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  • Nature Publishing Group  (362,947)
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  • 1
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-28
    Description: by Andy Hopker, Naveen Pandey, Aniruddha Dhamorikar, Sophie Hopker, Pradeep Gautam, Subash Pandey, Sharad Kumar, Narendra Rahangadale, Prakash Mehta, Rebecca Marsland, Neil Sargison
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 2
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-28
    Description: by Lottie W. Stipdonk, Marie-Christine J. P. Franken, Jeroen Dudink
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 3
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    Public Library of Science (PLoS)
    Publication Date: 2018-06-29
    Description: by Apisit Chaidee, Sudarat Onsurathum, Kitti Intuyod, Patchareewan Pannangpetch, Chatlert Pongchaiyakul, Porntip Pinlaor, Chawalit Pairojkul, Wannaporn Ittiprasert, Christina J. Cochran, Victoria H. Mann, Paul J. Brindley, Somchai Pinlaor Complications arising from infection with the carcinogenic liver fluke Opisthorchis viverrini cause substantial morbidity and mortality in Thailand and adjacent lower Mekong countries. In parallel, the incidence rate of diabetes mellitus (DM) is increasing in this same region, and indeed worldwide. Many residents in opisthorchiasis-endemic regions also exhibit DM, but the hepatobiliary disease arising during the co-occurrence of these two conditions remains to be characterized. Here, the histopathological profile during co-occurrence of opisthorchiasis and DM was investigated in a rodent model of human opisthorchiasis in which diabetes was induced with streptozotocin. The effects of excretory/secretory products from the liver fluke, O . viverrini (OVES) on hepatocyte and cholangiocyte responses during hyperglycemic conditions also were monitored. Both the liver fluke-infected hamsters (OV group) and hamsters with DM lost weight compared to control hamsters. Weight loss was even more marked in the hamsters with both opisthorchiasis and DM (OD group). Hypertrophy of hepatocytes, altered biliary canaliculi, and biliary hyperplasia were more prominent in the OD group, compared with OV and DM groups. Profound oxidative DNA damage, evidenced by 8-oxo-2'-deoxyguanosine, proliferating cell nuclear antigen, and periductal fibrosis characterized the OD compared to OV and DM hamsters. Upregulation of expression of cytokines in response to infection and impairment of the pathway for insulin receptor substrate (IRS)/phosphatidylinositol-3-kinases (PI3K)/protein kinase B (AKT) signaling attended these changes. In vitro , OVES and glucose provoked time- and dose-dependent effects on the proliferation of both hepatocytes and cholangiocytes. In overview, the co-occurrence of opisthorchiasis and diabetes exacerbated pathophysiological damage to the hepatobiliary tract. We speculate that opisthorchiasis and diabetes together aggravate hepatobiliary pathogenesis through an IRS/PI3K/AKT-independent pathway.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 4
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    Public Library of Science (PLoS)
    Publication Date: 2018-06-29
    Description: by The PLOS ONE Editors
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 5
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    Public Library of Science (PLoS)
    Publication Date: 2018-06-29
    Description: by Sergio Salvatore, Viviana Fini, Terri Mannarini, Giuseppe Alessandro Veltri, Evrinomi Avdi, Fiorella Battaglia, Jorge Castro-Tejerina, Enrico Ciavolino, Marco Cremaschi, Irini Kadianaki, Nikita A. Kharlamov, Anna Krasteva, Katrin Kullasepp, Anastassios Matsopoulos, Claudia Meschiari, Piergiorgio Mossi, Polivios Psinas, Rozlyn Redd, Alessia Rochira, Alfonso Santarpia, Gordon Sammut, Jaan Valsiner, Antonella Valmorbida, on behalf of the Re.Cri.Re. Consortium
    Electronic ISSN: 1932-6203
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2018-06-29
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 7
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    Public Library of Science (PLoS)
    Publication Date: 2018-06-29
    Description: by Moises B. da Silva, Juliana M. Portela, Wei Li, Mary Jackson, Mercedes Gonzalez-Juarrero, Andrea Sánchez Hidalgo, John T. Belisle, Raquel C. Bouth, Angélica R. Gobbo, Josafá G. Barreto, Antonio H. H. Minervino, Stewart T. Cole, Charlotte Avanzi, Philippe Busso, Marco A. C. Frade, Annemieke Geluk, Claudio G. Salgado, John S. Spencer Mycobacterium leprae ( M . leprae ) is a human pathogen and the causative agent for leprosy, a chronic disease characterized by lesions of the skin and peripheral nerve damage. Zoonotic transmission of M . leprae to humans by nine-banded armadillos ( Dasypus novemcinctus ) has been shown to occur in the southern United States, mainly in Texas, Louisiana, and Florida. Nine-banded armadillos are also common in South America, and residents living in some areas in Brazil hunt and kill armadillos as a dietary source of protein. This study examines the extent of M . leprae infection in wild armadillos and whether these New World mammals may be a natural reservoir for leprosy transmission in Brazil, similar to the situation in the southern states of the U.S. The presence of the M . leprae -specific repetitive sequence RLEP was detected by PCR amplification in purified DNA extracted from armadillo spleen and liver tissue samples. A positive RLEP signal was confirmed in 62% of the armadillos (10/16), indicating high rates of infection with M . leprae . Immunohistochemistry of sections of infected armadillo spleens revealed mycobacterial DNA and cell wall constituents in situ detected by SYBR Gold and auramine/rhodamine staining techniques, respectively. The M . leprae -specific antigen, phenolic glycolipid I (PGL-I) was detected in spleen sections using a rabbit polyclonal antibody specific for PGL-I. Anti-PGL-I titers were assessed by ELISA in sera from 146 inhabitants of Belterra, a hyperendemic city located in western Pará state in Brazil. A positive anti-PGL-I titer is a known biomarker for M . leprae infection in both humans and armadillos. Individuals who consumed armadillo meat most frequently (more than once per month) showed a significantly higher anti-PGL-I titer than those who did not eat or ate less frequently than once per month. Armadillos infected with M . leprae represent a potential environmental reservoir. Consequently, people who hunt, kill, or process or eat armadillo meat are at a higher risk for infection with M . leprae from these animals.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 8
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    Public Library of Science (PLoS)
    Publication Date: 2018-06-29
    Description: by Zhilin Wang, Jianhui Zhang, Fengzhi Wu, Xingang Zhou Phytotoxic effects of phenolic compounds have been extensively studied, but less attention has been given to the effects of these compounds on soil microbial communities, which are crucial to the productivity of agricultural systems. Responses of cucumber rhizosphere bacterial and fungal communities to syringic acid (SA), a phenolic compound with autotoxicity to cucumber, were analyzed by high-throughput sequencing of 16S rRNA gene and internal transcribed spacer amplicons. SA at the concentration of 0.1 μmol g -1 soil changed rhizosphere bacterial and fungal community compositions, decreased bacterial community diversity but increased fungal community richness and diversity (P
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
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    Publication Date: 2018-06-29
    Description: by Aleksandra Kroemeke, Ewelina Kubicka Background Perceived social support relates to infertility-related distress in couples undergoing assisted reproductive technology (ART) treatment. Studies examining the effect of other support types on both positive and negative adjustment among infertile couples are scarce or non-existent. Therefore, this study investigated the effects of support receipt, provision, invisibility (the discrepancy between one partner’s received and the other partner’s provided support), and equity (the discrepancy between each partner’s received and provided support) on the positive (life purpose) and negative (depressive symptoms) indices of well-being in couples undergoing ART treatment. Methods Depressive symptoms (CES-D), life purpose (PIL), and social support (BSSS) were assessed among 31 married couples (mean age 32.67 years) undergoing ART treatment. Data were analyzed by applying the Actor-Partner-Interdependence Model (APIM) using multilevel modeling. Findings Both receiving and providing support had beneficial effects in women and men. However, sub-analysis showed differences according to gender and the support exchange effects. Women reported higher depression and lower life purpose but benefited more from support, and their well-being was more dependent on their own perception of support provision and receipt. Men demonstrated higher adjustment to infertility but benefited less from support, and their well-being was mostly correlated with supportive behaviors of their wives. Discussion Adjustment mechanisms of women and men undergoing ART treatment vary considerably; thus, gender should be taken into consideration in interventions. Future studies should focus on costs/benefits and gender differences of visible and invisible support in infertility settings.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
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    Publication Date: 2018-06-29
    Description: by Yukiko Sakai, Yoko Sato, Masae Sato, Makiko Watanabe Objectives Considering that there is a lack of evidence regarding the contribution of library and information services to evidence-based medicine in actual clinical practice in Japan, the purpose of the study is to explore the current status of use and value of library and information services in clinical settings to examine the usefulness of information in implementing evidence-based medicine (EBM) into practice. Methods A Web-based survey was conducted at seven sites (hospitals with 300–1,200 beds) and interviews conducted at five sites to investigate information behavior among health professionals (physicians, residents, and nurses) in 2016, replicating the Value Study carried out in the United States in 2010 and 2011. Using a critical incident technique, respondents answered questions about their information topics, information resources used, search location, access points, and evaluation of the information. Results Analysis from 598 valid responses (275 physicians, 55 residents, and 268 nurses) revealed the characteristics of information use and recognition of the value of information. Physicians and residents showed their information needs regarding clinical care using PubMed (80.4%, 65.5%), Ichushi-Web (61.8%, 63.6%), and UpToDate (40.4%, 65.5%). While physicians rely more on electronic journals (37.8%), residents use more hybrid resources including Japanese print books (38.2%) and online books (30.9% for Japanese, 32.7% for English) to confirm their knowledge. Nurses need more information close to patients and explore a wider variety of information resources such as Japanese print books (60.4%), Ichushi -Web (40.3%), Japanese online books (20.5%), and websites of academic organizations (19.0%). Although the overall recognition of the value of information was relatively modest, concrete changes in clinical practice were found in some areas. Environments with insufficient information and availability of electronic resources should be improved to increase the use of library and information services for implementing EBM.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Publication Date: 2018-08-28
    Description: by Bryce A. Mendelsohn, Neal K. Bennett, Maxwell A. Darch, Katharine Yu, Mai K. Nguyen, Daniela Pucciarelli, Maxine Nelson, Max A. Horlbeck, Luke A. Gilbert, William Hyun, Martin Kampmann, Jean L. Nakamura, Ken Nakamura Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for regulating ATP levels are not systematically understood. We combined a pooled clustered regularly interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen to assay ATP concentrations in live human cells. We identified genes not known to be involved in energy metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-based therapies.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
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  • 12
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    Publication Date: 2018-08-28
    Description: by Jacob A. Tennessen, Na Wei, Shannon Straub, Rajanikanth Govindarajulu, Aaron Liston, Tia-Lynn Ashman Turnovers of sex-determining systems represent important diversifying forces across eukaryotes. Shifts in sex chromosomes—but conservation of the master sex-determining genes—characterize distantly related animal lineages. Yet in plants, in which separate sexes have evolved repeatedly and sex chromosomes are typically homomorphic, we do not know whether such translocations drive sex-chromosome turnovers within closely related taxonomic groups. This phenomenon can only be demonstrated by identifying sex-associated nucleotide sequences, still largely unknown in plants. The wild North American octoploid strawberries ( Fragaria ) exhibit separate sexes (dioecy) with homomorphic, female heterogametic (ZW) inheritance, yet sex maps to three different chromosomes in different taxa. To characterize these turnovers, we identified sequences unique to females and assembled their reads into contigs. For most octoploid Fragaria taxa, a short (13 kb) sequence was observed in all females and never in males, implicating it as the sex-determining region (SDR). This female-specific “SDR cassette” contains both a gene with a known role in fruit and pollen production and a novel retrogene absent on Z and autosomal chromosomes. Phylogenetic comparison of SDR cassettes revealed three clades and a history of repeated translocation. Remarkably, the translocations can be ordered temporally due to the capture of adjacent sequence with each successive move. The accumulation of the “souvenir” sequence—and the resultant expansion of the hemizygous SDR over time—could have been adaptive by locking genes into linkage with sex. Terminal inverted repeats at the insertion borders suggest a means of movement. To our knowledge, this is the first plant SDR shown to be translocated, and it suggests a new mechanism (“move-lock-grow”) for expansion and diversification of incipient sex chromosomes.
