bluuebunny/crossref_metadata_2025_split huggingface dataset:
Representational pattern similarity of electrical brain activity reveals rapid and specific prediction during language comprehension
Authors: Hubbard Ryan J. , Federmeier Kara D. 
Published: April 2020

AbstractPredicting upcoming stimuli and events is a critical function of the brain, and understanding the mechanisms of prediction has thus become a central topic in neuroscientific research. Language provides a fertile testing ground for examining predictive mechanisms, as comprehenders use context to predict different features of upcoming words. Although there is a substantive body of research on prediction in language, many aspects of the mechanisms of prediction remain elusive, in part due to a lack of methodological tools to probe prediction formation in the moment. To elucidate what features are neurally pre-activated and when, we used representational similarity analysis (RSA) on data from a sentence reading task (Federmeier et al., 2007). We compared EEG activity patterns elicited by expected and unexpected sentence final words to patterns from the preceding words of the sentence, in both strongly and weakly constraining sentences. Pattern similarity with the final word was increased in an early time window (suggestive of visual feature activation) following the presentation of the pre-final word, and this increase was modulated by both expectancy and constraint (greatest for strongly constrained expected words). This was not seen at earlier words, suggesting that predictions are precisely timed. Additionally, pre-final word activity – the predicted representation - had negative similarity with later final word activity, but only for strongly expected words. Together, these findings shed light on the mechanisms of prediction in the brain: features of upcoming stimuli are rapidly pre-activated following related cues, but the predicted information may receive reduced subsequent processing upon confirmation.
pDriver: A novel method for unravelling personalised coding and miRNA cancer drivers
Authors: Pham Vu VH , Liu Lin , Bracken Cameron P , Nguyen Thin , Goodall Gregory J , Li Jiuyong , Le Thuc D 
Published: April 2020

AbstractMotivationUnravelling cancer driver genes is important in cancer research. Although computational methods have been developed to identify cancer drivers, most of them detect cancer drivers at population level. However, two patients who have the same cancer type and receive the same treatment may have different outcomes because each patient has a different genome and their disease might be driven by different driver genes. Therefore new methods are being developed for discovering cancer drivers at individual level, but existing personalised methods only focus on coding drivers while microRNAs (miRNAs) have been shown to drive cancer progression as well. Thus, novel methods are required to discover both coding and miRNA cancer drivers at individual level.ResultsWe propose the novel method,pDriver, to discover personalised cancer drivers.pDriverincludes two stages: (1) Constructing gene networks for each cancer patient and (2) Discovering cancer drivers for each patient based on the constructed gene networks. To demonstrate the effectiveness ofpDriver, we have applied it to five TCGA cancer datasets and compared it with the state-of-the-art methods. The result indicates thatpDriveris more effective than other methods. Furthermore,pDrivercan also detect miRNA cancer drivers and most of them have been confirmed to be associated with cancer by literature. We further analyse the predicted personalised drivers for breast cancer patients and the result shows that they are significantly enriched in many GO processes and KEGG pathways involved in breast cancer.Availability and implementationpDriveris available athttps://github.com/pvvhoang/pDriverContactThuc.Le@unisa.edu.auSupplementary informationSupplementary data are available atBioinformaticsonline.
The trajectory of discrete gating charges in a voltage-gated potassium channel
Authors: Priest Michael F. , Lee Elizabeth E.L. , Bezanilla Francisco 
Published: April 2020

AbstractPositively-charged amino acids respond to membrane potential changes to drive voltage sensor movement in voltage-gated ion channels, but determining the trajectory of voltage sensor gating charges has proven difficult. We optically tracked the movement of the two most extracellular charged residues (R1, R2) in the Shaker potassium channel voltage sensor using a fluorescent positively-charged bimane derivative (qBBr) that is strongly quenched by tryptophan. By individually mutating residues to tryptophan within the putative trajectory of gating charges, we observed that the charge pathway during activation is a rotation and a tilted translation that differs between R1 and R2 and is distinct from their deactivation pathway. Tryptophan-induced quenching of qBBr also indicates that a crucial residue of the hydrophobic plug is linked to the Cole-Moore shift through its interaction with R1. Finally, we show that this approach extends to additional voltage-sensing membrane proteins using theCiona intestinalisvoltage sensitive phosphatase (CiVSP).
Auranofin resistance inToxoplasma gondiidecreases the accumulation of reactive oxygen species but does not target parasite thioredoxin reductase
Authors: Ma Christopher I. , Tirtorahardjo James A. , Jan Sharon , Schweizer Sakura S. , Rosario Shawn A. C. , Du Yanmiao , Zhang Jerry J. , Morrissette Naomi S. , Andrade Rosa M. 
Published: April 2020

ABSTRACTAuranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, includingToxoplasma gondii. We generated auranofin resistantT. gondiilines through chemical mutagenesis in order to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-typeT. gondiiexpressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistantlines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin inT. gondiienhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis.
Lower complexity of motor primitives ensures robust control of high-speed human locomotion
Authors: Santuz Alessandro , Ekizos Antonis , Kunimasa Yoko , Kijima Kota , Ishikawa Masaki , Arampatzis Adamantios 
Published: April 2020

AbstractWalking and running are mechanically and energetically different locomotion modes. For selecting one or another, speed is a parameter of paramount importance. Yet, both are likely controlled by similar low-dimensional neuronal networks that reflect in patterned muscle activations called muscle synergies. Here, we investigated how humans synergistically activate muscles during locomotion at different submaximal and maximal speeds. We analysed the duration and complexity (or irregularity) over time of motor primitives, the temporal components of muscle synergies. We found that the challenge imposed by controlling high-speed locomotion forces the central nervous system to produce muscle activation patterns that are wider and less complex relative to the duration of the gait cycle. The motor modules, or time-independent coefficients, were redistributed as locomotion speed changed. These outcomes show that robust locomotion control at challenging speeds is achieved by modulating the relative contribution of muscle activations and producing less complex and wider control signals, whereas slow speeds allow for more irregular control.
Ligand-independent EGFR oligomers do not rely on the active state asymmetric kinase dimer
Authors: Byrne Patrick O. , Hristova Kalina , Leahy Daniel J. 
Published: April 2020

AbstractThe human Epidermal Growth Factor Receptor (EGFR/ERBB1) is a Receptor Tyrosine Kinase (RTK) that forms active oligomers in response to ligand. Much evidence indicates that EGFR/ERBB1 forms oligomers in the absence of ligand, but the structure and physiological role of these ligand-independent dimers remain unclear. We use fluorescence microscopy to measure the oligomer stability and FRET efficiency for homo- and hetero-oligomers of fluorescent-protein labeled forms of EGFR and its paralog, Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) in vesicles derived from native cell membranes. Both receptors form ligand-independent oligomers at physiological plasma membrane concentrations. Mutations introduced in the EGFR kinase region at a key interface within the active state dimer alter the FRET efficiency within ligand-independent EGFR oligomers but do not affect their stability. These results indicate that ligand-independent EGFR oligomers do not require this interface and that the inactive state ensemble is distinct from the EGFR active state ensemble.
Expression ofACE2, the SARS-CoV-2 receptor, andTMPRSS2in prostate epithelial cells
Authors: Song Hanbing , Seddighzadeh Bobak , Cooperberg Matthew R. , Huang Franklin W. 
Published: April 2020

AbstractThe COVID-19 pandemic has spread across more than 200 countries and resulted in over 170,000 deaths. For unclear reasons, higher mortality rates from COVID-19 have been reported in men compared to women. While the SARS-CoV-2 receptorACE2and serine proteaseTMPRSS2have been detected in lung and other tissues, it is not clear what sex differences may exist. We analyzed a publicly-available normal human prostate single-cell RNA sequencing dataset and foundTMPRSS2andACE2co-expressing cells in epithelial cells, with a higher proportion in club and hillock cells. Then we investigated datasets of lung epithelial cells and also found club cells co-expressingTMPRSS2andACE2. A comparison ofACE2expression in lung tissue between males and females showed higher expression in males and a larger proportion ofACE2+ cells in male type II pneumocytes, with preliminary evidence that type II pneumocytes of all lung epithelial cell types showed the highest expression ofACE2. These results raise the possibility that sex differences inACE2expression and the presence of double-positive cells in the prostate may contribute to the observed disparities of COVID-19.
Subnanometer-resolution structure determinationin situby a hybrid subtomogram averaging – single particle cryoEM – workflow
Authors: Sanchez Ricardo , Zhang Yingyi , Chen Wenbo , Dietrich Lea , Kudryashev Misha 
Published: April 2020

ABSTRACTCryo electron tomography (cryo-ET) combined with subtomogram averaging (StA) enables structural determination of macromolecules in their native context. A few structures were reported by StA at resolution higher than 4.5 Å, however all of these are from viral structural proteins or vesicle coats. Reaching high resolution for a broader range of samples is uncommon due to beam-induced sample drift, poor signal-to-noise ratio (SNR) of images, challenges in CTF correction, limited number of particles. Here we propose a strategy to address these issues, which consists of a tomographic data collection scheme and a processing workflow. Tilt series are collected with higher electron dose at zero-degree tilt in order to increase SNR. Next, after performing StA conventionally, we extract 2D projections of the particles of interest from the higher SNR images and use the single particle analysis tools to refine the particle alignment and generate a reconstruction. We benchmarked our proposedhybrid StA (hStA)workflow and improved the resolution for tobacco mosaic virus from 7.2 to 5.2 Å and the resolution for the ion channel RyR1 in crowded native membranes from 12.9 to 9.1 Å. We demonstrate thathStAcan improve the resolution obtained by conventional StA and promises to be a useful tool for StA projects aiming at subnanometer resolution or higher.
Validation of a SARS-CoV-2 spike protein ELISA for use in contact investigations and sero-surveillance
Authors: Freeman Brandi , Lester Sandra , Mills Lisa , Rasheed Mohammad Ata Ur , Moye Stefany , Abiona Olubukola , Hutchinson Geoffrey B. , Morales-Betoulle Maria , Krapinunaya Inna , Gibbons Ardith , Chiang Cheng-Feng , Cannon Deborah , Klena John , Johnson Jeffrey A. , Owen Sherry Michele , Graham Barney S. , Corbett Kizzmekia S. , Thornburg Natalie J. 
Published: April 2020

