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  • 1
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Nirupama Krishnamurthi, Joseph Francis, Stephan D. Fihn, Craig S. Meyer, Mary A. Whooley
    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: 2018-07-04
    Description: by Nesrine Akkari, Anne-Sarah Ganske, Ana Komerički, Brian Metscher We present high-resolution X-ray microtomography (microCT) to enhance the standard morphological description of a recently described centipede, Eupolybothrus liburnicus Akkari, Komerički, Weigand, Edgecombe and Stoev, 2017. The 3D images of the holotype and paratype specimens are considered here as cybertypes for the species–a universal and virtual representation of the type material. This ‘avatar’ of the holotype is the first published male centipede cybertype. The microtomographic data of both types revealed further characters of systematic value and allowed us to hypothesise on the function of some of the male secondary structures and the mating behaviour of the species. Additionally, we compared part of the female reproductive system of E . liburnicus to species from the same genus, including E . cavernicolus Stoev & Komerički 2013, its closest congener. The high-resolution 3D image data have been uploaded to an open repository (MorphoSource.org) to serve in any subsequent study on the species and genus, as we believe this would catalyse biosystematic research on this and other arthropod groups.
    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: 2018-07-04
    Description: by Narges Alipanah, Leah Jarlsberg, Cecily Miller, Nguyen Nhat Linh, Dennis Falzon, Ernesto Jaramillo, Payam Nahid Background Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. Methods and findings We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73–0.89; RCT: RR 0.94, 95% CI 0.89–0.98), adherence (CS: RR 0.83, 95% CI 0.75–0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87–0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34–7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79–0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01–1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02–1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33–0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40–0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. Conclusion TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 4
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Matthew Mattingly, Kristin Weineck, Jennifer Costa, Robin L. Cooper Optogenetics offers a unique method to regulate the activity of select neural circuits. However, the electrophysiological consequences of targeted optogenetic manipulation upon the entire circuit remain poorly understood. Analysis of the sensory-CNS-motor circuit in Drosophil a larvae expressing eHpHR and ChR2-XXL revealed unexpected patterns of excitability. Optical stimulation of motor neurons targeted to express eNpHR resulted in inhibition followed by excitation of body wall contraction with repetitive stimulation in intact larvae. In situ preparations with direct electrophysiological measures showed an increased responsiveness to excitatory synaptic activity induced by sensory stimulation within a functional neural circuit. To ensure proper function of eNpHR and ChR2-XXL they were expressed in body wall muscle and direct electrophysiological measurements were obtained. Under eNpHR induced hyperpolarization the muscle remained excitable with increased amplitude of excitatory postsynaptic synaptic potentials. Theoretical models to explain the observations are presented. This study aids in increasing the understanding of the varied possible influences with light activated proteins within intact neural circuits.
    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: 2018-07-04
    Description: by Maximilian B. Maier, Tobias Schweiger, Christian A. Lenz, Rudi F. Vogel The effect of high pressure thermal (HPT) treatments on the inactivation of spores of non-proteolytic type E Clostridium botulinum TMW 2.990 was investigated at high pressures (300 to 600 MPa) and elevated temperatures (80 to 100 °C) in four low-acid foods (steamed sole, green peas with ham, vegetable soup, braised veal) and imidazole phosphate buffer (IPB). In addition, corresponding conventional thermal treatments at ambient pressure were performed to expose possible synergisms of pressure and temperature on spore inactivation. In general, spore count reduction was more efficient by combining pressure and temperatures 〈 100 °C and the overall process duration could be shortened due to accelerated heating rates (adiabatic effect). Processing at 90 °C and 600 MPa resulted in inactivation below the detection limit after 5 min in all foods except steamed sole. Traditional thermal processing of spores at 90 °C for 10 min, on the other hand, did not result in an estimated 6-log reduction. Additional HPT treatments in steamed sole and IPB did not reveal pronounced food matrix dependent protective effects. Here, varying pressure levels did not appear to be the driving force for spore count reduction in steamed sole at any temperature. By applying a Weibull distribution on destruction kinetics of isobaric/isothermal holding times, 6D-values were calculated. Compression and decompression phase (1 s pressure holding time) had a considerable impact on spore count reduction (max. -2.9 log units) in both, foods and buffer. Hence, compression and decompression phases should directly be included into the total lethal effect of HPT treatments to avoid prolonged holding times and overprocessing.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Andreas Finkelmeyer, Jiabao He, Laura Maclachlan, Andrew M. Blamire, Julia L. Newton Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p 〈 .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.
    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: 2018-07-04
    Description: by Liwei Li, Fei Gao, Hao Zheng, Yifeng Jiang, Wu Tong, Yanjun Zhou, Guangzhi Tong MicroRNAs (miRNAs) contribute to gene regulation at the post-transcriptional level and are capable of mRNA silencing by binding to target sites exhibiting high degrees of complementarity. Therefore, cloning host miRNA-recognition sequences into the genome of RNA viruses represents a rational strategy for manipulating viral replication. Here, we performed deep sequencing to obtain small-RNA (sRNA)-expression profiles from in vitro -cultured MARC-145 cells post infection with porcine reproductive and respiratory syndrome virus (PRRSV) and chose six candidate miRNAs of different abundance (miR-21, miR-140-3p, miR-185, miR-26a, miR-505, and miR-199a) for further study. Based on the full-length cDNA clone p7USC, we constructed a number of PRRSV mutants that provided complementary base-pairing target sites for the miRNAs in 3′ untranslated regions. Our results showed that all low- and moderate- abundant miRNA-target mutants showed similar growth properties, whereas the highest-abundant miRNA-target mutant blocked both viral transcription and replication. Discontinuous mutations in high-abundant miRNA-target sites subsequently recovered viral viability and propagation. These results demonstrated the copy number of endogenous miRNAs and the extent of sRNA complementarity were key factors to silence potential mRNA expression/translation, thereby determining PRRSV viability. Interestingly, the mutant containing miR-140-target sites (v140-t) showed strong suppression of viral replication from P1 to P3 in vitro , as shown by virus titer, plaque morphology, and qRT-PCR assays. To assess genetic stability, sequencing of v140-t (P1, P3, P5 and P10) revealed spontaneous mutations preferentially located among several nucleotides near the 3′ end of the insertion region and corresponding to the “seed region” of miR-140-3p, explaining the induced viral repression and the direction of virus evolution. This approach provided a general silencing strategy for limiting PRRSV replication by endogenous miRNAs in MARC-145 cells.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 8
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Eridan Rocha-Ferreira, Amy Vincent, Sarah Bright, Donald M. Peebles, Mariya Hristova Neonatal hypoxic-ischaemic encephalopathy (HIE) is major cause of neonatal mortality and morbidity. Therapeutic hypothermia is standard clinical care for moderate hypoxic-ischaemic (HI) brain injury, however it reduces the risk of death and disability only by 11% and 40% of the treated infants still develop disabilities. Thus it is necessary to develop supplementary therapies to complement therapeutic hypothermia in the treatment of neonatal HIE. The modified Rice-Vannucci model of HI in the neonatal mouse is well developed and widely applied with different periods of hypothermia used as neuroprotective strategy in combination with other agents. However, different studies use different periods, time of initiation and duration of hypothermia following HI, with subsequent varying degrees of neuroprotection. So far most rodent data is obtained using exposure to 5-6h of therapeutic hypothermia. Our aim was to compare the effect of exposure to three different short periods of hypothermia (1h, 1.5h and 2h) following HI insult in the postnatal day 7 C57/Bl6 mouse, and to determine the shortest period providing neuroprotection. Our data suggests that 1h and 1.5h of hypothermia delayed by 20min following a 60min exposure to 8%O 2 do not prove neuroprotective. However, 2h of hypothermia significantly reduced tissue loss, TUNEL+ cell death and microglia and astroglia activation. We also observed improved functional outcome 7 days after HI. We suggest that the minimal period of cooling necessary to provide moderate short term neuroprotection and appropriate for the development and testing of combined treatment is 2h.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Lijun Fan, Bill Lukin, Jingzhou Zhao, Jiandong Sun, Kaeleen Dingle, Rhonda Purtill, Sam Tapp, Xiang-Yu Hou Background This study aims to examine the costs associated with a Hospital in the Nursing Home (HiNH) program in Queensland Australia directed at patients from residential aged care facilities (RACFs) with emergency care needs. Methods A cost analysis was undertaken comparing the costs under the HiNH program and the current practice, in parallel with a pre-post controlled study design. The study was conducted in two Queensland public hospitals: the Royal Brisbane and Women’s Hospital (intervention hospital) and the Logan Hospital (control hospital). Main outcome measures were the associated incremental costs or savings concerning the HiNH program provision and the acute hospital care utilisation over one year after intervention. Results The initial deterministic analysis calculated the total induced mean costs associated with providing the HiNH program over one year as AU$488,116, and the total induced savings relating to acute hospital care service utilisation of AU$8,659,788. The total net costs to the health service providers were thus calculated at -AU$8,171,671 per annum. Results from the probabilistic sensitivity analysis (based on 10,000 simulations) showed the mean and median annual net costs associated with the HiNH program implementation were -AU$8,444,512 and–AU$8,202,676, and a standard deviation of 2,955,346. There was 95% certainty that the values of net costs would fall within the range from -AU$15,018,055 to -AU$3,358,820. Conclusions The costs relating to implementing the HiNH program appear to be much less than the savings in terms of associated decreases in acute hospital service utilisation. The HiNH service model is likely to have the cost-saving potential while improving the emergency care provision for RACF residents.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Justin Knox, Stephen M. Arpadi, Shuaib Kauchali, Murray Craib, Jane D. Kvalsvig, Myra Taylor, Fatimatou Bah, Claude Mellins, Leslie L. Davidson Background While neurodevelopmental abnormalities are common in children with HIV infection, their detection can be challenging in settings with limited availability of health professionals. The aim of this study was to assess the ability to identify developmental disability among HIV positive and HIV negative children living in South Africa with an internationally used screen. Methods and findings This analysis uses a sample of 1,330 4–6 year old children and 1,231 of their caregivers in KwaZulu-Natal, South Africa, including administration of the Ten Questions (TQ) screen, a standardized medical history and physical examination conducted by a medical doctor, with hearing and vision screening, psychological assessment for cognition and language delay, and voluntary HIV testing. There was a high prevalence of disability among the sample. Compared to HIV negative children, HIV positive children were more likely to screen positive on at least one TQ item (59.3 vs 42.8%, p = 0.01), be delayed in sitting, standing or walking (OR 3.89, 95% CI = 2.1–7.2) and have difficulty walking or weakness in the arms or legs (OR = 2.7, 95%CI = 0.8–9.37). By medical doctor assessment, HIV positive children were more likely to be diagnosed with gross motor disability (OR = 3.5, 95%CI = 1.3–9.2) and hearing disability (OR = 2.5, 95%CI = 1.2–5.3). By independent psychological assessment, HIV positive children were more likely to have cognitive delay (OR = 2.2, 95%CI = 1.2–3.9) and language delay (OR = 4.3, 95%CI = 2.2–8.4). Among HIV positive children, the sensitivity and specificity of the TQ for serious disability (vs. no disability) was 100% and 51.2%, respectively. Among HIV-negative children, the sensitivity and specificity of the TQ for serious disability (vs. no disability) was 90.2% and 63.9%, respectively. Conclusions In this first report of the use of the TQ screen in the isiZulu language, it was found to have high sensitivity for detecting serious developmental disabilities in children, especially HIV positive children. The performance of the TQ in this sample indicates utility for making best use of limited neurodevelopmental resources by screening HIV positive children.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Public Library of Science (PLoS)
    Publication Date: 2018-07-04
