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  • 1
    Publication Date: 2018-05-05
    Description: by Nathanaël Hozé, Sebastian Bonhoeffer, Roland Regoes Disease tolerance is a defense strategy against infections that aims at maintaining host health even at high pathogen replication or load. Tolerance mechanisms are currently intensively studied with the long-term goal of exploiting them therapeutically. Because tolerance-based treatment imposes less selective pressure on the pathogen it has been hypothesised to be “evolution-proof”. However, the primary public health goal is to reduce the incidence and mortality associated with a disease. From this perspective, tolerance-based treatment bears the risk of increasing the prevalence of the disease, which may lead to increased mortality. We assessed the promise of tolerance-based treatment strategies using mathematical models. Conventional treatment was implemented as an increased recovery rate, while tolerance-based treatment was assumed to reduce the disease-related mortality of infected hosts without affecting recovery. We investigated the endemic phase of two types of infections: acute and chronic. Additionally, we considered the effect of pathogen resistance against conventional treatment. We show that, for low coverage of tolerance-based treatment, chronic infections can cause even more deaths than without treatment. Overall, we found that conventional treatment always outperforms tolerance-based treatment, even when we allow the emergence of pathogen resistance. Our results cast doubt on the potential benefit of tolerance-based over conventional treatment. Any clinical application of tolerance-based treatment of infectious diseases has to consider the associated detrimental epidemiological feedback.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 2
    Publication Date: 2018-05-05
    Description: by Jenna E. Haines, Michael B. Eisen As the Drosophila embryo transitions from the use of maternal RNAs to zygotic transcription, domains of open chromatin, with relatively low nucleosome density and specific histone marks, are established at promoters and enhancers involved in patterned embryonic transcription. However it remains unclear how regions of activity are established during early embryogenesis, and if they are the product of spatially restricted or ubiquitous processes. To shed light on this question, we probed chromatin accessibility across the anterior-posterior axis (A-P) of early Drosophila melanogaster embryos by applying a transposon based assay for chromatin accessibility (ATAC-seq) to anterior and posterior halves of hand-dissected, cellular blastoderm embryos. We find that genome-wide chromatin accessibility is highly similar between the two halves, with regions that manifest significant accessibility in one half of the embryo almost always accessible in the other half, even for promoters that are active in exclusively one half of the embryo. These data support previous studies that show that chromatin accessibility is not a direct result of activity, and point to a role for ubiquitous factors or processes in establishing chromatin accessibility at promoters in the early embryo. However, in concordance with similar works, we find that at enhancers active exclusively in one half of the embryo, we observe a significant skew towards greater accessibility in the region of their activity, highlighting the role of patterning factors such as Bicoid in this process.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 3
    Publication Date: 2018-05-05
    Description: by Florian Aspart, Michiel W. H. Remme, Klaus Obermayer The rise of transcranial current stimulation (tCS) techniques have sparked an increasing interest in the effects of weak extracellular electric fields on neural activity. These fields modulate ongoing neural activity through polarization of the neuronal membrane. While the somatic polarization has been investigated experimentally, the frequency-dependent polarization of the dendritic trees in the presence of alternating (AC) fields has received little attention yet. Using a biophysically detailed model with experimentally constrained active conductances, we analyze the subthreshold response of cortical pyramidal cells to weak AC fields, as induced during tCS. We observe a strong frequency resonance around 10-20 Hz in the apical dendrites sensitivity to polarize in response to electric fields but not in the basal dendrites nor the soma. To disentangle the relative roles of the cell morphology and active and passive membrane properties in this resonance, we perform a thorough analysis using simplified models, e.g. a passive pyramidal neuron model, simple passive cables and reconstructed cell model with simplified ion channels. We attribute the origin of the resonance in the apical dendrites to (i) a locally increased sensitivity due to the morphology and to (ii) the high density of h-type channels. Our systematic study provides an improved understanding of the subthreshold response of cortical cells to weak electric fields and, importantly, allows for an improved design of tCS stimuli.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 4
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-05-05
    Description: by Khan Rubayet Rahaman, Quazi K. Hassan, Ehsan H. Chowdhury
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 5
    Publication Date: 2018-05-05
    Description: by Anne M. G. Neevel, Tessa Hemrika, Eric Claassen, Linda H. M. van de Burgwal Background Despite the existence of safe and effective vaccines, rabies disease still causes an estimated 59,000 human deaths a year in the endemic areas in Asia and Africa. These numbers reflect severe drawbacks regarding the implementation of PrEP and PEP in endemic settings, such as lack of political will and low priority given to rabies. Since these contextual factors have proven to be persistent, there is an urgency to improve current strategies or develop novel approaches in order to control rabies disease in the future. Methods/Findings This study aimed to identify and systematically prioritize the research needs, through interviews and questionnaires with key-opinion-leaders (KOLs). A total of 46 research needs were identified and prioritized. The top research needs are considered very high priority based on both importance for rabies control and need for improvement. KOLs agree that animal rabies control remains most important for rabies control, while research on human host, agent (rabies virus) and the environment should be prioritized in terms of need for improvement. A wide variety in perceptions is observed between and within the disciplines of virology, public health and veterinary health and between KOLs with more versus those with less experience in the field. Conclusion/Significance The results of this study give well-defined, prioritized issues that stress the drawbacks that are experienced by KOLs in daily practice. The most important research domains are: 1) cheap and scalable production system for RIG 2) efficacy of dog mass vaccination programs and 3) cheap human vaccines. Addressing these research needs should exist next to and may reinforce current awareness and mass vaccination campaigns. The differences in perspectives between actors revealed in this study are informative for effective execution of the One Health research agenda.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 6
    Publication Date: 2018-05-05
    Description: by Teboho N. Tsotetsi, Nicola E. Collins, Marinda C. Oosthuizen, Kgomotso P. Sibeko-Matjila The reliability of any quantitative real-time polymerase chain reaction (qPCR) experiment can be seriously compromised by variations between samples as well as between PCR runs. This usually result from errors in sample quantification, especially with samples that are obtained from different individuals and tissues and have been collected at various time intervals. Errors also arise from differences in qPCR efficiency between assays performed simultaneously to target multiple genes on the same plate. Consequently, the derived quantitative data for the target genes become distorted. To avoid this grievous error, an endogenous control, with relatively constant transcription levels in the target individual or tissue, is included in the qPCR assay to normalize target gene expression levels in the analysis. Several housekeeping genes (HKGs) have been used as endogenous controls in quantification studies of mRNA transcripts; however, there is no record in the literature of the evaluation of these genes for the tick-borne protozoan parasite, Theileria parva . Importantly, the expression of these genes should be invariable between different T . parva stocks, ideally under different experimental conditions, to gain extensive application in gene expression studies of this parasite. Thus, the expression of several widely used HKGs was evaluated in this study, including the genes encoding β-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 28S rRNA, cytochrome b and fructose-2.6-biphosphate aldolase (F6P) proteins. The qPCR analysis revealed that the expression of genes encoding cytochrome b, F6P and GAPDH varied considerably between the two T . parva stocks investigated, the cattle-derived T . parva Muguga and the buffalo-derived T . parva 7014. 28S rRNA and β-actin gene expression was the most stable; thus, these genes were considered suitable candidates to be used as endogenous control genes for mRNA quantification studies in T . parva .
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 7
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    In: PLoS ONE
    Publication Date: 2018-05-05
    Description: by Minjie Chen, Bruno Wichmann, Marty Luckert, Leigh Winowiecki, Wiebke Förch, Peter Läderach Smallholder farming systems are vulnerable to a number of challenges, including continued population growth, urbanization, income disparities, land degradation, decreasing farm size and productivity, all of which are compounded by uncertainty of climatic patterns. Understanding determinants of smallholder farming practices is critical for designing and implementing successful interventions, including climate change adaptation programs. We examine two dimensions wherein smallholder farmers may adapt agricultural practices; through intensification (i.e., adopt more practices) or diversification (i.e. adopt different practices). We use data on 5314 randomly sampled households located in 38 sites in 15 countries across four regions (East and West Africa, South Asia, and Central America). We estimate empirical models designed to assess determinants of both intensification and diversification of adaptation activities at global scales. Aspects of adaptive capacity that are found to increase intensification of adaptation globally include variables associated with access to information and human capital, financial considerations, assets, household infrastructure and experience. In contrast, there are few global drivers of adaptive diversification, with a notable exception being access to weather information, which also increases adaptive intensification. Investigating reasons for adaptation indicate that conditions present in underdeveloped markets provide the primary impetus for adaptation, even in the context of climate change. We also compare determinants across spatial scales, which reveals a variety of local avenues through which policy interventions can relax economic constraints and boost agricultural adaptation for both intensification and diversification. For example, access to weather information does not affect intensification adaptation in Africa, but is significant at several sites in Bangladesh and India. Moreover, this information leads to diversification of adaptive activities on some sites in South Asia and Central America, but increases specialization in West and East Africa.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 8
    Publication Date: 2018-05-05
    Description: by Edileuza Danieli da Silva, Martin Cancela, Karina Mariante Monteiro, Henrique Bunselmeyer Ferreira, Arnaldo Zaha Background Cystic hydatid disease is a zoonosis caused by the larval stage (hydatid) of Echinococcus granulosus (Cestoda, Taeniidae). The hydatid develops in the viscera of intermediate host as a unilocular structure filled by the hydatid fluid, which contains parasitic excretory/secretory products. The lipoprotein Antigen B (AgB) is the major component of E . granulosus metacestode hydatid fluid. Functionally, AgB has been implicated in immunomodulation and lipid transport. However, the mechanisms underlying AgB functions are not completely known. Methodology/Principal findings In this study, we investigated AgB interactions with different mammalian cell types and the pathways involved in its internalization. AgB uptake was observed in four different cell lines, NIH-3T3, A549, J774 and RH. Inhibition of caveolae/raft-mediated endocytosis causes about 50 and 69% decrease in AgB internalization by RH and A549 cells, respectively. Interestingly, AgB colocalized with the raft endocytic marker, but also showed a partial colocalization with the clathrin endocytic marker. Finally, AgB colocalized with an endolysosomal tracker, providing evidence for a possible AgB destination after endocytosis. Conclusions/Significance The results indicate that caveolae/raft-mediated endocytosis is the main route to AgB internalization, and that a clathrin-mediated entry may also occur at a lower frequency. A possible fate for AgB after endocytosis seems to be the endolysosomal system. Cellular internalization and further access to subcellular compartments could be a requirement for AgB functions as a lipid carrier and/or immunomodulatory molecule, contributing to create a more permissive microenvironment to metacestode development and survival.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 9
    Publication Date: 2018-05-05
    Description: by Annabelle de St. Maurice, Jessica Harmon, Luke Nyakarahuka, Stephen Balinandi, Alex Tumusiime, Jackson Kyondo, Sophia Mulei, Annemarion Namutebi, Barbara Knust, Trevor Shoemaker, Stuart T. Nichol, Anita K. McElroy, Christina F. Spiropoulou Rift Valley fever virus is an arbovirus that affects both livestock and humans throughout Africa and in the Middle East. Despite its endemicity throughout Africa, it is a rare event to identify an infected individual during the acute phase of the disease and an even rarer event to collect serial blood samples from the affected patient. Severely affected patients can present with hemorrhagic manifestations of disease. In this study we identified three Ugandan men with RVFV disease that was accompanied by hemorrhagic manifestations. Serial blood samples from these men were analyzed for a series of biomarkers specific for various aspects of human pathophysiology including inflammation, endothelial function and coagulopathy. There were significant differences between biomarker levels in controls and cases both early during the illness and after clearance of viremia. Positive correlation of viral load with markers of inflammation (IP-10, CRP, Eotaxin, MCP-2 and Granzyme B), markers of fibrinolysis (tPA and D-dimer), and markers of endothelial function (sICAM-1) were all noted. However, and perhaps most interesting given the fact that these individuals exhibited hemorrhagic manifestations of disease, was the finding of a negative correlation between viral load and P-selectin, ADAMTS13, and fibrinogen all of which are associated with coagulation pathways occurring on the endothelial surface.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 10
    Publication Date: 2018-05-05
    Description: by Lucas D. Caeiro, Catalina D. Alba-Soto, Mariana Rizzi, María Elisa Solana, Giselle Rodriguez, Agustina M. Chidichimo, Matías E. Rodriguez, Daniel O. Sánchez, Gabriela V. Levy, Valeria Tekiel TcTASV-C is a protein family of about 15 members that is expressed only in the trypomastigote stage of Trypanosoma cruzi . We have previously shown that TcTASV-C is located at the parasite surface and secreted to the medium. Here we report that the expression of different TcTASV-C genes occurs simultaneously at the trypomastigote stage and while some secreted and parasite-associated products are found in both fractions, others are different. Secreted TcTASV-C are mainly shedded through trypomastigote extracellular vesicles, of which they are an abundant constituent, despite its scarce expression on culture-derived trypomastigotes. In contrast, TcTASV-C is highly expressed in bloodstream trypomastigotes; its upregulation in bloodstream parasites was observed in different T . cruzi strains and was specific for TcTASV-C, suggesting that some host-molecules trigger TcTASV-C expression. TcTASV-C is also strongly secreted by bloodstream parasites. A DNA prime—protein boost immunization scheme with TcTASV-C was only partially effective to control the infection in mice challenged with a highly virulent T . cruzi strain. Vaccination triggered a strong humoral response that delayed the appearance of bloodstream trypomastigotes at the early phase of the infection. Linear epitopes recognized by vaccinated mice were mapped within the TcTASV-C family motif, suggesting that blockade of secreted TcTASV-C impacts on the settlement of infection. Furthermore, although experimental and naturally T . cruzi -infected hosts did not react with antigens from extracellular vesicles, vaccinated and challenged mice recognized not only TcTASV-C but also other vesicle-antigens. We hypothesize that TcTASV-C is involved in the establishment of the initial T . cruzi infection in the mammalian host. Altogether, these results point towards TcTASV-C as a novel secreted virulence factor of T . cruzi trypomastigotes.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 11
    Publication Date: 2018-05-05
    Description: by Frieder Graef, Stefan Sieber Research and development increasingly apply participatory approaches that involve both stakeholders and scientists. This article presents an evaluation of German and Tanzanian researchers’ perceptions during their activities as part of a large interdisciplinary research project in Tanzania. The project focused on prioritizing and implementing food-securing upgrading strategies across the components of rural food value chains. The participants involved during the course of the project were asked to provide feedback on 10 different research steps and to evaluate eight core features related to the functioning and potential shortcomings of the project. The study discriminated among evaluation differences linked to culture, gender, and institutional status. Perceptions differed between Tanzanian and German participants depending on the type and complexity of the participatory research steps undertaken and the intensity of stakeholder participation. There were differences in perception linked to gender and hierarchical status; however, those differences were not as concise and significant as those linked to nationality. These findings indicate that participatory action research of this nature requires more targeted strategies and planning tailored to the type of activity. Such planning would result in more efficient and satisfactory communication, close collaboration, and mutual feedback to avoid conflicts and other problems. We further conclude that it would be advisable to carefully incorporate training on these aspects into future project designs.