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  • 13
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    Publication Date: 2018-08-28
    Description: by JohnCarlo Kristofich, Andrew B. Morgenthaler, Wallis R. Kinney, Christopher C. Ebmeier, Daniel J. Snyder, William M. Old, Vaughn S. Cooper, Shelley D. Copley Synonymous mutations do not alter the specified amino acid but may alter the structure or function of an mRNA in ways that impact fitness. There are few examples in the literature, however, in which the effects of synonymous mutations on microbial growth rates have been measured, and even fewer for which the underlying mechanism is understood. We evolved four populations of a strain of Salmonella enterica in which a promiscuous enzyme has been recruited to replace an essential enzyme. A previously identified point mutation increases the enzyme’s ability to catalyze the newly needed reaction (required for arginine biosynthesis) but decreases its ability to catalyze its native reaction (required for proline biosynthesis). The poor performance of this enzyme limits growth rate on glucose. After 260 generations, we identified two synonymous mutations in the first six codons of the gene encoding the weak-link enzyme that increase growth rate by 41 and 67%. We introduced all possible synonymous mutations into the first six codons and found substantial effects on growth rate; one doubles growth rate, and another completely abolishes growth. Computational analyses suggest that these mutations affect either the stability of a stem-loop structure that sequesters the start codon or the accessibility of the region between the Shine-Dalgarno sequence and the start codon. Thus, these mutations would be predicted to affect translational efficiency and thereby indirectly affect mRNA stability because translating ribosomes protect mRNA from degradation. Experimental data support these hypotheses. We conclude that the effects of the synonymous mutations are due to a combination of effects on mRNA stability and translation efficiency that alter levels of the weak-link enzyme. These findings suggest that synonymous mutations can have profound effects on fitness under strong selection and that their importance in evolution may be under-appreciated.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 14
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    Publication Date: 2018-08-28
    Description: by Athma A. Pai, Joseph M. Paggi, Paul Yan, Karen Adelman, Christopher B. Burge Recursive splicing, a process by which a single intron is removed from pre-mRNA transcripts in multiple distinct segments, has been observed in a small subset of Drosophila melanogaster introns. However, detection of recursive splicing requires observation of splicing intermediates that are inherently unstable, making it difficult to study. Here we developed new computational approaches to identify recursively spliced introns and applied them, in combination with existing methods, to nascent RNA sequencing data from Drosophila S2 cells. These approaches identified hundreds of novel sites of recursive splicing, expanding the catalog of recursively spliced fly introns by 4-fold. A subset of recursive sites were validated by RT-PCR and sequencing. Recursive sites occur in most very long (〉 40 kb) fly introns, including many genes involved in morphogenesis and development, and tend to occur near the midpoints of introns. Suggesting a possible function for recursive splicing, we observe that fly introns with recursive sites are spliced more accurately than comparably sized non-recursive introns.
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  • 15
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    Publication Date: 2018-08-28
    Description: by Abantika Ganguly, Lan Guo, Lingling Sun, Fang Suo, Li-Lin Du, Paul Russell Hexavalent chromium [Cr(VI)] damages DNA and causes cancer, but it is unclear which DNA damage responses (DDRs) most critically protect cells from chromate toxicity. Here, genome-wide quantitative functional profiling, DDR measurements and genetic interaction assays in Schizosaccharomyces pombe reveal a chromate toxicogenomic profile that closely resembles the cancer chemotherapeutic drug camptothecin (CPT), which traps Topoisomerase 1 (Top1)-DNA covalent complex (Top1cc) at the 3’ end of single-stand breaks (SSBs), resulting in replication fork collapse. ATR/Rad3-dependent checkpoints that detect stalled and collapsed replication forks are crucial in Cr(VI)-treated cells, as is Mus81-dependent sister chromatid recombination (SCR) that repairs single-ended double-strand breaks (seDSBs) at broken replication forks. Surprisingly, chromate resistance does not require base excision repair (BER) or interstrand crosslink (ICL) repair, nor does co-elimination of XPA-dependent nucleotide excision repair (NER) and Rad18-mediated post-replication repair (PRR) confer chromate sensitivity in fission yeast. However, co-elimination of Tdp1 tyrosyl-DNA phosphodiesterase and Rad16-Swi10 (XPF-ERCC1) NER endonuclease synergistically enhances chromate toxicity in top1Δ cells. Pnk1 polynucleotide kinase phosphatase (PNKP), which restores 3’-hydroxyl ends to SSBs processed by Tdp1, is also critical for chromate resistance. Loss of Tdp1 ameliorates pnk1Δ chromate sensitivity while enhancing the requirement for Mus81. Thus, Tdp1 and PNKP, which prevent neurodegeneration in humans, repair an important class of Cr-induced SSBs that collapse replication forks.
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  • 16
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    Publication Date: 2018-08-29
    Description: by Theodore Clark Sex has consequences—indeed, where would we be without it? Yet for all its importance, remarkably little is known about how sex evolved, why it has persisted, or even what mechanisms allow sperm–egg fusion to occur. Fortunately, answers to these questions are beginning to emerge with studies of hapless 2/generative cell specific1 (HAP2/GCS1), a molecular machine that promotes gamete fusion in organisms ranging from protists to flowering plants and insects. In studies by Fedry and colleagues, key structural features of the HAP2 protein are revealed for the first time, lending new insights into its mode of action and reinforcing its relationship to viral proteins that accomplish a similar task and may be intimately linked to the origins of cell–cell fusion events (including sexual reproduction) across evolutionary time.
    Print ISSN: 1544-9173
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  • 17
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    Publication Date: 2018-08-29
    Description: by Daniel Nunes, Thomas Kuner Dendrodendritic synaptic interactions between olfactory bulb mitral and granule cells represent a key neuronal mechanism of odor discrimination. Dendritic release of gamma-aminobutyric acid (GABA) from granule cells contributes to stimulus-dependent, rapid, and accurate odor discrimination, yet the physiological mechanisms governing this release and its behavioral relevance are unknown. Here, we show that granule cells express the voltage-gated sodium channel α-subunit Na V 1.2 in clusters distributed throughout the cell surface including dendritic spines. Deletion of Na V 1.2 in granule cells abolished spiking and GABA release as well as inhibition of synaptically connected mitral cells (MCs). As a consequence, mice required more time to discriminate highly similar odorant mixtures, while odor discrimination learning remained unaffected. In conclusion, we show that expression of Na V 1.2 in granule cells is crucial for physiological dendritic GABA release and rapid discrimination of similar odorants with high accuracy. Hence, our data indicate that neurotransmitter-releasing dendritic spines function just like axon terminals.
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  • 18
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    Publication Date: 2018-08-29
    Description: by Waqas N. Chaudhry, Maroš Pleška, Nilang N. Shah, Howard Weiss, Ingrid C. McCall, Justin R. Meyer, Animesh Gupta, Călin C. Guet, Bruce R. Levin In experimental cultures, when bacteria are mixed with lytic (virulent) bacteriophage, bacterial cells resistant to the phage commonly emerge and become the dominant population of bacteria. Following the ascent of resistant mutants, the densities of bacteria in these simple communities become limited by resources rather than the phage. Despite the evolution of resistant hosts, upon which the phage cannot replicate, the lytic phage population is most commonly maintained in an apparently stable state with the resistant bacteria. Several mechanisms have been put forward to account for this result. Here we report the results of population dynamic/evolution experiments with a virulent mutant of phage Lambda, λ VIR , and Escherichia coli in serial transfer cultures. We show that, following the ascent of λ VIR -resistant bacteria, λ VIR is maintained in the majority of cases in maltose-limited minimal media and in all cases in nutrient-rich broth. Using mathematical models and experiments, we show that the dominant mechanism responsible for maintenance of λ VIR in these resource-limited populations dominated by resistant E . coli is a high rate of either phenotypic or genetic transition from resistance to susceptibility—a hitherto undemonstrated mechanism we term "leaky resistance." We discuss the implications of leaky resistance to our understanding of the conditions for the maintenance of phage in populations of bacteria—their “existence conditions.”
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  • 19
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    Publication Date: 2018-08-29
    Description: by Marija Matejčić, Guillaume Salbreux, Caren Norden Tissue shape is often established early in development and needs to be scaled isotropically during growth. However, the cellular contributors and ways by which cells interact tissue-wide to enable coordinated isotropic tissue scaling are not yet understood. Here, we follow cell and tissue shape changes in the zebrafish retinal neuroepithelium, which forms a cup with a smooth surface early in development and maintains this architecture as it grows. By combining 3D analysis and theory, we show how a global increase in cell height can maintain tissue shape during growth. Timely cell height increase occurs concurrently with a non-cell-autonomous actin redistribution. Blocking actin redistribution and cell height increase perturbs isotropic scaling and leads to disturbed, folded tissue shape. Taken together, our data show how global changes in cell shape enable isotropic growth of the developing retinal neuroepithelium, a concept that could also apply to other systems.
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  • 20
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    Publication Date: 2018-08-29
    Description: by Alice Antia, Hasan Ahmed, Andreas Handel, Nichole E. Carlson, Ian J. Amanna, Rustom Antia, Mark Slifka Determining the duration of protective immunity requires quantifying the magnitude and rate of loss of antibodies to different virus and vaccine antigens. A key complication is heterogeneity in both the magnitude and decay rate of responses of different individuals to a given vaccine, as well as of a given individual to different vaccines. We analyzed longitudinal data on antibody titers in 45 individuals to characterize the extent of this heterogeneity and used models to determine how it affected the longevity of protective immunity to measles, rubella, vaccinia, tetanus, and diphtheria. Our analysis showed that the magnitude of responses in different individuals varied between 12- and 200-fold (95% coverage) depending on the antigen. Heterogeneity in the magnitude and decay rate contribute comparably to variation in the longevity of protective immunity between different individuals. We found that some individuals have, on average, slightly longer-lasting memory than others—on average, they have higher antibody levels with slower decay rates. We identified different patterns for the loss of protective levels of antibodies to different vaccine and virus antigens. Specifically, we found that for the first 25 to 50 years, virtually all individuals have protective antibody titers against diphtheria and tetanus, respectively, but about 10% of the population subsequently lose protective immunity per decade. In contrast, at the outset, not all individuals had protective titers against measles, rubella, and vaccinia. However, these antibody titers wane much more slowly, with a loss of protective immunity in only 1% to 3% of the population per decade. Our results highlight the importance of long-term longitudinal studies for estimating the duration of protective immunity and suggest both how vaccines might be improved and how boosting schedules might be reevaluated.