    Description: by Alison Dougall, Francisca Martinez Pereira, Gustavo Molina, Caroline Eschevins, Blánaid Daly, Denise Faulks Introduction Persons unable to access oral health care in the conventional primary health care setting suffer from inequalities in oral health, particularly in terms of unmet dental need. The International Classification of Functioning, disability and health (ICF) is designed to look beyond medical diagnosis and to describe individuals or populations in terms of their ability to function and participate in a social environment. The objective of the study was to describe an adult population requiring specialist oral health care using the ICF and to identify common factors of functioning, participation and environmental context. Method The ICF Checklist for Oral Health was completed for 246 participants from five specialist dental services in five countries (mean age 36 ±16.44 years; 16–92). ‘Developmental disability’ and ‘Medically compromised’ groups were identified (72% and 28%). Results Participants presented with oral disease (92%) and dysfunction (66% impaired chewing). 33 ICF items were affected in over 50% of participants in both groups. Impaired body functions included ‘ingestion functions’, ‘energy and drive functions’ and ‘emotional functions’. Participation was restricted for “Acquiring, keeping and terminating a job”, “Intimate relationships”, “Handling stress and psychological demands”, “Economic self-sufficiency”, “Carrying out a daily routine”, “Recreation and leisure”, “Community life” and “Looking after one’s health”. In the environment domain, “Support and relationships” and “Attitudes” were rated as facilitators. Environmental barriers reported for over 25% of the whole group were related to “Services, systems and policies” including, health, social security, general support, transportation, and labour and employment. Discussion and perspectives Common aspects of functioning, participation and environment were found amongst a heterogeneous population of adults attending specialist dental services, alongside poor oral health and function. The ICF may be used to describe populations that suffer inequality in oral health in order to develop services that effectively target those in need of additional means.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by Huong Thi Pham, Nguyen Thi Hanh Nhiep, Thu Ngoc Minh Vu, TuAnh Ngoc Huynh, Yan Zhu, Anh Le Diep Huynh, Alolika Chakrabortti, Esteban Marcellin, Raquel Lo, Christopher B. Howard, Nidhi Bansal, Joshua J. Woodward, Zhao-Xun Liang, Mark S. Turner The broadly conserved bacterial signalling molecule cyclic-di-adenosine monophosphate (c-di-AMP) controls osmoresistance via its regulation of potassium (K + ) and compatible solute uptake. High levels of c-di-AMP resulting from inactivation of c-di-AMP phosphodiesterase activity leads to poor growth of bacteria under high osmotic conditions. To better understand how bacteria can adjust in response to excessive c-di-AMP levels and to identify signals that feed into the c-di-AMP network, we characterised genes identified in a screen for osmoresistant suppressor mutants of the high c-di-AMP Lactococcus Δ gdpP strain. Mutations were identified which increased the uptake of osmoprotectants, including gain-of-function mutations in a Kup family K + importer (KupB) and inactivation of the glycine betaine transporter transcriptional repressor BusR. The KupB mutations increased the intracellular K + level while BusR inactivation increased the glycine betaine level. In addition, BusR was found to directly bind c-di-AMP and repress expression of the glycine betaine transporter in response to elevated c-di-AMP. Interestingly, overactive KupB activity or loss of BusR triggered c-di-AMP accumulation, suggesting turgor pressure changes act as a signal for this second messenger. In another group of suppressors, overexpression of an operon encoding an EmrB family multidrug resistance protein allowed cells to lower their intracellular level of c-di-AMP through active export. Lastly evidence is provided that c-di-AMP levels in several bacteria are rapidly responsive to environmental osmolarity changes. Taken together, this work provides evidence for a model in which high c-di-AMP containing cells are dehydrated due to lower K + and compatible solute levels and that this osmoregulation system is able to sense and respond to cellular water stress.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 13
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-03
    Description: by Luisa M. R. Napolitano, Arin Marchesi, Alex Rodriguez, Matteo De March, Silvia Onesti, Alessandro Laio, Vincent Torre Several channels, ranging from TRP receptors to Gap junctions, allow the exchange of small organic solute across cell membrane. However, very little is known about the molecular mechanism of their permeation. Cyclic Nucleotide Gated (CNG) channels, despite their homology with K + channels and in contrast with them, allow the passage of larger methylated and ethylated ammonium ions like dimethylammonium (DMA) and ethylammonium (EA). We combined electrophysiology and molecular dynamics simulations to examine how DMA interacts with the pore and permeates through it. Due to the presence of hydrophobic groups, DMA enters easily in the channel and, unlike the alkali cations, does not need to cross any barrier. We also show that while the crystal structure is consistent with the presence of a single DMA ion at full occupancy, the channel is able to conduct a sizable current of DMA ions only when two ions are present inside the channel. Moreover, the second DMA ion dramatically changes the free energy landscape, destabilizing the crystallographic binding site and lowering by almost 25 kJ/mol the binding affinity between DMA and the channel. Based on the results of the simulation the experimental electron density maps can be re-interpreted with the presence of a second ion at lower occupancy. In this mechanism the flexibility of the channel plays a key role, extending the classical multi-ion permeation paradigm in which conductance is enhanced by the plain interaction between the ions.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 15
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by Akira Ehara In Japan, all citizens are covered by the national insurance system. Children’s medical expenses are subsidized by local government co-payments. This removed most economic barriers to visiting medical facilities, geographical obstacles to pediatric medical services remain, including distance to medical facilities and transportation time. However, information on geographic accessibility of pediatric inpatient services is scarce. In this study, I calculated the proportion of children resident in areas accessible to pediatric inpatient service providers within 30 and 60 minutes by automobile. Calculations were based on addresses of hospitals that met criteria for high reimbursement for secondary and tertiary pediatric inpatient services, data for residential blocks, and data for the average velocity of an automobile. In total, 88.0% of children lived within 30 minutes of these hospitals and 95.2% of children lived within 60 minutes. The percentage of children with such access was higher in regions with high population density (e.g., Kanto and Kinki) compared with regions with low population density (e.g., Hokkaido, Tohoku, and Shikoku). Furthermore, regions with high population density also had high rates of children that lived within reach of hospitals with at least five full-time pediatricians.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by Sunwoo Kim, Yuri Lee This study investigated the underlying reasons women desire to be beautiful in South Korean, Chinese, and Japanese cultures by proposing a new concept called human beauty value (HBV). This exploratory qualitative study includes a literature review in related disciplines and the results from ten focus group interviews. Based on the interviews, this study proposes four dimensions of HBV (i.e., superiority, self-development, individuality, and authenticity) and a hierarchical process among the antecedents (i.e., social comparison, social competition, and social norms), the pursuit of HBV, and the consequences (i.e., emotional, attitudinal, and behavioral aspects). Participants from each culture revealed a unique hierarchical process of HBV that reflects both cultural universality and specificity. The results of this study lead to new knowledge about East Asian women’s identities and perceptions of beauty. In addition, the proposed concept, HBV, can broaden the academic lens for beauty-related disciplines.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 17
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by Yong Shen, Saisai Wang, Fangfang Sun, Gang Zheng, Tingting Wu, Yushen Du, Suzhan Zhang, Jing Qian, Ren Sun Gamma interferon (IFN-γ) is known to negatively regulate murine gammaherpesvirus-68 (MHV-68 or γHV-68) replication. This process involves the suppression of the viral gene replication and transcription activator (RTA) promoter, as well as activation of signal transducers and activators of transcription (STAT1). Notably, this effect is gradually attenuated during MHV-68 infection of bone marrow-derived macrophages (BMMs), which raised the possibility that the virus may utilize a mechanism that counteracts the antiviral effect of IFN-γ. By identifying the cellular factors that negatively regulate JAK-STAT1 signaling, we revealed that the infection of BMMs by MHV-68 induces the expression of suppressor of cytokine signaling 1 (SOCS1) and that depletion of SOCS1 restores the inhibitory effect of IFN-γ on virus replication. Moreover, we demonstrated that the expression of SOCS1 was induced as a result of the Toll-like receptor 3 (TLR3) mediated activation of the NF-κB signaling cascade. In conclusion, we report that TLR3-TRAF-NF-κB signaling pathway play a role in the induction of SOCS1 that counteracts the antiviral effect of IFN-γ during MHV-68 infection. This process is cell type-specific: it is functional in macrophages, but not in epithelial cells or fibroblasts. Our study reveals a mechanism that balances the immune responses and the escape of a gamma-herpesvirus in some antigen-presenting cells.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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  • 18
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-07
    Description: by Alexis Hofherr, Claudia Seger, Fiona Fitzpatrick, Tilman Busch, Elisabeth Michel, Jingting Luan, Lea Osterried, Frieder Linden, Albrecht Kramer-Zucker, Barbara Wakimoto, Conny Schütze, Nils Wiedemann, Anna Artati, Jerzy Adamski, Gerd Walz, Edmund R. S. Kunji, Craig Montell, Terry Watnick, Michael Köttgen Cilia are organelles specialized in movement and signal transduction. The ciliary transient receptor potential ion channel polycystin-2 (TRPP2) controls elementary cilia-mediated physiological functions ranging from male fertility and kidney development to left–right patterning. However, the molecular components translating TRPP2 channel–mediated Ca 2+ signals into respective physiological functions are unknown. Here, we show that the Ca 2+ -regulated mitochondrial ATP-Mg/P i solute carrier 25 A 25 (SLC25A25) acts downstream of TRPP2 in an evolutionarily conserved metabolic signaling pathway. We identify SLC25A25 as an essential component in this cilia-dependent pathway using a genome-wide forward genetic screen in Drosophila melanogaster , followed by a targeted analysis of SLC25A25 function in zebrafish left–right patterning. Our data suggest that TRPP2 ion channels regulate mitochondrial SLC25A25 transporters via Ca 2+ establishing an evolutionarily conserved molecular link between ciliary signaling and mitochondrial metabolism.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 19
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by Jia Pei Chan, Bernice H. Wong, Cheen Fei Chin, Dwight L. A. Galam, Juat Chin Foo, Loo Chin Wong, Sujoy Ghosh, Markus R. Wenk, Amaury Cazenave-Gassiot, David L. Silver Brain development requires a massive increase in brain lipogenesis and accretion of the essential omega-3 fatty acid docosahexaenoic acid (DHA). Brain acquisition of DHA is primarily mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) expressed in the endothelium of the blood-brain barrier (BBB) and other abundant cell types within the brain. Mfsd2a transports DHA and other polyunsaturated fatty acids (PUFAs) esterified to lysophosphatidylcholine (LPC-DHA). However, the function of Mfsd2a and DHA in brain development is incompletely understood. Here, we demonstrate, using vascular endothelial-specific and inducible vascular endothelial-specific deletion of Mfsd2a in mice, that Mfsd2a is uniquely required postnatally at the BBB for normal brain growth and DHA accretion, with DHA deficiency preceding the onset of microcephaly. In Mfsd2a-deficient mouse models, a lipidomic signature was identified that is indicative of increased de novo lipogenesis of PUFAs. Gene expression profiling analysis of these DHA-deficient brains indicated that sterol regulatory-element binding protein (Srebp)-1 and Srebp-2 pathways were highly elevated. Mechanistically, LPC-DHA treatment of primary neural stem cells down-regulated Srebp processing and activation in a Mfsd2a-dependent fashion, resulting in profound effects on phospholipid membrane saturation. In addition, Srebp regulated the expression of Mfsd2a. These data identify LPC-DHA transported by Mfsd2a as a physiological regulator of membrane phospholipid saturation acting in a feedback loop on Srebp activity during brain development.
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    Publication Date: 2018-08-04
    Description: by Margaret J. Tse, Brian K. Chu, Cameron P. Gallivan, Elizabeth L. Read Stochastic simulation has been a powerful tool for studying the dynamics of gene regulatory networks, particularly in terms of understanding how cell-phenotype stability and fate-transitions are impacted by noisy gene expression. However, gene networks often have dynamics characterized by multiple attractors. Stochastic simulation is often inefficient for such systems, because most of the simulation time is spent waiting for rare, barrier-crossing events to occur. We present a rare-event simulation-based method for computing epigenetic landscapes and phenotype-transitions in metastable gene networks. Our computational pipeline was inspired by studies of metastability and barrier-crossing in protein folding, and provides an automated means of computing and visualizing essential stationary and dynamic information that is generally inaccessible to conventional simulation. Applied to a network model of pluripotency in Embryonic Stem Cells, our simulations revealed rare phenotypes and approximately Markovian transitions among phenotype-states, occurring with a broad range of timescales. The relative probabilities of phenotypes and the transition paths linking pluripotency and differentiation are sensitive to global kinetic parameters governing transcription factor-DNA binding kinetics. Our approach significantly expands the capability of stochastic simulation to investigate gene regulatory network dynamics, which may help guide rational cell reprogramming strategies. Our approach is also generalizable to other types of molecular networks and stochastic dynamics frameworks.
    Print ISSN: 1553-734X
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    Topics: Biology , Computer Science
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  • 21
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    Publication Date: 2018-08-04
    Description: by Yosra Bedoui, Claude Giry, Marie-Christine Jaffar-Bandjee, Jimmy Selambarom, Pascale Guiraud, Philippe Gasque Chikungunya virus (CHIKV) is a mosquito-transmitted RNA alphavirus causing major outbreaks of infectious chronic inflammatory rheumatisms (CIR). Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug has been used successfully to treat patients suffering from rheumatoid-like arthritis post-CHIK but its immunomodulatory activity in the context of viral persistence has been a matter of concerns. We herein used a model of primary human synovial fibroblasts (HSF) and the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic infectious settings in the joints of CHIKV infected patients. The innate antiviral immune and inflammatory responses were investigated in response to MTX used at the therapeutic concentration of 1 μM. We found that MTX did not affect cellular viability as indicated by the LDH release assay. By quantitative RT-PCR, we observed that HSF responded robustly to PIC by increasing ISG15 and IFNβ mRNA levels. Furthermore, PIC upregulated the mRNA expression of two of the major pattern recognition receptors, RIG-I and MDA5 involved in the innate immune detection of viral RNA. MTX did not impact the antiviral response of PIC on ISG15, IFNβ, RIG-I and MDA5 mRNA expressions. MTX alone or combined with PIC did not affect the expression of proinflammatory CCL2 and CXCL8 chemokines. PIC strongly upregulated the mRNA and protein expression of osteoclastogenic factors (IL-6, GM-CSF but not RANKL). Critically, MTX treatment alone or combined with PIC did not affect the expression of all three tested osteoclastogenic cytokines. We found that MTX alone did not increase the capacity of CHIKV to infect and replicate in HSF. In conclusion, our study argues for a beneficial effect of MTX to treat CIR post-CHIKV given that it does not critically impact the antiviral, the proinflammatory and the bone tissue remodeling responses of synovial cells.