    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: 2018-05-05
    Description: by Mónica Clavel San Emeterio, Rubén Fernández-Ortiz, Jesús Arteaga-Ortiz, Pablo Dorta-González The objective of this paper is to fill a gap in the literature on internationalization, in relation to the absence of objective and measurable performance indicators for the process of how firms sequentially enter external markets. To that end, this research develops a quantitative tool for use as a performance indicator of gradualness for firms entering external markets at a sectoral level. The performance indicator is based on firms’ export volumes, number of years operating in the export market, geographic areas targeted for export and when exports began to each area. The indicator is tested empirically in the wine sector. The main contribution of this study is the creation of a reliable international priority index, which can serve more widely as a valuable tool because of its potential use in other industry sectors and geographic areas, and which would allow the analysis of how geographically differentiated internationalization strategies develop.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
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    In: PLoS ONE
    Publication Date: 2018-05-05
    Description: by Hongyan Yang, Shenghua Tian, Constance Flamand-Roze, Ling Gao, Wei Zhang, Yan Li, Jiajia Wang, Zhou Sun, Ying Su, Libin Zhao, Zhihou Liang There is a severe lack of aphasia screening tools for bedside use in Chinese. A number of aphasia assessment tools have recently been developed abroad, but some of these scales were not suitable for patients with acute stroke. The Language Screening Test (which includes two parallel versions [a/b]) in French has been proven to be an effective and time-saving aphasia screening scale for early-stage stroke patients. Therefore, we worked out a Chinese version of the LAST taking into consideration Chinese language and culture. Two preliminary parallel versions (a/b) were tested on 154 patients with stroke at acute phase and 107 patients with stroke at non-acute phase, with the Western Aphasia Battery serving as a gold standard. The equivalence between the two parallel versions and the reliability/validity of each version were assessed. The median time to complete one preliminary Chinese version (each had some item redundancy) was 98 seconds. Two final parallel versions were established after adjustment/elimination of the redundant items and were found to be equivalent (intra-class correlation coefficient: 0.991). Internal consistency is(Cronbach α for each version [a/b] was 0.956 and 0.965, respectively) good. Internal validity was fine: (a) no floor or ceiling effect/item redundancy; (b) construct validity revealed a 1-dimension structure, just like the French version. The higher educated subjects scored higher than their lower educated counterparts ( p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
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    Publication Date: 2018-05-05
    Description: by Charlotte Ford, Andrea Nans, Emmanuel Boucrot, Richard D. Hayward Pathogens hijack host endocytic pathways to force their own entry into eukaryotic target cells. Many bacteria either exploit receptor-mediated zippering or inject virulence proteins directly to trigger membrane reorganisation and cytoskeletal rearrangements. By contrast, extracellular C . trachomatis elementary bodies (EBs) apparently employ facets of both the zipper and trigger mechanisms and are only ~400 nm in diameter. Our cryo-electron tomography of C . trachomatis entry revealed an unexpectedly diverse array of host structures in association with invading EBs, suggesting internalisation may progress by multiple, potentially redundant routes or several sequential events within a single pathway. Here we performed quantitative analysis of actin organisation at chlamydial entry foci, highlighting filopodial capture and phagocytic cups as dominant and conserved morphological structures early during internalisation. We applied inhibitor-based screening and employed reporters to systematically assay and visualise the spatio-temporal contribution of diverse endocytic signalling mediators to C . trachomatis entry. In addition to the recognised roles of the Rac1 GTPase and its associated nucleation-promoting factor (NPF) WAVE, our data revealed an additional unrecognised pathway sharing key hallmarks of macropinocytosis: i) amiloride sensitivity, ii) fluid-phase uptake, iii) recruitment and activity of the NPF N-WASP, and iv) the localised generation of phosphoinositide-3-phosphate (PI3P) species. Given their central role in macropinocytosis and affinity for PI3P, we assessed the role of SNX-PX-BAR family proteins. Strikingly, SNX9 was specifically and transiently enriched at C . trachomatis entry foci. SNX9 -/- cells exhibited a 20% defect in EB entry, which was enhanced to 60% when the cells were infected without sedimentation-induced EB adhesion, consistent with a defect in initial EB-host interaction. Correspondingly, filopodial capture of C . trachomatis EBs was specifically attenuated in SNX9 -/- cells, implicating SNX9 as a central host mediator of filopodial capture early during chlamydial entry. Our findings identify an unanticipated complexity of signalling underpinning cell entry by this major human pathogen, and suggest intriguing parallels with viral entry mechanisms.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 15
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-05-05
    Description: by Zilong Jiang, Shu Gao, Mingjiang Li Combining a deep neural network with fuzzy theory, this paper proposes an advertising click-through rate (CTR) prediction approach based on a fuzzy deep neural network (FDNN). In this approach, fuzzy Gaussian-Bernoulli restricted Boltzmann machine (FGBRBM) is first applied to input raw data from advertising datasets. Next, fuzzy restricted Boltzmann machine (FRBM) is used to construct the fuzzy deep belief network (FDBN) with the unsupervised method layer by layer. Finally, fuzzy logistic regression (FLR) is utilized for modeling the CTR. The experimental results show that the proposed FDNN model outperforms several baseline models in terms of both data representation capability and robustness in advertising click log datasets with noise.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
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    In: PLoS ONE
    Publication Date: 2018-05-05
    Description: by Yu-Tong Miao, Yao Deng, Hao-Kang Jia, Yu-Di Liu, Mao-Lin Hou The white-backed planthopper, Sogatella furcifera , is a phloem sap feeder that secretes watery and gelling saliva during feeding. In this study, we identified the major proteins in watery saliva of S . furcifera by shotgun LC-MS/MS analysis combined with transcriptomic analysis. A total of 161 proteins were identified, which were divided into 8 function categories, including enzymes, transporter, calcium ion binding protein, salivary sheath protein, cytoskeleton protein, DNA-, RNA-, and protein-binding or regulating proteins, other non-enzyme proteins and unknown proteins. Gene expression pattern of 11 secretory proteins were analyzed by real time quantitative-PCR. We detected the mucin-like protein, which had a unique expression level in salivary gland, most likely to be a candidate effector involved in regulation of plant defense. This study identified the watery saliva component of S . furcifera and it provided a list of proteins which may play a role in interaction between S . furcifera and rice.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
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    Publication Date: 2018-05-05
    Description: by Aaron C. Crawford, Laura E. Lehtovirta-Morley, Omran Alamir, Maria J. Niemiec, Bader Alawfi, Mohammad Alsarraf, Volha Skrahina, Anna C. B. P. Costa, Andrew Anderson, Sujan Yellagunda, Elizabeth R. Ballou, Bernhard Hube, Constantin F. Urban, Duncan Wilson Nutritional immunity describes the host-driven manipulation of essential micronutrients, including iron, zinc and manganese. To withstand nutritional immunity and proliferate within their hosts, pathogenic microbes must express efficient micronutrient uptake and homeostatic systems. Here we have elucidated the pathway of cellular zinc assimilation in the major human fungal pathogen Candida albicans . Bioinformatics analysis identified nine putative zinc transporters: four cytoplasmic-import Zip proteins (Zrt1, Zrt2, Zrt3 and orf19.5428) and five cytoplasmic-export ZnT proteins (orf19.1536/Zrc1, orf19.3874, orf19.3769, orf19.3132 and orf19.52). Only Zrt1 and Zrt2 are predicted to localise to the plasma membrane and here we demonstrate that Zrt2 is essential for C . albicans zinc uptake and growth at acidic pH. In contrast, ZRT1 expression was found to be highly pH-dependent and could support growth of the ZRT2 -null strain at pH 7 and above. This regulatory paradigm is analogous to the distantly related pathogenic mould, Aspergillus fumigatus , suggesting that pH-adaptation of zinc transport may be conserved in fungi and we propose that environmental pH has shaped the evolution of zinc import systems in fungi. Deletion of C . albicans ZRT2 reduced kidney fungal burden in wild type, but not in mice lacking the zinc-chelating antimicrobial protein calprotectin. Inhibition of zrt2Δ growth by neutrophil extracellular traps was calprotectin-dependent. This suggests that, within the kidney, C . albicans growth is determined by pathogen-Zrt2 and host-calprotectin. As well as serving as an essential micronutrient, zinc can also be highly toxic and we show that C . albicans deals with this potential threat by rapidly compartmentalising zinc within vesicular stores called zincosomes. In order to understand mechanistically how this process occurs, we created deletion mutants of all five ZnT-type transporters in C . albicans . Here we show that, unlike in Saccharomyces cerevisiae , C . albicans Zrc1 mediates zinc tolerance via zincosomal zinc compartmentalisation. This novel transporter was also essential for virulence and liver colonisation in vivo . In summary, we show that zinc homeostasis in a major human fungal pathogen is a multi-stage process initiated by Zrt1/Zrt2-cellular import, followed by Zrc1-dependent intracellular compartmentalisation.
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    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 18
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    Public Library of Science (PLoS)
    In: PLoS ONE
    Publication Date: 2018-05-05
    Description: by T. Gupalova, G. Leontieva, T. Kramskaya, K. Grabovskaya, E. Bormotova, D. Korjevski, A. Suvorov Streptococcus agalactiae , or group B streptococcus (GBS), is an important pathogen as it is the leading cause of neonatal deaths due to sepsis, meningitis or bacterial pneumonia. Although the development of an effective and safe GBS vaccine is on the agenda of many research labs, there is no GBS vaccine on the market yet. In the present study we attempted to engineer a live vaccine strain based on Bac, a surface protein of GBS, incorporated into a surface fimbrial protein of probiotic Enterococcus. The resulting strain induced specific systemic and local immune responses in mice and provided protection against GBS when administered via the intranasal, oral or intravaginal immunization routes.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 19
    Publication Date: 2018-05-05
    Description: by Yujiao Tang, Trishna Debnath, Eun-Ju Choi, Young Wook Kim, Jung Pyo Ryu, Sejin Jang, Sang Uk Chung, Young-Jin Choi, Eun-Kyung Kim Tenebrio molitor ( T . molitor ) larvae provide food at low environmental cost and contribute positively to livelihoods. In this research, we compared the amino acids compositions and antioxidant activities of various extracts of T . molitor to enhance their quality as food. For the comparison, distilled water extracts, enzymatic hydrolysates, and condensed enzymatic hydrolysates of T . molitor larvae were prepared. Their amino acids (AAs) profiles and antioxidant activities, including ferric-reducing antioxidant power, oxygen radical absorption capacity, and DPPH, hydroxyl radical, and hydrogen peroxide radical scavenging properties assay were analyzed. DW extracts had the lowest AAs contents and antioxidant activity compared with enzymatic extracts. Condensed hydrolysates with a combination of alcalase and flavourzyme (C-A+F) exhibited the highest levels of total free AAs (11.1759 g/100 g). C-A+F produced higher total hydrolyzed AAs (32.5292 g/100 g) compared with the other groups. The C-A+F possessed the strongest antioxidant activity. Notably, the antioxidant activities of the hydrolysates and the total hydrolyzed AAs amount were correlated. Taken together, our findings showed that C-A+F was a promising technique for obtaining extracts of T . molitor larvae with antioxidant activity as potential nutritious functional food.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 20
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    Publication Date: 2018-05-05
    Description: by Etai Rotem, Omri Faingold, Meital Charni, Yoel A. Klug, Daniel Harari, Liraz Shmuel-Galia, Alon Nudelman, Varda Rotter, Yechiel Shai The ability of the Lentivirus HIV-1 to inhibit T-cell activation by its gp41 fusion protein is well documented, yet limited data exists regarding other viral fusion proteins. HIV-1 utilizes membrane binding region of gp41 to inhibit T-cell receptor (TCR) complex activation. Here we examined whether this T-cell suppression strategy is unique to the HIV-1 gp41. We focused on T-cell modulation by the gp21 fusion peptide (FP) of the Human T-lymphotropic Virus 1 (HTLV-1), a Deltaretrovirus that like HIV infects CD4 + T-cells. Using mouse and human in-vitro T-cell models together with in-vivo T-cell hyper activation mouse model, we reveal that HTLV-1’s FP inhibits T-cell activation and unlike the HIV FP, bypasses the TCR complex. HTLV FP inhibition induces a decrease in Th1 and an elevation in Th2 responses observed in mRNA, cytokine and transcription factor profiles. Administration of the HTLV FP in a T-cell hyper activation mouse model of multiple sclerosis alleviated symptoms and delayed disease onset. We further pinpointed the modulatory region within HTLV-1’s FP to the same region previously identified as the HIV-1 FP active region, suggesting that through convergent evolution both viruses have obtained the ability to modulate T-cells using the same region of their fusion protein. Overall, our findings suggest that fusion protein based T-cell modulation may be a common viral trait.