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  • 21
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    Publication Date: 2018-08-29
    Description: by Chenxi Xu, Xing Liu, Huangyuan Zha, Sijia Fan, Dawei Zhang, Shan Li, Wuhan Xiao The essential role of pathogens in host metabolism is widely recognized, yet the mechanisms by which they affect host physiology remain to be fully defined. Here, we found that NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to possess N-acetylglucosamine (GlcNAc) transferase activity, GlcNAcylates HIF-1α, a master regulator of cellular O 2 homeostasis. We determined that NleB-mediated GlcNAcylation at a conserved arginine 18 (Arg18) at the N-terminus of HIF-1α enhanced HIF-1α transcriptional activity, thereby inducing HIF-1α downstream gene expression to alter host glucose metabolism. The arginine transferase activity of NleB was required for its enhancement of HIF-1α transactivity and the subsequent effect on glucose metabolism in a mouse model of EPEC infection. In addition, HIF-1α acted as a mediator to transact NleB-mediated induction of glucose metabolism-associated gene expression under hypoxia. Thus, our results further show a causal link between pathogen infection and host glucose metabolism, and we propose a new mechanism by which this occurs.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 22
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    Publication Date: 2018-08-29
    Description: by Yuka Otsuka, Kimberly Schmitt, Brian D. Quinlan, Matthew R. Gardner, Barnett Alfant, Adrian Reich, Michael Farzan, Hyeryun Choe Many broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus type 1 (HIV-1) were shown effective in animal models, and are currently evaluated in clinical trials. However, use of these antibodies in humans is hampered by the rapid emergence of resistant viruses. Here we show that soft-randomization can be used to accelerate the parallel identification of viral escape pathways. As a proof of principle, we soft-randomized the epitope regions of VRC01-class bNAbs in replication-competent HIV-1 and selected for resistant variants. After only a few passages, a surprisingly diverse population of antibody-resistant viruses emerged, bearing both novel and previously described escape mutations. We observed that the escape variants resistant to some VRC01-class bNAbs are resistant to most other bNAbs in the same class, and that a subset of variants was completely resistant to every well characterized VRC01-class bNAB, including VRC01, NIH45-46, 3BNC117, VRC07, N6, VRC-CH31, and VRC-PG04. Thus, our data demonstrate that soft randomization is a suitable approach for accelerated detection of viral escape, and highlight the challenges inherent in administering or attempting to elicit VRC01-class antibodies.
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  • 23
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-29
    Description: by Emily C. Woods, Adrianne N. Edwards, Kevin O. Childress, Joshua B. Jones, Shonna M. McBride To cause disease, Clostridioides ( Clostridium ) difficile must resist killing by innate immune effectors in the intestine, including the host antimicrobial peptide, cathelicidin (LL-37). The mechanisms that enable C . difficile to adapt to the intestine in the presence of antimicrobial peptides are unknown. Expression analyses revealed an operon, CD630_16170-CD630_16190 ( clnRAB ), which is highly induced by LL-37 and is not expressed in response to other cell-surface active antimicrobials. This operon encodes a predicted transcriptional regulator (ClnR) and an ABC transporter system (ClnAB), all of which are required for function. Analyses of a clnR mutant indicate that ClnR is a pleiotropic regulator that directly binds to LL-37 and controls expression of numerous genes, including many involved in metabolism, cellular transport, signaling, gene regulation, and pathogenesis. The data suggest that ClnRAB is a novel regulatory mechanism that senses LL-37 as a host signal and regulates gene expression to adapt to the host intestinal environment during infection.
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  • 24
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    Publication Date: 2018-08-29
    Description: by Thi Thu Phuong Tran, Karsten Eichholz, Patrizia Amelio, Crystal Moyer, Glen R. Nemerow, Matthieu Perreau, Franck J. D. Mennechet, Eric J. Kremer Following repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (T regs ). As peripherally induced T regs are generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific T regs . Our study reveals a mechanism by which an antiviral humoral responses could, counterintuitively, favor virus persistence.
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  • 25
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    Publication Date: 2018-08-29
    Description: by Guoxin Ni, Zhe Ma, Blossom Damania
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  • 26
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    Publication Date: 2018-08-29
    Description: by Dustin J. Little, Brian K. Coombes Enteropathogenic Escherichia coli (EPEC) use a needle-like injection apparatus known as the type III secretion system (T3SS) to deliver protein effectors into host cells. Effector translocation is highly stratified in EPEC with the translocated intimin receptor (Tir) being the first effector delivered into the host. CesT is a multi-cargo chaperone that is required for the secretion of Tir and at least 9 other effectors. However, the structural and mechanistic basis for differential effector recognition by CesT remains unclear. Here, we delineated the minimal CesT-binding region on Tir to residues 35–77 and determined the 2.74 Å structure of CesT bound to an N-terminal fragment of Tir. Our structure revealed that the CesT-binding region in the N-terminus of Tir contains an additional conserved sequence, distinct from the known chaperone-binding β-motif, that we termed the CesT-extension motif because it extends the β-sheet core of CesT. This motif is also present in the C-terminus of Tir that we confirmed to be a unique second CesT-binding region. Point mutations that disrupt CesT-binding to the N- or C-terminus of Tir revealed that the newly identified carboxy-terminal CesT-binding region was required for efficient Tir translocation into HeLa cells and pedestal formation. Furthermore, the CesT-extension motif was identified in the N-terminal region of NleH1, NleH2, and EspZ, and mutations that disrupt this motif reduced translocation of these effectors, and in some cases, overall effector stability, thus validating the universality of this CesT-extension motif. The presence of two CesT-binding regions in Tir, along with the presence of the CesT-extension motif in other highly translocated effectors, may contribute to differential cargo recognition by CesT.
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  • 27
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    Publication Date: 2018-08-29
    Description: by Shelbi L. Russell, Nassim Lemseffer, William T. Sullivan Widespread success of the intracellular bacterium Wolbachia across insects and nematodes is due to efficient vertical transmission and reproductive manipulations. Many strains, including wMel from Drosophila melanogaster , exhibit a specific concentration to the germplasm at the posterior pole of the mature oocyte, thereby ensuring high fidelity of parent-offspring transmission. Transport of Wolbachia to the pole relies on microtubules and the plus-end directed motor kinesin heavy chain (KHC). However, the mechanisms mediating Wolbachia’s association with KHC remain unknown. Here we show that reduced levels of the host canonical linker protein KLC results in dramatically increased levels of Wolbachia at the oocyte’s posterior, suggesting that KLC and some key associated host cargos outcompete Wolbachia for association with a limited amount of KHC motor proteins. Consistent with this interpretation, over-expression of KHC causes similarly increased levels of posteriorly localized Wolbachia . However, excess KHC has no effect on levels of Vasa, a germplasm component that also requires KHC for posterior localization. Thus, Wolbachia transport is uniquely KHC-limited because these bacteria are likely outcompeted for binding to KHC by some host cargo/linker complexes. These results reveal a novel host-symbiont interaction that underscores the precise regulation required for an intracellular bacterium to co-opt, but not disrupt, vital host processes.
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  • 28
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    Publication Date: 2018-08-29
    Description: by Thorsten Brink, Veronika Leiss, Peter Siegert, Doris Jehle, Julia K. Ebner, Carsten Schwan, Aliaksei Shymanets, Sebastian Wiese, Bernd Nürnberg, Michael Hensel, Klaus Aktories, Joachim H. C. Orth Salmonella enterica serotype Typhimurium ( S . Typhimurium) is one of the most frequent causes of food-borne illness in humans and usually associated with acute self-limiting gastroenteritis. However, in immunocompromised patients, the pathogen can disseminate and lead to severe systemic diseases. S . Typhimurium are facultative intracellular bacteria. For uptake and intracellular life, Salmonella translocate numerous effector proteins into host cells using two type-III secretion systems (T3SS), which are encoded within Salmonella pathogenicity islands 1 (SPI-1) and 2 (SPI-2). While SPI-1 effectors mainly promote initial invasion, SPI-2 effectors control intracellular survival and proliferation. Here, we elucidate the mode of action of Salmonella SPI-2 effector SseI, which is involved in control of systemic dissemination of S . Typhimurium. SseI deamidates a specific glutamine residue of heterotrimeric G proteins of the Gα i family, resulting in persistent activation of the G protein. G i activation inhibits cAMP production and stimulates PI3-kinase γ by Gα i -released Gβγ subunits, resulting in activation of survival pathways by phosphorylation of Akt and mTOR. Moreover, SseI-induced deamidation leads to non-polarized activation of Gα i and, thereby, to loss of directed migration of dendritic cells.
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  • 29
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    Publication Date: 2018-08-29
    Description: by Athma A. Pai, Joseph M. Paggi, Paul Yan, Karen Adelman, Christopher B. Burge Recursive splicing, a process by which a single intron is removed from pre-mRNA transcripts in multiple distinct segments, has been observed in a small subset of Drosophila melanogaster introns. However, detection of recursive splicing requires observation of splicing intermediates that are inherently unstable, making it difficult to study. Here we developed new computational approaches to identify recursively spliced introns and applied them, in combination with existing methods, to nascent RNA sequencing data from Drosophila S2 cells. These approaches identified hundreds of novel sites of recursive splicing, expanding the catalog of recursively spliced fly introns by 4-fold. A subset of recursive sites were validated by RT-PCR and sequencing. Recursive sites occur in most very long (〉 40 kb) fly introns, including many genes involved in morphogenesis and development, and tend to occur near the midpoints of introns. Suggesting a possible function for recursive splicing, we observe that fly introns with recursive sites are spliced more accurately than comparably sized non-recursive introns.
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  • 30
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    Publication Date: 2018-08-29
    Description: by Xiao-Ou Zhang, Yu Fu, Haiwei Mou, Wen Xue, Zhiping Weng Recursive splicing (RS) is an evolutionarily conserved process of removing long introns via multiple steps of splicing. It was first discovered in Drosophila and recently proven to occur also in humans. The detailed mechanism of recursive splicing is not well understood, in particular, whether it is kinetically coupled with transcription. To investigate the dynamic process that underlies recursive splicing, we systematically characterized 342 RS sites in three human cell types using published time-series data that monitored synchronized Pol II elongation and nascent RNA production with 4-thiouridine labeling. We found that half of the RS events occurred post-transcriptionally with long delays. For at least 18–47% RS introns, we detected RS junction reads only after detecting canonical splicing junction reads, supporting the notion that these introns were removed by both recursive splicing and canonical splicing. Furthermore, the choice of which splicing mechanism was used showed cell type specificity. Our results suggest that recursive splicing supplements, rather than replaces, canonical splicing for removing long introns.
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  • 31
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    Publication Date: 2018-08-29
    Description: by Xiaohuan Liang, Takiko Daikoku, Jumpei Terakawa, Yuya Ogawa, Ayesha R. Joshi, Lora H. Ellenson, Xiaofei Sun, Sudhansu K. Dey Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using Pgr-Cre driver ( Pten f/f Pgr Cre/+ ) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Pten f/f Pgr Cre/+ uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver ( Pten f/f /Ltf Cre/+ ) develops uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Pten f/f Pgr Cre/+ uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Pten f/f Ltf Cre/+ hyperplastic epithelia do not undergo stratification, but massive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten , highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma.
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  • 32
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    Publication Date: 2018-08-29
    Description: by Oneil G. Bhalala, Artika P. Nath, UK Brain Expression Consortium , Michael Inouye, Christopher R. Sibley Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Here we evaluated whether schizophrenia and affective disorder associated-SNPs are correlated with gene expression within human brain tissue. Specifically, to identify expression quantitative trait loci (eQTLs), we leveraged disorder-associated SNPs identified from 11 genome-wide association studies with gene expression levels in post-mortem, neurologically-normal tissue from two independent human brain tissue expression datasets (UK Brain Expression Consortium (UKBEC) and Genotype-Tissue Expression (GTEx)). Utilizing stringent multi-region meta-analyses, we identified 2,224 cis -eQTLs associated with expression of 40 genes, including 11 non-coding RNAs. One cis -eQTL, rs16969968, results in a functionally disruptive missense mutation in CHRNA5 , a schizophrenia-implicated gene. Importantly, comparing across tissues, we find that blood eQTLs capture 〈 10% of brain cis -eQTLs. Contrastingly, 〉 30% of brain-associated eQTLs are significant in tibial nerve. This study identifies putatively causal genes whose expression in region-specific tissue may contribute to the risk of schizophrenia and affective disorders.