    Print ISSN: 1935-2727
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    Topics: Medicine
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  • 22
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-04
    Description: by Eva Gravesen, Anders Nordholm, Maria Mace, Marya Morevati, Estrid Høgdall, Carsten Nielsen, Andreas Kjær, Klaus Olgaard, Ewa Lewin Uremic vascular calcification is a regulated cell-mediated process wherein cells in the arterial wall transdifferentiate to actively calcifying cells resulting in a process resembling bone formation. Wnt signalling is established as a major driver for vessel formation and maturation and for embryonic bone formation, and disturbed Wnt signalling might play a role in vascular calcification. ICG-001 is a small molecule Wnt inhibitor that specifically targets the coactivator CREB binding protein (CBP)/β-catenin-mediated signalling. In the present investigation we examined the effect of ICG-001 on vascular calcification in uremic rats. Uremic vascular calcification was induced in adult male rats by 5/6-nephrectomy, high phosphate diet and alfacalcidol. The presence of uremic vascular calcification in the aorta was associated with induction of gene expression of the Wnt target gene and marker of proliferation, cyclinD1; the mediator of canonical Wnt signalling, β-catenin and the matricellular proteins, fibronectin and periostin. Furthermore, genes from fibrosis-related pathways, TGF-β and activin A, as well as factors related to epithelial-mesenchymal transition, snail1 and vimentin were induced. ICG-001 treatment had significant effects on gene expression in kidney and aorta from healthy rats. These effects were however limited in uremic rats, and treatment with ICG-001 did not reduce the Ca-content of the uremic vasculature.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 23
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    Publication Date: 2018-08-04
    Description: by Luca Ronda, Barbara Pioselli, Silvia Catinella, Fabrizio Salomone, Marialaura Marchetti, Stefano Bettati CHF5633 (Chiesi Farmaceutici, Italy) is a synthetic surfactant developed for respiratory distress syndrome replacement therapy in pre-term newborn infants. CHF5633 contains two phospholipids (dipalmitoylphosphatidylcholine and 1-palmitoyl-2oleoyl- sn -glycero-3-phosphoglycerol sodium salt), and peptide analogues of surfactant protein C (SP-C analogue) and surfactant protein B (SP-B analogue). Both proteins are fundamental for an optimal surfactant activity in vivo and SP-B genetic deficiency causes lethal respiratory failure after birth. Fluorescence emission of the only tryptophan residue present in SP-B analogue (SP-C analogue has none) could in principle be exploited to probe SP-B analogue conformation, localization and interaction with other components of the pharmaceutical formulation. However, the high light scattering activity of the multi-lamellar vesicles suspension characterizing the pharmaceutical surfactant formulation represents a challenge for such studies. We show here that quenching of tryptophan fluorescence and Singular Value Decomposition analysis can be used to accurately calculate and subtract background scattering. The results indicate, with respect to Trp microenvironment, a conformationally homogeneous population of SP-B. Trp is highly accessible to the water phase, suggesting a surficial localization on the membrane of phospholipid vesicles, similarly to what observed for full length SP-B in natural lung surfactant, and supporting an analogous role in protein anchoring to the lipid phase.
    Electronic ISSN: 1932-6203
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  • 24
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    Publication Date: 2018-07-06
    Description: by H. K. Jeevan Dhanarisi, Indika B. Gawarammana, Fahim Mohamed, Michael Eddleston Introduction The importance of alcohol co-ingestion for outcome in organophosphorus (OP) insecticide self-poisoning has only been studied for the relatively hydrophilic dimethyl insecticide, dimethoate. We aimed to assess the effect of alcohol in acute poisoning with the lipophilic S-alkyl OP insecticide, profenofos. Methodology Demographic and clinical data, including an alcohol history, were prospectively collected from all cases of acute poisoning with agricultural profenofos EC50 presenting to two Sri Lankan hospitals over seven years. Results Of 1859 patients with acute OP insecticide self-poisoning, 243 (13.1%) reported ingestion of profenofos (male 182/243, 74.9%). Alcohol co-ingestion was reported by 64/243 (26.3%). All patients reporting alcohol co-ingestion were male (64/64 [100%] vs 118/179 [65.9%] not reporting alcohol ingestion, p 35 years vs ≤35 years) and alcohol co-ingestion (OR 3.1 [1.2 to 7.9]) were independently associated with increased risk of death. Increased risk of intubation was independently associated with age (OR 3.2 [1.6 to 6.6] for age 〉 35 years vs ≤35 years) and alcohol co-ingestion (OR 3.2 [1.6 to 6.4]). Conclusion A history of alcohol co-ingestion, as well as older age, is independently associated with worse outcome in patients’ self-poisoned with profenofos.
    Electronic ISSN: 1932-6203
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  • 25
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    Publication Date: 2018-07-06
    Description: by Thiago Veiga Jardim, Thomas A. Gaziano, Flávia Miquetichuc Nascente, Carolina de Souza Carneiro, Polyana Morais, Vanessa Roriz, Karla Lorena Mendonça, Thaís Inácio Rolim Póvoa, Weimar Kunz Sebba Barroso, Ana Luiza Lima Sousa, Paulo César Brandão Veiga Jardim Multiple cardiovascular risk factors are directly related to the severity of atherosclerosis, even in children and adolescents. In this context accurate assessment of risk factors at the individual level play a decisive role in cardiovascular disease (CVD) prevention. The objective of this study was to estimate the prevalence of cardiovascular risk factors, the frequency of their coexistence in individuals, and identify possible determinants associated with this coexistence in Brazilian adolescents. A cross-sectional study with 1170 students (12–17 years) from public and private schools of a large city was conducted. In addition to family history, modifiable cardiovascular risk factors were assessed including: tobacco use, alcohol consumption, sedentary lifestyle, overweight/obesity, increased waist circumference, and high blood pressure (office and home). We built a linear regression model to identify determinants associated with increasing number of modifiable risk factors. Mean study population age was 14.7±1.6 years, 67% were enrolled in public schools and 33% in private ones. The majority of the adolescents had at least two risk factors (68.9%), more than 10% had more than 4 risk factors, and in only 6.7% of the sample no risk factor was identified. Family history of CVD (β-coefficient = 1.20; 95%CI 1.07–1.34; p
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-07-06
    Description: by Anne-Claire Langlois, Carine Marinach, Giulia Manzoni, Olivier Silvie Sporozoite forms of the malaria parasite Plasmodium are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. The molecular mechanisms involved during sporozoite invasion of hepatocytes remain poorly understood. In previous studies, two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the Scavenger Receptor BI (SR-BI), were shown to play an important role during entry of Plasmodium sporozoites into hepatocytic cells. In contrast to HCV entry, which requires both CD81 and SR-BI together with additional host factors, CD81 and SR-BI operate independently during malaria liver infection, as sporozoites can use CD81 and/or SR-BI, depending on the Plasmodium species, to invade hepatocytes. However, the molecular function of CD81 and SR-BI during parasite entry remains unknown. Another HCV entry factor, the Ephrin receptor A2 (EphA2), was recently reported to play a key role as a host cell entry factor during malaria liver infection. Here, we investigated the contribution of EphA2 during CD81-dependent and SR-BI-dependent sporozoite infection. Using small interfering RNA (siRNA) and antibodies against EphA2, combined with direct detection of parasites by flow cytometry or microscopy, we show that blocking EphA2 has no significant impact on P . yoelii or P . berghei host cell infection, irrespective of the entry route. Thus, our findings argue against an important role of EphA2 during malaria liver infection.
    Electronic ISSN: 1932-6203
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  • 27
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    Publication Date: 2018-07-06
    Description: by Adam S. Dingens, Priyamvada Acharya, Hugh K. Haddox, Reda Rawi, Kai Xu, Gwo-Yu Chuang, Hui Wei, Baoshan Zhang, John R. Mascola, Bridget Carragher, Clinton S. Potter, Julie Overbaugh, Peter D. Kwong, Jesse D. Bloom Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross-reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape both delineate pathways of resistance to these fusion peptide-directed antibodies and provide a strategy to improve the breadth or potency of future vaccine-induced antibodies against Env’s fusion peptide.
    Print ISSN: 1553-7366
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  • 28
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    Publication Date: 2018-07-06
    Description: by Johan van den Hoogen, Francine Govers
    Print ISSN: 1553-7366
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  • 29
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-07
    Description: by Lizhen Wu, Jian Cao, Wesley L. Cai, Sabine M. Lang, John R. Horton, Daniel J. Jansen, Zongzhi Z. Liu, Jocelyn F. Chen, Meiling Zhang, Bryan T. Mott, Katherine Pohida, Ganesha Rai, Stephen C. Kales, Mark J. Henderson, Xin Hu, Ajit Jadhav, David J. Maloney, Anton Simeonov, Shu Zhu, Akiko Iwasaki, Matthew D. Hall, Xiaodong Cheng, Gerald S. Shadel, Qin Yan Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection and cancer. STING agonists induce both innate and adaptive immune responses and are a new class of cancer immunotherapy agents tested in multiple clinical trials. However, STING is commonly silenced in cancer cells via unclear mechanisms, limiting the application of these agonists. Here, we report that the expression of STING is epigenetically suppressed by the histone H3K4 lysine demethylases KDM5B and KDM5C and is activated by the opposing H3K4 methyltransferases. The induction of STING expression by KDM5 blockade triggered a robust interferon response in a cytosolic DNA-dependent manner in breast cancer cells. This response resulted in resistance to infection by DNA and RNA viruses. In human tumors, KDM5B expression is inversely associated with STING expression in multiple cancer types, with the level of intratumoral CD8 + T cells, and with patient survival in cancers with a high level of cytosolic DNA, such as human papilloma virus (HPV)-positive head and neck cancer. These results demonstrate a novel epigenetic regulatory pathway of immune response and suggest that KDM5 demethylases are potential targets for antipathogen treatment and anticancer immunotherapy.
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  • 30
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    Publication Date: 2018-08-07
    Description: by Maria D. Sallee, Jennifer C. Zonka, Taylor D. Skokan, Brian C. Raftrey, Jessica L. Feldman Non-centrosomal microtubule organizing centers (ncMTOCs) are found in most differentiated cells, but how these structures regulate microtubule organization and dynamics is largely unknown. We optimized a tissue-specific degradation system to test the role of the essential centrosomal microtubule nucleators γ-tubulin ring complex (γ-TuRC) and AIR-1/Aurora A at the apical ncMTOC, where they both localize in Caenorhabditis elegans embryonic intestinal epithelial cells. As at the centrosome, the core γ-TuRC component GIP-1/GCP3 is required to recruit other γ-TuRC components to the apical ncMTOC, including MZT-1/MZT1, characterized here for the first time in animal development. In contrast, AIR-1 and MZT-1 were specifically required to recruit γ-TuRC to the centrosome, but not to centrioles or to the apical ncMTOC. Surprisingly, microtubules remain robustly organized at the apical ncMTOC upon γ-TuRC and AIR-1 co-depletion, and upon depletion of other known microtubule regulators, including TPXL-1/TPX2, ZYG-9/ch-TOG, PTRN-1/CAMSAP, and NOCA-1/Ninein. However, loss of GIP-1 removed a subset of dynamic EBP-2/EB1–marked microtubules, and the remaining dynamic microtubules grew faster. Together, these results suggest that different microtubule organizing centers (MTOCs) use discrete proteins for their function, and that the apical ncMTOC is composed of distinct populations of γ-TuRC-dependent and -independent microtubules that compete for a limited pool of resources.
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  • 31
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    Publication Date: 2018-08-07
    Description: by Ewa M. Michalak, Michael J. G. Milevskiy, Rachel M. Joyce, Johanna F. Dekkers, Paul R. Jamieson, Bhupinder Pal, Caleb A. Dawson, Yifang Hu, Stuart H. Orkin, Warren S. Alexander, Geoffrey J. Lindeman, Gordon K. Smyth, Jane E. Visvader Distinct transcriptional states are maintained through organization of chromatin, resulting from the sum of numerous repressive and active histone modifications, into tightly packaged heterochromatin versus more accessible euchromatin. Polycomb repressive complex 2 (PRC2) is the main mammalian complex responsible for histone 3 lysine 27 trimethylation (H3K27me3) and is integral to chromatin organization. Using in vitro and in vivo studies, we show that deletion of Suz12 , a core component of all PRC2 complexes, results in loss of H3K27me3 and H3K27me2 dimethylation (H3K27me2), completely blocks normal mammary gland development, and profoundly curtails progenitor activity in 3D organoid cultures. Through the application of mammary organoids to bypass the severe phenotype associated with Suz12 loss in vivo , we have explored gene expression and chromatin structure in wild-type and Suz12 -deleted basal-derived organoids. Analysis of organoids led to the identification of lineage-specific changes in gene expression and chromatin structure, inferring cell type–specific PRC2-mediated gene silencing of the chromatin state. These expression changes were accompanied by cell cycle arrest but not lineage infidelity. Together, these data indicate that canonical PRC2 function is essential for development of the mammary gland through the repression of alternate transcription programs and maintenance of chromatin states.
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  • 32
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    Publication Date: 2018-08-07
    Description: by Tianwei Yu Dynamic correlations are pervasive in high-throughput data. Large numbers of gene pairs can change their correlation patterns in response to observed/unobserved changes in physiological states. Finding changes in correlation patterns can reveal important regulatory mechanisms. Currently there is no method that can effectively detect global dynamic correlation patterns in a dataset. Given the challenging nature of the problem, the currently available methods use genes as surrogate measurements of physiological states, which cannot faithfully represent true underlying biological signals. In this study we develop a new method that directly identifies strong latent dynamic correlation signals from the data matrix, named DCA: Dynamic Correlation Analysis. At the center of the method is a new metric for the identification of pairs of variables that are highly likely to be dynamically correlated, without knowing the underlying physiological states that govern the dynamic correlation. We validate the performance of the method with extensive simulations. We applied the method to three real datasets: a single cell RNA-seq dataset, a bulk RNA-seq dataset, and a microarray gene expression dataset. In all three datasets, the method reveals novel latent factors with clear biological meaning, bringing new insights into the data.
