bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineered transfer RNAs for suppression of premature termination codons
Authors: Lueck John D. , Yoon Jae Seok , Perales-Puchalt Alfredo , Mackey Adam L. , Infield Daniel T. , Behlke Mark A. , Pope Marshall R. , Weiner David B. , Skach William R. , McCray Paul B. , Ahern Christopher A. 
Published: August 2018

ABSTRACTPremature termination codons (PTCs) are responsible for 10-15% of all inherited disease. PTC suppression during translation offers a promising approach to treat a variety of genetic disorders, yet small molecules that promote PTC read-through have yielded mixed performance in clinical trials. We present a high-throughput, cell-based assay to identify anticodon engineered transfer RNAs (ACE-tRNA) which can effectively suppress in-frame PTCs and faithfully encode their cognate amino acid. In total, we identified ACE-tRNA with a high degree of suppression activity targeting the most common human disease-causing nonsense codons. Genome-wide transcriptome ribosome profiling of cells expressing ACE-tRNA at levels which repair PTC indicate that there are limited interactions with translation termination codons. These ACE-tRNAs display high suppression potency in mammalian cells, Xenopus oocytes and mice in vivo, producing PTC repair in multiple genes, including disease causing mutations within the cystic fibrosis transmembrane conductance regulator (CFTR).
Evidence for the Modulation of the Immune Response in Peripheral Blood Mononuclear Cells after Stimulation with a High Molecular Weight β-glucan Isolated fromLactobacillus fermentumLf2
Authors: Vitlic Ana , Sadiq Sohaib , Ahmed Hafiz I. , Ale Elisa C. , Binetti Ana G. , Collett Andrew , Humpreys Paul N. , Laws Andrew P. 
Published: August 2018

ABSTRACTLactobacillus fermentumLf 2 produces large amounts of exopolysaccharides under optimized conditions (∼2 g/L, EPS) which have been shown to possess immunomodulatory activity. In this study, the crude EPS was fractionated to give a high molecular weight (HMw) homoglycan and a mixture of medium molecular weight heteroglycans. The HMw EPS was isolated and identified as a β-glucan.Peripheral blood mononuclear cells (PBMC) were pre-treated with purified polysaccharide to determine if the HMw β-glucan is responsible for the immunomodulatory activity. Cells were also stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) and their effects, both with and without β-glucan pre-treatment, compared.Exposure of the cells to β-glucan increased their metabolic activity and whilst a small but statistically significant drop in CD14 expression was observed at Day 1, the levels were significantly elevated at Day 2. High levels of CD14 expression were observed in cells initially exposed to the β-glucan and subsequently stimulated with either LPS or PHA. In contrast, reduced levels of TLR-2 expression were observed for cells initially exposed to the β-glucan and subsequently stimulated with LPS.TNF-α levels were elevated in β-glucan treated cells (Day1) with the levels dropping back once the β-glucan had been removed (Day 2). The stimulants LPS and PHA both induced significant rises in TNF-α levels, however, this induction was completely (LPS) or partially blocked (PHA) in β-glucan pre-treated cells.The results indicate a role for the bacterial β-glucan in modulating the immune response following exposure to agonists such as bacterial LPS.
Multichannel Silicon Probes for Awake Hippocampal Recordings in Large Animals
Authors: Ulyanova Alexandra V. , Cottone Carlo , Adam Christopher D. , Gagnon Kimberly G. , Cullen D. Kacy , Holtzmann Tahl , Jameison Brian , Koch Paul F. , Chen H. Isaac , Johnson Victoria E. , Wolf John A. 
Published: August 2018

