bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural Basis of Sensorimotor Plasticity in Speech Motor Adaptation
Authors: Darainy Mohammad , Vahdat Shahabeddin , Ostry David J 
Published: June 2018

Abstract
When we speak, we get correlated sensory feedback from speech sounds and from the muscles and soft tissues of the vocal tract. Here we dissociate the contributions of auditory and somatosensory feedback to identify brain networks that underlie the somatic contribution to speech motor learning. The technique uses a robotic device that selectively alters somatosensory inputs in combination with resting-state fMRI scans that reveal learning-related changes in functional connectivity. A partial correlation analysis is used to identify connectivity changes that are not explained by the time course of activity in any other learning-related areas. This analysis revealed changes related to behavioral improvements in movement and separately, to changes in auditory perception: Speech motor adaptation itself was associated with connectivity changes that were primarily in non-motor areas of brain, specifically, to a strengthening of connectivity between auditory and somatosensory cortex and between presupplementary motor area and the inferior parietal lobule. In contrast, connectively changes associated with alterations to auditory perception were restricted to speech motor areas, specifically, primary motor cortex and inferior frontal gyrus. Overall, our findings show that during adaptation, somatosensory inputs result in a broad range of changes in connectivity in areas associated with speech motor control and learning.
Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications
Authors: Ferdinandy Péter , Baczkó István , Bencsik Péter , Giricz Zoltán , Görbe Anikó , Pacher Pál , Varga Zoltán V , Varró András , Schulz Rainer 
Published: June 2018

Abstract
Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of ‘hidden cardiotoxicity’, defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.
On the Mean Euler Characteristic of Gorenstein Toric Contact Manifolds
Authors: Abreu Miguel , Macarini Leonardo 
Published: June 2018

AbstractWe prove that the mean Euler characteristic of a Gorenstein toric contact manifold, that is, a good toric contact manifold with zero 1st Chern class, is equal to half the normalized volume of the corresponding toric diagram and give some applications. A particularly interesting one, obtained using a result of Batyrev and Dais, is the following: twice the mean Euler characteristic of a Gorenstein toric contact manifold is equal to the Euler characteristic of any crepant toric symplectic filling, that is, any toric symplectic filling with zero 1st Chern class.
Does cross-Strait tourism induce peace? Evidence from survey data on Chinese tourists and non-tourists
Authors: Pan Hsin-Hsin , Wu Wen-Chin , Chang Yu-Tzung 
Published: June 2018

Abstract
Recent studies revisit the debate over whether tourism promotes peace via intergroup contacts. In this article, we examine the case of China-Taiwan confrontation and argue that the increase of Chinese tourists visiting Taiwan contributes to peace across the Taiwan Strait. Specifically, the touristic experiences and interactions with Taiwanese improve Chinese people’s understanding of Taiwan, fostering a patient and peaceful attitude toward the prospect of cross-Strait relations. With the survey data collected during July and September 2013, we find that Chinese people who were visiting Taiwan for the first time were less likely to support a rapid pace to the unification between China and Taiwan or unification by force than those who had never visited Taiwan. Additionally, the attitude is stronger among independent tourists than those who came in escorted tour groups. Our findings suggest that contacts between tourists and locals are effective in alleviating political tension across the Taiwan Strait.
Design and implementation of pragmatic clinical trials using the electronic medical record and an adaptive design
Authors: Simon Kelly Claire , Tideman Samuel , Hillman Laura , Lai Rebekah , Jathar Raman , Ji Yuan , Bergman-Bock Stuart , Castle James , Franada Tiffani , Freedom Thomas , Marcus Revital , Mark Angela , Meyers Steven , Rubin Susan , Semenov Irene , Yucus Chad , Pham Anna , Garduno Lisette , Szela Monika , Frigerio Roberta , Maraganore Demetrius M 
Published: June 2018