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  • 33
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    Publication Date: 2018-08-07
    Description: by Rui Zhang, Yuan Gao, Xiaotong Zhao, Mei Gao, Yanjun Wu, Yingying Han, Yuemei Qiao, Zheng Luo, Li Yang, Jianfeng Chen, Gaoxiang Ge Adipocyte progenitors reside in the stromal vascular fraction (SVF) of adipose tissues that are composed of fibroblasts, immune cells, and endothelial cells. It remains to be elucidated how the SVF regulates adipocyte progenitor fate determination and adipose homeostasis. Here, we report that fibroblast-specific protein-1 (FSP1) + fibroblasts in the SVF are essential to adipose homeostasis. FSP1 + fibroblasts, devoid of adipogenic potential, are adjacent to the preadipocytes in the SVF. Ablation of FSP1 + fibroblasts in mice severely diminishes fat content of adipose depots. Activation of canonical Wnt signaling in the FSP1 + fibroblasts results in gradual loss of adipose tissues and resistance to diet-induced obesity. Alterations in the FSP1 + fibroblasts reduce platelet-derived growth factor (PDGF)-BB signaling and result in the loss of preadipocytes. Reduced PDGF-BB signaling, meanwhile, impairs the adipogenic differentiation capability of preadipocytes by regulating matrix metalloproteinase (MMP) expression, extracellular matrix remodeling, and the activation of Yes-associated protein (YAP) signaling. Thus, FSP1 + fibroblasts are an important niche essential to the maintenance of the preadipocyte pool and its adipogenic potential in adipose homeostasis.
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  • 34
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    Publication Date: 2018-08-07
    Description: by Hefei Zhang, Quan Zhang, Ge Gao, Xinjian Wang, Tiantian Wang, Zhitao Kong, Guoxiang Wang, Cuizhen Zhang, Yun Wang, Gang Peng The mTOR signaling pathways regulate cell growth and are involved in multiple human diseases. Here, we identify UBTOR , a previously unannotated gene as a functional player in regulating cell growth and mTOR signaling. Reduction of UBTOR function in cultured hippocampal neurons and PC12 cells promotes neurite outgrowth. UBTOR depletion activates mTOR signaling and promotes cell growth, whilst UBTOR overexpression suppresses colony formation in cancer cell lines. Studies in cultured cells and zebrafish model show that UBTOR inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, and ubtor gene disruption result in higher mTOR activity and aggravate HRAS(G12V) induced neoplasia in the zebrafish. Lastly, UBTOR depletion promotes tumor growth and mTOR signaling in a xenograft mouse model. Together, our results demonstrate how UBTOR regulates cell growth and neoplasia via mTOR signaling.
    Print ISSN: 1553-7390
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  • 35
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    Publication Date: 2018-08-07
    Description: by Sergio Córdoba, Carlos Estella The mechanisms that control tissue patterning and cell behavior are extensively studied separately, but much less is known about how these two processes are coordinated. Here we show that the Drosophila transcription factor Dysfusion (Dysf) directs leg epithelial folding and joint formation through the regulation of Rho1 activity. We found that Dysf-induced Rho1 activity promotes apical constriction specifically in folding epithelial cells. Here we show that downregulation of Rho1 or its downstream effectors cause defects in fold and joint formation. In addition, Rho1 and its effectors are sufficient to induce the formation of epithelial folds when misexpressed in a flat epithelium. Furthermore, as apoptotic cells can actively control tissue remodeling, we analyzed the role of cell death in the formation of tarsal folds and its relation to Rho1 activity. Surprisingly, we found no defects in this process when apoptosis is inhibited. Our results highlight the coordination between a patterning transcription factor and the cellular processes that cause the cell shape changes necessary to sculpt a flat epithelium into a three dimensional structure.
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  • 36
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    Publication Date: 2018-08-07
    Description: by Patrick Torbey, Elodie Thierion, Samuel Collombet, Anne de Cian, Carole Desmarquet-Trin-Dinh, Mathilde Dura, Jean-Paul Concordet, Patrick Charnay, Pascale Gilardi-Hebenstreit Cis -regulation plays an essential role in the control of gene expression, and is particularly complex and poorly understood for developmental genes, which are subject to multiple levels of modulation. In this study, we performed a global analysis of the cis -acting elements involved in the control of the zebrafish developmental gene krox20 . krox20 encodes a transcription factor required for hindbrain segmentation and patterning, a morphogenetic process highly conserved during vertebrate evolution. Chromatin accessibility analysis reveals a cis -regulatory landscape that includes 6 elements participating in the control of initiation and autoregulatory aspects of krox20 hindbrain expression. Combining transgenic reporter analyses and CRISPR/Cas9-mediated mutagenesis, we assign precise functions to each of these 6 elements and provide a comprehensive view of krox20 cis -regulation. Three important features emerged. First, cooperation between multiple cis -elements plays a major role in the regulation. Cooperation can surprisingly combine synergy and redundancy, and is not restricted to transcriptional enhancer activity (for example, 4 distinct elements cooperate through different modes to maintain autoregulation). Second, several elements are unexpectedly versatile, which allows them to be involved in different aspects of control of gene expression. Third, comparative analysis of the elements and their activities in several vertebrate species reveals that this versatility is underlain by major plasticity across evolution, despite the high conservation of the gene expression pattern. These characteristics are likely to be of broad significance for developmental genes.
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  • 37
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    Publication Date: 2018-08-07
    Description: by Douglas J. Brusich, Ashlyn M. Spring, Thomas D. James, Catherine J. Yeates, Timothy H. Helms, C. Andrew Frank Gain-of-function mutations in the human Ca V 2.1 gene CACNA1A cause familial hemiplegic migraine type 1 (FHM1). To characterize cellular problems potentially triggered by Ca V 2.1 gains of function, we engineered mutations encoding FHM1 amino-acid substitutions S218L (SL) and R192Q (RQ) into transgenes of Drosophila melanogaster Ca V 2/ cacophony . We expressed the transgenes pan-neuronally. Phenotypes were mild for RQ-expressing animals. By contrast, single mutant SL- and complex allele RQ,SL-expressing animals showed overt phenotypes, including sharply decreased viability. By electrophysiology, SL- and RQ,SL-expressing neuromuscular junctions (NMJs) exhibited enhanced evoked discharges, supernumerary discharges, and an increase in the amplitudes and frequencies of spontaneous events. Some spontaneous events were gigantic (10–40 mV), multi-quantal events. Gigantic spontaneous events were eliminated by application of TTX–or by lowered or chelated Ca 2+ –suggesting that gigantic events were elicited by spontaneous nerve firing. A follow-up genetic approach revealed that some neuronal hyperexcitability phenotypes were reversed after knockdown or mutation of Drosophila homologs of phospholipase Cβ (PLCβ), IP 3 receptor, or ryanodine receptor (RyR)–all factors known to mediate Ca 2+ release from intracellular stores. Pharmacological inhibitors of intracellular Ca 2+ store release produced similar effects. Interestingly, however, the decreased viability phenotype was not reversed by genetic impairment of intracellular Ca 2+ release factors. On a cellular level, our data suggest inhibition of signaling that triggers intracellular Ca 2+ release could counteract hyperexcitability induced by gains of Ca V 2.1 function.
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    Publication Date: 2018-08-07
    Description: by Nadia Amanzougaghene, Florence Fenollar, Claude Nappez, Amira Ben-Amara, Philippe Decloquement, Said Azza, Yassina Bechah, Eric Chabrière, Didier Raoult, Oleg Mediannikov Ivermectin has emerged as very promising pediculicide, particularly in cases of resistance to commonly used pediculicides. Recently, however, the first field-evolved ivermectin-resistance in lice was reported. To gain insight into the mechanisms underlying ivermectin-resistance, we both looked for mutations in the ivermectin-target site (GluCl) and searched the entire proteome for potential new loci involved in resistance from laboratory susceptible and ivermectin-selected resistant body lice. Polymorphism analysis of cDNA GluCl showed no non-silent mutations. Proteomic analysis identified 22 differentially regulated proteins, of which 13 were upregulated and 9 were downregulated in the resistant strain. We evaluated the correlation between mRNA and protein levels by qRT-PCR and found that the trend in transcriptional variation was consistent with the proteomic changes. Among differentially expressed proteins, a complexin i.e. a neuronal protein which plays a key role in regulating neurotransmitter release, was shown to be the most significantly down-expressed in the ivermectin-resistant lice. Moreover, DNA-mutation analysis revealed that some complexin transcripts from resistant lice gained a premature stop codon, suggesting that this down-expression might be due, in part, to secondary effects of a nonsense mutation inside the gene. We further confirmed the association between complexin and ivermectin-resistance by RNA-interfering and found that knocking down the complexin expression induces resistance to ivermectin in susceptible lice. Our results provide evidence that complexin plays a significant role in regulating ivermectin resistance in body lice and represents the first evidence that links complexin to insecticide resistance.
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    Publication Date: 2018-08-07
    Description: by Prakitchai Chotewutmontri, Alice Barkan Plants and algae adapt to fluctuating light conditions to optimize photosynthesis, minimize photodamage, and prioritize energy investments. Changes in the translation of chloroplast mRNAs are known to contribute to these adaptations, but the scope and magnitude of these responses are unclear. To clarify the phenomenology, we used ribosome profiling to analyze chloroplast translation in maize seedlings following dark-to-light and light-to-dark shifts. The results resolved several layers of regulation. (i) The psbA mRNA exhibits a dramatic gain of ribosomes within minutes after shifting plants to the light and reverts to low ribosome occupancy within one hour in the dark, correlating with the need to replace damaged PsbA in Photosystem II. (ii) Ribosome occupancy on all other chloroplast mRNAs remains similar to that at midday even after 12 hours in the dark. (iii) Analysis of ribosome dynamics in the presence of lincomycin revealed a global decrease in the translation elongation rate shortly after shifting plants to the dark. The pausing of chloroplast ribosomes at specific sites changed very little during these light-shift regimes. A similar but less comprehensive analysis in Arabidopsis gave similar results excepting a trend toward reduced ribosome occupancy at the end of the night. Our results show that all chloroplast mRNAs except psbA maintain similar ribosome occupancy following short-term light shifts, but are nonetheless translated at higher rates in the light due to a plastome-wide increase in elongation rate. A light-induced recruitment of ribosomes to psbA mRNA is superimposed on this global response, producing a rapid and massive increase in PsbA synthesis. These findings highlight the unique translational response of psbA in mature chloroplasts, clarify which steps in psbA translation are light-regulated in the context of Photosystem II repair, and provide a foundation on which to explore mechanisms underlying the psbA- specific and global effects of light on chloroplast translation.
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    Publication Date: 2018-08-07
    Description: by Yan-Yi Xing, Xiao-Ning Cheng, Yu-Long Li, Chong Zhang, Audrey Saquet, Yuan-Yuan Liu, Ming Shao, De-Li Shi Wnt signaling plays critical roles in dorsoventral fate specification and anteroposterior patterning, as well as in morphogenetic cell movements. Dishevelled proteins, or Dvls, mediate the activation of Wnt/ß-catenin and Wnt/planar cell polarity pathways. There are at least three highly conserved Dvl proteins in vertebrates, but the implication of each Dvl in key early developmental processes remains poorly understood. In this study, we use genome-editing approach to generate different combinations of maternal and zygotic dvl mutants in zebrafish, and examine their functions during early development. Maternal transcripts for dvl2 and dvl3a are most abundantly expressed, whereas the transcript levels of other dvl genes are negligible. Phenotypic and molecular analyses show that early dorsal fate specification is not affected in maternal and zygotic dvl2 and dvl3a double mutants, suggesting that the two proteins may be dispensable for the activation of maternal Wnt/ß-catenin signaling. Interestingly, convergence and extension movements and anteroposterior patterning require both maternal and the zygotic functions of Dvl2 and Dvl3a, but these processes are more sensitive to Dvl2 dosage. Zygotic dvl2 and dvl3a double mutants display mild axis extension defect with correct anteroposterior patterning. However, maternal and zygotic double mutants exhibit most strongly impaired convergence and extension movements, severe trunk and posterior deficiencies, and frequent occurrence of cyclopia and craniofacial defects. Our results suggest that Dvl2 and Dvl3a products are required for the activation of zygotic Wnt/ß-catenin signaling and Wnt/planar cell polarity pathway, and regulate zygotic developmental processes in a dosage-dependent manner. This work provides insight into the mechanisms of Dvl-mediated Wnt signaling pathways during early vertebrate development.
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    Publication Date: 2018-08-07
    Description: by Toni Whistler, Patranuch Sapchookul, David W. McCormick, Ornuma Sangwichian, Possawat Jorakate, Sirirat Makprasert, Anchalee Jatapai, Sathapana Naorat, Uraiwan Surin, Surathinee Koosakunwat, Surachai Supcharassaeng, Barameht Piralam, Mathew Mikoleit, Henry C. Baggett, Julia Rhodes, Christopher J. Gregory Introduction Invasive salmonellosis is a common cause of bloodstream infection in Southeast Asia. Limited epidemiologic and antimicrobial resistance data are available from the region. Methods Blood cultures performed in all 20 hospitals in the northeastern province of Nakhon Phanom (NP) and eastern province of Sa Kaeo (SK), Thailand were captured in a bloodstream infection surveillance system. Cultures were performed as clinically indicated in hospitalized patients; patients with multiple positive cultures had only the first included. Bottles were incubated using the BacT/Alert system (bioMérieux, Thailand) and isolates were identified using standard microbiological techniques; all Salmonella isolates were classified to at least the serogroup level. Antimicrobial resistance was assessed using disk diffusion. Results Salmonella was the fifth most common pathogen identified in 147,535 cultures with 525 cases (211 in Nakhon Phanom (NP) and 314 in Sa Kaeo (SK)). The overall adjusted iNTS incidence rate in NP was 4.0 cases/100,000 person-years (95% CI 3.5–4.5) and in SK 6.4 cases/100,000 person-years (95% CI 5.7–7.1; p = 0.001). The most common serogroups were C (39.4%), D (35.0%) and B (9.9%). Serogroup D predominated in NP (103/211) with 59.2% of this serogroup being Salmonella serovar Enteritidis. Serogroup C predominated in SK (166/314) with 84.3% of this serogroup being Salmonella serovar Choleraesuis. Antibiotic resistance was 68.2% (343/503) for ampicillin, 1.2% (6/482) for ciprofloxacin (or 58.1% (280/482) if both intermediate and resistant phenotypes are considered), 17.0% (87/512) for trimethoprim-sulfamethoxazole, and 12.2% (59/484) for third-generation cephalosporins (cefotaxime or ceftazidime). Multidrug resistance was seen in 99/516 isolates (19.2%). Conclusions The NTS isolates causing bloodstream infections in rural Thailand are commonly resistant to ampicillin, cefotaxime, and TMP-SMX. Observed differences between NP and SK indicate that serogroup distribution and antibiotic resistance may substantially differ throughout Thailand and the region.