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  • 33
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    Publication Date: 2018-08-29
    Description: by Christian E. Rocheleau
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  • 34
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    Publication Date: 2018-08-29
    Description: by Sonia Verma, Urmila Jagtap, Anita Goyala, Arnab Mukhopadhyay Diet profoundly affects metabolism and incidences of age-related diseases. Animals adapt their physiology to different food-types, modulating complex life-history traits like aging. The molecular mechanisms linking adaptive capacity to diet with aging are less known. We identify FLR-4 kinase as a novel modulator of aging in C . elegans , depending on bacterial diet. FLR-4 functions to prevent differential activation of the p38MAPK pathway in response to diverse food-types, thereby maintaining normal life span. In a kinase-dead flr-4 mutant, E . coli HT115 (K12 strain), but not the standard diet OP50 (B strain), is able to activate p38MAPK, elevate expression of cytoprotective genes through the nuclear hormone receptor NHR-8 and enhance life span. Interestingly, flr-4 and dietary restriction utilize similar pathways for longevity assurance, suggesting cross-talks between cellular modules that respond to diet quality and quantity. Together, our study discovers a new C . elegans gene-diet pair that controls the plasticity of aging.
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  • 35
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    Publication Date: 2018-08-29
    Description: by Huai-Ju Chen, Tsu-Yu Fu, Shao-Li Yang, Hsu-Liang Hsieh
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  • 36
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    Publication Date: 2018-08-29
    Description: by Xue Wang, Baijun Dong, Kai Zhang, Zhongzhong Ji, Chaping Cheng, Huifang Zhao, Yaru Sheng, Xiaoxia Li, Liancheng Fan, Wei Xue, Wei-Qiang Gao, Helen He Zhu Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.
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  • 37
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    Publication Date: 2018-08-29
    Description: by Madeline C. Weiss, Martina Preiner, Joana C. Xavier, Verena Zimorski, William F. Martin All known life forms trace back to a last universal common ancestor (LUCA) that witnessed the onset of Darwinian evolution. One can ask questions about LUCA in various ways, the most common way being to look for traits that are common to all cells, like ribosomes or the genetic code. With the availability of genomes, we can, however, also ask what genes are ancient by virtue of their phylogeny rather than by virtue of being universal. That approach, undertaken recently, leads to a different view of LUCA than we have had in the past, one that fits well with the harsh geochemical setting of early Earth and resembles the biology of prokaryotes that today inhabit the Earth's crust.
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  • 38
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    Publication Date: 2018-08-29
    Description: by Miguel A. Muñoz-Lorente, Paula Martínez, Águeda Tejera, Kurt Whittemore, Ana Carolina Moisés-Silva, Fàtima Bosch, Maria A. Blasco Short and dysfunctional telomeres are sufficient to induce a persistent DNA damage response at chromosome ends, which leads to the induction of senescence and/or apoptosis and to various age-related conditions, including a group of diseases known as “telomere syndromes”, which are provoked by extremely short telomeres owing to germline mutations in telomere genes. This opens the possibility of using telomerase activation as a potential therapeutic strategy to rescue short telomeres both in telomere syndromes and in age-related diseases, in this manner maintaining tissue homeostasis and ameliorating these diseases. In the past, we generated adeno-associated viral vectors carrying the telomerase gene (AAV9- Tert ) and shown their therapeutic efficacy in mouse models of cardiac infarct, aplastic anemia, and pulmonary fibrosis. Although we did not observe increased cancer incidence as a consequence of Tert overexpression in any of those models, here we set to test the safety of AAV9-mediated Tert overexpression in the context of a cancer prone mouse model, owing to expression of oncogenic K-ras. As control, we also treated mice with AAV9 vectors carrying a catalytically inactive form of Tert, known to inhibit endogenous telomerase activity. We found that overexpression of Tert does not accelerate the onset or progression of lung carcinomas, even when in the setting of a p53-null background. These findings indicate that telomerase activation by using AAV9-mediated Tert gene therapy has no detectable cancer-prone effects in the context of oncogene-induced mouse tumors.
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  • 39
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    Publication Date: 2018-08-29
    Description: by Scott Barish, Sarah Nuss, Ilya Strunilin, Suyang Bao, Sayan Mukherjee, Corbin D. Jones, Pelin C. Volkan In Drosophila , 50 classes of olfactory receptor neurons (ORNs) connect to 50 class-specific and uniquely positioned glomeruli in the antennal lobe. Despite the identification of cell surface receptors regulating axon guidance, how ORN axons sort to form 50 stereotypical glomeruli remains unclear. Here we show that the heterophilic cell adhesion proteins, DIPs and Dprs, are expressed in ORNs during glomerular formation. Many ORN classes express a unique combination of DIPs / dprs , with neurons of the same class expressing interacting partners, suggesting a role in class-specific self-adhesion between ORN axons. Analysis of DIP/Dpr expression revealed that ORNs that target neighboring glomeruli have different combinations, and ORNs with very similar DIP/Dpr combinations can project to distant glomeruli in the antennal lobe. DIP/Dpr profiles are dynamic during development and correlate with sensilla type lineage for some ORN classes. Perturbations of DIP / dpr gene function result in local projection defects of ORN axons and glomerular positioning, without altering correct matching of ORNs with their target neurons. Our results suggest that context-dependent differential adhesion through DIP/Dpr combinations regulate self-adhesion and sort ORN axons into uniquely positioned glomeruli.
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  • 40
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    Publication Date: 2018-08-29
    Description: by Lars Åke Persson Despite its clear biological benefits, many infants globally do not receive exclusive breastfeeding. In a Guest Editorial, Lars Åke Persson discusses what is needed to make breastfeeding the social norm.
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  • 41
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    Publication Date: 2018-08-29
    Description: by Martin White, Jean Adams In a Perspective, Martin White and Jean Adams discuss challenges in the evaluation of interventions intended to benefit population health.
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  • 42
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    Publication Date: 2018-08-29
    Description: by Ga Eun Nam, Seon Mee Kim, Kyungdo Han, Nan Hee Kim, Hye Soo Chung, Jin Wook Kim, Byoungduck Han, Sung Jung Cho, Ji Hee Yu, Yong Gyu Park, Kyung Mook Choi Background The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population. Methods and findings Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS ( n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS ( n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21–1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10–1.16 for abdominal obesity; 1.13, 1.10–1.15 for hypertriglyceridemia; 1.23, 1.20–1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03–1.08 for high blood pressure; 1.21, 1.18–1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p 〈 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components ( p 〈 0.001). A significant interaction between age and MetS on the risk of incident PD was observed ( p for interaction 〈 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those
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  • 43
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    Publication Date: 2018-08-29
    Description: by QiPing Feng, Wei-Qi Wei, Cecilia P. Chung, Rebecca T. Levinson, Alexandra C. Sundermann, Jonathan D. Mosley, Lisa Bastarache, Jane F. Ferguson, Nancy J. Cox, Dan M. Roden, Joshua C. Denny, MacRae F. Linton, Digna R. Velez Edwards, C. Michael Stein Background Observations from statin clinical trials and from Mendelian randomization studies suggest that low low-density lipoprotein cholesterol (LDL-C) concentrations may be associated with increased risk of type 2 diabetes mellitus (T2DM). Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations in increased risk of T2DM. Methods and findings We used de-identified electronic health records (EHRs) at Vanderbilt University Medical Center to compare the risk of T2DM in a cross-sectional study among individuals with very low (≤60 mg/dl, N = 8,943) and normal (90–130 mg/dl, N = 71,343) LDL-C levels calculated using the Friedewald formula. LDL-C levels associated with statin use, hospitalization, or a serum albumin level 〈 3 g/dl were excluded. We used a 2-phase approach: in 1/3 of the sample (discovery) we used T2DM phenome-wide association study codes (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) we identified T2DM cases and controls using a validated algorithm. The analysis plan for the validation phase was constructed at the time of the design of that component of the study. The prevalence of T2DM in the very low and normal LDL-C groups was compared using logistic regression with adjustment for age, race, sex, body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and duration of care. Secondary analyses included prespecified stratification by sex, race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM were significantly more frequent in the very low LDL-C group. In the validation cohort ( N = 33,039 after applying the T2DM algorithm to identify cases and controls), the risk of T2DM was increased in the very low compared to normal LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80–2.37; P 〈 2 × 10 −16 ). The findings remained significant in sensitivity analyses. The association between low LDL-C levels and T2DM was significant in males (OR 2.43, 95% CI 2.00–2.95; P 〈 2 × 10 −16 ) and females (OR 1.74, 95% CI 1.42–2.12; P = 6.88 × 10 −8 ); in normal weight (OR 2.18, 95% CI 1.59–2.98; P = 1.1× 10 −6 ), overweight (OR 2.17, 95% CI 1.65–2.83; P = 1.73× 10 −8 ), and obese (OR 2.00, 95% CI 1.65–2.41; P = 8 × 10 −13 ) categories; and in individuals with LDL-C 〈 40 mg/dl (OR 2.31, 95% CI 1.71–3.10; P = 3.01× 10 −8 ) and LDL-C 40–60 mg/dl (OR 1.99, 95% CI 1.71–2.32; P 〈 2.0× 10 −16 ). The association was significant in individuals of European ancestry (OR 2.67, 95% CI 2.25–3.17; P 〈 2 × 10 −16 ) but not in those of African ancestry (OR 1.09, 95% CI 0.81–1.46; P = 0.56). A limitation was that we only compared groups with very low and normal LDL-C levels; also, since this was not an inception cohort, we cannot exclude the possibility of reverse causation. Conclusions Very low LDL-C concentrations occurring in the absence of statin treatment were significantly associated with T2DM risk in a large EHR population; this increased risk was present in both sexes and all BMI categories, and in individuals of European ancestry but not of African ancestry. Longitudinal cohort studies to assess the relationship between very low LDL-C levels not associated with lipid-lowering therapy and risk of developing T2DM will be important.
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    Publication Date: 2018-08-29
    Description: by Joshua A. Bell, David Carslake, Kaitlin H. Wade, Rebecca C. Richmond, Ryan J. Langdon, Emma E. Vincent, Michael V. Holmes, Nicholas J. Timpson, George Davey Smith Background Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity. Methods and findings One-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry–based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with −1.38 kg/m 2 of BMI at age 18 y (or −0.34 SD units, 95% CI −0.46, −0.23; P = 9.77 × 10 −09 ). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to −0.12 kg/m 2 (or −0.03 SDs, 95% CI −0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with −0.77 kg/m 2 of pre-pubertal BMI measured at age 8 y (or −0.39 SDs, 95% CI −0.50, −0.29; P = 6.28 × 10 −13 ), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m 2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by −0.26 y, 95% CI −0.37, −0.16; P = 1.16 × 10 −06 ), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with −0.81 kg/m 2 of adult BMI (or −0.17 SD units, 95% CI −0.21, −0.12; P = 4.00 × 10 −15 ). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10 −15 ). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors. Conclusions Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.