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  • 21
    Publication Date: 2018-04-18
    Description: by Karin Källander, Tobias Alfvén, Tjede Funk, Ayalkibet Abebe, Abreham Hailemariam, Dawit Getachew, Max Petzold, Laura C. Steinhardt, Julie R. Gutman Background With declining malaria prevalence and improved use of malaria diagnostic tests, an increasing proportion of children seen by community health workers (CHWs) have unclassified fever. Current community management guidelines by WHO advise that children seen with non-severe unclassified fever (on day 1) should return to CHWs on day 3 for reassessment. We compared the safety of conditional follow-up reassessment only in cases where symptoms do not resolve with universal follow-up on day 3. Methods and findings We undertook a 2-arm cluster-randomised controlled non-inferiority trial among children aged 2–59 months presenting with fever and without malaria, pneumonia, diarrhoea, or danger signs to 284 CHWs affiliated with 25 health centres (clusters) in Southern Nations, Nationalities, and Peoples’ Region, Ethiopia. The primary outcome was treatment failure (persistent fever, development of danger signs, hospital admission, death, malaria, pneumonia, or diarrhoea) at 1 week (day 8) of follow-up. Non-inferiority was defined as a 4% or smaller difference in the proportion of treatment failures with conditional follow-up compared to universal follow-up. Secondary outcomes included the percentage of children brought for reassessment, antimicrobial prescription, and severe adverse events (hospitalisations and deaths) after 4 weeks (day 29). From December 1, 2015, to November 30, 2016, we enrolled 4,595 children, of whom 3,946 (1,953 universal follow-up arm; 1,993 conditional follow-up arm) adhered to the CHW’s follow-up advice and also completed a day 8 study visit within ±1 days. Overall, 2.7% had treatment failure on day 8: 0.8% (16/1,993) in the conditional follow-up arm and 4.6% (90/1,953) in the universal follow-up arm (risk difference of treatment failure −3.81%, 95% CI −∞, 0.65%), meeting the prespecified criterion for non-inferiority. There were no deaths recorded by day 29. In the universal follow-up arm, 94.6% of caregivers reported returning for reassessment on day 3, in contrast to 7.5% in the conditional follow-up arm (risk ratio 22.0, 95% CI 17.9, 27.2, p 〈 0.001). Few children sought care from another provider after their initial visit to the CHW: 3.0% (59/1,993) in the conditional follow-up arm and 1.1% (22/1,953) in the universal follow-up arm, on average 3.2 and 3.4 days later, respectively, with no significant difference between arms (risk difference 1.79%, 95% CI −1.23%, 4.82%, p = 0.244). The mean travel time to another provider was 2.2 hours (95% CI 0.01, 5.3) in the conditional follow-up arm and 2.6 hours (95% CI 0.02, 4.5) in the universal follow-up arm ( p = 0.82); the mean cost for seeking care after visiting the CHW was 26.5 birr (95% CI 7.8, 45.2) and 22.8 birr (95% CI 15.6, 30.0), respectively ( p = 0.69). Though this study was an important step to evaluate the safety of conditional follow-up, the high adherence seen may have resulted from knowledge of the 1-week follow-up visit and may therefore not transfer to routine practice; hence, in an implementation setting it is crucial that CHWs are well trained in counselling skills to advise caregivers on when to come back for follow-up. Conclusions Conditional follow-up of children with non-severe unclassified fever in a low malaria endemic setting in Ethiopia was non-inferior to universal follow-up through day 8. Allowing CHWs to advise caregivers to bring children back only in case of continued symptoms might be a more efficient use of resources in similar settings. Trial registration www.clinicaltrials.gov, identifier NCT02926625
    Print ISSN: 1549-1277
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  • 22
    Publication Date: 2018-04-18
    Description: by Luke C. Mullany, Elburg W. van Boetzelaer, Julie R. Gutman, Laura C. Steinhardt, Pascal Ngoy, Yolanda Barbera Lainez, Alison Wittcoff, Steven A. Harvey, Lara S. Ho Background The World Health Organization’s integrated community case management (iCCM) guidelines recommend that all children presenting with uncomplicated fever and no danger signs return for follow-up on day 3 following the initial consultation on day 1. Such fevers often resolve rapidly, however, and previous studies suggest that expectant home care for uncomplicated fever can be safely recommended. We aimed to determine if a conditional follow-up visit was non-inferior to a universal follow-up visit for these children. Methods and findings We conducted a cluster-randomized, community-based non-inferiority trial among children 2–59 months old presenting to community health workers (CHWs) with non-severe unclassified fever in Tanganyika Province, Democratic Republic of the Congo. Clusters ( n = 28) of CHWs were randomized to advise caregivers to either (1) return for a follow-up visit on day 3 following the initial consultation on day 1, regardless of illness resolution (as per current WHO guidelines; universal follow-up group) or (2) return for a follow-up visit on day 3 only if illness continued (conditional follow-up group). Children in both arms were assessed again at day 8, and classified as a clinical failure if fever (caregiver-reported), malaria, diarrhea, pneumonia, or decline of health status (development of danger signs, hospitalization, or death) was noted (failure definition 1). Alternative failure definitions were examined, whereby caregiver-reported fever was first restricted to caregiver-reported fever of at least 3 days (failure definition 2) and then replaced with fever measured via axillary temperature (failure definition 3). Study participants, providers, and investigators were not masked. Among 4,434 enrolled children, 4,141 (93.4%) met the per-protocol definition of receipt of the arm-specific advice from the CHW and a timely day 8 assessment (universal follow-up group: 2,210; conditional follow-up group: 1,931). Failure was similar (difference: –0.7%) in the conditional follow-up group ( n = 188, 9.7%) compared to the universal follow-up group ( n = 230, 10.4%); however, the upper bound of a 1-sided 95% confidence interval around this difference (−∞, 5.1%) exceeded the prespecified non-inferiority margin of 4.0% (non-inferiority p = 0.089). When caregiver-reported fever was restricted to fevers lasting ≥3 days, failure in the conditional follow-up group ( n = 159, 8.2%) was similar to that in the universal follow-up group ( n = 200, 9.1%) (difference: −0.8%; 95% CI: −∞, 4.1%; p = 0.053). If caregiver-reported fever was replaced by axillary temperature measurement in the definition of failure, failure in the conditional follow-up group ( n = 113, 5.9%) was non-inferior to that in the universal follow-up group ( n = 160, 7.2%) (difference: −1.4%; 95% CI: −∞, 2.5%; p = 0.012). In post hoc analysis, when the definition of failure was limited to malaria, diarrhea, pneumonia, development of danger signs, hospitalization, or death, failure in the conditional follow-up group ( n = 108, 5.6%) was similar to that in the universal follow-up group ( n = 147, 6.7%), and within the non-inferiority margin (95% CI: −∞, 2.9%; p = 0.017). Limitations include initial underestimation of the proportion of clinical failures as well as substantial variance in cluster-specific failure rates, reducing the precision of our estimates. In addition, heightened security concerns slowed recruitment in the final months of the study. Conclusions We found that advising caregivers to return only if children worsened or remained ill on day 3 resulted in similar rates of caregiver-reported fever and other clinical outcomes on day 8, compared to advising all caregivers to return on day 3. Policy-makers could consider revising guidelines for management of uncomplicated fever within the iCCM framework. Trial registration ClinicalTrials.gov NCT02595827
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  • 23
    Publication Date: 2018-04-18
    Description: by Michael Kahsay Ghebremariam, Tiny Hlokwe, Victor P. M. G. Rutten, Alberto Allepuz, Simeon Cadmus, Adrian Muwonge, Suelee Robbe-Austerman, Anita L. Michel Mycobacterium bovis ( M . bovis ) is the main causative agent for bovine tuberculosis (BTB) and can also be the cause of zoonotic tuberculosis in humans. In view of its zoonotic nature, slaughterhouse surveillance, potentially resulting in total or partial condemnation of the carcasses and organs, is conducted routinely.Spoligotyping, VNTR profiling, and whole genome sequencing (WGS)of M . bovis isolated from tissues with tuberculosis-like lesions collected from 14 cattle at Eritrea’s largest slaughterhouse in the capital Asmara, were conducted.The 14 M . bovis isolates were classified into three different spoligotype patterns (SB0120, SB0134 and SB0948) and six VNTR profiles. WGSresults matched those of the conventional genotyping methodsand further discriminatedthe six VNTR profiles into 14 strains.Furthermore, phylogenetic analysis of the M . bovis isolates suggests two independent introductions of BTB into Eritrea possibly evolving from a common ancestral strain in Europe.This molecular study revealed the most important strains of M . bovis in Eritrea and their (dis)similarities with the strains generally present in East Africa and Europe, as well as potential routes of introduction of M . bovis . Though the sample size is small, the current study provides important information as well as platform for future in-depth molecular studies on isolates from both the dairy and the traditional livestock sectors in Eritrea and the region. This study provides information onthe origin of some of the M . bovis strains in Eritrea, its genetic diversity, evolution and patterns of spread between dairy herds. Such information is essential in the development and implementation of future BTB control strategy for Eritrea.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 24
    Publication Date: 2018-04-18
    Description: by David G. Glass, Niall McAlinden, Owain R. Millington, Amanda J. Wright
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 25
    Publication Date: 2018-04-18
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 26
    Publication Date: 2018-04-18
    Description: by Daniela Astudillo-Rubio, Andrés Delgado-Gaete, Carlos Bellot-Arcís, José María Montiel-Company, Agustín Pascual-Moscardó, José Manuel Almerich-Silla
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 27
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    Publication Date: 2018-05-08
    Description: by Maria A. Vicent, Conor L. Mook, Matthew E. Carter When core body temperature increases, appetite and food consumption decline. A higher core body temperature can occur during exercise, during exposure to warm environmental temperatures, or during a fever, yet the mechanisms that link relatively warm temperatures to appetite suppression are unknown. A recent study in PLOS Biology demonstrates that neurons in the mouse hypothalamus that express pro-opiomelanocortin (POMC), a neural population well known to suppress food intake, also express a temperature-sensitive ion channel, transient receptor potential vanilloid 1 (TRPV1). Slight increases in body temperature cause a TRPV1-dependent increase in activity in POMC neurons, which suppresses feeding in mice. Taken together, this study suggests a novel mechanism linking body temperature and food-seeking behavior.
    Print ISSN: 1544-9173
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  • 28
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    Publication Date: 2018-05-08
    Description: by Sarah Carmona, Benjamin Lin, Tristan Chou, Katti Arroyo, Sha Sun Mammalian X chromosome dosage compensation balances X-linked gene products between sexes and is coordinated by the long noncoding RNA (lncRNA) Xist . Multiple cis and trans -acting factors modulate Xist expression; however, the primary competence factor responsible for activating Xist remains a subject of dispute. The lncRNA Jpx is a proposed competence factor, yet it remains unknown if Jpx is sufficient to activate Xist expression in mice. Here, we utilize a novel transgenic mouse system to demonstrate a dose-dependent relationship between Jpx copy number and ensuing Jpx and Xist expression. By localizing transcripts of Jpx and Xist using RNA Fluorescence in situ Hybridization (FISH) in mouse embryonic cells, we provide evidence of Jpx acting in both trans and cis to activate Xist . Our data contribute functional and mechanistic insight for lncRNA activity in mice, and argue that Jpx is a competence factor for Xist activation in vivo .
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 29
    Publication Date: 2018-05-08
    Description: by Han Du, Qiushi Zheng, Jian Bing, Richard J. Bennett, Guanghua Huang Sexual reproduction is a universal mechanism for generating genetic diversity in eukaryotes. Fungi exhibit diverse strategies for sexual reproduction both in nature and in the laboratory. In this study, we report the discovery of same-sex (homothallic) mating in the human fungal pathogen Candida tropicalis . We show that same-sex mating occurs between two cells carrying the same mating type ( MTL a/a or α/α) and requires the presence of pheromone from the opposite mating type as well as the receptor for this pheromone. In ménage à trois mating mixes (i.e., “a x a + α helper” or “α x α + a helper” mixes), pheromone secreted by helper strains promotes diploid C . tropicalis cells to undergo same-sex mating and form tetraploid products. Surprisingly, however, the tetraploid mating products can then efficiently mate with cells of the opposite mating type to generate hexaploid products. The unstable hexaploid progeny generated from this coupled process of same- and opposite-sex mating undergo rapid chromosome loss and generate extensive genetic variation. Phenotypic analysis demonstrated that the mating progeny-derived strains exhibit diverse morphologies and phenotypes, including differences in secreted aspartic proteinase (Sap) activity and susceptibility to the antifungal drugs. Thus, the coupling of same- and opposite-sex mating represents a novel mode to generate polyploidy and genetic diversity, which may facilitate the evolution of new traits in C . tropicalis and adaptation to changing environments.