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    Publication Date: 2018-08-07
    Description: by Gilbert Adjimon Ayelo, Ghislain Emmanuel Sopoh, Jean-Gabin Houezo, René Fiodessihoue, Dissou Affolabi, Ange Dodji Dossou, Yves Thierry Barogui, Akpeedje Anita Carolle Wadagni, Didier Codjo Agossadou, Epco Hasker, Françoise Portaels, Bouke C. de Jong, Miriam Eddyani Background Buruli ulcer (BU) is a chronic necrotizing infectious skin disease caused by Mycobacterium ulcerans . The treatment with BU-specific antibiotics is initiated after clinical suspicion based on the WHO clinical and epidemiological criteria. This study aimed to estimate the predictive values of these criteria and how they could be improved. Methodology/Principal findings A total of 224 consecutive patients presenting with skin and soft tissue lesions that could be compatible with BU, including those recognized as unlikely BU by experienced clinicians, were recruited in two BU treatment centers in southern Benin between March 2012 and March 2015. For every participant, the WHO and four additional epidemiological and clinical diagnostic criteria were recorded. For microbiological confirmation, direct smear examination and IS 2404 PCR were performed. We fitted a logistic regression model with PCR positivity for BU confirmation as outcome variable. On univariate analysis, most of the clinical and epidemiological WHO criteria were associated with a positive PCR result. However, lesions on the lower limbs and WHO category 3 lesions were rather associated with a negative PCR result (respectively OR: 0.4, 95%CI: 0.3–0.8; OR: 0.5, 95%IC: 0.3–0.9). Among the additional characteristics studied, the characteristic smell of BU was strongest associated with a positive PCR result (OR = 16.4; 95%CI = 7.5–35.6). Conclusion/Significance The WHO diagnostic criteria could be improved upon by differentiating between lesions on the upper and lower limbs and by including lesion size and the characteristic smell recognized by experienced clinicians.
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  • 43
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    Publication Date: 2018-08-07
    Description: by N. R. Ramesh Masthi, Pruthvi S. Need for study Rabies is a neglected zoonotic disease. Given the low incidence, apart from the existing reporting syst, there is a need to look for other means of case detection strategies for rabies. Contact tracing is one such method to efficiently capture information. Objectives To find out the rabid status of biting animal through contact tracing and to determine health seeking behavior of the bite victims. Materials and methods An exploratory study using contact tracing was conducted during the first quarter of 2017 in villages coming under three Public Health Centers. The households of the bite victims were visited and details of rabies exposure obtained from the bite victim/ adult responsible respondent using a standardized questionnaire. Results A total of 69 dog/cat bite cases were identified. 69.5% of bites were by stray dogs. 97.1% bite victims had Category III bites. Only 4.5% bite victims had taken PEP. 70.1% of animal bite cases were administered ARV. Only 7.2% bite victims had exposure to probable rabid animals. All dog bite victims were alive after 3 months of follow up. Conclusion Contact tracing was successful in case detection of probable rabid animal exposures and suitable for a period of one year.
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  • 44
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    Publication Date: 2018-08-07
    Description: by Sunamita de Carvalho Lima, Lucas de Carvalho Porta, Álvaro da Costa Lima, Joana D’Arc Campeiro, Ywlliane Meurer, Nathália Bernardes Teixeira, Thiago Duarte, Eduardo Brandt Oliveira, Gisele Picolo, Rosely Oliveira Godinho, Regina Helena Silva, Mirian Akemi Furuie Hayashi The high medical importance of Crotalus snakes is unquestionable, as this genus is the second in frequency of ophidian accidents in many countries, including Brazil. With a relative less complex composition compared to other genera venoms, as those from the Bothrops genus, the Crotalus genus venom from South America is composed basically by the neurotoxin crotoxin (a phospholipase A2), the thrombin-like gyroxin (a serinoprotease), a very potent aggregating protein convulxin, and a myotoxic polypeptide named crotamine. Interestingly not all Crotalus snakes express crotamine, which was first described in early 50s due to its ability to immobilize animal hind limbs, contributing therefore to the physical immobilization of preys and representing an important advantage for the envenoming efficacy, and consequently, for the feeding and survival of these snakes in nature. Representing about 10–25% of the dry weight of the crude venom of crotamine-positive rattlesnakes, the polypeptide crotamine is also suggested to be of importance for antivenom therapy, although the contribution of this toxin to the main symptoms of envenoming process remains far unknown until now. Herein, we concomitantly performed in vitro and in vivo assays to show for the first time the dose-dependent response of crotamine-triggered hind limbs paralysis syndrome, up to now believed to be observable only at high (sub-lethal) concentrations of crotamine. In addition, ex vivo assay performed with isolated skeletal muscles allowed us to suggest here that compounds active on voltage-sensitive sodium and/or potassium ion channels could both affect the positive inotropic effect elicited by crotamine in isolated diaphragm, besides also affecting the hind limbs paralysis syndrome imposed by crotamine in vivo . By identifying the potential molecular targets of this toxin, our data may contribute to open new roads for translational studies aiming to improve the snakebite envenoming treatment in human. Interestingly, we also demonstrate that the intraplantal or intraperitoneal ( ip ) injections of crotamine in mice do not promote pain. Therefore, this work may also suggest the profitable utility of non-toxic analogs of crotamine as a potential tool for targeting voltage-gated ion channels in skeletal muscles, aiming its potential use in the therapy of neuromuscular dysfunctions and envenoming therapy.
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  • 45
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    Publication Date: 2018-08-07
    Description: by Kelly M. Hennessey, Ilse C. Rogiers, Han-Wei Shih, Matthew A. Hulverson, Ryan Choi, Molly C. McCloskey, Grant R. Whitman, Lynn K. Barrett, Ethan A. Merritt, Alexander R. Paredez, Kayode K. Ojo There is need for a more efficient cell-based assay amenable to high-throughput drug screening against Giardia lamblia . Here, we report the development of a screening method utilizing G . lamblia engineered to express red-shifted firefly luciferase. Parasite growth and replication were quantified using D-luciferin as a substrate in a bioluminescent read-out platform. This assay was validated for reproducibility and reliability against the Medicines for Malaria Venture (MMV) Pathogen Box compounds. For G . lamblia , forty-three compounds showed ≥ 75% inhibition of parasite growth in the initial screen (16 μM), with fifteen showing ≥ 95% inhibition. The Pathogen Box was also screened against Nanoluciferase expressing (Nluc) C . parvum , yielding 85 compounds with ≥ 75% parasite growth inhibition at 10 μM, with six showing ≥ 95% inhibition. A representative set of seven compounds with activity against both parasites were further analyzed to determine the effective concentration that causes 50% growth inhibition (EC 50 ) and cytotoxicity against mammalian HepG2 cells. Four of the seven compounds were previously known to be effective in treating either Giardia or Cryptosporidium . The remaining three shared no obvious chemical similarity with any previously characterized anti-parasite diarrheal drugs and offer new medicinal chemistry opportunities for therapeutic development. These results suggest that the bioluminescent assays are suitable for large-scale screening of chemical libraries against both C . parvum and G . lamblia .
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  • 46
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    Publication Date: 2018-08-07
    Description: by Jean Claude Dejon-Agobé, Jeannot Fréjus Zinsou, Yabo Josiane Honkpehedji, Ulysse Ateba-Ngoa, Jean-Ronald Edoa, Bayodé Roméo Adegbite, Ghyslain Mombo-Ngoma, Selidji Todagbe Agnandji, Michael Ramharter, Peter Gottfried Kremsner, Bertrand Lell, Martin Peter Grobusch, Ayôla Akim Adegnika Background Malaria burden remains high in the sub-Saharan region where helminths are prevalent and where children are often infected with both types of parasites. Although the effect of helminths on malaria infection is evident, the impact of these co-infections is not clearly elucidated yet and the scarce findings are conflicting. In this study, we investigated the effect of schistosomiasis, considering soil-transmitted helminths (STH), on prevalence and incidence of Plasmodium falciparum infection. Methodology This longitudinal survey was conducted in school-age children living in two rural communities in the vicinity of Lambaréné, Gabon. Thick blood smear light microscopy, urine filtration and the Kato-Katz technique were performed to detect malaria parasites, S . haematobium eggs and, STH eggs, respectively. P . falciparum carriage was assessed at inclusion, and incidence of malaria and time to the first malaria event were recorded in correlation with Schistosoma carriage status. Stratified multivariate analysis using generalized linear model was used to assess the risk of plasmodium infection considering interaction with STH, and survival analysis to assess time to malaria. Main findings The overall prevalence on subject enrolment was 30%, 23% and 9% for S . haematobium , P . falciparum infections and co-infection with both parasites, respectively. Our results showed that schistosomiasis in children tends to increase the risk of plasmodium infection but a combined effect with Trichuris trichiura or hookworm infection clearly increase the risk (aOR = 3.9 [ 95% CI: 1.7–9.2]). The incidence of malaria over time was 0.51[ 95% CI: 0.45–0.57] per person-year and was higher in the Schistosoma-infected group compared to the non-infected group (0.61 vs 0.43, p = 0.02), with a significant delay of time-to first-malaria event only in children aged from 6 to 10-years-old infected with Schistosoma haematobium . Conclusions Our results suggest that STH enhance the risk for P . falciparum infection in schistosomiasis-positive children, and when infected, that schistosomiasis enhances susceptibility to developing malaria in young children but not in older children.
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  • 47
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    Publication Date: 2018-08-07
    Description: by Akhilesh C. Mishra, Vidya A. Arankalle, Swapnil A. Gadhave, Pritam H. Mahadik, Shubham Shrivastava, Mandar Bhutkar, Varsha M. Vaidya Background In India, dengue disease is emerging as the most important vector borne public health problem due to rapid and unplanned urbanization, high human density and week management of the disease. Clinical cases are grossly underreported and not much information is available on prevalence and incidence of the disease. Methodology A cross sectional, stratified, facility based, multistage cluster sampling was conducted between May 4 and June 27, 2017 in Pune city. A total of 1,434 participants were enrolled. The serum samples were tested for detection of historical dengue IgG antibodies by ELISA using the commercial Panbio Dengue IgG Indirect ELISA kit. Anti-dengue IgG-capture Panbio ELISA was used for detection of high titered antibodies to detect recent secondary infection. We used this data to estimate key transmission parameters like force of infection and basic reproductive number. A subset of 120 indirect ELISA positive samples was also tested for Plaque Reduction Neutralizing Antibodies for determining serotype-specific prevalence. Findings Overall, 81% participants were infected with dengue virus (DENV) at least once if not more. The positivity was significantly different in different age groups. All the adults above 70 years were positive for DENV antibodies. Over 69% participants were positive for neutralizing antibodies against all 4 serotypes suggesting intense transmission of all DENV serotypes in Pune. Age-specific seroprevalence was consistent with long-term, endemic circulation of DENV. There was an increasing trend with age, from 21.6% among
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  • 48
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    Publication Date: 2018-08-07
    Description: by The PLOS ONE Editors
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Publication Date: 2018-08-07
    Description: by The PLOS ONE Staff
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    Publication Date: 2018-08-07
    Description: by Jolynne Mokaya, Anna L. McNaughton, Martin J. Hadley, Apostolos Beloukas, Anna-Maria Geretti, Dominique Goedhals, Philippa C. Matthews International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with compensatory mutations, and identified in both reportedly treatment-naïve and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.
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    Publication Date: 2018-08-07
    Description: by Katyuce de S. Farias, Thierry Delatte, Rosani do C. de O. Arruda, Flavio M. Alves, Denise B. Silva, Jules Beekwilder, Carlos A. Carollo Plants produce a wide range of secondary metabolites. Within a single species, chemotypes can be distinguished by the differences in the composition of the secondary metabolites. Herein, we evaluated Nectandra megapotamica (Spreng.) chemotypes and the balance of different classes of metabolites to verify how significant differences in plant metabolism are regarding chemotypes. We collected N . megapotamica leaves from eight adult plants in two Brazilian states. The essential oils and ethanol/water extracts were analyzed by GC-MS and LC-DAD-MS, respectively. Histochemical tests were performed, as well as chemical analyses of leaves from adaxial and abaxial foliar surfaces of N . megapotamica , and the stereochemistry of α-bisabolol was determined. Two different chemotypes, based on volatile compounds, were identified, distinguished by the presence of isospathulenol, α-bisabolol, β-bisabolene, and (E)-nerolidol for chemotype A, and bicyclogermacrene and elemicin for chemotype B. A stereochemical analysis of chemotype A extract revealed (+)-α-bisabolol enantiomer. Histochemical tests of chemotypes showed similar results and suggested the presence of essential oil in idioblasts stained with the dye NADI. The analyses of chemotype A leaves by GC-MS revealed similar compositions for abaxial and adaxial surfaces, such pattern was also observed for chemotype B. Medium and high polarity metabolites showed high chemical similarities between the chemotypes, highlighting the presence of proanthocyanidins and glycosylated flavonoids ( O - and C -glycosides). Thus, N . megapotamica produced distinct volatile chemotypes with highly conserved medium to high polarity compounds. Such results suggest that phenolic derivatives have a basal physiological function, while genetic or environmental differences lead to differentiation in volatile profiles of N . megapotamica .