AbstractDecoding laminar information across deep brain structures and cortical regions is necessary in order to understand the spatiotemporal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. One of the major obstacles to applying the approaches currently utilized in lower order animals are technical limitations in silicon probes, specifically a lack of long-length probes with appropriate stiffness to penetrate to deeper structures with minimal damage to the neural interface. We tested various solutions and designs of multichannel silicon probes developed for large animal electrophysiology by recording neurophysiological signals from deep laminar structures in an acute preparation and in chronically implanted awake behaving Yucatan pigs. Electrophysiological parameters of single units and local field potentials were analyzed to evaluate performance over time of given silicon probes in chronic implantations. The cross-sectional area of silicon probes was found to be a crucial determinant of silicon probes’ single unit performance over time, potentially due to reduction of damage to the neural interface. EDGE-style probes had the highest yields during intra-hippocampal recordings in pigs, making them the most suitable for chronic implantations and awake behavioral experimentation. Novel CAMB 64-channel EDGE-style probes with linear and poly-2 site arrangement tested acutely had optimal single unit separation and a denser sampling of the laminar structure, identifying them as potential candidates for chronic implantations with less cortical damage above the active portion of the probe. This study provides an analysis of multichannel silicon probes designed for large animal laminar electrophysiology of deep brain structures, and suggests that current designs are reaching the physical thresholds necessary for long-term (~ 1 month) recordings from laminar deep structures with single-unit resolution.
Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population
Authors: Guo Jianping , Zhang Tao , Cao Hongzhi , Li Xiaowei , Liang Hao , Liu Mengru , Zou Yundong , Zhang Yuanwei , Sun Xiaolin , Hu Fanlei , Du Yan , Mo Xiaodong , Liu Xu , Yang Yue , Yang Huanjie , Wu Xinyu , Zhang Xuewu , Jia Huijue , Jiang Hui , Hou Yong , Liu Xin , Su Yin , Zhang Mingrong , Yang Huanming , Wang Jian , Sun Liangdan , Liu Liang , Padyukov Leonid , Lai Luhua , Yamamoto Kazuhiko , Zhang Xuejun , Klareskog Lars , Xu Xun , Li Zhanguo 
Published: August 2018

ABSTRACTThe strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the ‘real’ or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQα1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 × 10−36, OR=2.29). Further stepwise conditional analysis revealed that DRβ1:37N has an independent protective effect on ACPA–positive RA (P = 5.81 × 10−16, OR=0.49). The DQα1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 × 10−5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQα1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DRβ1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.In this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.
Visual intensity ratio modulates operant learning responses in larval zebrafish
Authors: Yang Wenbin , Meng Yutong , Li Danyang , Wen Quan 
Published: August 2018

AbstractLarval zebrafish is a promising vertebrate model for understanding neural mechanisms underlying learning and memory. Here, we report on a high-throughput operant learning system for zebrafish larvae and demonstrate that lower visual intensity ratio of the conditioned stimulus to the background can enhance learning ability, highlighted by several behavioral metrics. We further characterize the learning curves as well as memory extinction for each conditioned pattern. Finally, we show how this learning process developed from 7 days old to 10 days old zebrafish.HighlightsConditioned visual patterns with lower intensity ratio to the background elicited stronger operant learning responsesMemory extinction was modulated by the visual intensity ratio of the conditioned stimulus to the backgroundA high-throughput automated system for acquiring and analyzing behavioral data
Differential amplicons for the evaluation of RNA integrity extracted from complex environmental samples
Authors: Cholet Fabien , Ijaz Umer Z. , Smith Cindy J. 
Published: August 2018

AbstractBackgroundReliability and reproducibility of transcriptomics-based studies are highly dependent on the integrity of RNA. Microfluidics-based techniques based on ribosomal RNA such as the RNA Integrity Number (RIN) are currently the only approaches to evaluate RNA integrity. However, it is not known if ribosomal RNA reflects the integrity of the meaningful part of the sample, the mRNA. Here we test this assumption and present a new integrity index, the Ratio amplicon, Ramp, to monitor mRNA integrity based on the differential amplification of long to short RT-Q-PCR amplicons of the glutamine synthetase A (glnA) transcript.ResultsWe successfully designed and tested two Rampindexes targetingglnAtranscripts. We showed in a suite of experimental degradations of RNA extracted from sediment that while the RIN in general did reflect the degradation status of the RNA well the Rampmapped mRNA degradation better as reflected by changes in Reverse Transcriptase Quantitative PCR (RT-Q-PCR) results. Furthermore, we examined the effect of degradation on transcript community structure by amplicon sequencing of the16S rRNA, amoAandglnAtranscript which was successful even form the highly-degraded samples. While RNA degradation changed the community structure of the mRNA profiles, no changes were observed between successively degraded 16S rRNA transcripts profiles.ConclusionAs demonstrated, transcripts can be quantified and sequenced even from highly degraded samples. Therefore, we strongly recommend that a quality check of RNA is conducted to ensure validity of results. For this both the RIN and Rampare useful, with the Rampbetter evaluating mRNA integrity in this study.
Modulation of the spontaneous hemodynamic response function across levels of consciousness
Authors: Wu Guo-Rong , Perri Carol Di , Charland-Verville Vanessa , Martial Charlotte , Laureys Steven , Marinazzo Daniele 
Published: August 2018