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  • 30
    Publication Date: 2018-05-08
    Description: by Soumya Chaurasia, Christian F. Lehner Sister kinetochores are connected to the same spindle pole during meiosis I and to opposite poles during meiosis II. The molecular mechanisms controlling the distinct behavior of sister kinetochores during the two meiotic divisions are poorly understood. To study kinetochore behavior during meiosis, we have optimized time lapse imaging with Drosophila spermatocytes, enabling kinetochore tracking with high temporal and spatial resolution through both meiotic divisions. The correct bipolar orientation of chromosomes within the spindle proceeds rapidly during both divisions. Stable bi-orientation of the last chromosome is achieved within ten minutes after the onset of kinetochore-microtubule interactions. Our analyses of mnm and tef mutants, where univalents instead of bivalents are present during meiosis I, indicate that the high efficiency of normal bi-orientation depends on pronounced stabilization of kinetochore attachments to spindle microtubules by the mechanical tension generated by spindle forces upon bi-orientation. Except for occasional brief separation episodes, sister kinetochores are so closely associated that they cannot be resolved individually by light microscopy during meiosis I, interkinesis and at the start of meiosis II. Permanent evident separation of sister kinetochores during M II depends on spindle forces resulting from bi-orientation. In mnm and tef mutants, sister kinetochore separation can be observed already during meiosis I in bi-oriented univalents. Interestingly, however, this sister kinetochore separation is delayed until the metaphase to anaphase transition and depends on the Fzy/Cdc20 activator of the anaphase-promoting complex/cyclosome. We propose that univalent bi-orientation in mnm and tef mutants exposes a release of sister kinetochore conjunction that occurs also during normal meiosis I in preparation for bi-orientation of dyads during meiosis II.
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  • 31
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    Publication Date: 2018-05-08
    Description: by Uta Meyer zum Büschenfelde, Laura Isabel Brandenstein, Leonie von Elsner, Kristina Flato, Tess Holling, Martin Zenker, Georg Rosenberger, Kerstin Kutsche RIT1 belongs to the RAS family of small GTPases. Germline and somatic RIT1 mutations have been identified in Noonan syndrome (NS) and cancer, respectively. By using heterologous expression systems and purified recombinant proteins, we identified the p21-activated kinase 1 (PAK1) as novel direct effector of RIT1. We found RIT1 also to directly interact with the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. These interactions are independent of the guanine nucleotide bound to RIT1. Disease-causing RIT1 mutations enhance protein-protein interaction between RIT1 and PAK1, CDC42 or RAC1 and uncouple complex formation from serum and growth factors. We show that the RIT1-PAK1 complex regulates cytoskeletal rearrangements as expression of wild-type RIT1 and its mutant forms resulted in dissolution of stress fibers and reduction of mature paxillin-containing focal adhesions in COS7 cells. This effect was prevented by co-expression of RIT1 with dominant-negative CDC42 or RAC1 and kinase-dead PAK1. By using a transwell migration assay, we show that RIT1 wildtype and the disease-associated variants enhance cell motility. Our work demonstrates a new function for RIT1 in controlling actin dynamics via acting in a signaling module containing PAK1 and RAC1/CDC42, and highlights defects in cell adhesion and migration as possible disease mechanism underlying NS.
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  • 32
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    In: PLoS ONE
    Publication Date: 2018-05-08
    Description: by Ryo Komura, Wataru Aoki, Keisuke Motone, Atsushi Satomura, Mitsuyoshi Ueda Cis-regulatory elements (CREs) are one of the important factors in controlling gene expression and elucidation of their roles has been attracting great interest. We have developed an improved method for analyzing a large variety of mutant CRE sequences in a simple and high-throughput manner. In our approach, mutant CREs with unique barcode sequences were obtained by biased randomization in a single PCR amplification. The original T7 promoter sequence was randomized by biased randomization, and the target number of base substitutions was set to be within the range of 0 to 5. The DNA library and subsequent transcribed RNA library were sequenced by next generation sequencers (NGS) to quantify transcriptional activity of each mutant. We succeeded in producing a randomized T7 promoter library with high coverage rate at each target number of base substitutions. In a single NGS analysis, we quantified the transcriptional activity of 7847 T7 promoter variants. We confirmed that the bases from −9 to −7 play an important role in the transcriptional activity of the T7 promoter. This information coincides with the previous researches and demonstrated the validity of our methodology. Furthermore, using an in vitro transcription/translation system, we found that transcriptional activities of these T7 variants were well correlated with the resultant protein abundance. We demonstrate that our method enables simple and high-throughput analysis of the effects of various CRE mutations on transcriptional regulation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 33
    Publication Date: 2018-05-08
    Description: by Katherine R. Stanford, Thomas E. Taylor-Clark Inflammation causes nociceptive sensory neuron activation, evoking debilitating symptoms and reflexes. Inflammatory signaling pathways are capable of modulating mitochondrial function, resulting in reactive oxygen species (ROS) production, mitochondrial depolarization and calcium release. Previously we showed that mitochondrial modulation with antimycin A, a complex III inhibitor, selectively stimulated nociceptive bronchopulmonary C-fibers via the activation of transient receptor potential (TRP) ankyrin 1 (A1) and vanilloid 1 (V1) cation channels. TRPA1 is ROS-sensitive, but there is little evidence that TRPV1 is activated by ROS. Here, we used dual imaging of dissociated vagal neurons to investigate the correlation of mitochondrial superoxide production (mitoSOX) or mitochondrial depolarization (JC-1) with cytosolic calcium (Fura-2AM), following mitochondrial modulation by antimycin A, rotenone (complex I inhibitor) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP, mitochondrial uncoupling agent). Mitochondrial modulation by all agents selectively increased cytosolic calcium in a subset of TRPA1/TRPV1-expressing (A1/V1+) neurons. There was a significant correlation between antimycin A-induced calcium responses and mitochondrial superoxide in wild-type ‘responding’ A1/V1+ neurons, which was eliminated in TRPA1 -/- neurons, but not TRPV1 -/- neurons. Nevertheless, antimycin A-induced superoxide production did not always increase calcium in A1/V1+ neurons, suggesting a critical role of an unknown factor. CCCP caused both superoxide production and mitochondrial depolarization but neither correlated with calcium fluxes in A1/V1+ neurons. Rotenone-induced calcium responses in ‘responding’ A1/V1+ neurons correlated with mitochondrial depolarization but not superoxide production. Our data are consistent with the hypothesis that mitochondrial dysfunction causes calcium fluxes in a subset of A1/V1+ neurons via ROS-dependent and ROS-independent mechanisms.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 34
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    In: PLoS ONE
    Publication Date: 2018-05-08
    Description: by Corey L. Bretz, Wesley D. Frey, Ryoichi Teruyama, Joomyeong Kim The biological impetus for gene dosage and allele specificity of mammalian imprinted genes is not fully understood. To address this, we generated and analyzed four sets of mice from a single breeding scheme with varying allelic expression and gene dosage of the Peg3 domain. The mutants with abrogation of the two paternally expressed genes, Peg3 and Usp29 , showed a significant decrease in growth rates for both males and females, while the mutants with biallelic expression of Peg3 and Usp29 resulted in an increased growth rate of female mice only. The mutant cohort with biallelic expression of Peg3 and Usp29 tended to have greater numbers of pups compared to the other genotypes. The mutants with switched active alleles displayed overall similar phenotypes to the wild type, but did show some differences in gene expression, suggesting potential non-redundant roles contributed by the maternal and paternal alleles. Overall, this study demonstrates a novel in vivo approach to investigate the allele and dosage specificity of mammalian imprinted domains.
    Electronic ISSN: 1932-6203
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  • 35
    Publication Date: 2018-05-08
    Description: by Yuri Rassovsky, Walter Dunn, Jonathan K. Wynn, Allan D. Wu, Marco Iacoboni, Gerhard Hellemann, Michael F. Green Over the last decades, the treatment of schizophrenia has shifted fundamentally from a focus on symptom reduction to a focus on recovery and improving aspects of functioning. In this study, we examined the effect of transcranial direct current stimulation (tDCS) on social cognitive and nonsocial neurocognitive functions, as well as on electroencephalogram (EEG) measures, in individuals with schizophrenia. Thirty-seven individuals with schizophrenia were administered one of three different tDCS conditions (cathodal, anodal, and sham) per visit over the course of three visits, with approximately one week between each visit. Order of conditions was randomized and counterbalanced across subjects. For the active conditions, the electrode was placed over the left dorsolateral prefrontal cortex with the reference electrode over right supraorbital cortex. Current intensity was 2 mA and was maintained for two 20-minute sessions, with a one hour break between the sessions. Assessments were conducted immediately following each session, in a counterbalanced order of administration. No systematic effects were found across the social and nonsocial cognitive domains, and no significant effects were detected on event-related potentials (ERPs). The very small effect sizes, further validated by post-hoc power analyses (large Critical Ns), demonstrated that these findings were not due to lack of statistical power. Except for mild local discomfort, no significant side effects were reported. Findings demonstrate the safety and ease of administration of this procedure, but suggest that a single dose of tDCS over these areas does not yield a therapeutic effect on cognition in schizophrenia. Trial registration: ClinicalTrials.gov NCT02539797.