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  • 52
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    Publication Date: 2018-08-07
    Description: by Tram T. Vuong, Sissel B. Rønning, Tamer A. E. Ahmed, Kristiane Brathagen, Vibeke Høst, Maxwell T. Hincke, Henri-Pierre Suso, Mona E. Pedersen Avian eggshell membrane (ESM) is a natural biomaterial that has been used as an alternative natural bandage to cure wounds, and is available in large quantities from egg industries. We have previously demonstrated that processed eggshell membrane powder (PEP), aiming to be used in a low cost wound healing product, possesses anti-inflammatory properties. In this study, we further investigated effects of PEP on MMP activities in vitro (a dermal fibroblast cell culture system) and in vivo (a mouse skin wound healing model). Three days incubation with PEP in cell culture led to rearrangement of the actin-cytoskeleton and vinculin in focal adhesions and increased syndecan-4 shedding. In addition, we observed increased matrix metalloproteinase type 2 (MMP-2) enzyme activation, without effects on protein levels of MMP-2 or its regulators (membrane type 1 (MT1)-MMP and tissue inhibitor of matrix metalloproteinase type 2 (TIMP-2). Longer incubation (10 days) led to increased protein levels of MMP-2 and its regulators. We also observed an increased alpha-smooth muscle actin (α-SMA) production, suggesting an effect of PEP on myofibroblast differentiation. In vivo , using the mouse skin wound healing model, PEP treatment (3 days) increased MMP activity at the wound edges, along with increased MMP-2 and MMP-9 protein levels, and increased keratinocyte cell proliferation. Altogether, our data suggest PEP stimulates MMP activity, and with a positive effect on early cellular events during wound healing.
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  • 53
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    Publication Date: 2018-08-07
    Description: by Samson Gebremedhin Background In developing countries lacking functional vital registration system, statistical models are being increasingly used for estimating maternal mortality ratio (MMR). Yet, most of the models have limited applicability at sub-country level. This paper introduces a new model for estimating MMR at national and sub-national levels based on maternal health-related indicators. Further, it applies the model for explaining sub-national variations of MMR in Ethiopia. Methods Country level data on MMR and other nine potential predictors of maternal death were extracted from 248 national Demographic and Health Surveys and other related surveys conducted in 80 low- and middle-income countries since 1990. Additional data were obtained from the World Bank and the World Health Organization databases. The potential model predictors were: contraceptive prevalence rate (CPR); utilizations of antenatal care (ANC), health institution delivery (HID), Caesarian section (CS) and postnatal care (PNC); and prevalence of maternal anemia, thinness (Body Mass Index (BMI 〈 18.5 kg/m 2 ), short stature (height less than 145 cms) and HIV. Stepwise Generalized Estimating Equation (GEE) with Negative Log-binomial link was employed to model MMR as a function of the covariates. Results The ultimate model comprised six significant predictors and the equation is provided as: Ln (MMR) = 6 . 464–0 . 013(CPR)– 0 . 006(HID)– 0 . 003(PNC)– 0 . 027(CS rate) + 0 . 060(HIV prevalence) + 0 . 011 (thinness prevalence) . The variation explained by the model was 54.3%) and the mean (±SD) relative standard error (8.6±2.6%) suggested the model has a reasonable precision. Application of the model to describe sub-national variation of maternal mortality in Ethiopia indicated, in 2016 the highest MMRs per 100,000 live births were in Somali (805) and Afar (795) regions. Between 2000 and 2016, all the regions of Ethiopia have significantly reduced MMRs; yet the rate of decline was lower in the aforementioned two regions. Oromiya region contributed for 46% of all maternal deaths in Ethiopia. Conclusion In developing countries lacking dependable maternal mortality data; the model can be used to estimate national and sub-national MMR with reasonable accuracy and precision.
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    Publication Date: 2018-08-07
    Description: by Yannick Bantel, Rabih Darwiche, Steffen Rupp, Roger Schneiter, Kai Sohn Members of the Cysteine-rich secretory protein, Antigen 5 and Pathogenesis-related 1 (CAP) protein superfamily are important virulence factors in fungi but remain poorly characterized on molecular level. Here, we investigate the cellular localization and molecular function of Rbe1p and Rbt4p, two CAP family members from the human pathogen Candida albicans . We unexpectedly found that Rbe1p localizes to budding sites of yeast cells in a disulfide bond-dependent manner. Furthermore, we show that Rbe1p and Rbt4p bind free cholesterol in vitro and export cholesteryl acetate in vivo . These findings suggest a previously undescribed role for Rbe1p in cell wall-associated processes and a possible connection between the virulence attributes of fungal CAP proteins and sterol binding.
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    Publication Date: 2018-08-07
    Description: by Leonel N. Leal, Josue M. Romao, Guido J. Hooiveld, Fernando Soberon, Harma Berends, Mark V. Boekshoten, Michael E. Van Amburgh, Javier Martín-Tereso, Michael A. Steele Performance of dairy cows can be influenced by early life nutrient supply. Adipose tissue is diet sensitive and an important component in that process as it is involved in the regulation of energetic, reproductive and immunological functions. However, it is not clear how early life nutrition alters the molecular regulation of adipose tissue in calves and potentially adult individuals. This study aimed at determining how differences in pre-weaning nutrient supply alter gene expression profiles and physiology in omental adipose tissue. A total of 12 female Holstein calves were fed two levels of milk replacer supply: a restricted amount of 11.72 MJ of metabolizable energy (ME) intake per day (n = 6) or an enhanced amount of 1.26 MJ ME intake per kg of metabolic body weight (BW 0.75 ), resulting in supply from 17.58 to 35.17 MJ ME intake per day (n = 6). All calves had ad libitum access to a commercial calf starter and water. Analysis of the transcriptome profiles at 54 ± 2 days of age revealed that a total of 396 out of 19,968 genes were differentially expressed (DE) between groups (p 〈 0.001, FDR 〈 0.1). The directional expression of DE genes through Ingenuity Pathway Analysis showed that an enhanced nutrient supply alters adipose tissue physiology of pre-weaned calves. Several biological functions were increased (Z-score 〉 +2), including Lipid Metabolism (Fatty Acid Metabolism), Cell Cycle (Entry into Interphase, Interphase, Mitosis and Cell Cycle Progression), Cellular Assembly and Organization (Cytoskeleton Formation and Cytoplasm Development) and Molecular Transport (Transport of Carboxylic Acid). These changes were potentially orchestrated by the activation/inhibition of 17 upstream regulators genes. Our findings indicate that adipose tissue of calves under an enhanced nutrient supply is physiologically distinct from restricted calves due to an increased development/expansion rate and also a higher metabolic activity through increased fatty acid metabolism.
    Electronic ISSN: 1932-6203
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  • 56
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    Publication Date: 2018-08-07
    Description: by Chih-Hsiung Hsieh, Chueh-Hsuan Lu, Yu-Yi Kuo, Wei-Ting Chen, Chih-Yu Chao Cancer is one of the most troublesome diseases and a leading cause of death worldwide. Recently, novel treatments have been continuously developed to improve the disadvantages of conventional therapies, such as prodigious expenses, unwanted side effects, and tumor recurrence. Here, we provide the first non-invasive treatment that has combined epigallocatechin gallate (EGCG), the most abundant catechin in green tea, with a low strength pulsed electric field (PEF) and a low energy ultrasound (US). It has been observed that the cell viability of human pancreatic cancer PANC-1 was decreased approximately to 20% of the control after this combination treatment for 72 h. Besides, the combined triple treatment significantly reduced the high tolerance of HepG2 cells to the EGCG-induced cytotoxicity and similarly exhibited compelling proliferation-inhibitory effects. We also found the combined triple treatment increased the intracellular reactive oxygen species (ROS) and acidic vesicles, and the EGCG-induced inhibition of Akt phosphorylation was dramatically intensified. In this study, the apoptosis inhibitor Z-VAD-FMK and the autophagy inhibitor 3-MA were, respectively, shown to attenuate the anticancer effects of the triple treatment. This indicates that the triple treatment-induced autophagy was switched from cytoprotective to cytotoxic, and hence, cooperatively caused cell death with the apoptosis. Since the EGCG is easily accessible from the green tea and mild for a long-term treatment, and the non-invasive physical stimulations could be modified to focus on a specific location, this combined triple treatment may serve as a promising strategy for anticancer therapy.
    Electronic ISSN: 1932-6203
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  • 57
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    Publication Date: 2018-08-08
    Description: by Allen Van Deynze, Pablo Zamora, Pierre-Marc Delaux, Cristobal Heitmann, Dhileepkumar Jayaraman, Shanmugam Rajasekar, Danielle Graham, Junko Maeda, Donald Gibson, Kevin D. Schwartz, Alison M. Berry, Srijak Bhatnagar, Guillaume Jospin, Aaron Darling, Richard Jeannotte, Javier Lopez, Bart C. Weimer, Jonathan A. Eisen, Howard-Yana Shapiro, Jean-Michel Ané, Alan B. Bennett Plants are associated with a complex microbiota that contributes to nutrient acquisition, plant growth, and plant defense. Nitrogen-fixing microbial associations are efficient and well characterized in legumes but are limited in cereals, including maize. We studied an indigenous landrace of maize grown in nitrogen-depleted soils in the Sierra Mixe region of Oaxaca, Mexico. This landrace is characterized by the extensive development of aerial roots that secrete a carbohydrate-rich mucilage. Analysis of the mucilage microbiota indicated that it was enriched in taxa for which many known species are diazotrophic, was enriched for homologs of genes encoding nitrogenase subunits, and harbored active nitrogenase activity as assessed by acetylene reduction and 15 N 2 incorporation assays. Field experiments in Sierra Mixe using 15 N natural abundance or 15 N-enrichment assessments over 5 years indicated that atmospheric nitrogen fixation contributed 29%–82% of the nitrogen nutrition of Sierra Mixe maize.
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  • 58
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    Publication Date: 2018-08-08
    Description: by James T. Yurkovich, Miguel A. Alcantar, Zachary B. Haiman, Bernhard O. Palsson Allosteric regulation has traditionally been described by mathematically-complex allosteric rate laws in the form of ratios of polynomials derived from the application of simplifying kinetic assumptions. Alternatively, an approach that explicitly describes all known ligand-binding events requires no simplifying assumptions while allowing for the computation of enzymatic states. Here, we employ such a modeling approach to examine the “catalytic potential” of an enzyme—an enzyme’s capacity to catalyze a biochemical reaction. The catalytic potential is the fundamental result of multiple ligand-binding events that represents a “tug of war” among the various regulators and substrates within the network. This formalism allows for the assessment of interacting allosteric enzymes and development of a network-level understanding of regulation. We first define the catalytic potential and use it to characterize the response of three key kinases (hexokinase, phosphofructokinase, and pyruvate kinase) in human red blood cell glycolysis to perturbations in ATP utilization. Next, we examine the sensitivity of the catalytic potential by using existing personalized models, finding that the catalytic potential allows for the identification of subtle but important differences in how individuals respond to such perturbations. Finally, we explore how the catalytic potential can help to elucidate how enzymes work in tandem to maintain a homeostatic state. Taken together, this work provides an interpretation and visualization of the dynamic interactions and network-level effects of interacting allosteric enzymes.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
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  • 59
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    Publication Date: 2018-08-08
    Description: by Rebecca Kahn, Annette Rid, Peter G. Smith, Nir Eyal, Marc Lipsitch In a Policy Forum, Marc Lipsitch and colleagues discuss trial design issues in infectious disease outbreaks.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
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  • 60
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    Publication Date: 2018-08-08
    Description: by Cesar A. O. Coelho, Tatiana L. Ferreira, Juliana C. Kramer-Soares, João R. Sato, Maria Gabriela M. Oliveira Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear conditioning (CFC). Although the content learned in the latter have been discussed, alternative regions supporting CFC learning were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using inter-regional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belonging to the SHAM network. These results suggest that dHPC network engaged in CFC learning is partially different, and engage alternative hubs. We next tested if pre-training lesions of dHPC and one of the new dHPC network hubs (perirhinal, Per; or disgranular retrosplenial, RSC, cortices) would impair CFC. Only dHPC-RSC, but not dHPC-Per, impaired CFC. Interestingly, only RSC showed a consistently higher centrality in the dHPC network, suggesting that the increased centrality reflects an increased functional dependence on RSC. Our results provide evidence that, without hippocampus, the RSC, an anatomically central region in the medial temporal lobe memory system might support CFC learning and memory.
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  • 61
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    Publication Date: 2018-08-08
    Description: by Carlos F. Gould, Steven N. Chillrud, Douglas Phillips, Matthew S. Perzanowski, Diana Hernández
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 62
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    Publication Date: 2018-08-08
    Description: by Anna Sidorchuk, Kayoko Isomura, Yasmina Molero, Clara Hellner, Paul Lichtenstein, Zheng Chang, Johan Franck, Lorena Fernández de la Cruz, David Mataix-Cols Background Pharmacoepidemiological studies have long raised concerns on widespread use of benzodiazepines and benzodiazepine-related drugs (BZDs), in particular long-term use, among adults and the elderly. In contrast, evidence pertaining to the rates of BZD use at younger ages is still scarce, and the factors that influence BZD utilisation and shape the different prescribing patterns in youths remain largely unexplored. We examined the prevalence rates, relative changes in rates over time, and prescribing patterns for BZD dispensation in young people aged 0–24 years in Sweden during the period January 1, 2006–December 31, 2013, and explored demographic, clinical, pharmacological, and prescriber-related attributes of BZD prescribing in this group. Methods and findings Through the linkage of 3 nationwide Swedish health and administrative registers, we collected data on 17,500 children (0–11 years), 15,039 adolescents (12–17 years), and 85,200 young adults (18–24 years) with at least 1 dispensed prescription for a BZD during 2006–2013, out of 3,726,818 Swedish inhabitants aged 0–24 years. Age-specific annual prevalence rates of BZD dispensations were adjusted for population growth, and relative changes in rates were calculated between 2006 and 2013. We analysed how BZD dispensation varied by sex, psychiatric morbidity and epilepsy, concurrent dispensation of psychotropic medication, type of dispensed BZD, and type of healthcare provider prescribing the BZD. Prescribing patterns were established in relation to duration (3 months, 〉3 to ≤6 months, or 〉6 months), dosage (
    Print ISSN: 1549-1277
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  • 63
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    Publication Date: 2018-08-08
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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  • 64
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    Publication Date: 2018-08-08
    Description: by Cosetta Minelli, Diana A. van der Plaat, Bénédicte Leynaert, Raquel Granell, Andre F. S. Amaral, Miguel Pereira, Osama Mahmoud, James Potts, Nuala A. Sheehan, Jack Bowden, John Thompson, Debbie Jarvis, George Davey Smith, John Henderson Background Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males. Methods and findings MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early ( 14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10 −5 ) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10 −4 ), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking. Conclusions This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.