AbstractSince emergence of SARS-CoV-2 in late 2019, there has been a critical need to understand prevalence, transmission patterns, to calculate the burden of disease and case fatality rates. Molecular diagnostics, the gold standard for identifying viremic cases, are not ideal for determining true case counts and rates of asymptomatic infection. Serological detection of SARS-CoV-2 specific antibodies can contribute to filling these knowledge gaps. In this study, we describe optimization and validation of a SARS-CoV-2-specific-enzyme linked immunosorbent assay (ELISA) using the prefusion-stabilized form of the spike protein [1]. We performed receiver operator characteristic (ROC) analyses to define the specificities and sensitivities of the optimized assay and examined cross reactivity with immune sera from persons confirmed to have had infections with other coronaviruses. These assays will be used to perform contact investigations and to conduct large-scale, cross sectional surveillance to define disease burden in the population.
Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia
Authors: Lillywhite Amanda , Woodhams Stephen G. , Watson David J. G. , Li Li , Burston James J. , Gowler Peter R. W. , Canals Meritxell , Walsh David A. , Hathway Gareth J. , Chapman Victoria 
Published: April 2020

AbstractChronic pain states such as osteoarthritis (OA) are often associated with negative affect, including anxiety and depression. This is, in turn, associated with greater opioid analgesic use, potentially contributing to current and future opioid crises. We utilise an animal model to investigate the neurobiological mechanisms underlying increased opioid use associated with high anxiety and chronic pain.Combining a genetic model of negative affect, the Wistar Kyoto (WKY) rat, and intra-articular injection of monosodium iodoacetate (MIA; 1mg), our model of high anxiety and augmented OA-like pain behaviour mirrors the clinical problem. Effects of morphine (0.5-6mg.kg-1) on pain behaviour and spinal nociceptive neuronal activity were determined in WKY rats, and normo-anxiety Wistar rats, 3 weeks after MIA injection. WKY rats developed augmented OA-like pain, and had blunted inhibitory responses to morphine, when compared to Wistar rats. Potential alterations in endogenous opioid function were probed via systemic blockade of opioid receptors with naloxone (0.1-1mg.kg-1), quantification of circulating levels of β-endorphin, and determination of spinal expression of the mu-opioid receptor (MOR). These studies revealed increased opioidergic tone, and increased spinal desensitization of MORs via the master phosphorylation site at serine residue 375, in this model.We demonstrate attenuated MOR function in the absence of previous exogenous opioid ligand exposure in our model of high anxiety and OA-like pain, which may account for reduced analgesic effect of morphine and provide a potential explanation for increased opioid analgesic intake in high anxiety chronic pain patients.Significance StatementChronic pain affects large numbers of people, and pain management often relies on poorly effective opioid analgesics, the iatrogenic effects of which are increasingly recognised. The endogenous opioid system - the target for exogenous opioid analgesics - plays key roles in emotional affective states and pain control, but the complex interplay between anxiety, chronic pain, and endogenous opioid system function is challenging to study in people. Here, we have addressed this using a clinically-relevant experimental model. Anxiety-like behaviour was associated with increased chronic arthritis-like pain behaviour, altered opioid receptor function, and reduced efficacy of opioid analgesics. We provide new evidence, which may explain why chronic pain patients with comorbid high anxiety have higher opioid analgesic use.
Investigation of a night soil compost psychrotrophic bacteriumGlutamicibacter arilaitensisLJH19 for its safety, efficient hydrolytic and plant growth-promoting potential
Authors: Borker Shruti Sinai , Thakur Aman , Kumar Sanjeet , Kumari Sareeka , Kumar Rakshak , Kumar Sanjay 
Published: April 2020