    Electronic ISSN: 1932-6203
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  • 36
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    In: PLoS ONE
    Publication Date: 2018-05-08
    Description: by Kyu Jin Han, Young Hoon Lee Purpose To investigate the thickness of retinal layers and association with final visual acuity using spectral-domain optical coherence tomography (SD-OCT) in macular area of macula-off rhegmatogenous retinal detachment (RRD) patients after a successful macular re-attachment. Methods In retrospective study, a total 24 eyes with macula-off RRD were enrolled. All patients underwent vitrectomy to repair RRD. Outer plexiform layer (OPL), outer nuclear layer (ONL), photoreceptor layer (PR), retinal pigment epithelium (RPE) thicknesses were measured by the Spectralis (Heidelberg Engineering, Heidelberg, Germany) SD-OCT with automated segmentation software. The relationship between the thicknesses of each retinal layer and postoperative logarithm of the minimum angle of resolution scale (LogMAR) visual acuity was analyzed. Results OPL and RPE thicknesses were not significantly different between the retinal detachment eyes and fellow eyes (P = 0.839, 0.999, respectively). The ONL and photoreceptor thickness were significantly thinner in the retinal detachment eyes (P
    Electronic ISSN: 1932-6203
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  • 37
    Publication Date: 2018-05-08
    Description: by Sean M. Evans, Kyle G. Rodino, Haley E. Adcox, Jason A. Carlyon Orientia tsutsugamushi causes scrub typhus, a potentially fatal infection that threatens over one billion people. Nuclear translocation of the transcription factor, NF-κB, is the central initiating cellular event in the antimicrobial response. Here, we report that NF-κB p65 nuclear accumulation and NF-κB-dependent transcription are inhibited in O . tsutsugamushi infected HeLa cells and/or primary macrophages, even in the presence of TNFα. The bacterium modulates p65 subcellular localization by neither degrading it nor inhibiting IκBα degradation. Rather, it exploits host exportin 1 to mediate p65 nuclear export, as this phenomenon is leptomycin B-sensitive. O . tsutsugamushi antagonizes NF-κB-activated transcription even when exportin 1 is inhibited and NF-κB consequently remains in the nucleus. Two ankyrin repeat-containing effectors (Anks), Ank1 and Ank6, each of which possess a C-terminal F-box and exhibit 58.5% amino acid identity, are linked to the pathogen’s ability to modulate NF-κB. When ectopically expressed, both translocate to the nucleus, abrogate NF-κB-activated transcription in an exportin 1-independent manner, and pronouncedly reduce TNFα-induced p65 nuclear levels by exportin 1-dependent means. Flag-tagged Ank 1 and Ank6 co-immunoprecipitate p65 and exportin 1. Both also bind importin β1, a host protein that is essential for the classical nuclear import pathway. Importazole, which blocks importin β1 activity, abrogates Ank1 and Ank6 nuclear translocation. The Ank1 and Ank6 regions that bind importin β1 also mediate their transport into the nucleus. Yet, these regions are distinct from those that bind p65/exportin 1. The Ank1 and Ank6 F-box and the region that lies between it and the ankyrin repeat domain are essential for blocking p65 nuclear accumulation. These data reveal a novel mechanism by which O . tsutsugamushi modulates the activity and nuclear transport of NF-κB p65 and identify the first microbial proteins that co-opt both importin β1 and exportin 1 to antagonize a critical arm of the antimicrobial response.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 38
    Publication Date: 2018-05-09
    Description: by Nathan J. Hawkshaw, Jonathan A. Hardman, Iain S. Haslam, Asim Shahmalak, Amos Gilhar, Xinhong Lim, Ralf Paus Hair growth disorders often carry a major psychological burden. Therefore, more effective human hair growth–modulatory agents urgently need to be developed. Here, we used the hypertrichosis-inducing immunosuppressant, Cyclosporine A (CsA), as a lead compound to identify new hair growth–promoting molecular targets. Through microarray analysis we identified the Wnt inhibitor, secreted frizzled related protein 1 (SFRP1), as being down-regulated in the dermal papilla (DP) of CsA-treated human scalp hair follicles (HFs) ex vivo. Therefore, we further investigated the function of SFRP1 using a pharmacological approach and found that SFRP1 regulates intrafollicular canonical Wnt/β-catenin activity through inhibition of Wnt ligands in the human hair bulb. Conversely, inhibiting SFRP1 activity through the SFRP1 antagonist, WAY-316606, enhanced hair shaft production, hair shaft keratin expression, and inhibited spontaneous HF regression (catagen) ex vivo. Collectively, these data (a) identify Wnt signalling as a novel, non–immune-inhibitory CsA target; (b) introduce SFRP1 as a physiologically important regulator of canonical β-catenin activity in a human (mini-)organ; and (c) demonstrate WAY-316606 to be a promising new promoter of human hair growth. Since inhibiting SFRP1 only facilitates Wnt signalling through ligands that are already present, this ‘ligand-limited’ therapeutic strategy for promoting human hair growth may circumvent potential oncological risks associated with chronic Wnt over-activation.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 39
    Publication Date: 2018-05-09
    Description: by Matthew E. MacGilvray, Evgenia Shishkova, Deborah Chasman, Michael Place, Anthony Gitter, Joshua J. Coon, Audrey P. Gasch Cells respond to stressful conditions by coordinating a complex, multi-faceted response that spans many levels of physiology. Much of the response is coordinated by changes in protein phosphorylation. Although the regulators of transcriptome changes during stress are well characterized in Saccharomyces cerevisiae , the upstream regulatory network controlling protein phosphorylation is less well dissected. Here, we developed a computational approach to infer the signaling network that regulates phosphorylation changes in response to salt stress. We developed an approach to link predicted regulators to groups of likely co-regulated phospho-peptides responding to stress, thereby creating new edges in a background protein interaction network. We then use integer linear programming (ILP) to integrate wild type and mutant phospho-proteomic data and predict the network controlling stress-activated phospho-proteomic changes. The network we inferred predicted new regulatory connections between stress-activated and growth-regulating pathways and suggested mechanisms coordinating metabolism, cell-cycle progression, and growth during stress. We confirmed several network predictions with co-immunoprecipitations coupled with mass-spectrometry protein identification and mutant phospho-proteomic analysis. Results show that the cAMP-phosphodiesterase Pde2 physically interacts with many stress-regulated transcription factors targeted by PKA, and that reduced phosphorylation of those factors during stress requires the Rck2 kinase that we show physically interacts with Pde2. Together, our work shows how a high-quality computational network model can facilitate discovery of new pathway interactions during osmotic stress.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 40
    Publication Date: 2018-05-09
    Description: by Nicole E. Wheeler, Paul P. Gardner, Lars Barquist Emerging pathogens are a major threat to public health, however understanding how pathogens adapt to new niches remains a challenge. New methods are urgently required to provide functional insights into pathogens from the massive genomic data sets now being generated from routine pathogen surveillance for epidemiological purposes. Here, we measure the burden of atypical mutations in protein coding genes across independently evolved Salmonella enterica lineages, and use these as input to train a random forest classifier to identify strains associated with extraintestinal disease. Members of the species fall along a continuum, from pathovars which cause gastrointestinal infection and low mortality, associated with a broad host-range, to those that cause invasive infection and high mortality, associated with a narrowed host range. Our random forest classifier learned to perfectly discriminate long-established gastrointestinal and invasive serovars of Salmonella . Additionally, it was able to discriminate recently emerged Salmonella Enteritidis and Typhimurium lineages associated with invasive disease in immunocompromised populations in sub-Saharan Africa, and within-host adaptation to invasive infection. We dissect the architecture of the model to identify the genes that were most informative of phenotype, revealing a common theme of degradation of metabolic pathways in extraintestinal lineages. This approach accurately identifies patterns of gene degradation and diversifying selection specific to invasive serovars that have been captured by more labour-intensive investigations, but can be readily scaled to larger analyses.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 41
    Publication Date: 2018-05-09
    Description: by Joachim Spergser, Igor Loncaric, Alexander Tichy, Johannes Fritz, Alexandra Scope
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 42
    Publication Date: 2018-05-09
    Description: by Mohammad Enamul Haque, Bing Han, Bin Wang, Yue Wang, Aizhong Liu Chromatin immunoprecipitation (ChIP) is usually a reliable technique to find the binding sites of a transcription factor. In the current study, we developed a suitable ChIP method using developing castor bean seeds. A castor bean seed with large and persistent endosperm contains high amounts of storage lipids (ca. 50–60%) and is often considered as a model material to studying seed biology. In oleaginous seeds, due to the rich oils which could seriously affect immunoprecipitation and DNA isolation, it is often difficult to carry out a successful ChIP experiment. Thus, the development of an efficient ChIP method for oleaginous seeds is required. In this study, we modified different steps, including tissue preparation for cross-linking, chromatin washing, sonication and immunoprecipitation of other existing methods. As exemplified by the targeted gene identification of a master regulator WRI1, which regulates fatty acid biosynthesis, we found that the improved ChIP method worked well. We analyzed percentage input and fold changes of the ChIPed DNA. We also made successful ChIP-seq libraries using this method. This method provides a technical support not only for use on castor bean seeds; it might be used equally to analyze protein-DNA interaction in vivo in other oleaginous seeds.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 43
    Publication Date: 2018-05-09
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 44
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    Publication Date: 2018-05-09
    Description: by Michael S. Sinha, Aaron S. Kesselheim In a Guest Editorial, Aaron S. Kesselheim and Michael S. Sinha show how federal and state legislation to allow promotion of drugs for non-approved uses threatens to undermine the FDA's public health mission.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 45
    Publication Date: 2018-05-09
    Description: by Alicia Meconi, Ryan C. Wortman, David K. Wright, Katie J. Neale, Melissa Clarkson, Sandy R. Shultz, Brian R. Christie Repeated concussion is becoming increasingly recognized as a serious public health concern around the world. Moreover, there is a greater awareness amongst health professionals of the potential for repeated pediatric concussions to detrimentally alter the structure and function of the developing brain. To better study this issue, we developed an awake closed head injury (ACHI) model that enabled repeated concussions to be performed reliably and reproducibly in juvenile rats. A neurological assessment protocol (NAP) score was generated immediately after each ACHI to help quantify the cumulative effects of repeated injury on level of consciousness, and basic motor and reflexive capacity. Here we show that we can produce a repeated ACHI (4 impacts in two days) in both male and female juvenile rats without significant mortality or pain. We show that both single and repeated injuries produce acute neurological deficits resembling clinical concussion symptoms that can be quantified using the NAP score. Behavioural analyses indicate repeated ACHI acutely impaired spatial memory in the Barnes maze, and an interesting sex effect was revealed as memory impairment correlated moderately with poorer NAP score performance in a subset of females. These cognitive impairments occurred in the absence of motor impairments on the Rotarod, or emotional changes in the open field and elevated plus mazes. Cresyl violet histology and structural magnetic resonance imaging (MRI) indicated that repeated ACHI did not produce significant structural damage. MRI also confirmed there was no volumetric loss in the cortex, hippocampus, or corpus callosum of animals at 1 or 7 days post-ACHI. Together these data indicate that the ACHI model can provide a reliable, high throughput means to study the effects of concussions in juvenile rats.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 46
    Publication Date: 2018-05-09
    Description: by María Mercedes Elizalde, Paula Soledad Pérez, Ina Sevic, Daniel Grasso, Alejandro Ropolo, Luciana Barbini, Rodolfo Héctor Campos, María Inés Vaccaro, Diego Martín Flichman Hepatitis B virus (HBV) genotypes and mutants have been associated with differences in clinical and virological characteristics. Autophagy is a cellular process that degrades long-lived proteins and damaged organelles. Viruses have evolved mechanisms to alter this process to survive in host cells. In this work, we studied the modulation of autophagy by the replication of HBV subgenotypes F1b and F4, and the naturally occurring mutants BCP and preCore. HBV subgenotypes F1b and F4 replication induced accumulation of autophagosomes in hepatoma cells. However, no autophagic protein degradation was observed, indicating a blockage of autophagic flux at later stages. This inhibition of autophagy flux might be due to an impairment of lysosomal acidification in hepatoma cells. Moreover, HBV-mediated autophagy modulation was independent of the viral subgenotypes and enhanced in viruses with BCP and preCore naturally occurring mutations. These results contribute to understand the mechanisms by which different HBV variants contribute to the pathogenesis of HBV infections. In addition, this study is the first to describe the role that two highly prevalent naturally occurring mutations exert on the modulation of HBV-induced autophagy.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 47
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    Publication Date: 2018-05-09
    Description: by Erin L. Heinzen, Adam C. O'Neill, Xiaolin Zhu, Andrew S. Allen, Melanie Bahlo, Jamel Chelly, William B. Dobyns, Saskia Freytag, Renzo Guerrini, Richard J. Leventer, Annapurna Poduri, Stephen P. Robertson, Christopher A. Walsh, Mengqi Zhang, for the Epi4K Consortium , Epilepsy Phenome/Genome Project Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10 -7 ), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B , including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 48
    Publication Date: 2018-05-09
    Description: by Sohyun Cho, Lari M. Hiott, John B. Barrett, Elizabeth A. McMillan, Sandra L. House, Shaheen B. Humayoun, Eric S. Adams, Charlene R. Jackson, Jonathan G. Frye Surface waters are important sources of water for drinking, industrial, agricultural, and recreational uses; hence, contamination of water by fecal, pathogenic, or antimicrobial resistant (AR) bacteria is a major environmental and public health concern. However, very little data is available on prevalence of these bacteria in surface water throughout a watershed. This study aimed to characterize Escherichia coli present in the Upper Oconee Watershed, a mixed-use watershed in Athens, GA, USA for potential pathogenicity and AR. E . coli were enumerated by colony counts, cultured by enrichment and direct plating, and characterized by phylo-groups, diarrheagenic pathotypes, and antimicrobial susceptibility. From the analysis, 99.3% (455/458) of the total samples were positive for E . coli resulting in 496 isolates. E . coli counts were as high as 1.2×10 4 CFU/100 ml, which is above the United States Environmental Protection Agency (U.S. EPA) threshold for recreational water (235 CFU/100 ml based on a one-time measurement). Phylo-groups B2 (31.7%; 157/496) and B1 (30.8%; 153/496) were the most prevalent among the isolates. Enteropathogenic E . coli (EPEC) (19/496) and Shiga toxin-producing E . coli (STEC) (1/496) were the only diarrheagenic pathotypes detected. AR was observed in 6.9% (34/496) of the isolates, 15 of which were multidrug resistant (MDR; resistance to two or more classes of antimicrobials). Tetracycline resistance was most often detected (76.5%; 26/34), followed by ampicillin (32.4%; 11/34), streptomycin (23.5%; 8/34), sulfisoxazole (23.5%; 8/34), and nalidixic acid (14.7%; 5/34). Results from this study showed that E . coli is prevalent in high levels in the Upper Oconee Watershed, suggesting possible widespread fecal contamination. The presence of pathogenic, AR E . coli in the watershed indicates that environmental water can serve as a reservoir of resistant bacteria that may be transferred to humans through drinking and recreational activities.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 49
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    In: PLoS ONE
    Publication Date: 2018-05-09
    Description: by Allison R. Sirois, Daniela A. Deny, Samantha R. Baierl, Katia S. George, Sarah J. Moore Mesothelin is a cell surface protein that is overexpressed in numerous cancers, including breast, ovarian, lung, liver, and pancreatic tumors. Aberrant expression of mesothelin has been shown to promote tumor progression and metastasis through interaction with established tumor biomarker CA125. Therefore, molecules that specifically bind to mesothelin have potential therapeutic and diagnostic applications. However, no mesothelin-targeting molecules are currently approved for routine clinical use. While antibodies that target mesothelin are in development, some clinical applications may require a targeting molecule with an alternative protein fold. For example, non-antibody proteins are more suitable for molecular imaging and may facilitate diverse chemical conjugation strategies to create drug delivery complexes. In this work, we engineered variants of the fibronectin type III domain (Fn3) non-antibody protein scaffold to bind to mesothelin with high affinity, using directed evolution and yeast surface display. Lead engineered Fn3 variants were solubly produced and purified from bacterial culture at high yield. Upon specific binding to mesothelin on human cancer cell lines, the engineered Fn3 proteins internalized and co-localized to early endosomes. To our knowledge, this is the first report of non-antibody proteins engineered to bind mesothelin. The results validate that non-antibody proteins can be engineered to bind to tumor biomarker mesothelin, and encourage the continued development of engineered variants for applications such as targeted diagnostics and therapeutics.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 50