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  • 65
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    Publication Date: 2018-08-08
    Description: by Tereza Kubasova, Lenka Davidova-Gerzova, Vladimir Babak, Darina Cejkova, Lucile Montagne, Nathalie Le-Floc'h, Ivan Rychlik Since microbiota may influence the physiology of its host including body weight increase, growth rate or feed intake, in this study we determined the microbiota composition in high or low residual feed intake (HRFI and LRFI) pig lines, of different age and/or subjected to sanitary stress by sequencing the V3/V4 variable region of 16S rRNA genes. Allisonella , Megasphaera , Mitsuokella , Acidaminococcus (all belonging to Firmicutes /class Negativicutes ), Lactobacillus , Faecalibacterium , Catenibacterium , Butyrivibrio , Erysipelotrichaceae , Holdemania , Olsenella and Collinsella were more abundant in HRFI pigs. On the other hand, 26 genera including Bacteroides , Clostridium sensu stricto , Oscillibacter , Paludibacter , Elusimicrobium , Bilophila , Pyramidobacter and TM7 genera, and Clostridium XI and Clostridium XIVa clusters were more abundant in LRFI than HRFI pigs. Adaptation of microbiota to new diet after weaning was slower in LRFI than in HRFI pigs. Sanitary stress was of relatively minor influence on pig microbiota composition in both tested lines although abundance of Helicobacter increased in LRFI pigs subjected to stress. Selection for residual feed intake thus resulted in a selection of fecal microbiota of different composition. However, we cannot conclude whether residual feed intake was directly affected by different microbiota composition or whether the residual feed intake and microbiota composition are two independent consequences of yet unknown genetic traits differentially selected in the pigs of the two lines.
    Electronic ISSN: 1932-6203
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  • 66
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    Publication Date: 2018-08-08
    Description: by Ju Yeon Kim, Sung Wan Byun, Seung-Ho Shin, Mi Sun Chun Background When evaluating hearing disability in medicolegal cases, an average of thresholds at several frequencies is calculated using pure tone audiometry. Occasionally, there are instances in which thresholds at certain frequencies are omitted. One typical example is the threshold at 3 kHz (H3k). The American Academy of Otolaryngology–Head and Neck Surgery Committee on Hearing and Equilibrium (1995) suggested that the average of thresholds at 2 kHz and 4 kHz (H24k) could replace H3k for a comparison of results between studies. However, to the best of our knowledge, there is no report in the literature that compares H3k and H24k. Objective This study aimed to investigate the agreement between H3k and H24k. Methods This study is based on the Korea National Health and Nutrition Examination Survey (KNHANES) 2010–2012, which was conducted by the Korean government. A total of 18,472 participants (unweighted) who represented 39,357,497 Koreans (weighted) were included. To verify the agreement of H3k and H24k, a paired t-test, Cohen’s d, Pearson’s correlation, Cronbach’s coefficient, intraclass correlation coefficient (ICC), a Bland–Altman plot, and linear regression analysis were used. Results The means of H3k and H24k were 16.2 dBHL and 16.6 dBHL, respectively. They were significantly different in a paired t-test (p
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  • 67
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    Publication Date: 2018-08-08
    Description: by Mirjana Nacka-Aleksić, Marija Stojanović, Ivan Pilipović, Zorica Stojić-Vukanić, Duško Kosec, Gordana Leposavić An accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCRαβ-mediated signaling and activation thresholds, on CD4+CD8+ TCRαβ lo/hi thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCRαβ hi thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16 INK4a accumulation). The higher circulating level of TNF-α in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.
    Electronic ISSN: 1932-6203
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  • 68
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    Publication Date: 2018-08-08
    Description: by Dávid Szatmári, Bo Xue, Balakrishnan Kannan, Leslie D. Burtnick, Beáta Bugyi, Miklós Nyitrai, Robert C. Robinson Gelsolin is a severing and capping protein that targets filamentous actin and regulates filament lengths near plasma membranes, contributing to cell movement and plasma membrane morphology. Gelsolin binds to the plasma membrane via phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in a state that cannot cap F-actin, and gelsolin-capped actin filaments are uncapped by PIP 2 leading to filament elongation. The process by which gelsolin is removed from PIP 2 at the plasma membrane is currently unknown. Gelsolin also binds ATP with unknown function. Here we characterize the role of ATP on PIP 2 -gelsolin complex dynamics. Fluorophore-labeled PIP 2 and ATP were used to study their interactions with gelsolin using steady-state fluorescence anisotropy, and Alexa488-labeled gelsolin was utilized to reconstitute the regulation of gelsolin binding to PIP 2 -containing phospholipid vesicles by ATP. Under physiological salt conditions ATP competes with PIP 2 for binding to gelsolin, while calcium causes the release of ATP from gelsolin. These data suggest a cycle for gelsolin activity. Firstly, calcium activates ATP-bound gelsolin allowing it to sever and cap F-actin. Secondly, PIP 2 -binding removes the gelsolin cap from F-actin at low calcium levels, leading to filament elongation. Finally, ATP competes with PIP 2 to release the calcium-free ATP-bound gelsolin, allowing it to undergo a further round of severing.
    Electronic ISSN: 1932-6203
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  • 69
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    Publication Date: 2018-08-08
    Description: by Cristian Rodelo-Haad, Maria E. Rodríguez-Ortiz, Alejandro Martin-Malo, M. Victoria Pendon-Ruiz de Mier, M. Luisa Agüera, Juan R. Muñoz-Castañeda, Sagrario Soriano, Francisco Caravaca, M. Antonia Alvarez-Lara, Arnold Felsenfeld, Pedro Aljama, Mariano Rodriguez Background In hemodialysis patients, high levels of Fibroblast Growth Factor 23 (FGF23) predict mortality. Our study was designed to test whether the control of serum phosphate is associated with a reduction in serum FGF23 levels. Additionally other variables with a potential effect on FGF23 levels were evaluated. Material and methods The effect of sustained (40-weeks) control of serum phosphate on FGF23 levels (intact and c-terminal) was evaluated in 21 stable hemodialysis patients that were not receiving calcimimetics or active vitamin D. Patients received non-calcium phosphate binders to maintain serum phosphate below 4.5 mg/dl. In an additional analysis, values of intact-FGF23 (iFGF23) and c-terminal FGF23 (cFGF23) from 150 hemodialysis patients were correlated with parameters of mineral metabolism and inflammation. Linear mixed models and linear regression were performed to evaluate longitudinal trajectories of variables and the association between FGF23 and the other variables examined. Results During the 40-week treatment, 12 of 21 patients achieved the target of serum phosphate 4.5 mg, iFGF23 and cFGF23 increased two and four-fold respectively as compared with baseline. Furthermore, changes in serum phosphate correlated with changes in C-reactive protein ( hs -CRP). In our 150 hemodialysis patients, those in the higher tertile of serum phosphate also showed increased hs -CRP, iPTH, iFGF23 and cFGF23. Multiple regression analysis revealed that iFGF23 levels directly correlated with both serum phosphate and calcium, whereas cFGF23 correlated with serum phosphate and hs -CRP but not with calcium. Conclusions The control of serum phosphate reduced iFGF23. This reduction was also associated with a decreased in inflammatory parameters. Considering the entire cohort of hemodialysis patients, iFGF23 levels correlated directly with serum phosphate levels and also correlated inversely with serum calcium concentration. The levels of cFGF23 were closely related to serum phosphate and parameters of inflammation.
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  • 70
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    Publication Date: 2018-08-08
    Description: by Lorna M. Gibson, Francesca M. Chappell, David Summers, Donald A. Collie, Robin Sellar, Jonathan Best, Richard Knight, James W. Ironside, Joanna M. Wardlaw The relationship between magnetic resonance imaging (MRI) and clinical variables in patients suspected to have Creutzfeldt-Jakob Disease (CJD) is uncertain. We aimed to determine which MRI features of CJD (positive or negative), previously described in vivo, accurately identify CJD, are most reliably detected, vary with disease duration, and whether combined clinical and imaging features increase diagnostic accuracy for CJD. Prospective patients suspected of having CJD were referred to the National CJD Research and Surveillance Unit between 1994–2004; post-mortem, brains were sent for MRI and histopathology. Two neuroradiologists independently assessed MRI for atrophy, white matter hyperintensities, and caudate, lentiform and pulvinar signals, blind to histopathological diagnosis and clinical details. We examined differences in variable frequencies using Fisher’s exact tests, and associations between variables and CJD in logistic regression models. Amongst 200 cases, 118 (59%) with a histopathological diagnosis of CJD and 82 (41%) with histopathological diagnoses other than CJD, a logistic regression model including age, disease duration at death, atrophy, white matter hyperintensities, bright or possibly bright caudate, and present pulvinar sign correctly classified 81% of cases as CJD versus not CJD. Pulvinar sign alone was not independently associated with an increased likelihood of histopathologically-confirmed CJD (of any subtype) or sporadic CJD after adjustment for age at death, disease duration, atrophy, white matter hyperintensities or caudate signal; despite the large sample, data sparsity precluded investigation of the association of pulvinar sign with variant CJD. No imaging feature varied significantly with disease duration. Of the positive CJD signs, neuroradiologists most frequently agreed on the presence or absence of atrophy (agreements in 169/200 cases [84.5%]). Combining patient age, and disease duration, with absence of atrophy and white matter hyperintensities and presence of increased caudate signal and pulvinar sign predicts CJD with good accuracy. Autopsy remains essential.
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  • 71
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    Publication Date: 2018-08-09
    Description: by Niansheng Ju, Rundong Jiang, Stephen L. Macknik, Susana Martinez-Conde, Shiming Tang Whereas optogenetic techniques have proven successful in their ability to manipulate neuronal populations—with high spatial and temporal fidelity—in species ranging from insects to rodents, significant obstacles remain in their application to nonhuman primates (NHPs). Robust optogenetics-activated behavior and long-term monitoring of target neurons have been challenging in NHPs. Here, we present a method for all-optical interrogation (AOI), integrating optical stimulation and simultaneous two-photon (2P) imaging of neuronal populations in the primary visual cortex (V1) of awake rhesus macaques. A red-shifted channel-rhodopsin transgene (ChR1/VChR1 [C1V1]) and genetically encoded calcium indicators (genetically encoded calmodulin protein [GCaMP]5 or GCaMP6s) were delivered by adeno-associated viruses (AAVs) and subsequently expressed in V1 neuronal populations for months. We achieved optogenetic stimulation using both single-photon (1P) activation of neuronal populations and 2P activation of single cells, while simultaneously recording 2P calcium imaging in awake NHPs. Optogenetic manipulations of V1 neuronal populations produced reliable artificial visual percepts. Together, our advances show the feasibility of precise and stable AOI of cortical neurons in awake NHPs, which may lead to broad applications in high-level cognition and preclinical testing studies.