AbstractObjectivesTo demonstrate the feasibility of pragmatic clinical trials comparing the effectiveness of treatments using the electronic medical record (EMR) and an adaptive assignment design.MethodsWe have designed and are implementing pragmatic trials at the point-of-care using custom-designed structured clinical documentation support and clinical decision support tools within our physician’s typical EMR workflow. We are applying a subgroup based adaptive design (SUBA) that enriches treatment assignments based on baseline characteristics and prior outcomes. SUBA uses information from a randomization phase (phase 1, equal randomization, 120 patients), to adaptively assign treatments to the remaining participants (at least 300 additional patients total) based on a Bayesian hierarchical model. Enrollment in phase 1 is underway in our neurology clinical practices for 2 separate trials using this method, for migraine and mild cognitive impairment (MCI).ResultsWe are successfully collecting structured data, in the context of the providers’ clinical workflow, necessary to conduct our trials. We are currently enrolling patients in 2 point-of-care trials of non-inferior treatments. As of March 1, 2018, we have enrolled 36% of eligible patients into our migraine study and 63% of eligible patients into our MCI study. Enrollment is ongoing and validation of outcomes has begun.DiscussionThis proof of concept article demonstrates the feasibility of conducting pragmatic trials using the EMR and an adaptive design.ConclusionThe demonstration of successful pragmatic clinical trials based on a customized EMR and adaptive design is an important next step in achieving personalized medicine and provides a framework for future studies of comparative effectiveness.
Can the Provision of Long-Term Liquidity Help to Avoid a Credit Crunch? Evidence from the Eurosystem’s LTRO
Authors: Andrade Philippe , Cahn Christophe , Fraisse Henri , Mésonnier Jean-Stéphane 
Published: June 2018

AbstractWe exploit the Eurosystem’s longer-term refinancing operations (LTROs) of 2011–2012 to assess whether a large provision of central bank liquidity to banks during a financial crisis has a positive impact on banks’ credit supply to firms. We control for credit demand by examining firms that borrow from several banks, in addition to controlling for confounding factors at the level of banks. We find that the LTROs enhanced loan supply: according to our baseline estimate, banks borrowing 1 billion euros from the facility increased their loan supply by 186 million euros over one year. We also find that the transmission mostly took place with the first operation of December 2011, in which banks that were more capital constrained bid more. Moreover, we show that the opportunity to substitute long-term central bank liquidity for short-term liquidity enhanced this transmission. Lastly, the operations benefited larger borrowers more and did not lead banks to increase their lending to riskier firms.
Diverse novel residentWolbachiastrains in Culicine mosquitoes from Madagascar
Authors: Jeffries Claire Louise , Tantely Luciano M , Raharimalala Fara Nantenaina , Hurn Eliot , Boyer Sébastien , Walker Thomas 
Published: June 2018

AbstractWolbachiaendosymbiotic bacteria are widespread throughout insect species andWolbachiatransinfected inAedesmosquito species has formed the basis for biocontrol programs asWolbachiastrains inhibit arboviral replication and can spread through populations. Resident strains in wild Culicine mosquito populations (the vectors of most arboviruses) requires further investigation given resident strains can also affect arboviral transmission. As Madagascar has a large diversity of both Culicine species and has had recent arboviral outbreaks, an entomology survey was undertaken, in five ecologically diverse sites, to determine theWolbachiaprevalence. We detected diverse novel residentWolbachiastrains within theAedeomyia, Culex, Ficalbia, MansoniaandUranotaeniagenera.Wolbachiaprevalence rates and strain characterisation through Sanger sequencing with multilocus sequence typing (MLST) and phylogenetic analysis revealed significant diversity and we detected co-infections with the environmentally acquired bacterial endosymbiontAsaia. Mosquitoes were screened for major arboviruses to investigate if any evidence could be provided for their potential role in transmission and we report the presence of Rift Valley fever virus in threeCulexspecies:Culex tritaeniorhynchus, Culex antennatusandCulex decens. The implications of the presence of residentWolbachiastrains are discussed and how the discovery of novel strains can be utilized for applications in the development of biocontrol strategies.
An Atlas of Human and Murine Genetic Influences on Osteoporosis
Authors: Morris John A. , Kemp John P. , Youlten Scott E. , Laurent Laetitia , Logan John G. , Chai Ryan , Vulpescu Nicholas A. , Forgetta Vincenzo , Kleinman Aaron , Mohanty Sindhu , Sergio C. Marcelo , Quinn Julian , Nguyen-Yamamoto Loan , Luco Aimee Lee , Vijay Jinchu , Simon Marie-Michelle , Pramatarova Albena , Medina-Gomez Carolina , Trajanoska Katerina , Ghirardello Elena J. , Butterfield Natalie C. , Curry Katharine F. , Leitch Victoria D. , Sparkes Penny C. , Adoum Anne-Tounsia , Mannan Naila S. , Komla-Ebri Davide , Pollard Andrea S. , Dewhurst Hannah F. , Hassall Thomas , Beltejar Michael-John G , Adams Douglas J , Vaillancourt Suzanne M. , Kaptoge Stephen , Baldock Paul , Cooper Cyrus , Reeve Jonathan , Ntzani Evangelia , Evangelou Evangelos , Ohlsson Claes , Karasik David , Rivadeneira Fernando , Kiel Douglas P. , Tobias Jonathan H. , Gregson Celia L. , Harvey Nicholas C. , Grundberg Elin , Goltzman David , Adams David J. , Lelliott Christopher J. , Hinds David A. , Ackert-Bicknell Cheryl L. , Hsu Yi-Hsiang , Maurano Matthew T. , Croucher Peter I. , Williams Graham R. , Bassett J. H. Duncan , Evans David M. , Richards J. Brent 
Published: June 2018