    Publication Date: 2018-05-09
    Description: by Chung Hyun Cho, Ji Won Choi, Daryl W. Lam, Kyeong Mi Kim, Hwan Su Yoon The red algal subclass Nemaliophycidae includes both marine and freshwater taxa that contribute to more than half of the freshwater species in Rhodophyta. Given that these taxa inhabit diverse habitats, the Nemaliophycidae is a suitable model for studying environmental adaptation. For this purpose, we characterized plastid genomes of two freshwater species, Kumanoa americana (Batrachospermales) and Thorea hispida (Thoreales), and one marine species Palmaria palmata (Palmariales). Comparative genome analysis identified seven genes ( ycf 34, ycf 35, ycf 37, ycf 46, ycf 91, grx , and pbs A) that were different among marine and freshwater species. Among currently available red algal plastid genomes (127), four genes ( pbs A, ycf 34, ycf 35, ycf 37) were retained in most of the marine species. Among these, the pbs A gene, known for encoding heme oxygenase, had two additional copies ( HMOX1 and HMOX2 ) that were newly discovered and were reported from previously red algal nuclear genomes. Each type of heme oxygenase had a different evolutionary history and special modifications ( e . g ., plastid targeting signal peptide). Based on this observation, we suggest that the plastid-encoded pbs A contributes to the iron controlling system in iron-deprived conditions. Thus, we highlight that this functional requirement may have prevented gene loss during the long evolutionary history of red algal plastid genomes.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 51
    Publication Date: 2018-05-09
    Description: by Dorien Clarisse, Karlien Van Wesemael, Jan Tavernier, Fritz Offner, Ilse M. Beck, Karolien De Bosscher Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation. Here, we examined whether the combination of CpdA with the classic GC dexamethasone (Dex) may improve GC responsiveness of MM and ALL cell lines. We find that the combination of Dex and CpdA does not substantially enhance GC-mediated cell killing. In line, several apoptosis hallmarks, such as caspase 3/7 activity, PARP cleavage and the levels of cleaved-caspase 3 remain unchanged upon combining Dex with CpdA. Moreover, we monitor no additional inhibition of cell proliferation and the homologous downregulation of GR is not counteracted by the combination of Dex and CpdA. In addition, CpdA is unable to modulate Dex-liganded GR transactivation and transrepression, yet, Dex-mediated transrepression is also aberrant in these lymphoid cell lines. Together, transrepression-favoring compounds, alone or combined with GCs, do not seem a valid strategy in the treatment of lymphoid malignancies.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 52
    Publication Date: 2018-05-09
    Description: by Cassio Geremia Freire, Admir José Giachini, João Peterson Pereira Gardin, Ana Claudia Rodrigues, Renato Luis Vieira, César Milton Baratto, Simone Silmara Werner, Bernardo Haas Abreu Like many other species of trees native to the Brazilian Mata Atlântica (Atlantic Forest), the Myrtaceae, such as the Red Araza ( Psidium cattleianum Sabine), are widely cited as arbuscular mycorrhizal formers. Nevertheless, recent studies show evidence that Myrtaceae from different tropical, subtropical and neotropical ecosystems can also prompt the formation of ectomycorrhizae, indicating that this species' ectomycorrhizal status should be further explored. Because of this, this research effort studied the in vitro interaction between the Red Araza and two ectomycorrhizal fungi isolates, belonging to the Pisolithus microcarpus (D17) and Scleroderma citrinum (UFSC-Sc133) species. An analysis was performed to determine the formation of ectomycorrhizal structures, or lack thereof, and the developmental differences between the in vitro mycorrhized and non-mycorrhized plants. The analysis proved that indeed an ectomycorrhizal association was developed between the Red Araza, and the D17 and UFSC-Sc133 isolates, a fact never before registered in the existing literature. After an in vitro period of 110 days, it was confirmed that the D17 and UFSC-Sc133 isolates formed mycorrhizal colonization of 91.6% and 15.7%, respectively. Furthermore, both isolates also promoted root thickening, and the formation of a fungal mantle and a Hartig net. However, when compared to the Control plants, the fungal isolates did not contribute to an increase in the development of the subject plants, possibly due to the specific experimental conditions used, such as a high humidity environment and high availability of nutrients in the symbiotic substrate.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 53
    Publication Date: 2018-05-09
    Description: by Lisiery N. Paiatto, Fernanda G. D. Silva, Áureo T. Yamada, Wirla M. S. C. Tamashiro, Patricia U. Simioni Introduction In addition to conventional therapies, several new strategies have been proposed for modulating autoimmune diseases, including the adoptive transfer of immunological cells. In this context, dendritic cells (DCs) appear to be one of the most promising treatments for autoimmune disorders. The present study aimed to evaluate the effects of adoptive transfer of DCs obtained from both naïve and ovalbumin (OVA)-tolerant mice on the severity of TNBS induced colitis and analyze the eventual protective mechanisms. Methods and results To induce oral tolerance, BALB/c mice were fed 4mg/mL OVA solution for seven consecutive days. Spleen DCs were isolated from tolerant (tDC) and naïve (nDC) mice, and then adoptively transferred to syngeneic mice. Three days later, colitis was induced in DC treated mice by intrarectal instillation of 100μg2,4,6-trinitrobenzenesulfonic acid (TNBS) dissolved in 50% ethanol. Control subjects received only intrarectal instillation of either TNBS solution or a vehicle. Five days later, mice from all groups were euthanized and examined for physiological and immunological parameters. Regarding the phenotype, we observed that the frequencies of CD11 + MHC II + and CD11 + MHCII + CD86 + cells were significantly lower in DCs isolated from tolerant mice than in those from naive mice. However, pretreatment with both types of DCs was able to significantly reduce clinical signs of colitis such as diarrhea, rectal prolapse, bleeding, and cachexia, although only treatment with tDCs was able to prevent weight loss from instillation of TNBS. In vitro proliferation of spleen cells from mice treated with either type of DCs was significantly lower than that observed in splenic cell cultures of naïve mice. Although no significant difference was observed in the frequencies of Treg cells in the experimental groups, the frequency of Th17 + CD4 + cellsand the secretion of IL-17 were more reduced in the cultures of spleen cells from mice treated with either type of DCs. The levels of IL-9 and IFN-γ were lower in supernatants of cells from mice treated with nDCs. Conclusion The results allow us to conclude that the adoptive transfer of cells expressing CD11c is able to reduce the clinical and immunological signs of drug-induced colitis. Adoptive transfer of CD11c + DC isolated from both naive and tolerant mice altered the proliferative and T cell responses. To the best of our knowledge, there is no previously published data showing the protective effects of DCs from naïve or tolerant mice in the treatment of colitis.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 54
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    In: PLoS ONE
    Publication Date: 2018-05-09
    Description: by Philipp Solbach, Patrick Chhatwal, Sabrina Woltemate, Evelina Tacconelli, Michael Buhl, Markus Gerhard, Christoph K. Thoeringer, Maria J. G. T. Vehreschild, Nathalie Jazmati, Jan Rupp, Michael P. Manns, Oliver Bachmann, Sebastian Suerbaum Background Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea. Secondary bile acids were shown to confer resistance to colonization by C . difficile . 7α-dehydroxylation is a key step in transformation of primary to secondary bile acids and required genes have been located in a single bile acid-inducible (bai) operon in C . scindens as well as in C . hiranonis , two Clostridium sp. recently reported to protect against C . difficile colonization. Aim To analyze baiCD gene abundance in C . difficile positive and negative fecal samples. Material & methods A species-specific qPCR for detecting baiCD genes was established. Fecal samples of patients with CDI, asymptomatic toxigenic C . difficile colonization (TCD), non-toxigenic C . difficile colonization (NTCD), of C . difficile negative (NC) patients, and of two patients before and after fecal microbiota transplantation (FMT) for recurrent CDI (rCDI) were tested for the presence of the baiCD genes. Results The prevalence of the baiCD gene cluster was significantly higher in C . difficile negative fecal samples than in samples of patients diagnosed with CDI (72.5% (100/138) vs. 35.9% (23/64; p
    Electronic ISSN: 1932-6203
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  • 55
    Publication Date: 2018-05-09
    Description: by Andrea Kosovac, Jes Johannesen, Oliver Krstić, Milana Mitrović, Tatjana Cvrković, Ivo Toševski, Jelena Jović The stolbur phytoplasma vector Hyalesthes obsoletus is generally considered as a polyphagous species associated with numerous wild and cultivated plants. However, recent research in southeastern Europe, the distribution centre of H . obsoletus and the area of most stolbur-inflicted crop diseases, points toward specific host-plant associations of the vector, indicating specific vector-based transmission routes. Here, we study the specificity of populations associated with four host-plants using mitochondrial and nuclear genetic markers, and we evaluate the evolution of host-shifts in H . obsoletus . Host-plant use was confirmed for Convolvulus arvensis , Urtica dioica , Vitex agnus-castus and Crepis foetida . Mitochondrial genetic analysis showed sympatric occurrence of three phylogenetic lineages that were ecologically delineated by host-plant preference, but were morphologically inseparable. Nuclear data supported the existence of three genetic groups (Evanno’s ΔK(3) = 803.72) with average genetic membership probabilities 〉 90%. While populations associated with C . arvensis and U . dioica form a homogenous group, populations affiliated with V . agnus-castus and C . foetida constitute two independent plant-associated lineages. The geographical signal permeating the surveyed populations indicated complex diversification processes associated with host-plant selection and likely derived from post-glacial refugia in the eastern Mediterranean. This study provides evidence for cryptic species diversification within H . obsoletus sensu lato : i) consistent mitochondrial differentiation (1.1–1.5%) among host-associated populations in syntopy and in geographically distant areas, ii) nuclear genetic variance supporting mitochondrial data, and iii) average mitochondrial genetic distances among host-associated meta-populations are comparable to the most closely related, morphologically distinguishable species, i.e., Hyalesthes thracicus (2.1–3.3%).
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 56
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    In: PLoS ONE
    Publication Date: 2018-05-09
    Description: by Maria Elena Andreis, Umberto Polito, Maria Cristina Veronesi, Massimo Faustini, Mauro Di Giancamillo, Silvia C. Modina The largest differences in intraspecific head shape among the Carnivora order are to be found in dogs. Based on their skull morphotypes, dog breeds are currently classified as dolichocephalic, mesaticephalic and brachycephalic. Due to the fact that some breeds have not been yet defined, this classification is incomplete; moreover, multi-breed studies on the skull morphology of puppies have never been performed. The aim of this work was to verify (i) whether differences in the skull conformation of purebred puppies are already present within the first week of age; (ii) whether radiographic and anatomic measures could be considered interchangeable, and (iii) to possibly classify puppies from non-categorized breeds thanks to their radiographic cranial measurements using neural nets. One hundred and thirty-seven dead puppies aged 0–7 days were examined considering their anatomic and radiographic measures. All linear measures and anatomic indices significantly differed among brachycephalic and non-brachycephalic puppies. Radiographic indices, with the exception of CI, identified the three skull morphotypes ( p
    Electronic ISSN: 1932-6203
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  • 57
    Publication Date: 2018-05-09
    Description: by Jason G. Walling, Leslie A. Zalapa, Marcus A. Vinje Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is a popular method for measuring transcript abundance. The most commonly used method of interpretation is relative quantification and thus necessitates the use of normalization controls (i.e. reference genes) to standardize transcript abundance. The most popular gene targets for RT-qPCR are housekeeping genes because they are thought to maintain a static transcript level among a variety of samples. However, more recent studies have shown, several housekeeping genes are not reliably stable. This is the first study to examine the potential of several reference genes for use in RT-qPCR normalization during barley malting. The process of malting barley mechanizes the imbibition and subsequent germination of barley seeds under controlled conditions. Malt quality is controlled by many pleiotropic genes that are determined by examining the result of physiological changes the barley seed undergoes during the malting process. We compared the stability of 13 reference genes across both two-and six-row malting barleys (Conrad and Legacy, respectfully) throughout the entirety of the malting process. Initially, primer target specificity, amplification efficiency and average Ct values were determined for each of the selected primer pairs. Three statistical programs (geNorm, NormFinder, and BestKeeper) were used to rank the stability of each reference gene. Rankings were similar between the two- and six-row with the exception of BestKeeper’s ranking of glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ). A consensus ranking among programs was determined using RefFinder. Our results show that Actin (A CT ) and Heat Shock Protein 70 ( HSP70 ) were the most stable throughout micromalting, while GAPDH and Cyclophilin ( CYP ) were the least stable. Two reference genes are necessary for stable transcript normalization according to geNorm and the best two reference genes ( ACT and HSP70 ) provided a sufficient level of stability.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 58
    Publication Date: 2018-05-10
    Description: by Michel F. Guiraldelli, Anna Felberg, Luciana P. Almeida, Aniruddha Parikh, Rodrigo O. de Castro, Roberto J. Pezza Chromosome segregation errors during meiosis result in the formation of aneuploid gametes and are the leading cause of pregnancy loss and birth defects in humans. Proper chromosome segregation requires pairwise associations of maternal and paternal homologous chromosomes. Chiasmata, which are the cytological manifestations of crossovers (COs), provide a physical link that holds the homologs together as a pair, facilitating their orientation on the spindle at meiosis I. Although CO-promoting activities ensure a balanced number and position of COs, their identity and mechanism of action in mammals remain understudied. Previous work in yeast and Arabidopsis has shown that Zip2 and Shoc1 are ortholog proteins with an important role in promoting the formation of COs. Our work is the first study in mammals showing the in vivo and in vitro function of mouse and human SHOC1. We show that purified recombinant human SHOC1, an XPF/MUS81 family member, preferentially binds branched DNA molecules but apparently lacks in vitro endonuclease activity, despite its conserved ERCC4-(HhH) 2 core structure. Cytological observations suggest that initial steps of recombination are normal in a majority of spermatocytes from SHOC1 hypomorphic mice. However, late stages of recombination appear abnormal, as chromosomal localization of MLH1 is reduced. In agreement, chiasma formation is reduced, and cells arrest at metaphase I with a few lagging chromosomes and subsequent apoptosis. This analysis of SHOC1-deficient mice and the selective localization of SHOC1 to a subset of recombination sites show that SHOC1 acts at key mid-stage steps of the CO formation process. The formation of chromosome axial elements and homologous pairing are apparently normal, but synapsis is altered with SYCP1 frequently failing to extend the full length of the chromosome axes. Finally, we describe that SHOC1 interacts with TEX11, another protein important for the formation of COs, connecting SHOC1 to chromosome axis and structure.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 59
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-11
    Description: by Serafeim Perdikis, Luca Tonin, Sareh Saeedi, Christoph Schneider, José del R. Millán This work aims at corroborating the importance and efficacy of mutual learning in motor imagery (MI) brain–computer interface (BCI) by leveraging the insights obtained through our participation in the BCI race of the Cybathlon event. We hypothesized that, contrary to the popular trend of focusing mostly on the machine learning aspects of MI BCI training, a comprehensive mutual learning methodology that reinstates the three learning pillars (at the machine, subject, and application level) as equally significant could lead to a BCI–user symbiotic system able to succeed in real-world scenarios such as the Cybathlon event. Two severely impaired participants with chronic spinal cord injury (SCI), were trained following our mutual learning approach to control their avatar in a virtual BCI race game. The competition outcomes substantiate the effectiveness of this type of training. Most importantly, the present study is one among very few to provide multifaceted evidence on the efficacy of subject learning during BCI training. Learning correlates could be derived at all levels of the interface—application, BCI output, and electroencephalography (EEG) neuroimaging—with two end-users, sufficiently longitudinal evaluation, and, importantly, under real-world and even adverse conditions.