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  • 72
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    Publication Date: 2018-08-09
    Description: by Luis Carlos Dominguez, Laurents Stassen, Willem de Grave, Alvaro Sanabria, Edgar Alfonso, Diana Dolmans
    Electronic ISSN: 1932-6203
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  • 73
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    Publication Date: 2018-08-09
    Description: by Odin Goovaerts, Pauline N. M. Mwinzi, Erick M. O. Muok, Ann Ceulemans, Robert Colebunders, Luc Kestens Background Among the different faces of immune reconstitution inflammatory syndrome (IRIS) developing in HIV-patients, no clinical definition has been reported for Schistosomiasis-IRIS (Schisto-IRIS). Although Schisto-IRIS remains largely uninvestigated, matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) have previously been associated with S . mansoni infection and tuberculosis-IRIS. Here, we aimed to investigate the relevance of these markers in Schisto-IRIS. Methodology Patients were diagnosed with IRIS related to S . mansoni within a cohort of patients with Schistosomiasis-HIV co-infection, using a clinical working definition of Schisto-IRIS. We compared 9 patients who developed Schisto-IRIS to 9 Schisto + HIV + controls who did not, and 9 Schisto - HIV + controls. Plasma levels of MMP-1, MMP-7, MMP-10, TIMP-1, TIMP-2, sCD14, intestinal fatty-acid binding protein, C-reactive protein, and 8 anti-nuclear antibodies (ANA) were analyzed prior to and during 3 months of ART. Principal findings Although no differences were observed for MMP-1 and -7, MMP-10 levels decreased significantly in Schisto + HIV + controls during 3 months of ART (p = 0.005) while persisting in Schisto-IRIS patients at significantly higher levels compared to Schisto - HIV + controls (p≤0.030). In contrast TIMP-1 levels only decreased significantly in Schisto-IRIS patients (p = 0.012), while TIMP-2 levels were lower compared to Schisto + HIV + controls at 2 weeks (p = 0.007), 1 month (p = 0.005) and 3 months (p = 0.031) of ART. Five out of 8 ANAs studied decreased significantly in Schisto-IRIS patients after 1 month of ART(p≤0.039), whereas only 1 ANA decreased for Schisto + HIV + controls (p = 0.027). Conclusions/Significance In this study, we propose a working definition for the diagnosis of Schisto-IRIS in resource limited settings. We report persistent plasma levels of MMP-10, along with a more pronounced decrease in TIMP-1 and ANA-levels, and low levels of TIMP-2 during 3 months of ART. Corresponding to the clinical symptoms, these data suggest that Schisto-IRIS is marked by unbalanced MMP/TIMP dynamics which favor inflammation.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
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  • 74
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    Publication Date: 2018-08-09
    Description: by Ante Rađa, Johnny Padulo, Igor Jelaska, Luca Paolo Ardigò, Luca Fumarco The main objective of this research was to determine the existence of relative age effect (RAE) in five European soccer leagues and their second-tier competitions. Even though RAE is a well-known phenomenon in professional sports environments it seems that the effect does not decline over the years. Moreover, additional information is required, especially when taking into account second-tier leagues. Birthdates from 1,332 first-tier domestic players from France, England, Spain, Germany and Italy and birthdates from 1,992 second-tier domestic players for the 2014/2015 season were taken for statistical analysis. In addition to standard statistical tests, the data were analyzed using econometric techniques for count data using Poisson and negative binomial regressions. The results obtained confirmed a biased distribution of birthdates in favor of players born earlier in the calendar year. For all of the five first-tier soccer leagues there was an unequal distribution of birthdates (France χ 2 = 40.976, P
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 75
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    Publication Date: 2018-08-09
    Description: by Jinpu Yang, Siyu Sun, Shu Zhang, Marlyn Gonzalez, Qianhua Dong, Zhongxuan Chi, Yu-hang Chen, Fei Li Centromere is a specialized chromatin domain that plays a vital role in chromosome segregation. In most eukaryotes, centromere is surrounded by the epigenetically distinct heterochromatin domain. Heterochromatin has been shown to contribute to centromere function, but the precise role of heterochromatin in centromere specification remains elusive. Centromeres in most eukaryotes, including fission yeast ( Schizosaccharomyces pombe ), are defined epigenetically by the histone H3 (H3) variant CENP-A. In contrast, the budding yeast Saccharomyces cerevisiae has genetically-defined point centromeres. The transition between regional centromeres and point centromeres is considered as one of the most dramatic evolutionary events in centromere evolution. Here we demonstrated that Cse4, the budding yeast CENP-A homolog, can localize to centromeres in fission yeast and partially substitute fission yeast CENP-A Cnp1 . But overexpression of Cse4 results in its localization to heterochromatic regions. Cse4 is subject to efficient ubiquitin-dependent degradation in S . pombe , and its N-terminal domain dictates its centromere distribution via ubiquitination. Notably, without heterochromatin and RNA interference (RNAi), Cse4 fails to associate with centromeres. We showed that RNAi-dependent heterochromatin mediates centromeric localization of Cse4 by protecting Cse4 from ubiquitin-dependent degradation. Heterochromatin also contributes to the association of native CENP-A Cnp1 with centromeres via the same mechanism. These findings suggest that protection of CENP-A from degradation by heterochromatin is a general mechanism used for centromere assembly, and also provide novel insights into centromere evolution.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 76
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    Publication Date: 2018-08-09
    Description: by Deepika Dhawan, Noah M. Hahn, José A. Ramos-Vara, Deborah W. Knapp There is growing evidence that molecular subtypes (e.g. luminal and basal subtypes) affect the prognosis and treatment response in patients with muscle invasive urinary bladder cancer (invasive urothelial carcinoma, iUC). Modeling these subtypes in pre-clinical animal studies is essential, but it is challenging to produce these subtypes, along with other critical host and tumor features, in experimentally-induced animal models. This study was conducted to determine if luminal and basal molecular subtypes are present in naturally-occurring canine iUC, a cancer that mimics the human condition in other key aspects. RNA sequencing was performed on 29 canine treatment naive iUC tissue samples and on four normal canine bladder mucosal samples. Data were aligned to CanFam 3.1, and differentially expressed genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups (n = 13, n = 16). When genes that distinguish basal and luminal subtypes in human cancer (n = 2015) were used to probe genes differentially expressed between normal canine bladder and iUC, 829 enriched signature genes were identified. Unsupervised hierarchical clustering of these genes revealed two distinct groups comprised of 18 luminal subtype tumors and 11 basal subtype tumors. The enriched genes included MMP9 , SERPINE2 , CAV1 , KRT14 , and RASA3 in basal tumors, and PPARG , LY6E , CTSE , CDK3 , and TBX2 in luminal tumors. In supervised clustering, additional genes of importance in human iUC were identified in canine iUC associated with claudin-low and infiltrated tumors. A smaller panel of genes (n = 60) was identified that distinguished canine luminal and basal iUC with overall 93.1% accuracy. Immune signature patterns similar to those in human iUC were also identified with the greatest enrichment of immune genes being in the basal subtype tumors. These findings provide additional compelling evidence that naturally-occurring canine iUC is a highly relevant and much needed model of human iUC for translational research.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 77
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    Public Library of Science (PLoS)
    Publication Date: 2018-08-09
    Description: by Betânia M. F. Nogueira, Valéria C. Rolla, Kevan M. Akrami, Susan M. Kiene
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 78
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    Publication Date: 2018-08-09
    Description: by Maite Martínez-Eixarch, Carles Alcaraz, Marc Viñas, Joan Noguerol, Xavier Aranda, Francesc Xavier Prenafeta-Boldú, Jesús Antonio Saldaña-De la Vega, Maria del Mar Català, Carles Ibáñez
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 79
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    Publication Date: 2018-08-09
    Description: by Jun Young Lee, Jae-Seok Kim, Jae-Won Yang, Seung Ok Choi, Joon Hyung Sohn, Byoung-Geun Han Objective Malnutrition is very complex in patients with end-stage renal disease (ESRD) and is associated with poor prognosis. This is because hemodynamic changes, hormonal changes, persistent inflammatory reactions, and fluid overloads are more complicated as uremia is worsening. Bio-impedance spectroscopy (BIS) is a useful method to estimate fluid balance (Overhydration/ extracellular water, OH/ECW) and nutritional status (Phase angle, PhA). We aimed to evaluate the volume and nutritional status by BIS and to investigate the relationship between the appetite regulating hormones and the parameters of BIS in patients with stage 5 chronic kidney disease not undergoing dialysis (CKD5-ND). Methods We enrolled a total of 91 CKD5-ND patients. We measured routine serum markers including albumin and NT-proBNP and the appetite regulating hormones, leptin and ghrelin. We defined poor nutritional status as a PhA 〈 4.5°, and proper nutritional status as a PhA ≥ 4.5°. We also evaluated each patient’s nutritional status by assessing their geriatric nutritional risk index (GNRI) and their volume status by measuring NT-proBNP. Results Forty-one patients (45%) had poor nutritional status. Patients with a poor nutritional status had significantly higher OH/ECW (29.6 ± 12.7% vs. 6.2 ± 10.3%, p
    Electronic ISSN: 1932-6203
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  • 80
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    Publication Date: 2018-08-09
    Description: by Andrea Renata Cornelio Geyer, Varley Dias Sousa, Dâmaris Silveira The circulation of poor quality medicines, especially in the developing countries, is a public health concern. Compliance with good manufacturing practices (GMP) is essential to ensure the quality, efficacy, and safety of medicines. This study evaluated the outcomes of the Brazilian Health Regulatory Agency’s (ANVISA) international inspections of two years (2015 and 2016) and compared these to those of other regulatory authorities. The information from 255 inspection reports was analyzed, and the type and extent of deficiencies were collected. In the period evaluated, 62.75% of ANVISA-inspected companies were classified as GMP “satisfactory,” 24.71% were classified as having “on demand” status, and 12.55% of inspections concluded that the company did not comply with Brazilian GMP regulations (“unsatisfactory”). The most common areas of deficiency were documentation (28.63%) and premises (26.27%). The pattern of deficiencies was similar to the findings of other regulatory agencies. However, ANVISA detected a more significant number of non-compliance results than other authorities, which may be caused by differences in classifications adopted by each Agency. Furthermore, manufacturers inspected by ANVISA may follow different standards and practices for products manufactured for the Brazilian market. Disclosure of main GMP deficiencies found can be useful for encouraging the industry to comply with GMP, and additional guidelines in the specific areas where deficiencies are often identified may be useful to industry to improve GMP compliance. Harmonization of GMP guidelines and inspection procedures are the key steps to avoid duplicate work, but regulatory authorities also need to work together to enforce the proper level of GMP compliance by pharmaceutical manufacturers, assuring high quality and safe medicines supply.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Publication Date: 2018-08-09
    Description: by Jared R. Fletcher, Brian R. MacIntosh During prolonged running, the magnitude of Achilles tendon (AT) length change may increase, resulting in increased tendon strain energy return with each step. AT elongation might also affect the magnitude of triceps surae (TS) muscle shortening and shortening velocity, requiring greater activation and increased muscle energy cost. Therefore, we aimed to quantify the tendon strain energy return and muscle energy cost necessary to allow energy storage to occur prior to and following prolonged running. 14 trained male (n = 10) and female (n = 4) distance runners (24±4 years, 1.72±0.09 m, 61±10 kg, V˙O2max 64.6±5.8 ml•kg -1 •min -1 ) ran 90 minutes (RUN) at approximately 85% of lactate threshold speed (sLT). Prior to and following RUN, AT stiffness and running energy cost (E run ) at 85% sLT were determined. AT energy return was calculated from AT stiffness, measured with dynamometry and ultrasound and estimated TS force during stance. TS energy cost was estimated on the basis of AT force and assumed crossbridge mechanics and energetics. Following RUN, AT stiffness was reduced from 328±172 N•mm -1 to 299±148 N•mm -1 (p = 0.022). E run increased from 4.56±0.32 J•kg -1 •m -1 to 4.62±0.32 J•kg -1 •m -1 (p = 0.049). Estimated AT energy return was not different following RUN (p = 0.99). Estimated TS muscle energy cost increased significantly by 11.8±12.3 J•stride -1 , (p = 0.0034), accounting for much of the post-RUN increase in E run (8.6±14.5 J•stride -1 ,r 2 = 0.31). These results demonstrate that a prolonged, submaximal run can reduce AT stiffness and increase E run in trained runners, and that the elevated TS energy cost contributes substantially to the elevated E run .
    Electronic ISSN: 1932-6203
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  • 82
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    Publication Date: 2018-08-09
    Description: by Ya-Ting Ke, I-Jung Feng, Chien-Chin Hsu, Jhi-Joung Wang, Shih-Bin Su, Chien-Cheng Huang, Hung-Jung Lin Nurses have high work stress that may contribute to an increased overdose for sedatives, hypnotics, and antipsychotics (OSHA). We conducted this nationwide population-based cross-sectional study to clarify this still unclear issue. We used a nationwide database to identify 110,379 nurses, 22,032 other healthcare providers (HCPs), and an identical number of individuals from the general population matched by age and sex. We compared the period prevalence of OSHA between nurses and the general population, other HCPs and the general population, and nurses and other HCPs, among nurse subgroups from 2006 to 2012. The risk for OSHA in nurses and in the general population was not significantly different after adjusting for anxiety, insomnia, depression, schizophrenia, and affective disorders (adjusted odds ratio [AOR]: 1.145; 95% confidence interval [CI]: 0.974–1.346). However, in the age subgroups 〈 35 years, nurses had higher risk than the general population of having OSHA (AOR: 1.333; 95% CI: 1.109–1.601). Other HCPs had a significantly lower risk for OSHA than the general population (AOR: 0.237; 95% CI: 0.122–0.460). Nurses had a significantly higher risk for OSHA than other HCPs (AOR: 3.902; 95% CI: 2.159–7.048). Comparison among nurses showed that younger nurses ( 〈 35 years) had a significantly higher risk for OSHA than the older nurses (≥ 50 years) (AOR: 3.569; 95% CI: 1.252–10.330). Registered nurses had significantly higher risk for OSHA than registered professional nurses (AOR: 1.810; 95% CI: 1.405–2.332); and nurses from clinics, local hospitals, and regional hospitals had significantly higher risk than nurses from medical centers. This study delineated that nurses had a nearly four-fold risk for OSHA when compared to other HCPs. Younger nurses, registered nurses, and nurses from clinics, local hospitals, and regional hospitals had higher risks for OSHA than their respective nurse controls; it suggests that more attention should be given to the occupational health of these populations.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 83
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    Publication Date: 2018-08-09
    Description: by Sophie-Anne Beauprez, Lucette Toussaint, Christel Bidet-Ildei Numerous studies in the field of embodied cognition have shown a crosstalk between language and sensorimotor processes. In particular, it has been demonstrated that perceiving an action influences subsequent language processing. However, when studying the effect of action observation on language processing it has not been considered whether the context of action presentation could modulate this influence. To test this assumption, the participants in our study observed a prime, specifically a cartoon picture of a person performing an action in either a usual or an unusual context, and then had to perform a semantic decision task involving action verbs that could be congruent or incongruent with the action in the prime. Data analyses showed a significant difference on response times for congruent action verbs compared with incongruent action verbs in the usual context, whereas no difference was observed in the unusual context. This finding indicates that the influence of action observation on language appears only with usual actions, suggesting that the context of action presentation is crucial to enable the influence of action observation on action verbs processing.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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