AbstractFunctional imaging research has already contributed with several results to the study of neural correlates of consciousness. Apart from task-related activation derived in fMRI, PET based glucose metabolism rate or cerebral blood flow account for a considerable proportion of the study of brain activity under different levels of consciousness. Resting state functional connectivity MRI is playing a crucial role to explore the consciousness related functional integration, successfully complementing PET, another widely used neuroimaging technique. Here, spontaneous hemodynamic response is introduced to characterize resting state brain activity giving information on the local metabolism (neurovascular coupling), and useful to improve the time-resolved activity and connectivity measures based on BOLD fMRI. This voxel-wise measure is then used to investigate the loss of consciousness under Propofol anesthesia and unresponsive wakefulness syndrome. The dysfunction of hemodynamic response in precuneus and posterior cingulate is found to be a common principle underlying loss of consciousness in both conditions. The thalamus appears to be less obviously modulated by Propofol, compared with frontoparietal regions. However, a significant increase in spontaneous thalamic hemodynamic response was found in patients in unresponsive wakefulness syndrome compared with healthy control. Our results ultimately show that anesthesia- or pathology-induced neurovascular coupling could be tracked by modulated spontaneous hemodynamic response derived from resting state fMRI.
Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity
Authors: Gomes Martim Dias , Letzian Soriba , Saynisch Michael , Iden Sandra 
Published: August 2018

ABSTRACTEpithelial homeostasis requires balanced progenitor cell proliferation and differentiation, whereas disrupting this equilibrium fosters degeneration or cancer. Here we studied how cell polarity signaling orchestrates epidermal self-renewal and differentiation. Using genetic ablation, quantitative imaging, mechanochemical reconstitution and atomic force microscopy, we find that mammalian Par3 couples genome integrity and epidermal fate through shaping keratinocyte mechanics, rather than mitotic spindle orientation. Par3 inactivation impairs actomyosin contractility and viscoelasticity, and elicits mitotic failures that trigger aneuploidy, mitosis-dependent DNA damage responses, p53 stabilization and premature differentiation. Importantly, reconstituting myosin activity is sufficient to restore mitotic fidelity, genome integrity, and balanced differentiation and stratification. Collectively, this study deciphers a mechanical signaling network in which Par3 acts upstream of Rho/ROCK-mediated actomyosin contractility to promote intrinsic force generation, thereby maintaining mitotic accuracy and cellular fitness at the genomic level. Disturbing this network may compromise not only epidermal homeostasis but potentially also that of other self-renewing epithelia.
Plasticity and environmental heterogeneity predict geographic resilience patterns of foundation species to future change
Authors: Telesca Luca , Peck Lloyd S. , Sanders Trystan , Thyrring Jakob , Sejr Mikael K. , Harper Elizabeth M. 
Published: August 2018

ABSTRACTAlthough geographic patterns of species’ sensitivity to global environmental changes are defined by interacting multiple stressors, little is known about the biological mechanisms shaping regional differences in organismal vulnerability. Here, we examine large-scale spatial variations in biomineralisation under heterogeneous environmental gradients of temperature, salinity and food availability across a 30° latitudinal range (3,334 km), to test whether plasticity in calcareous shell production and composition, from juveniles to large adults, mediates geographic patterns of resilience to climate change in critical foundation species, the musselsMytilus edulisandM. trossulus. We find mussels produced thinner shells with a higher organic content in polar than temperature regions, indicating decreasing shell calcification towards high latitudes. Salinity was the major driver of regional differences in mussel shell deposition, and in shell mineral and organic composition. In low-salinity environments, the production of calcite and organic shell layers was increased, providing higher resistance against dissolution in more corrosive waters. Conversely, under higher-salinity regimes, increased aragonite deposition suggests enhanced mechanical protection from predators. Interacting strong effects of decreasing salinity and increasing food availability on the compositional shell plasticity in polar and subpolar mussels during growth predict the deposition of a thicker external organic layer (periostracum) under forecasted future environmental conditions. This marked response potential ofMytilusspecies suggests a capacity for increased protection of high-latitude mussel populations from ocean acidification. Our work illustrates that mechanisms driving plastic responses to the spatial structure of multiple stressors can define geographic patterns of unforeseen species resilience to global environmental change.
Hepatocyte-Specific Hepatocyte Nuclear Factor 4 alpha (HNF4α) Deletion Decreases Resting Energy Expenditure By Disrupting Lipid and Carbohydrate Homeostasis
Authors: Huck Ian , Matthew Morris E. , Thyfault John , Apte Udayan 
Published: August 2018