    Print ISSN: 1549-1277
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  • 45
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    Publication Date: 2018-08-29
    Description: by Avery I. McIntosh, Helen E. Jenkins, Laura F. White, Marinus Barnard, Dana R. Thomson, Tania Dolby, John Simpson, Elizabeth M. Streicher, Mary B. Kleinman, Elizabeth J. Ragan, Paul D. van Helden, Megan B. Murray, Robin M. Warren, Karen R. Jacobson Background South Africa has the highest tuberculosis incidence globally (781/100,000), with an estimated 4.3% of cases being rifampicin resistant (RR). Control and elimination strategies will require detailed spatial information to understand where drug-resistant tuberculosis exists and why it persists in those communities. We demonstrate a method to enable drug-resistant tuberculosis monitoring by identifying high-burden communities in the Western Cape Province using routinely collected laboratory data. Methods and findings We retrospectively identified cases of microbiologically confirmed tuberculosis and RR-tuberculosis from all biological samples submitted for tuberculosis testing ( n = 2,219,891) to the Western Cape National Health Laboratory Services (NHLS) between January 1, 2008, and June 30, 2013. Because the NHLS database lacks unique patient identifiers, we performed a series of record-linking processes to match specimen records to individual patients. We counted an individual as having a single disease episode if their positive samples came from within two years of each other. Cases were aggregated by clinic location ( n = 302) to estimate the percentage of tuberculosis cases with rifampicin resistance per clinic. We used inverse distance weighting (IDW) to produce heatmaps of the RR-tuberculosis percentage across the province. Regression was used to estimate annual changes in the RR-tuberculosis percentage by clinic, and estimated average size and direction of change was mapped. We identified 799,779 individuals who had specimens submitted from mappable clinics for testing, of whom 222,735 (27.8%) had microbiologically confirmed tuberculosis. The study population was 43% female, the median age was 36 years (IQR 27–44), and 10,255 (4.6%, 95% CI: 4.6–4.7) cases had documented rifampicin resistance. Among individuals with microbiologically confirmed tuberculosis, 8,947 (4.0%) had more than one disease episode during the study period. The percentage of tuberculosis cases with rifampicin resistance documented among these individuals was 11.4% (95% CI: 10.7–12.0). Overall, the percentage of tuberculosis cases that were RR-tuberculosis was spatially heterogeneous, ranging from 0% to 25% across the province. Our maps reveal significant yearly fluctuations in RR-tuberculosis percentages at several locations. Additionally, the directions of change over time in RR-tuberculosis percentage were not uniform. The main limitation of this study is the lack of unique patient identifiers in the NHLS database, rendering findings to be estimates reliant on the accuracy of the person-matching algorithm. Conclusions Our maps reveal striking spatial and temporal heterogeneity in RR-tuberculosis percentages across this province. We demonstrate the potential to monitor RR-tuberculosis spatially and temporally with routinely collected laboratory data, enabling improved resource targeting and more rapid locally appropriate interventions.
    Print ISSN: 1549-1277
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  • 46
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    Publication Date: 2018-08-29
    Description: by Ruixia Dai, Baiqing Wei, Haoming Xiong, Xiaoyan Yang, Yao Peng, Jian He, Juan Jin, Yumeng Wang, Xi Zha, Zhikai Zhang, Ying Liang, Qingwen Zhang, Jianguo Xu, Zuyun Wang, Wei Li The Qinghai-Tibet plateau is a natural plague focus and is the largest such focus in China. In this area, while Marmota himalayana is the primary host, a total of 18 human plague outbreaks associated with Tibetan sheep (78 cases with 47 deaths) have been reported on the Qinghai-Tibet plateau since 1956. All of the index infectious cases had an exposure history of slaughtering or skinning diseased or dead Tibetan sheep. In this study, we sequenced and compared 38 strains of Yersinia pestis isolated from different hosts, including humans, Tibetan sheep, and M . himalayana . Phylogenetic relationships were reconstructed based on genome-wide single-nucleotide polymorphisms identified from our isolates and reference strains. The phylogenetic relationships illustrated in our study, together with the finding that the Tibetan sheep plague clearly lagged behind the M . himalayana plague, and a previous study that identified the Tibetan sheep as a plague reservoir with high susceptibility and moderate sensitivity, indicated that the human plague was transmitted from Tibetan sheep, while the Tibetan sheep plague originated from marmots. Tibetan sheep may encounter this infection by contact with dead rodents or through being bitten by fleas originating from M . himalayana during local epizootics.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
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  • 47
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    Publication Date: 2018-08-29
    Description: by Sören L. Becker, Harvy Joy Liwanag, Jedidiah S. Snyder, Oladele Akogun, Vicente Belizario. Jr, Matthew C. Freeman, Theresa W. Gyorkos, Rubina Imtiaz, Jennifer Keiser, Alejandro Krolewiecki, Bruno Levecke, Charles Mwandawiro, Rachel L. Pullan, David G. Addiss, Jürg Utzinger
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
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  • 48
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    Publication Date: 2018-08-29
    Description: by Laura D. Tamayo, Felipe Guhl, Gustavo A. Vallejo, Juan David Ramírez The increase in the global land temperature, expected under predictions of climate change, can directly affect the transmission of some infectious diseases, including Chagas disease, an anthropozoonosis caused by Trypanosoma cruzi and transmitted by arthropod vectors of the subfamily Triatominae. This work seeks to study the effects of temperature on the development of the life cycle, fertility and fecundity of the insect vector Rhodnius prolixus and on the metacyclogenesis of T . cruzi . All of the variables were subjected to 3 temperatures: 26°C, 28°C and 30°C. Hatching time was evaluated, along with time to fifth instar, time to adult, fecundity studied using the e-value, and egg viability during the first 3 reproductive cycles. In addition, the amounts of metacyclic trypomastigotes of the TcI and TcII DTUs in R . prolixus were evaluated from days 2 to 20 at two-day intervals and from weeks 6 to 8 post-infection. Decreases were observed in time to hatching (15–10 days on average) and in time to fifth instar (70–60 days on average) and transition to adult (100–85 days on average). No significant differences in egg viability were observed in any of the reproductive cycles evaluated, but an increase in fecundity was observed at 30°C during the third reproductive cycle. At 30°C, there was also an increase in the number of infective forms and a decrease in the time at which metacyclic trypomastigotes were detected in the rectal ampulla of the insects for both TcI and TcII. According to these results, the expected temperature increase under climate change would cause an increase in the number of insects and a greater probability of infection of the parasite, which affects the transmission of Chagas disease.
    Print ISSN: 1935-2727
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  • 49
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    Publication Date: 2018-08-29
    Description: by Soyoung Park, Jihee Kang, Sanghaeng Choi, Haryung Park, Eunchong Hwang, Yoongu Kang, Aram Kim, Wilhelm Holzapfel, Yosep Ji Thanks to recent scientific progress a relationship between the intestinal microbiota and metabolic diseases could be established. A deeper understanding of underlying mechanisms has opened ways towards new approaches for alleviating conditions associated with metabolic diseases. Dysbiosis appears to be a major underlying factor associated with metabolic syndrome and related adverse health conditions. A major focus has therefore shifted to controlling of the gut microbiota through administration of functional lactic acid bacteria (LAB). The scope for health promotion and/or support by probiotics such as LAB has thereby been widened beyond the improving of intestinal health, also to include anti-obesity, anti-diabetic and cholesterol-lowering effects. In this study we investigated the cholesterol-lowering and microbiota modulatory potential of a LAB strain, Lactobacillus rhamnosus BFE5264, isolated from Maasai fermented milk. A mouse model receiving a high-cholesterol diet served as model for evaluating its functionality. The administration of L . rhamnosus BFE5264 resulted in a significant reduction of the serum cholesterol level that was accompanied by changes in intestinal microbiota and the production of short chain fatty acid (SCFA) in comparison to the control group. This strain also beneficially influenced the regulation of cholesterol metabolism in the liver in a pattern similar to that resulting from statin treatment, a drug inhibiting cholesterol biosynthesis in the liver.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 50
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    Publication Date: 2018-08-29
    Description: by Chao-Yan Yue, Lou-kai-yi Lu, Meng Li, Qian-Lan Zhang, Chun-Mei Ying Objective We intended to establish the threshold for anti-Mullerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) in China. Methods A total of 771 women (653 with PCOS and 118 healthy controls) were enrolled. The serum AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), FSH/LH, prolactin, estradiol, testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), 17α-OH progesterone (17α-OHP), fasting insulin (INS), fasting glucose, free androgen index (FAI%) and homeostasis model assessment for insulin resistance (HOMA-IR) index were analyzed, and the diagnostic utility of AMH, LH/FSH, T and INS was established using receiver operator characteristic (ROC) curves. With AMH, LH/FSH, T and INS as independent variables, a logistic regression model was established, and the ROC curve for combined detection was fitted with the probability value of the model. Results The serum level of FSH, LH, LH/FSH, AMH, FAI%, 17α-OHP, fasting INS, T, SHBG, DHEA-S and HOMA-IR were altered in the PCOS patients. The best compromise between sensitivity and specificity was found at an AMH cut-off level of 8.16 ng/ml and 5.89 ng/ml for the age groups 20–29 and 30–39 years, with the corresponding area under the curve being 0.846 and 0.865 respectively. The area under the ROC curve for combined detection was 0.951, which was significantly greater than that of each index. Finally, the concentration of AMH was associated with FSH, LH, LH/FSH, T, and ovarian volume in PCOS patients. Conclusion The optimal AMH diagnostic threshold for PCOS was 8.16 ng/ml (20–29 years) and 5.89 ng/ml (30–39 years) in the Chinese population of this study. Moreover, serum AMH, LH/FSH, T and INS could be used in combination to improve the diagnostic specificity and sensitivity for the detection of PCOS.
    Electronic ISSN: 1932-6203
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  • 51
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    Publication Date: 2018-08-29
    Description: by Félix Cuneo, Jean-Philippe Antonietti, Christine Mohr Cognitive style is thought to be a stable marker of one’s way to approach mental operations. While of wide interest over the last decades, its operationalization remains a challenge. The literature indicates that cognitive styles assessed via i) questionnaires are predicted by personality and ii) performance tests (e.g., Group Embedded Figures Test; GEFT) are related to general intelligence. In the first study, we tested the psychometric relationship between the Cognitive Style Index questionnaire (CSI) and personality inventories (NEO Five Factor Inventory; NEO-FFI, HEXACO Personality Inventory Revised; HEXACO-PI-R). In the second study, we assessed the CSI, NEO-FFI, GEFT and a general intelligence test (Raven’s Standard Progressive Matrices Test; RSMT). We found that CSI scores were largely predicted by personality and that CSI was uncorrelated with GEFT performance. Instead, better performance on the GEFT was associated with better performance on the RSMT. We conclude that i) cognitive style questionnaires overlap with personality inventories, ii) cognitive style performance tests do not measure cognitive styles and should not be used as such and iii) the cognitive style concept needs to be assessed with alternative measurement types. We discuss possible future directions.
    Electronic ISSN: 1932-6203
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  • 52
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    Publication Date: 2018-08-29
    Description: by Yuan-Pin Hsu, Chin-Wang Hsu, Chyi-Huey Bai, Sheng-Wei Cheng, Kuan-Chou Chen, Chiehfeng Chen Silodosin, a recently introduced selective α-blocker, has a much higher selectivity for the α-1A receptor. The efficacy and safety of silodosin compared to tamsulosin in medical expulsive therapy (MET) are controversial. The objective of this study was to assess the efficacy and safety of silodosin compared to tamsulosin for treating ureteral stones
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  • 53
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    Publication Date: 2018-08-29
    Description: by Yukihiro Yano, Hiroyuki Kurebe, Ryuya Edahiro, Yuki Hosono, Saeko Nakatsubo, Kohei Nishida, Nobuyuki Sawa, Mikako Ishijima, Takeshi Uenami, Masaki Kanazu, Yuki Akazawa, Toshihiko Yamaguchi, Masahide Mori Objectives The effectiveness of treatment after cessation of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) has not been well investigated. The aim of the present study was to clarify the clinical benefit of post-nivolumab treatment in such patients. Materials and methods A retrospective review was conducted on patients who received treatment after cessation of nivolumab due to disease progression or adverse events at the Toneyama National Hospital between January 2016 and April 2017. Results Among 64 patients treated with nivolumab, 26 patients received treatment after cessation of nivolumab due to disease progression (n = 21) or adverse events (n = 5). The median age of the patients was 68 years and 19 patients were male. Nineteen patients had performance status (PS) 1 or less at initiation of post-nivolumab treatment. Four, 20, and 2 patients were treated with platinum doublets, a single agent, and molecular targeting agents, respectively. Response rate, disease control rate, and median progression-free survival of first-line post-nivolumab treatment were 34.6% (9 patients), 73.1% (19 patients), and 2.8 months (95% confidence interval [CI]: 1.7–5.2), respectively. Adverse events (≥ grade 3) and treatment cessation were observed in 57.7% (15 patients) and 19.2% (5 patients), respectively. There were no statistically significant differences for the majority of patient characteristics between the groups with (n = 26) and without post-nivolumab treatment. However, PS at cessation of nivolumab and post-progression survival (PPS) after cessation of nivolumab (median PPS: 12.6 vs. 1.4 months, 95% CI: 3.8–14.7 vs. 0.4–2.2) were significantly different between the groups. A multivariate Cox regression analysis showed significant correlation of PS at cessation of nivolumab (hazard ratio [HR]: 0.34, 95% CI: 0.13–0.87) and post-nivolumab treatment (HR: 0.19, 95% CI: 0.08–0.43) with prolonged PPS after nivolumab. Conclusion Median post-progression survival in patients with advanced NSCLC who received post-nivolumab treatment was approximately 1 year.