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  • 60
    Publication Date: 2018-05-11
    Description: by Thanos Manos, Magteld Zeitler, Peter A. Tass Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies. However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered. This work presents the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.
    Print ISSN: 1553-734X
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  • 61
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    Publication Date: 2018-05-11
    Description: by Vicente Botella-Soler, Stéphane Deny, Georg Martius, Olivier Marre, Gašper Tkačik Retina is a paradigmatic system for studying sensory encoding: the transformation of light into spiking activity of ganglion cells. The inverse problem, where stimulus is reconstructed from spikes, has received less attention, especially for complex stimuli that should be reconstructed “pixel-by-pixel”. We recorded around a hundred neurons from a dense patch in a rat retina and decoded movies of multiple small randomly-moving discs. We constructed nonlinear (kernelized and neural network) decoders that improved significantly over linear results. An important contribution to this was the ability of nonlinear decoders to reliably separate between neural responses driven by locally fluctuating light signals, and responses at locally constant light driven by spontaneous-like activity. This improvement crucially depended on the precise, non-Poisson temporal structure of individual spike trains, which originated in the spike-history dependence of neural responses. We propose a general principle by which downstream circuitry could discriminate between spontaneous and stimulus-driven activity based solely on higher-order statistical structure in the incoming spike trains.
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  • 62
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    Publication Date: 2018-05-11
    Description: by Tim van Mourik, Lukas Snoek, Tomas Knapen, David G. Norris The field of neuroimaging is rapidly adopting a more reproducible approach to data acquisition and analysis. Data structures and formats are being standardised and data analyses are getting more automated. However, as data analysis becomes more complicated, researchers often have to write longer analysis scripts, spanning different tools across multiple programming languages. This makes it more difficult to share or recreate code, reducing the reproducibility of the analysis. We present a tool, Porcupine, that constructs one’s analysis visually and automatically produces analysis code. The graphical representation improves understanding of the performed analysis, while retaining the flexibility of modifying the produced code manually to custom needs. Not only does Porcupine produce the analysis code, it also creates a shareable environment for running the code in the form of a Docker image. Together, this forms a reproducible way of constructing, visualising and sharing one’s analysis. Currently, Porcupine links to Nipype functionalities, which in turn accesses most standard neuroimaging analysis tools. Our goal is to release researchers from the constraints of specific implementation details, thereby freeing them to think about novel and creative ways to solve a given problem. Porcupine improves the overview researchers have of their processing pipelines, and facilitates both the development and communication of their work. This will reduce the threshold at which less expert users can generate reusable pipelines. With Porcupine, we bridge the gap between a conceptual and an implementational level of analysis and make it easier for researchers to create reproducible and shareable science. We provide a wide range of examples and documentation, as well as installer files for all platforms on our website: https://timvanmourik.github.io/Porcupine. Porcupine is free, open source, and released under the GNU General Public License v3.0.
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  • 63
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    Publication Date: 2018-05-11
    Description: by Charles A. Seller, Patrick H. O’Farrell In preparation for dramatic morphogenetic events of gastrulation, rapid embryonic cell cycles slow at the mid-blastula transition (MBT). In Drosophila melanogaster embryos, down-regulation of cyclin-dependent kinase 1 (Cdk1) activity initiates this slowing by delaying replication of heterochromatic satellite sequences and extending S phase. We found that Cdk1 activity inhibited the chromatin association of Rap1 interacting factor 1 (Rif1), a candidate repressor of replication. Furthermore, Rif1 bound selectively to satellite sequences following Cdk1 down-regulation at the MBT. In the next S phase, Rif1 dissociated from different satellites in an orderly schedule that anticipated their replication. Rif1 lacking potential phosphorylation sites failed to dissociate and dominantly prevented completion of replication. Loss of Rif1 in mutant embryos shortened the post-MBT S phase and rescued embryonic cell cycles disrupted by depletion of the S phase–promoting kinase, cell division cycle 7 (Cdc7). Our work shows that Rif1 and S phase kinases compose a replication timer controlling first the developmental onset of late replication and then the precise schedule of replication within S phase. In addition, we describe how onset of late replication fits into the progressive maturation of heterochromatin during development.
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  • 64
    Publication Date: 2018-05-11
    Description: by Xinxin Ding, Leah M. Pervere, Carl Bascom Jr., Jeffrey P. Bibeau, Sakshi Khurana, Allison M. Butt, Robert G. Orr, Patrick J. Flaherty, Magdalena Bezanilla, Luis Vidali Our ability to identify genes that participate in cell growth and division is limited because their loss often leads to lethality. A solution to this is to isolate conditional mutants where the phenotype is visible under restrictive conditions. Here, we capitalize on the haploid growth-phase of the moss Physcomitrella patens to identify conditional loss-of-growth (CLoG) mutants with impaired growth at high temperature. We used whole-genome sequencing of pooled segregants to pinpoint the lesion of one of these mutants ( clog1 ) and validated the identified mutation by rescuing the conditional phenotype by homologous recombination. We found that CLoG1 is a novel and ancient gene conserved in plants. At the restrictive temperature, clog1 plants have smaller cells but can complete cell division, indicating an important role of CLoG1 in cell growth, but not an essential role in cell division. Fluorescent protein fusions of CLoG1 indicate it is localized to microtubules with a bias towards depolymerizing microtubule ends. Silencing CLoG1 decreases microtubule dynamics, suggesting that CLoG1 plays a critical role in regulating microtubule dynamics. By discovering a novel gene critical for plant growth, our work demonstrates that P . patens is an excellent genetic system to study genes with a fundamental role in plant cell growth.
    Print ISSN: 1553-7390
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  • 65
    Publication Date: 2018-05-11
    Description: by Arturo Blazquez-Navarro, Thomas Schachtner, Ulrik Stervbo, Anett Sefrin, Maik Stein, Timm H. Westhoff, Petra Reinke, Edda Klipp, Nina Babel, Avidan U. Neumann, Michal Or-Guil BK virus (BKV) associated nephropathy affects 1–10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.
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  • 66
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    Publication Date: 2018-05-11
    Description: by Paul Bilinski, Patrice S. Albert, Jeremy J. Berg, James A. Birchler, Mark N. Grote, Anne Lorant, Juvenal Quezada, Kelly Swarts, Jinliang Yang, Jeffrey Ross-Ibarra While the vast majority of genome size variation in plants is due to differences in repetitive sequence, we know little about how selection acts on repeat content in natural populations. Here we investigate parallel changes in intraspecific genome size and repeat content of domesticated maize ( Zea mays ) landraces and their wild relative teosinte across altitudinal gradients in Mesoamerica and South America. We combine genotyping, low coverage whole-genome sequence data, and flow cytometry to test for evidence of selection on genome size and individual repeat abundance. We find that population structure alone cannot explain the observed variation, implying that clinal patterns of genome size are maintained by natural selection. Our modeling additionally provides evidence of selection on individual heterochromatic knob repeats, likely due to their large individual contribution to genome size. To better understand the phenotypes driving selection on genome size, we conducted a growth chamber experiment using a population of highland teosinte exhibiting extensive variation in genome size. We find weak support for a positive correlation between genome size and cell size, but stronger support for a negative correlation between genome size and the rate of cell production. Reanalyzing published data of cell counts in maize shoot apical meristems, we then identify a negative correlation between cell production rate and flowering time. Together, our data suggest a model in which variation in genome size is driven by natural selection on flowering time across altitudinal clines, connecting intraspecific variation in repetitive sequence to important differences in adaptive phenotypes.
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  • 67
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    Publication Date: 2018-05-11
    Description: by Swarna Bais, Corbett T. Berry, Xiaohong Liu, Gordon Ruthel, Bruce D. Freedman, Robert M. Greenberg Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease estimated to affect over 200 million people worldwide. Praziquantel is the only antischistosomal currently available for treatment, and there is an urgent need for new therapeutics. Ion channels play key roles in physiology and are targets for many anthelmintics, yet only a few representatives have been characterized in any detail in schistosomes and other parasitic helminths. The transient receptor potential (TRP) channel superfamily comprises a diverse family of non-selective cation channels that play key roles in sensory transduction and a wide range of other functions. TRP channels fall into several subfamilies. Members of both the TRPA and TRPV subfamilies transduce nociceptive and inflammatory signals in mammals, and often also respond to chemical and thermal signals. We previously showed that although schistosomes contain no genes predicted to encode TRPV channels, TRPV1-selective activators such as capsaicin and resiniferatoxin elicit dramatic hyperactivity in adult worms and schistosomula. Surprisingly, this response requires expression of a S . mansoni TRPA1-like orthologue (SmTRPA). Here, we show that capsaicin induces a rise in intracellular Ca 2+ in mammalian cells expressing either SmTRPA or a S . haematobium TRPA1 orthologue (ShTRPA). We also test SmTRPA and ShTRPA responses to various TRPV1 and TRPA1 modulators. Interestingly, in contrast to SmTRPA, ShTRPA is not activated by the TRPA1 activator AITC (allyl isothiocyanate), nor do S . haematobium adult worms respond to this compound, a potentially intriguing species difference. Notably, 4-hydroxynonenal (4-HNE), a host-derived, inflammatory product that directly activates mammalian TRPA1, also activates both SmTRPA and ShTRPA. Our results point to parasite TRPA1-like channels which exhibit atypical, mixed TRPA1/TRPV1-like pharmacology, and which may also function to transduce endogenous host signals.
    Print ISSN: 1935-2727
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  • 68
    Publication Date: 2018-05-11
    Description: by Francis Bakewell, Sarah Addleman, Garth Dickinson, Venkatesh Thiruganasambandamoorthy Introduction In June 2012, the federal government made cuts to the Interim Federal Health (IFH) Program that reduced or eliminated health insurance for refugee claimants in Canada. The purpose of this study was to examine the effect of the cuts on emergency department (ED) use among patients claiming IFH benefits. Methods We conducted a health records review at two tertiary care EDs in Ottawa. We reviewed all ED visits where an IFH claim was made at triage, for 18 months before and 18 months after the changes to the program on June 30, 2012 (2011–2013). Claims made before and after the cuts were compared in terms of basic demographics, chief presenting complaints, acuity, diagnosis, presence of primary care, and financial status of the claim. Bivariate or multivariate logistic regression analysis was performed to yield odds ratios (OR) with 95% confidence intervals. Results There were a total of 612 IFH claims made in the ED from 2011–2013. The demographic characteristics, acuity of presentation and discharge diagnoses were similar during both the before and after periods. Overall, 28.6% fewer claims were made under the IFH program after the cuts. Of the claims made, significantly more were rejected after the cuts than before (13.7% after vs. 3.9% before, adjusted OR 4.28, 95% CI: 2.18–8.40; p
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 69
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    In: PLoS ONE
    Publication Date: 2018-05-11
    Description: by Éva Szentirmai, Levente Kapás We previously identified brown adipose tissue (BAT) as a source of sleep-inducing signals. Pharmacological activation of BAT enhances sleep while sleep loss leads to increased BAT thermogenesis. Recovery sleep after sleep loss is diminished in mice that lack uncoupling protein 1 (UCP-1), and also in wild-type (WT) mice after sensory denervation of the BAT. Systemic inflammation greatly affects metabolism and the function of adipose tissue, and also induces characteristic sleep responses. We hypothesized that sleep responses to acute inflammation are mediated by BAT-derived signals. To test this, we determined the effects of systemic inflammation on sleep and body temperature in UCP-1 knockout (KO) and WT mice. Intraperitoneal injections of lipopolysaccharide, tumor necrosis factor-α, interleukin-1 beta and clodronate containing liposomes were used to induce systemic inflammation. In WT animals, non-rapid-eye movement sleep (NREMS) was elevated in all four inflammatory models. All NREMS responses were completely abolished in UCP-1 KO animals. Systemic inflammation elicited an initial hypothermia followed by fever in WT mice. The hypothermic phase, but not the fever, was abolished in UCP-1 KO mice. The only recognized function of UCP-1 is to promote thermogenesis in brown adipocytes. Present results indicate that the presence of UCP-1 is necessary for increased NREMS but does not contribute to the development of fever in systemic inflammation.