AbstractNight soil compost (NSC) has traditionally been a source of organic manure in north-western Himalaya. Lately, this traditional method is declining due to modernization, its unhygienic conditions and social apprehensions. Reduction in the age-old traditional practice has led to excessive usage of chemical fertilizers and shortage of water in the eco-sensitive region. Microbiological intervention was attempted to obtain bacterial consortia for accelerated degradation of human faeces in cold climate to improvise this traditional knowledge.Glutamicibacter arilaitensisLJH19, a psychrotrophic bacteria was identified as one such potential candidate for the proposed consortia. The bacterium was isolated from NSC of Lahaul valley and exhibited potential hydrolytic activities, the specific activities of amylase, cellulase and xylanase was observed as 186.76 U/mg, 21.85 U/mg and 11.31 U/mg respectively. Additionally, the strain possessed multiple plant growth-promoting (PGP) traits. The bacterium produced 166.11 µg/ml indole acetic acid and 85.72 % siderophore units, and solubilized 44.76 µg/ml phosphate. Whole genome sequence (3,602,821 bps) endorsed the cold adaptation, polysaccharide metabolism, PGP potential of the bacterium. Genome mining revealed biosynthetic gene clusters for type III polyketide synthase (PKS), terpene, and siderophore in agreement with its potential PGP traits. Comparative genomics within the genus revealed 217 unique genes specific to hydrolytic and PGP activity. Negative haemolysis and biofilm production and susceptibility towards all 12 tested antibiotics indicated the bacterium to be a safe bioinoculant. Genomic investigation supported the bacterium safety with absence of any virulence and antibiotic resistance genes. We propose the strain LJH19 to be a potentially safe bioinoculant candidate for efficient degradation of night soil owing to its survivability in cold and its efficient hydrolytic and PGP potential.
Regulation of Neural Circuit Development by Cadherin-11 Provides Implications for Autism
Authors: Frei Jeannine A. , Niescier Robert F. , Bridi Morgan S. , Durens Madel , Nestor Jonathan E. , Kilander Michaela B. C. , Yuan Xiaobing , Dykxhoorn Derek M. , Nestor Michael W. , Huang Shiyong , Blatt Gene J. , Lin Yu-Chih 
Published: April 2020

AbstractAutism spectrum disorder (ASD) is a neurological condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels while CDH11 expression levels were downregulated. We usedCdh11knockout mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism.Cdh11-/-hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated inCdh11knockout brains. Additionally, excitatory synaptic markers neuroligin-1 and PSD-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.Significance StatementAutism is a neurodevelopmental condition with high genetic and phenotypic heterogeneity. Multiple genes have been implicated in autism, including the cadherin superfamily of adhesion molecules, cadherin-8 and cadherin-11. This study first characterizes the expression profiles of cadherin-8 and cadherin-11 to understand the potential roles they play in the development of neurons. The study further describes novel contributions of cadherin-11 in neural circuit formation. Loss of cadherin-11 in mice results in altered levels of several synaptic proteins, including PSD-95, neuroligin-1, and cadherin-8, and changes the morphology and activity of excitatory neurons. The levels of cadherin-8 and cadherin-11 in human cells of autistic individuals are both altered, strengthening the hypothesis that these two cadherins may involve in aspects of autism etiology.
Repeated gain and loss of a single gene modulates the evolution of vascular pathogen lifestyles
Authors: Gluck-Thaler Emile , Cerutti Aude , Perez-Quintero Alvaro , Butchacas Jules , Roman-Reyna Verónica , Madhaven Vishnu Narayanan , Shantharaj Deepak , Merfa Marcus V. , Pesce Céline , Jauneau Alain , Vancheva Taca , Lang Jillian M. , Allen Caitilyn , Verdier Valerie , Gagnevin Lionel , Szurek Boris , Cunnac Sébastien , Beckham Gregg , de la Fuente Leonardo , Patel Hitendra Kumar , Sonti Ramesh V , Bragard Claude , Leach Jan E. , Noël Laurent D. , Slot Jason C. , Koebnik Ralf , Jacobs Jonathan M. 
Published: April 2020

AbstractVascular pathogens travel long distances through host veins leading to life-threatening, systemic infections. In contrast, non-vascular pathogens remain restricted to infection sites, triggering localized symptom development. The contrasting features of vascular and non-vascular diseases suggest distinct etiologies, but the basis for each remains unclear. Here, we show that the hydrolase CbsA acts as a phenotypic switch between vascular and non-vascular plant pathogenesis.cbsAwas enriched in genomes of vascular phytopathogenic bacteria in the Xanthomonadaceae family and absent in most non-vascular species. CbsA expression allowed non-vascularXanthomonasto cause vascular blight whilecbsAmutagenesis resulted in reduction of vascular or enhanced non-vascular symptom development. Phylogenetic hypothesis testing further revealed thatcbsAwas lost in multiple non-vascular lineages and more recently gained by some vascular subgroups, suggesting that vascular pathogenesis is ancestral. Our results overall demonstrate how the gain and loss of single loci can facilitate the evolution of complex ecological traits.