    Electronic ISSN: 1932-6203
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  • 54
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    Publication Date: 2018-08-29
    Description: by Hongzhao Li, Yan Hai, So-Yon Lim, Nikki Toledo, Jose Crecente-Campo, Dane Schalk, Lin Li, Robert W. Omange, Tamara G. Dacoba, Lewis R. Liu, Mohammad Abul Kashem, Yanmin Wan, Binhua Liang, Qingsheng Li, Eva Rakasz, Nancy Schultz-Darken, Maria J. Alonso, Francis A. Plummer, James B. Whitney, Ma Luo HIV mutates rapidly and infects CD4 + T cells, especially when they are activated. A vaccine targeting conserved, essential viral elements while limiting CD4 + T cell activation could be effective. Learning from natural immunity observed in a group of highly HIV-1 exposed seronegative Kenyan female sex workers, we are testing a novel candidate HIV vaccine targeting the 12 viral protease cleavage sites (PCSs) (the PCS vaccine), in comparison with a vaccine targeting full-length Gag and Env (the Gag/Env vaccine) in a Mauritian cynomolgus macaque/SIV model. In this study we evaluated these vaccines for induction of mucosal antibodies to SIV immunogens at the female genital tract. Bio-Plex and Western blot analyses of cervicovaginal lavage samples showed that both the PCS and Gag/Env vaccines can elicit mucosal IgG antibody responses to SIV immunogens. Significantly higher increase of anti-PCS antibodies was induced by the PCS vaccine than by the Gag/Env vaccine (p
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  • 55
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    Publication Date: 2018-08-29
    Description: by Sonam Kumari, Mohit Kumar, Nitesh Kumar Khandelwal, Priya Kumari, Mahendra Varma, Poonam Vishwakarma, Garima Shahi, Suman Sharma, Andrew M. Lynn, Rajendra Prasad, Naseem A. Gaur ATP-binding cassette (ABC) is one of the two major superfamilies of transporters present across the evolutionary scale. ABC superfamily members came to prominence due to their ability to extrude broad spectrum of substrates and to confer multi drug resistance (MDR). Overexpression of some ABC transporters in clinical isolates of Candida species was attributed to the development of MDR phenotypes. Among Candida species, Candida glabrata is an emerging drug resistant species in human fungal infections. A comprehensive analysis of such proteins in C . glabrata is required to untangle their role not only in MDR but also in other biological processes. Bioinformatic analysis of proteins encoded by genome of human pathogenic yeast C . glabrata identified 25 putative ABC protein coding genes. On the basis of phylogenetic analysis, domain organization and nomenclature adopted by the Human Genome Organization (HUGO) scheme, these proteins were categorized into six subfamilies such as Pleiotropic Drug Resistance (PDR)/ABCG, Multi Drug Resistance (MDR)/ABCB, Multi Drug Resistance associated Protein (MRP)/ABCC, Adrenoleukodystrophy protein (ALDp)/ABCD, RNase L Inhibitor (RLI)/ABCE and Elongation Factor 3 (EF3)/ABCF. Among these, only 18 ABC proteins contained transmembrane domains (TMDs) and were grouped as membrane proteins, predominantly belonging to PDR, MDR, MRP, and ALDp subfamilies. A comparative phylogenetic analysis of these ABC proteins with other yeast species revealed their orthologous relationship and pointed towards their conserved functions. Quantitative real time PCR (qRT-PCR) analysis of putative membrane localized ABC protein encoding genes of C . glabrata confirmed their basal expression and showed variable transcriptional response towards antimycotic drugs. This study presents first comprehensive overview of ABC superfamily proteins of a human fungal pathogen C . glabrata , which is expected to provide an important platform for in depth analysis of their physiological relevance in cellular processes and drug resistance.
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  • 56
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    Publication Date: 2018-08-30
    Description: by Karl G. Thieme, Jennifer Gerke, Christoph Sasse, Oliver Valerius, Sabine Thieme, Razieh Karimi, Antje K. Heinrich, Florian Finkernagel, Kristina Smith, Helge B. Bode, Michael Freitag, Arthur F. J. Ram, Gerhard H. Braus
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 57
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    Publication Date: 2018-08-30
    Description: by Ilya Patrushev, Christina James-Zorn, Aldo Ciau-Uitz, Roger Patient, Michael J. Gilchrist The precise anatomical location of gene expression is an essential component of the study of gene function. For most model organisms this task is usually undertaken via visual inspection of gene expression images by interested researchers. Computational analysis of gene expression has been developed in several model organisms, notably in Drosophila which exhibits a uniform shape and outline in the early stages of development. Here we address the challenge of computational analysis of gene expression in Xenopus , where the range of developmental stages of interest encompasses a wide range of embryo size and shape. Embryos may have different orientation across images, and, in addition, embryos have a pigmented epidermis that can mask or confuse underlying gene expression. Here we report the development of a set of computational tools capable of processing large image sets with variable characteristics. These tools efficiently separate the Xenopus embryo from the background, separately identify both histochemically stained and naturally pigmented regions within the embryo, and can sort images from the same gene and developmental stage according to similarity of gene expression patterns without information about relative orientation. We tested these methods on a large, but highly redundant, collection of 33,289 in situ hybridization images, allowing us to select representative images of expression patterns at different embryo orientations. This has allowed us to put a much smaller subset of these images into the public domain in an effective manner. The ‘isimage’ module and the scripts developed are implemented in Python and freely available on https://pypi.python.org/pypi/isimage/.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 58
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    Publication Date: 2018-08-30
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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  • 59
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    Publication Date: 2018-08-30
    Description: by The PLOS ONE Editors
    Electronic ISSN: 1932-6203
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  • 60
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    Publication Date: 2018-08-30
    Description: by Jan Spindler, Souska Zandi, Isabel B. Pfister, Christin Gerhardt, Justus G. Garweg Purpose To identify disease-specific cytokine profile differences in the aqueous humor (AH) (other than the vascular endothelial growth factor) between patients with dry and treated wet age-related macular degeneration (AMD) and healthy controls. Methods This retrospective study drew on a case-series of patients diagnosed with dry AMD ( n = 25) and treated wet AMD ( n = 19), as well as on healthy controls (no systemic therapy; n = 20) undergoing phacoemulsification or vitrectomy. Samples of AH and serum were collected in parallel at the beginning of surgery. The levels of 43 cytokines were simultaneously determined using the Bio-Plex® multiplex beads system. Differences between the three groups were statistically compared using the Kruskal-Wallis H-Test after applying the Bonferroni correction for multiple comparisons ( p
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  • 61
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    Publication Date: 2018-08-30
    Description: by Xinyuan Li, Li Cui, Yunbo Li, Lijun Zhu, Chenglin Wang, Jing Liu, Shaokuan Fang Background Previous results regarding the prevalence of Factor V Leiden (FVL) in patients with cerebral venous thrombosis (CVT) varied remarkably. Therefore, we performed a meta-analysis to evaluate the potential association between FVL and CVT. Methods The PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for relevant case-control studies. The data were pooled for analysis of the association between FVL and CVT with a random-effects model. Subgroup and sensitivity analyses were performed to evaluate the robustness of the results. Publication bias was assessed by funnel plot and the Egger’s test. Results A total of 39 case-control studies including 1807 cases of CVT and 7699 control cases were included. FVL was more common in patients with CVT (195/1822) than in controls(369/7795), [odds ratio(OR) = 2.70, 95% confidence interval(CI) 2.16–3.38, P 〈 0.00001]. Results of subgroup analyses indicated that the association between FVL and CVT varied according to geographic regions. The associations between FVL and CVT were significant in studies from Germany (OR = 2.42, 95%CI 1.70–3.45, P 〈 0.00001), Brazil(OR = 2.82, 95%CI 1.24–6.42, P = 0.01), France (OR = 5.44, 95%CI 1.35–21.92, P = 0.02), Iran (OR = 6.61, 95%CI 1.83–23.93, P = 0.004), and Tunisia (OR = 6.54, 95%CI 2.89–14.82, P 〈 0.00001), but not in those from Italy (OR = 1.49, 95%CI 0.59–3.78, P = 0.40) or the US (OR = 2.37, 95%CI 0.59–9.42, P = 0.22). Conclusion FVL may be more common in patients with CVT. However, the association between FVL and CVT varied depending on the geographic origin of the studies.
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  • 62
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    Publication Date: 2018-08-30
    Description: by Mikio Shoji, Keiko Sato, Hideharu Yukitake, Yoshio Kondo, Yuka Narita, Tomoko Kadowaki, Mariko Naito, Koji Nakayama
    Electronic ISSN: 1932-6203
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  • 63
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    Publication Date: 2018-08-30
    Description: by Clémentine Brun, Martin Gagné, Candida S. McCabe, Catherine Mercier Sensorimotor conflict induces both sensory and motor disturbances, but the specific factors playing a role in conflict-induced disturbances are still misunderstood. For example, we still do not know the role played by motor intention (vs. a purely visuo-proprioceptive conflict) or the influence of specific types of incongruent visual feedback. The objective of this study was threefold: 1- to compare the effect of passive and active movement during sensorimotor conflict on sensory disturbances measured with a questionnaire; 2- to compare the effect of three incongruent visual feedback conditions on sensory and motor (mediolateral drift and movement amplitude) disturbances; 3- to test whether conflict-induced sensory and motor disturbances were stable over time. 20 healthy participants realized active or passive cyclic upper limb movements while viewing either congruent or incongruent visual feedback about their movement using a robotized exoskeleton combined with 2D virtual reality interface. First, results showed that in condition of conflict, participants reported higher sensory disturbances during active movements compared to passive movements (p = 0.034), suggesting that the efference copy reinforces the conflict between vision and proprioception. Second, the three conditions of incongruence in the active condition induced similar sensory (all p〉0.45) and motor disturbances (medio-lateral drift: all p〉0.59 and amplitude: all p〉0.25), suggesting that conflict induced motor disturbances could be related more to the observation of another movement rather than to a detection of conflict between motor intention and sensory feedback. Finally, both sensory and motor disturbances were stable over time (all ICCs between 0.76 and 0.87), demonstrating low variability within participants. Overall, our results suggest that the efference copy is more involved in sensory disturbances than in motor disturbances, suggesting that they might rely on independent processes.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-08-30
    Description: by Artyom M. Marchenkov, Darya P. Petrova, Alexey A. Morozov, Yulia R. Zakharova, Michael A. Grachev, Alexander A. Bondar Silicon transporters (SIT) are the proteins, which capture silicic acid in the aquatic environment and direct it across the plasmalemma to the cytoplasm of diatoms. Diatoms utilize silicic acid to build species-specific ornamented exoskeletons and make a significant contribution to the global silica cycle, estimated at 240 ±40 Tmol a year. Recently SaSIT genes of the freshwater araphid pennate diatom Synedra acus subsp. radians are found to be present in the genome as a cluster of two structural genes ( SaSIT-TD and SaSIT-TRI ) encoding several concatenated copies of a SIT protein each. These structural genes could potentially be transformed into “mature” SIT proteins by means of posttranslational proteolytic cleavage. In the present study, we discovered three similar structural SuSIT genes in the genome of a closely related freshwater diatom Synedra ulna subsp. danica . Structural gene SuSIT1 is identical to structural gene SuSIT2 , and the two are connected by a non-coding nucleotide DNA sequence. All the putative “mature” SITs contain conserved amino acid motifs, which are believed to be important in silicon transport. The data obtained suggest that the predicted “mature” SIT proteins may be the minimal units necessary for the transport of silicon is S . ulna subsp. danica . The comparative analysis of all available multi-SITs has allowed us to detect two conservative motifs YQXDXVYL and DXDID, located between the “mature” proteins. Aspartic acid-rich DXDID motif can, in our opinion, serve as a proteolysis site during the multi-SIT cleavage. The narrow distribution of the distances between CMLD and DXDID motifs can serve as additional evidence to the conservation of their function.