    Electronic ISSN: 1932-6203
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  • 70
    Publication Date: 2018-05-11
    Description: by Young Bong Choi, Yeeun Choi, Edward William Harhaj Human herpesvirus 8 (HHV-8) is causally related to human malignancies. HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its expression is regulated is largely unknown. In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes. Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner. Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases. Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis.
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  • 71
    Publication Date: 2018-05-11
    Description: by Zsuzsanna Sasvari, Nikolay Kovalev, Paulina Alatriste Gonzalez, Kai Xu, Peter D. Nagy Positive-strand RNA viruses assemble numerous membrane-bound viral replicase complexes within large replication compartments to support their replication in infected cells. Yet the detailed mechanism of how given subcellular compartments are subverted by viruses is incompletely understood. Although, Tomato bushy stunt virus (TBSV) uses peroxisomal membranes for replication, in this paper, we show evidence that the ER-resident SNARE (soluble NSF attachment protein receptor) proteins play critical roles in the formation of active replicase complexes in yeast model host and in plants. Depletion of the syntaxin 18-like Ufe1 and Use1, which are components of the ER SNARE complex in the ERAS (ER arrival site) subdomain, in yeast resulted in greatly reduced tombusvirus accumulation. Over-expression of a dominant-negative mutant of either the yeast Ufe1 or the orthologous plant Syp81 syntaxin greatly interferes with tombusvirus replication in yeast and plants, thus further supporting the role of this host protein in tombusvirus replication. Moreover, tombusvirus RNA replication was low in cell-free extracts from yeast with repressed Ufe1 or Use1 expression. We also present evidence for the mislocalization of the tombusviral p33 replication protein to the ER membrane in Ufe1p-depleted yeast cells. The viral p33 replication protein interacts with both Ufe1p and Use1p and co-opts them into the TBSV replication compartment in yeast and plant cells. The co-opted Ufe1 affects the virus-driven membrane contact site formation, sterol-enrichment at replication sites, recruitment of several pro-viral host factors and subversion of the Rab5-positive PE-rich endosomes needed for robust TBSV replication. In summary, we demonstrate a critical role for Ufe1 and Use1 SNARE proteins in TBSV replication and propose that the pro-viral functions of Ufe1 and Use1 are to serve as assembly hubs for the formation of the extensive TBSV replication compartments in cells. Altogether, these findings point clearly at the ERAS subdomain of ER as a critical site for the biogenesis of the TBSV replication compartment.
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  • 72
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    In: PLoS ONE
    Publication Date: 2018-05-11
    Description: by Sojung Yi, Yihan Lin, Grace Kansayisa, Ainhoa Costas-Chavarri Access to surgical care in low- and middle-income countries (LMICs) remains deficient without an adequate workforce. There is limited understanding of the gender gap in surgical trainees in LMICs. In Rwanda, females fill only one of 20 positions available. Understanding surgeons’ experiences and perceptions of surgical careers may help facilitate support for females to contribute to the global surgical workforce. We performed qualitative analysis on perceptions of surgical careers through semi-structured interviews of all female surgeons (n = 6) and corresponding male surgeons (n = 6) who are training or have trained at University of Rwanda. Transcripts were analyzed with code structure formed through an integrated approach. Question categories formed the deductive framework, while theoretical saturation was reached through inductive grounded theory. Themes were organized within two key points of the career timeline. First, for developing interest in surgery, three main themes were identified: role models, patient case encounters, and exposure to surgery. Second, for selecting and sustaining surgical careers, four main themes emerged: social expectations about roles within the family, physical and mental challenges, professional and personal support, and finances. All female surgeons emphasized gender assumptions and surgical working culture as obstacles, with a corresponding strong sense of self-confidence and internal motivation that drew them to select and maintain careers in surgery. Family, time, and physical endurance were cited as persistent challenges for female participants. Our study reveals concepts for further exploration about gendered perceptions of surgical careers. Efforts to improve support for female surgical careers as a strategy for shaping surgical work culture and professional development in Rwanda should be considered. Such strategies may be beneficial for improving the global surgical workforce.
    Electronic ISSN: 1932-6203
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  • 73
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    Publication Date: 2018-05-11
    Description: by Verena J. Schuenemann, Charlotte Avanzi, Ben Krause-Kyora, Alexander Seitz, Alexander Herbig, Sarah Inskip, Marion Bonazzi, Ella Reiter, Christian Urban, Dorthe Dangvard Pedersen, G. Michael Taylor, Pushpendra Singh, Graham R. Stewart, Petr Velemínský, Jakub Likovsky, Antónia Marcsik, Erika Molnár, György Pálfi, Valentina Mariotti, Alessandro Riga, M. Giovanna Belcastro, Jesper L. Boldsen, Almut Nebel, Simon Mays, Helen D. Donoghue, Sonia Zakrzewski, Andrej Benjak, Kay Nieselt, Stewart T. Cole, Johannes Krause Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae , the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16 th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M . leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M . leprae genomes including the so far oldest M . leprae genome from one of the earliest known cases of leprosy in the United Kingdom—a skeleton from the Great Chesterford cemetery with a calibrated age of 415–545 C.E. This dataset provides a genetic time transect of M . leprae diversity in Europe over the past 1500 years. We find M . leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M . leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M . leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M . leprae strains improves understanding the history of leprosy worldwide.
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  • 74
    Publication Date: 2018-05-11
    Description: by Priya Uppuluri, Lin Lin, Abdullah Alqarihi, Guanpingsheng Luo, Eman G. Youssef, Sondus Alkhazraji, Nannette Y. Yount, Belal A. Ibrahim, Michael Anthony Bolaris, John E. Edwards Jr., Marc Swidergall, Scott G. Filler, Michael R. Yeaman, Ashraf S. Ibrahim Different pathogens share similar medical settings and rely on similar virulence strategies to cause infections. We have previously applied 3-D computational modeling and bioinformatics to discover novel antigens that target more than one human pathogen. Active and passive immunization with the recombinant N-terminus of Candida albicans Hyr1 (rHyr1p-N) protect mice against lethal candidemia. Here we determine that Hyr1p shares homology with cell surface proteins of the multidrug resistant Gram negative bacterium, Acinetobacter baumannii including hemagglutinin (FhaB) and outer membrane protein A (OmpA). The A . baumannii OmpA binds to C . albicans Hyr1p, leading to a mixed species biofilm. Deletion of HYR1 , or blocking of Hyr1p using polyclonal antibodies, significantly reduce A . baumannii binding to C . albicans hyphae. Furthermore, active vaccination with rHyr1p-N or passive immunization with polyclonal antibodies raised against specific peptide motifs of rHyr1p-N markedly improve survival of diabetic or neutropenic mice infected with A . baumannii bacteremia or pneumonia. Antibody raised against one particular peptide of the rHyr1p-N sequence (peptide 5) confers majority of the protection through blocking A . baumannii invasion of host cells and inducing death of the bacterium by a putative iron starvation mechanism. Anti-Hyr1 peptide 5 antibodies also mitigate A . baumannii /C . albicans mixed biofilm formation in vitro . Consistent with our bioinformatic analysis and structural modeling of Hyr1p, anti-Hyr1p peptide 5 antibodies bound to A . baumannii FhaB, OmpA, and an outer membrane siderophore binding protein. Our studies highlight the concept of cross-kingdom vaccine protection against high priority human pathogens such as A . baumannii and C . albicans that share similar ecological niches in immunocompromised patients.
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  • 75
    Publication Date: 2018-05-11
    Description: by Cara West, Neal Silverman The fruit fly Drosophila melanogaster is a powerful model system for the study of innate immunity in vector insects as well as mammals. For vector insects, it is particularly important to understand all aspects of their antiviral immune defenses, which could eventually be harnessed to control the transmission of human pathogenic viruses. The immune responses controlling RNA viruses in insects have been extensively studied, but the response to DNA virus infections is poorly characterized. Here, we report that infection of Drosophila with the DNA virus Invertebrate Iridescent Virus 6 (IIV-6) triggers JAK-STAT signaling and the robust expression of the Turandots , a gene family encoding small secreted proteins. To drive JAK-STAT signaling, IIV-6 infection more immediately induced expression of the unpaireds , a family of IL-6-related cytokine genes, via a pathway that required one of the three Drosophila p38 homologs, p38b. In fact, both Stat92E and p38b were required for the survival of IIV-6 infected flies. In addition, in vitro induction of the unpaireds required an NADPH-oxidase, and in vivo studies demonstrated Nox was required for induction of TotA . These results argue that ROS production, triggered by IIV-6 infection, leads to p38b activation and unpaired expression, and subsequent JAK-STAT signaling, which ultimately protects the fly from IIV-6 infection.
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  • 76
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    Publication Date: 2018-05-11
    Description: by Hans C. Leier, William B. Messer, Fikadu G. Tafesse
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  • 77
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    Publication Date: 2018-05-12
    Description: by Marie Ménard, Clélia Costechareyre, Gabriel Ichim, Jonathan Blachier, David Neves, Loraine Jarrosson-Wuilleme, Reinhard Depping, Jan Koster, Pierre Saintigny, Patrick Mehlen, Servane Tauszig-Delamasure The neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified the basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) as direct interactors of TrkC intracellular domain, and we show that Hey1 is required for TrkC-induced apoptosis. We propose here that the cleaved proapoptotic portion of TrkC intracellular domain (called TrkC killer-fragment [TrkC-KF]) is translocated to the nucleus by importins and interacts there with Hey1. We also demonstrate that Hey1 and TrkC-KF transcriptionally silence mouse double minute 2 homolog (MDM2), thus contributing to p53 stabilization. p53 transcriptionally regulates the expression of TrkC-KF cytoplasmic and mitochondrial interactors cofactor of breast cancer 1 (COBRA1) and B cell lymphoma 2–associated X (BAX), which will subsequently trigger the intrinsic pathway of apoptosis. Of interest, TrkC was proposed to constrain tumor progression in neuroblastoma (NB), and we demonstrate in an avian model that TrkC tumor suppressor activity requires Hey1 and p53.
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  • 78
    Publication Date: 2018-05-12
    Description: by Jingjing Liang, Thu H. Le, Digna R. Velez Edwards, Bamidele O. Tayo, Kyle J. Gaulton, Jennifer A. Smith, Yingchang Lu, Richard A. Jensen, Guanjie Chen, Lisa R. Yanek, Karen Schwander, Salman M. Tajuddin, Tamar Sofer, Wonji Kim, James Kayima, Colin A. McKenzie, Ervin Fox, Michael A. Nalls, J. Hunter Young, Yan V. Sun, Jacqueline M. Lane, Sylvia Cechova, Jie Zhou, Hua Tang, Myriam Fornage, Solomon K. Musani, Heming Wang, Juyoung Lee, Adebowale Adeyemo, Albert W. Dreisbach, Terrence Forrester, Pei-Lun Chu, Anne Cappola, Michele K. Evans, Alanna C. Morrison, Lisa W. Martin, Kerri L. Wiggins, Qin Hui, Wei Zhao, Rebecca D. Jackson, Erin B. Ware, Jessica D. Faul, Alex P. Reiner, Michael Bray, Joshua C. Denny, Thomas H. Mosley, Walter Palmas, Xiuqing Guo, George J. Papanicolaou, Alan D. Penman, Joseph F. Polak, Kenneth Rice, Ken D. Taylor, Eric Boerwinkle, Erwin P. Bottinger, Kiang Liu, Neil Risch, Steven C. Hunt, Charles Kooperberg, Alan B. Zonderman, Cathy C. Laurie, Diane M. Becker, Jianwen Cai, Ruth J. F. Loos, Bruce M. Psaty, David R. Weir, Sharon L. R. Kardia, Donna K. Arnett, Sungho Won, Todd L. Edwards, Susan Redline, Richard S. Cooper, D. C. Rao, Jerome I. Rotter, Charles Rotimi, Daniel Levy, Aravinda Chakravarti, Xiaofeng Zhu, Nora Franceschini
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 79
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-12
    Description: by Michael J. Chao, Kyung-Hee Kim, Jun Wan Shin, Diane Lucente, Vanessa C. Wheeler, Hong Li, Jared C. Roach, Leroy Hood, Nancy S. Wexler, Laura B. Jardim, Peter Holmans, Lesley Jones, Michael Orth, Seung Kwak, Marcy E. MacDonald, James F. Gusella, Jong-Min Lee Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2–21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1 , which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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