-day northern Europeans.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 78
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    Publication Date: 2018-01-10
    Description: by Hadayet Ullah, Ivan Nagelkerken, Silvan U. Goldenberg, Damien A. Fordham Global warming and ocean acidification are forecast to exert significant impacts on marine ecosystems worldwide. However, most of these projections are based on ecological proxies or experiments on single species or simplified food webs. How energy fluxes are likely to change in marine food webs in response to future climates remains unclear, hampering forecasts of ecosystem functioning. Using a sophisticated mesocosm experiment, we model energy flows through a species-rich multilevel food web, with live habitats, natural abiotic variability, and the potential for intra- and intergenerational adaptation. We show experimentally that the combined stress of acidification and warming reduced energy flows from the first trophic level (primary producers and detritus) to the second (herbivores), and from the second to the third trophic level (carnivores). Warming in isolation also reduced the energy flow from herbivores to carnivores, the efficiency of energy transfer from primary producers and detritus to herbivores and detritivores, and the living biomass of detritivores, herbivores, and carnivores. Whilst warming and acidification jointly boosted primary producer biomass through an expansion of cyanobacteria, this biomass was converted to detritus rather than to biomass at higher trophic levels—i.e., production was constrained to the base of the food web. In contrast, ocean acidification affected the food web positively by enhancing trophic flow from detritus and primary producers to herbivores, and by increasing the biomass of carnivores. Our results show how future climate change can potentially weaken marine food webs through reduced energy flow to higher trophic levels and a shift towards a more detritus-based system, leading to food web simplification and altered producer–consumer dynamics, both of which have important implications for the structuring of benthic communities.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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    Public Library of Science (PLoS)
    Publication Date: 2018-01-10
    Description: by Wesley Wong, Edward A. Wenger, Daniel L. Hartl, Dyann F. Wirth Unlike in most pathogens, multiple-strain (polygenomic) infections of P . falciparum are frequently composed of genetic siblings. These genetic siblings are the result of sexual reproduction and can coinfect the same host when cotransmitted by the same mosquito. The degree with which coinfecting strains are related varies among infections and populations. Because sexual recombination occurs within the mosquito, the relatedness of cotransmitted strains could depend on transmission dynamics, but little is actually known of the factors that influence the relatedness of cotransmitted strains. Part of the uncertainty stems from an incomplete understanding of how within-host and within-vector dynamics affect cotransmission. Cotransmission is difficult to examine experimentally but can be explored using a computational model. We developed a malaria transmission model that simulates sexual reproduction in order to understand what determines the relatedness of cotransmitted strains. This study highlights how the relatedness of cotransmitted strains depends on both within-host and within-vector dynamics including the complexity of infection. We also used our transmission model to analyze the genetic relatedness of polygenomic infections following a series of multiple transmission events and examined the effects of superinfection. Understanding the factors that influence the relatedness of cotransmitted strains could lead to a better understanding of the population-genetic correlates of transmission and therefore be important for public health.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-10
    Description: by Xiaoyun Lei, Shi Huang
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 81
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-10
    Description: by Sun-Hee Ahn, Seongmin Cheon, Chungoo Park, Jong-Hee Lee, Seok-Woo Lee, Tae-Hoon Lee
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 82
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-10
    Description: by Leno S. Rocha, Frederico S. A. Rocha, Thársis T. P. Souza
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 83
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-01-10
    Description: by Miguel Andreu-Cazenave, Maria Dulce Subida, Miriam Fernandez
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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