    Electronic ISSN: 1932-6203
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  • 65
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    Publication Date: 2018-08-30
    Description: by Mingui Kong, Jaemoon Yoon, Don-Il Ham Reticular pseudodrusen (RPD) could be present not only in the posterior pole but extramacular area also as a confluent morphological pattern. Thus RPD can be classified by the fundus distribution for the assessment of visual prognosis. The electrophysiological function in eyes with reticular pseudodrusen (RPD), showing various fundus distribution were evaluated using full-field electroretinogram (ERG). Retinal distribution of RPD was divided into three types (localized, intermediate, and diffuse) according to the extent of involvement of retinal areas by fundus photograph montages. RPD were present with the diffuse type in 21 eyes (25.6%), with the intermediate type in 30 eyes (36.6%), and with the localized type in 31 eyes (37.8%). The average age was 74.76 ± 4.52 (range, 65–81) years in the diffuse type, 72.47 ± 9.13 (range, 55–91) years in the intermediate type, and 70.26 ± 7.77 (range, 61–89) years in the localized type. The mean amplitudes of the scotopic rod response, scotopic maximal combined response, oscillatory potentials (OP), photopic cone response, and 30Hz cone flicker response were more decreased in the diffuse, intermediate, and localized types in order, except for the photopic cone a-wave response. The diffuse type showed reduced amplitudes of ERG responses than the normal control group under all testing conditions except for the photopic a-wave response, and differences were statistically significant with the age restriction and adjustment methods (Bonferroni-corrected P 〈 0.05). The mean implicit times of ERG responses were significantly delayed in the diffuse type in the photopic b-wave. (Bonferroni-corrected P 〈 0.05). Extensive retinal involvement of RPD correlates with severely reduced electrophysiological retinal function. This acquired form of decreased electrophysiological function should be regarded as different from those of hereditary retinal degeneration.
    Electronic ISSN: 1932-6203
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  • 66
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    Publication Date: 2018-08-30
    Description: by Daniel E. Felsing, Noelle C. Anastasio, Joanna M. Miszkiel, Scott R. Gilbertson, John A. Allen, Kathryn A. Cunningham The serotonin (5-HT) 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C receptor (5-HT 2C R) in the central nervous system are implicated in a range of normal behaviors (e.g., appetite, sleep) and physiological functions (e.g., endocrine secretion) while dysfunctional 5-HT 2A R and/or 5-HT 2C R are implicated in neuropsychiatric disorders (e.g., addiction, obesity, schizophrenia). Preclinical studies suggest that the 5-HT 2A R and 5-HT 2C R may act in concert to regulate the neural bases for behavior. Here, we utilize three distinct biophysical and immunocytochemistry-based approaches to identify and study this receptor complex in cultured cells. Employing a split luciferase complementation assay (LCA), we demonstrated that formation of the 5-HT 2A R:5-HT 2C R complex exists within 50 nm, increases proportionally to the 5-HT 2C R:5-HT 2A R protein expression ratio, and is specific to the receptor interaction and not due to random complementation of the luciferase fragments. Using a proximity ligation assay (PLA), we found that cells stably expressing both the 5-HT 2A R and 5-HT 2C R exhibit 5-HT 2A R:5-HT 2C R heteroreceptor complexes within 40 nm of each other. Lastly, bioluminescence resonance energy transfer (BRET) analyses indicates the formation of a specific and saturable 5-HT 2A R:5-HT 2C R interaction, suggesting that the 5-HT 2A R and 5-HT 2C R form a close interaction within 10 nm of each other in intact live cells. The bioengineered receptors generated for the LCA and the BRET exhibit 5-HT-mediated intracellular calcium signaling as seen for the native receptors. Taken together, this study validates a very close 5-HT 2A R:5-HT 2C R interaction in cultured cells.
    Electronic ISSN: 1932-6203
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  • 67
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    Publication Date: 2018-08-30
    Description: by Yoko Moriyama, Nanako Tamiya, Akira Kawamura, Thomas D. Mayers, Haruko Noguchi, Hideto Takahashi Objective Home independence is an important issue for the elderly in many countries and cultures. The aim of this study was to examine the effect of short-stay service use on stay-at-home duration for elderly people by level of care need under the Japanese long-term care insurance system. Methods We analyzed anonymous, Ministry of Health, Labour and Welfare of Japan Long-Term Care Insurance claims data from Ibaraki Prefecture. All participants were certified as eligible for long-term care insurance and had moved into a facility under long-term care insurance after certification between April 2006 and March 2012. Data was analyzed for 2,454 participants aged 65 years or older who entered residential care at least 1 month after initial use of care services. The participants were divided into 2 groups (low- and high-care need), depending on their required level of care. Cox proportional hazard modeling was used to calculate the adjusted hazard ratio (HR) of residential care admission after initial use of care services. Results Use of short-stay services was positively correlated to delay of residential care admission compared to non-use in the low-care need group (HR; 0.834, 95% confidence interval (CI); 0.740–0.939). In the high-care need group, however, use of short-stay services was somewhat correlated with earlier admission (HR; 1.254, 95% CI; 1.084–1.451). Conclusions The results of this study show that appropriate timing short-stay service use is necessary for the elderly to stay at home longer.
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  • 68
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    Publication Date: 2018-08-30
    Description: by Yifeng Liu, Emma Pencheon, Rachael Maree Hunter, Joanna Moncrieff, Nick Freemantle Background Recruitment and retention challenges are very common in mental health randomised trials. Investigators utilise different methods to improve recruitment or retention. However, evidence of the effectiveness and efficiency of these strategies in mental health has not been synthesised. This systematic review is to investigate and assess the effectiveness and cost-effectiveness of different strategies to improve recruitment and retention in mental health randomised trials. Methods and materials MEDLINE, EMBASE, the Cochrane Methodology Register and PsycINFO were searched from beginning of record up to July 2016. Randomised trials involving participants with mental health problems which compared different strategies for recruitment or retention were selected. Two authors independently screened identified studies for eligibility. Results A total of 5,157 citations were identified. Thirteen articles were included, 11 on recruitment and 2 on retention. Three randomised controlled trials compared different recruitment strategies, none of which found statistically significant differences between the interventional recruitment strategies and the routine recruitment methods. Retrospective comparisons of recruitment methods showed that non-web-based advertisement and recruitment by clinical research staff each have advantages in efficiency. Web-based adverts had the lowest cost per person recruited (£13.41 per person recruited). Specialised care referral cost £183.24 per person, non-web-based adverts cost £372.03 per patient and recruitment via primary care cost £407.65 for each patient. Financial incentives, abridged questionnaires and pre-notification had a positive effect on retention rates. Conclusion The recruitment studies included showed differences in strategies, clinical settings, mental health conditions and study design. It is difficult to assess the overall effectiveness of any particular recruitment strategy as some strategies that worked well for a particular population may not work as well for others. Paying attention to the accessibility of information and consent materials may help improve recruitment. More research in this area is needed given its important implications.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-08-30
    Description: by Sergio Jarque, Eva Fetter, Wouter J. Veneman, Herman P. Spaink, Ravindra Peravali, Uwe Strähle, Stefan Scholz The knowledge on environmentally relevant chemicals that may interfere with thyroid signaling is scarce. Here, we present a method for the screening of goitrogens, compounds that disrupt the thyroid gland function, based on the automatic orientation of zebrafish in a glass capillary and a subsequent imaging of reporter gene fluorescence in the thyroid gland of embryos of the transgenic zebrafish line tg(tg:mCherry). The tg(tg:mCherry) reporter gene indicates a compensatory upregulation of thyroglobulin, the thyroid hormone precursor, in response to inhibition of thyroid hormone synthesis. Fish embryos were exposed to a negative control compound (3,4-dichloroaniline), or a concentration series of known goitrogenic compounds (resorcinol, methimazole, potassium perchlorate, 6-propyl-2-thiouracil, ethylenethiourea, phloroglucinol, pyrazole) with maximum exposure concentration selected based on mortality and/or solubility. Exposure to 3,4-dichloroaniline decreased the fluorescence signal. All goitrogenic compounds exhibited clear concentration-dependent inductions of reporter fluorescence 1.4 to 2.6 fold above control levels. Concentration-response modelling was used to calculate goitrogenic potencies based on EC 50 values. The new automated method offers an efficient screening approach for goitrogenic activity.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-08-30
    Description: by Shweta Singh, Zeeshan Fatima, Kamal Ahmad, Saif Hameed Among the several mechanisms of multidrug resistance (MDR), overexpression of drug efflux pumps CaCdr1p and CaMdr1p belonging to ATP binding cassette (ABC) and major facilitator superfamily (MFS) respectively remain the predominant mechanisms of candidal infections. Therefore inhibiting or modulating the function of these transporters continues to draw attention as effective strategy to combat MDR. We have previously reported the antifungal potential of Geraniol (Ger), a natural monoterpenoid from Palmarosa oil, against Candida albicans . Herein, we explored the fungicidal nature of Ger. The Rhodamine 6G (R6G) and Nile red accumulation confirms the specific effect on CaCdr1p. Mechanistic insights with Candida cells overexpressing CaCdr1p and CaMdr1p revealed that Ger specifically modulates CaCdr1p activity. Kinetic studies further unraveled the competitive inhibition of Ger for R6G efflux as evident from increased apparent Km without affecting V max value. The effect of Ger on CaCdr1p was substantiated by molecular docking analyses, which depicted in-silico binding affinity of Ger with CaCdr1p and explored that Ger binds to the active site of CaCdr1p with higher binding energy. Although RT-PCR and western blot revealed no change in expressions of CDR1 and CaCdr1p, confocal microscopy images however depicted CaCdr1p mislocalization in presence of Ger. Interestingly, Ger was synergistic (FICI
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  • 71
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    Publication Date: 2018-08-30
    Description: by Gregory E. Bigford, Andrew J. Darr, Valerie C. Bracchi-Ricard, Han Gao, Mark S. Nash, John R. Bethea Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.
    Electronic ISSN: 1932-6203
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  • 72
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    Publication Date: 2018-08-30
    Description: by Emma M. Rath, Yuen Yee Cheng, Mark Pinese, Kadir H. Sarun, Amanda L. Hudson, Christopher Weir, Yiwei D. Wang, Anders P. Håkansson, Viive M. Howell, Guo Jun Liu, Glen Reid, Robert B. Knott, Anthony P. Duff, W. Bret Church Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.
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  • 73
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    Publication Date: 2018-08-30
    Description: by Bertrand D. Lequeux, Miguel-Angel Ahumada-Sempoal, Andrés López-Pérez, Cristóbal Reyes-Hernández There are many marine protected areas (MPAs) containing coral reef aggregations in the eastern Pacific region. However, the connectivity of corals between MPAs is still poorly known, especially in the Marine Conservation Corridor of the Eastern Tropical Pacific (MCCETP). Here, we assess the potential connectivity of corals across equatorial eastern Pacific MPAs through a Lagrangian particle-tracking algorithm coupled offline with an ocean-circulation numerical model. Connectivity metrics and graph theory were used to analyze the networks and highlight those MPAs that are critical for maintaining the connectivity of corals across the region. Our results show that the equatorial eastern Pacific MPAs form a relatively well-connected network, at least 40% of coral larvae released per year end up within the boundaries of an MPA. MPAs like Malpelo and Gorgona islands included in the MCCETP were found to be critical for connectivity of corals because of their high betweenness centrality and potential role as stepping-stones between coastal MPAs and offshore MPAs such as the Galapagos Islands. Two pelagic larval duration (PLD) scenarios (40 and 130 days) indicate a quasi-unidirectional larval flow from coastal MPAs toward oceanic MPAs, where the only resilient MPAs (Coiba and Malpelo islands) depend mostly on subsidiary recruitment from MPAs located along the coast of Costa Rica, Panama and Colombia. In the two PLD scenarios, Cocos Island maintains a very low resilience potential. Our results indicate the imperative need to include coastal MPAs in the MCCETP network initiative, since connectivity and resilience of coral reefs in the equatorial eastern Pacific region rely heavily on coastal MPAs.