AbstractHepatocyte Nuclear Factor 4 alpha (HNF4α) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4α in metabolism, its overall role in whole body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4α deletion (HNF4α-KO) in mice on whole body energy expenditure (EE) and substrate utilization in fed, fasted, and high fat diet (HFD) conditions. HNF4α-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4α-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4α-KO mice were able to upregulate lipid oxidation during HFD suggesting that their metabolic flexibility was intact. However, only hepatocyte specific HNF4α-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4α-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic β-oxidation in HNF4α-KO livers across all feeding conditions. Together, our data suggest deletion of hepatic HNF4α increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole body energy expenditure. These data clarify the role of hepatic HNF4α on systemic metabolism and energy homeostasis.
Defining and Evaluating Microbial Contributions to Metabolite Variation in Microbiome-Metabolome Association Studies
Authors: Noecker Cecilia , Chiu Hsuan-Chao , McNally Colin P. , Borenstein Elhanan 
Published: August 2018

AbstractCorrelation-based analysis of paired microbiome-metabolome datasets is becoming a widespread research approach, aiming to comprehensively identify microbial drivers of metabolic variation. To date, however, the limitations of this approach have not been comprehensively evaluated. To address this challenge, we introduce a mathematical framework to quantify the contribution of each taxon to metabolite variation based on uptake and secretion fluxes. We additionally use a multi-species metabolic model to simulate simplified gut communities, generating idealized microbiome-metabolome datasets. We then compare observed taxon-metabolite correlations in these datasets to calculated ground-truth taxonomic contribution values. We find that in simulations of both a model 10-species community and of complex human gut microbiota, correlation-based analysis poorly identifies key contributors, with extremely low predictive value despite the idealized setting. We further demonstrate that the predictive value of correlation analysis is strongly influenced by both metabolite and taxon properties, as well as exogenous environmental variation. We finally discuss the practical implications of our findings for interpreting microbiome-metabolome studies.ImportanceIdentifying the key microbial taxa responsible for metabolic differences between microbiomes is an important step towards understanding and manipulating microbiome metabolism. To achieve this goal, researchers commonly conduct microbiome-metabolome association studies, comprehensively measuring both the composition of species and the concentration of metabolites across a set of microbial community samples, and then testing for correlations between microbes and metabolites. Here, we evaluated the utility of this general approach by first developing a rigorous mathematical definition of the contribution of each microbial taxon to metabolite variation, and then examining these contributions in simulated datasets of microbial community metabolism. We found that standard correlation-based analysis of our simulated microbiome-metabolome datasets identifies true contributions with very low predictive value, and that its performance depends strongly on specific properties of both metabolites and microbes, as well as on the surrounding environment. Combined, our findings can guide future interpretation and validation of microbiome-metabolome studies.
Hepatitis B mother-to-child transmission in the Eastern Region of Ghana: A cross-sectional pilot study
Authors: Hambridge Thomas , Nartey Yvonne , Duah Amoako , Plymoth Amelie 
Published: August 2018

AbstractBackgroundHepatitis B is a major health concern in Ghana, where prevalence of the virus remains high and most chronic patients are infected during childhood or at birth. There are several factors which can influence transmission risk from an infected mother to her infant, such as the presence of viral markers, the viral load and the use of prophylactic interventions. It is therefore important to determine the prevalence and main factors associated with mother-to-child transmission of hepatitis B in the context of Ghana.Materials and methodsIn this cross-sectional pilot study, hepatitis B testing was performed on infants born to infected mothers at a single site in the Eastern Region of Ghana. Test results were matched to a questionnaire which consisted of variables related to pregnancy and birth conditions. This was primarily a descriptive study to determine the prevalence of hepatitis B mother-to-child transmission as well as the preventive interventions and diagnostic methods used. The study variables were also analysed independently using Fisher’s exact test, while mother’s age at the time of delivery was assessed using univariate logistic regression.ResultsA total of 51 cases were included in the study and three (5.9%) of the infants tested positive. No significant association was observed between mother’s age and mother-to-child transmission (OR: 1.077, 95% CI: 0.828 – 1.403, p=0.58). A majority of infants received the standard hepatitis B vaccination schedule (96.1%) while two-thirds received the birth dose. There was no significant association observed between the clinical interventions reported in the study and mother-to-child transmission. Testing for viral markers and the use of antiviral therapy during pregnancy were absent in the population and could not be reliably assessed.ConclusionThere was a low prevalence of HBV mother-to-child transmission observed despite a clear absence of viral marker and viral load testing. It is recommended that viral profile analysis is performed for hepatitis B positive pregnancies to identify high risk cases.