AbstractOsteoporosis is a common debilitating chronic disease diagnosed primarily using bone mineral density (BMD). We undertook a comprehensive assessment of human genetic determinants of bone density in 426,824 individuals, identifying a total of 518 genome-wide significant loci, (301 novel), explaining 20% of the total variance in BMD—as estimated by heel quantitative ultrasound (eBMD). Next, meta-analysis identified 13 bone fracture loci in ~1.2M individuals, which were also associated with BMD. We then identified target genes from cell-specific genomic landscape features, including chromatin conformation and accessible chromatin sites, that were strongly enriched for genes known to influence bone density and strength (maximum odds ratio = 58, P = 10−75). We next performed rapid throughput skeletal phenotyping of 126 knockout mice lacking eBMD Target Genes and showed that these mice had an increased frequency of abnormal skeletal phenotypes compared to 526 unselected lines (P < 0.0001). In-depth analysis of one such Target Gene,DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This comprehensive human and murine genetic atlas provides empirical evidence testing how to link associated SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.
Analysis of phage-resistant mechanisms inStaphylococcus aureusSA003 reveals a different binding mechanism for the closely related Twort-like phages ϕSA012 and ϕSA039
Authors: Azam Aa Haeruman , Hoshiga Fumiya , Takeuchi Ippei , Miyanaga Kazuhiko , Tanji Yasunori 
Published: June 2018

ABSTRACTWe have previously generated strains ofStaphylococcus aureusSA003 resistant to its specific phage ϕSA012 through long-term coevolution experiment. However, the DNA mutations responsible for the phenotypic change of phage resistance are unknown. Whole-genome analysis revealed six genes that acquired unique point mutations: five missense mutations and one nonsense mutation. Moreover, one deletion, 1.779-bp, resulted in the deletion of the genes encoding glycosyltransferase, TarS, and iron-sulfure repair protein, ScdA. The deletion occurred from the second round of coculture (SA003R2) and remained through the last round. The ϕSA012 infection toward SA003R2 had decreased to 79.77±7.50% according to plating efficiency. Complementation of the phage-resistant strain by the wild-type allele showed two mutated host genes were linked to the inhibition of post-adsorption, and five genes were linked to phage adsorption of ϕSA012. Unlike ϕSA012, infection by ϕSA039, a close relative of ϕSA012, onto SA003R2 was impaired drastically. Complementation of SA003R2 by wild-typetarSrestores the infectivity of ϕSA039. Thus, we concluded that ϕSA039 requires β-GlcNAc in Wall Teichoic Acid (WTA) for its binding. In silico analysis of the ϕSA039 genome revealed that several proteins in the tail and baseplate region were different from ϕSA012; notably the partial deletion oforf96of ϕSA039, a homolog oforf99of ϕSA012.Orf100of ϕSA039, a homolog ofOrf103of ϕSA012, a previously reported receptor binding protein (RBP), had low similarity (86%) to that of ϕSA012. The difference in tail and baseplate proteins might be the factor for specificity difference between ϕSA012 and ϕSA039.
The Global State of Genome Editing
Authors: Siwo Geoffrey H. 
Published: June 2018

AbstractGenome editing technologies hold great promise in fundamental biomedical research, development of treatments for animal and plant diseases, and engineering biological organisms for food and industrial applications. Therefore, a global understanding of the growth of the field is needed to identify challenges, opportunities and biases that could shape the impact of the technology. To address this, this work applies automated literature mining of scientific publications on genome editing in the past year to infer research trends in 2 key genome editing technologies-CRISPR/Cas systems and TALENs. The study finds that genome editing research is disproportionately distributed between and within countries, with researchers in the US and China accounting for 50% of authors in the field whereas countries across Africa are underrepresented. Furthermore, genome editing research is also disproportionately being explored on diseases such as cancer, Duchene Muscular Dystrophy, sickle cell disease and malaria. Gender biases are also evident in genome editing research with considerably fewer women as principal investigators. The results of this study suggest that automated mining of scientific literature could help identify biases in genome editing research as a means to mitigate future inequalities and tap the full potential of the technology.
Reliable Multiplex Sequencing with Rare Index Mis-Assignment on DNB-Based NGS Platform
Authors: Li Qiaoling , Zhao Xia , Zhang Wenwei , Wang Lin , Wang Jingjing , Xu Dongyang , Mei Zhiying , Liu Qiang , Du Shiyi , Li Zhanqing , Liang Xinming , Wang Xiaman , Wei Hanmin , Liu Pengjuan , Zou Jing , Shen Hanjie , Chen Ao , Drmanac Snezana , Liu Jia Sophie , Li Li , Jiang Hui , Zhang Yongwei , Wang Jian , Yang Huanming , Xu Xun , Drmanac Radoje , Jiang Yuan 
Published: June 2018