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  • 74
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    Publication Date: 2018-08-30
    Description: by Nirbhay Kumar Kushwaha, Mansi, Supriya Chakraborty
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 75
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    Publication Date: 2018-08-30
    Description: by Vittorio Favero, Shigeru Sakuma, Karol Alí Apaza Alccayhuaman, Guillermo Alejandro Benedetto, Franco Bengazi, Daniele Botticelli The aim of the experiment was to study the healing at implants installed in site prepared in bone type 1 using different rotation speeds and cooling strategies. The tibiae of twelve sheep were used as experimental sites. Two implant sites were prepared in each tibia using drills either at a high or a mixed speed under irrigation. At the mixed-speed sites, 60 rpm without irrigation were applied for the last drill, the countersink and during implant installation. Biopsies representing the healing after 1, 2, and 6 weeks were obtained and ground sections were prepared. At the histological analyses, after 1 week of healing, no new bone was found at both high- and mixed-speed sites. After 2 weeks of healing, small amounts of newly formed bone were observed in the cortical layer, reaching percentages of 3.6±3.0% at the mixed-speed sites, and of 2.2±1.5% at the high-speed sites. An irrelevant quantity of new bone was seen in the marrow compartments of a few specimens. After 6 weeks of healing, new bone was found in higher quantity, reaching in the cortical compartment 66.9±6.8% and 67.3±17.7% at the mixed- and high-speed sites, respectively. The respective percentages in the marrow compartment were 23.2±13.0% and 30.6±29.2%. No statistically significant differences between high- and mixed-speed groups were found. It was concluded that the use of the last drill and the installation of the implant with or without irrigation yielded similar bone healing and osseointegration.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-08-30
    Description: by Kirill Shumilov, M. Ángeles Real, Alejandra Valderrama-Carvajal, Alicia Rivera The striatum is a complex structure in which the organization in two compartments (striosomes and matrix) have been defined by their neurochemical profile and their input-output connections. The striosomes receive afferences from the limbic brain areas and send projections to the dopamine neurons of the substantia nigra pars compacta. Thereby, it has been suggested that the striosomes exert a limbic control over the motor function mediated by the surrounding matrix. However, the functionality of the striosomes are not completely understood. To elucidate the role of the striosomes on the regulation of the nigral dopamine neurons, we have induced specific ablation of this compartment by striatal injections of the neurotoxin dermorphin-saporin (DS) and dopamine neurotransmission markers have been analyzed by immunohistochemistry. The degeneration of the striosomes resulted in a nigrostriatal projections imbalance between the two striatal compartments, with an increase of the dopamine neurotransmission in the striosomes and a decrease in the matrix. The present results highlight the key function of the striosomes for the maintenance of the striatal dopamine tone and would contribute to the understanding of their involvement in some neurological disorders such as Huntington’s disease.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-08-30
    Description: by Sarah Jane Hobbs, Sandra Nauwelaerts, Jonathan Sinclair, Hilary M. Clayton, Willem Back Asymmetry in forelimb dorsal hoof wall angles, termed unevenness, is associated with forelimb gait asymmetries, but compensatory mechanisms and out of plane ground reaction forces (GRFs) due to unevenness have yet to be documented. The aim of this study was therefore to investigate the effects of fore hoof unevenness on contralateral fore and hind limb force vectors patterns, in both sagittal and frontal planes. A group of n = 34 riding horses were classified into four groups: hoof angle difference of more than 1.5 degrees (UNEVEN; n = 27), including higher left fore (HIGH-LF; n = 12), higher right fore (HIGH-RF; n = 15), and hoof angle difference of less than 1.5 degrees (EVEN; n = 7). Three dimensional ground reaction forces GRFs were collected during trotting. GRF summary vectors representing the magnitude (VecMag) and angular direction (VecAng) of the entire stance phase in the sagittal and the frontal plane were calculated. The effects of unevenness on GRF production were explored using linear regression, repeated measures ANOVA and statistical parametric mapping (SPM) with significance at (P
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  • 78
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    Publication Date: 2018-08-30
    Description: by Cristina M. Pulido, Gisela Redondo-Sama, Teresa Sordé-Martí, Ramon Flecha The social impact of research has usually been analysed through the scientific outcomes produced under the auspices of the research. The growth of scholarly content in social media and the use of altmetrics by researchers to track their work facilitate the advancement in evaluating the impact of research. However, there is a gap in the identification of evidence of the social impact in terms of what citizens are sharing on their social media platforms. This article applies a social impact in social media methodology (SISM) to identify quantitative and qualitative evidence of the potential or real social impact of research shared on social media, specifically on Twitter and Facebook. We define the social impact coverage ratio (SICOR) to identify the percentage of tweets and Facebook posts providing information about potential or actual social impact in relation to the total amount of social media data found related to specific research projects. We selected 10 projects in different fields of knowledge to calculate the SICOR, and the results indicate that 0.43% of the tweets and Facebook posts collected provide linkages with information about social impact. However, our analysis indicates that some projects have a high percentage (4.98%) and others have no evidence of social impact shared in social media. Examples of quantitative and qualitative evidence of social impact are provided to illustrate these results. A general finding is that novel evidences of social impact of research can be found in social media, becoming relevant platforms for scientists to spread quantitative and qualitative evidence of social impact in social media to capture the interest of citizens. Thus, social media users are showed to be intermediaries making visible and assessing evidence of social impact.
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  • 79
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    Publication Date: 2018-08-30
    Description: by Cinthy L. Jiménez-Silva, María Fernanda Carreño, Ayda Susana Ortiz-Baez, Luz Aida Rey, Christian Julián Villabona-Arenas, Raquel E. Ocazionez Dengue is a prevalent disease in Colombia and all dengue virus serotypes (DENV-1 to -4) co-circulate in the country since 2001. However, the relative impact of gene flow and local diversification on epidemic dynamics is unknown due to heterogeneous sampling and lack of sufficient genetic data. The region of Santander is one of the areas with the highest incidence of dengue in Colombia. To provide a better understanding of the epidemiology of dengue, we inferred DENV population dynamics using samples collected between 1998 and 2015. We used Bayesian phylogenetic analysis and included 143 new envelope gene sequences from Colombia, mainly from the region of Santander, and 235 published sequences from representative countries in the Americas. We documented one single genotype for each serotype but multiple introductions. Whereas the majority of DENV-1, DENV-2, and DENV-4 strains fell into one single lineage, DENV-3 strains fell into two distinct lineages that co-circulated. The inferred times to the most recent common ancestors for the most recent clades of DENV-1, DENV-2, and DENV-4 fell between 1977 and 1987, and for DENV-3 was around 1995. Demographic reconstructions suggested a gradual increase in viral diversity over time. A phylogeographical analysis underscored that Colombia mainly receives viral lineages and a significant diffusion route between Colombia and Venezuela. Our findings contribute to a better understanding of the viral diversity and dengue epidemiology in Colombia.
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    Publication Date: 2018-08-30
    Description: by Eric A. Hunt, Thomas C. Evans Jr., Nathan A. Tanner Prokaryotic argonautes are a unique class of nucleic acid-guided endonucleases putatively involved in cellular defense against foreign genetic elements. While their eukaryotic homologs and Cas protein counterparts require single-stranded RNAs as guides, some prokaryotic argonautes are able to utilize short single-stranded DNAs as guides for sequence-specific endonuclease activity. Many complications currently prevent the use of prokaryotic argonautes for in vivo gene-editing applications; however, they do exhibit potential as a new class of in vitro molecular tools if certain challenges can be overcome, specifically the limitations on substrate accessibility which leads to unequal levels of activity across a broad palate of substrates and the inability to act on double-stranded DNA substrates. Here we demonstrate the use of accessory factors, including thermostable single-stranded DNA binding proteins and UvrD-like helicase, in conjunction with prokaryotic argonautes to significantly improve enzymatic activity and enable functionality with a broader range of substrates, including linear double-stranded DNA substrates. We also demonstrate the use of Thermus thermophilus argonaute with accessory factors as a programmable restriction enzyme to generate long, unique single-stranded overhangs from linear double-stranded substrates compatible with downstream ligation.
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-30
    Description: by Lisa Redford, Ghanim Alhilal, Stephanie Needham, Ottie O’Brien, Julie Coaker, John Tyson, Leonardo Maldaner Amorim, Iona Middleton, Osagi Izuogu, Mark Arends, Anca Oniscu, Ángel Miguel Alonso, Sira Moreno Laguna, Richard Gallon, Harsh Sheth, Mauro Santibanez-Koref, Michael S. Jackson, John Burn Somatic mutations in mononucleotide repeats are commonly used to assess the mismatch repair status of tumours. Current tests focus on repeats with a length above 15bp, which tend to be somatically more unstable than shorter ones. These longer repeats also have a substantially higher PCR error rate, and tests that use capillary electrophoresis for fragment size analysis often require expert interpretation. In this communication, we present a panel of 17 short repeats (length 7–12bp) for sequence-based microsatellite instability (MSI) testing. Using a simple scoring procedure that incorporates the allelic distribution of the mutant repeats, and analysis of two cohort of tumours totalling 209 samples, we show that this panel is able to discriminate between MMR proficient and deficient tumours, even when constitutional DNA is not available. In the training cohort, the method achieved 100% concordance with fragment analysis, while in the testing cohort, 4 discordant samples were observed (corresponding to 97% concordance). Of these, 2 showed discrepancies between fragment analysis and immunohistochemistry and one was reclassified after re-testing using fragment analysis. These results indicate that our approach offers the option of a reliable, scalable routine test for MSI.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-30
    Description: by Sivasankaran Munusamy Ponnan, Soumya Swaminathan, Kannan Tiruvengadam, Vidyavijayan K. K., Narayana Cheedarla, Manohar Nesakumar, Sujitha Kathirvel, Rajat Goyal, Nikhil Singla, Joyeeta Mukherjee, Philip Bergin, Jakub T. Kopycinski, Jill Gilmour, Srikanth Prasad Tripathy, Luke Hanna Elizabeth A Phase I HIV-1 vaccine trial sponsored by the International AIDS Vaccine Initiative (IAVI) was conducted in India in 2009 to test a subtype C prophylactic vaccine in a prime-boost regimen comprising of a DNA prime (ADVAX) and MVA (TBC-M4) boost. The trial demonstrated that the regimen was safe and well tolerated and resulted in enhancement of HIV-specific immune responses. Preliminary observations on vaccine-induced immune responses were limited to analysis of neutralizing antibodies and IFN-γ ELISPOT response. The present study involves a more detailed analysis of the nature of the vaccine-induced humoral immune response using specimens that were archived from the volunteers at the time of the trial. Interestingly, we found vaccine induced production of V1/V2 and V3 region-specific antibodies in a significant proportion of vaccinees. Variable region antibody levels correlated directly with the frequency of circulating T follicular helper cells (Tfh) and regulatory T cells (Treg). Our findings provide encouraging evidence to demonstrate the immunogenicity of the tested vaccine. Better insights into vaccine-induced immune responses can aid in informing future design of a successfulHIV-1 vaccine.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 83
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-30