AbstractBackgroundMassively-parallel-sequencing, coupled with sample multiplexing, has made genetic tests broadly affordable. However, intractable index mis-assignments (commonly exceeds 1%) were repeatedly reported on some widely used sequencing platforms.ResultsHere, we investigated this quality issue on BGI sequencers using three library preparation methods: whole genome sequencing (WGS) with PCR, PCR-free WGS, and two-step targeted PCR. BGI’s sequencers utilize a unique DNB technology which uses rolling circle replication for DNA-nanoball preparation; this linear amplification is PCR free and can avoid error accumulation. We demonstrated that single index mis-assignment from free indexed oligos occurs at a rate of one in 36 million reads, suggesting virtually no index hopping during DNB creation and arraying. Furthermore, the DNB-based NGS libraries have achieved an unprecedentedly low sample-to-sample mis-assignment rate of 0.0001% to 0.0004% under recommended procedures.ConclusionsSingle indexing with DNB technology provides a simple but effective method for sensitive genetic assays with large sample numbers.
A Novel Compound, ML336, Inhibits VEEV Replication by Interfering with Viral RNA Synthesis
Authors: Skidmore Andrew M. , Adcock Robert S. , Lee Jasper , Jonsson Colleen B. , Golden Jennifer E. , Chung Dong-Hoon 
Published: June 2018

AbstractVenezuelan equine encephalitis virus (VEEV) is an alphavirus that is endemic to Central and South America. VEEV is known to cause periodic outbreaks of encephalitis in both humans and equids. There are currently no treatments or preventatives for VEEV disease. Our group has previously reported on the development of a novel VEEV inhibitor, ML336, which showed a potent antiviral effect in cell culture models. However, the mechanism of action had yet to be elucidated. Based on the discovery of mutations conferring resistance within nonstructural proteins, we hypothesized that ML336 inhibits viral RNA synthesis. We found that ML336 was able to inhibit VEEV RNA synthesis with an IC50value of 1.1 nM in a metabolic labelling assay. ML336 marginally affected cellular transcription at levels 20,000-fold above the IC50, and did not show any cytotoxicity up to 50 µM. Using a combination of fluorography, strand-specific qRT-PCR, and a metabolic labelling assay, we found that ML336 inhibits the synthesis of all forms of VEEV RNA. Structural analogues of ML336 showed a correlation between their RNA synthesis inhibitory activity and their antiviral activity in cells, leading us to propose that the primary mechanism of action of this class of compounds is viral RNA synthesis inhibition. The activities of ML336 were highly specific to VEEV, without measurable activity against Chikungunya virus. ML336 was efficacious even in a cell-free viral RNA synthesis assay, suggesting a direct interaction with viral proteins.ImportanceVenezuelan equine encephalitis virus (VEEV) is a pathogenic alphavirus that circulates in the Americas which can cause a lethal encephalitis in humans and equids. There are currently no licensed treatments or vaccines for VEEV. Due to the high potential for aerosol infection and severe outcomes, it is classified as an NIAID Category B agent. To address the unmet need for VEEV antivirals, we continue to advance a novel amidine compound, ML336, through medicinal chemistry and mechanism of action (MOA) studies. Here, we present the molecular MOA by which ML336 inhibits VEEV replication using cellular and biochemical approaches. Our data suggest that ML336 is a direct-acting antiviral that inhibits viral RNA synthesis by interfering with the viral replicase complex. Our studies provide new insights into approaches for the development of novel RNA virus replication inhibitors and the molecular mechanism of alphavirus RNA synthesis.
A single cell-based atlas of human microglial states reveals associations with neurological disorders and histopathological features of the aging brain
Authors: Olah Marta , Menon Vilas , Habib Naomi , Taga Mariko , Yung Christina , Cimpean Maria , Khairalla Anthony , Dionne Danielle , Hopp Sarah , Frosch Matthew P. , Hyman Bradley T. , Beach Thomas , Sarkis Rani , Cosgrove Garth R , Helgager Jeffrey , Golden Jeffrey A. , Pennell Page B. , Schneider Julie A. , Bennett David A. , Regev Aviv , Elyaman Wassim , Bradshaw Elizabeth M. , De Jager Philip L. 
Published: June 2018

AbstractRecent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.