bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligomeric hypercomplex of the complete oxidative phosphorylation system in heart mitochondria
Authors: Nesterov S.V. , Chesnokov Yu.M. , Kamyshinsky R.A. , Panteleeva A.A , Lyamzaev K.G. , Vasilov R.G. , Yaguzhinsky L.S. 
Published: August 2020

AbstractThe existence of a complete oxidative phosphorylation system supercomplex including both electron transport system and ATP synthases has long been assumed based on functional evidence. However, no conclusive structural confirmation has been obtained. In this study cryo-electron tomography was used to reveal the supramolecular architecture of the rat heart mitochondria cristae. We show that rows of respiratory chain supercomplexes are connected with rows of ATP synthases forming the oligomeric hypercomplex. The discovered hypercomplexes may increase the effectiveness of oxidative phosphorylation ensuring a direct proton transfer from pumps to ATP synthase along the membrane without energy dissipation.
Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection
Authors: Ashraf Bilal , Lawson Daniel John 
Published: August 2020

AbstractMost complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.
Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms
Authors: Kwon Buki , Fansler Mervin M. , Patel Neil D. , Lee Jihye , Ma Weirui , Mayr Christine 
Published: August 2020

SummaryMulti-UTR genes are widely transcribed but show cell type-specific 3′UTR isoform expression. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate mRNA isoform expression. Deletion of an endogenous enhancer of a multi-UTR gene did not impair transcript production but prevented a switch in 3′UTR isoform expression. Also, the same enhancers are able to increase transcript production in the context of single-UTR gene promoters, but they increase 3′ end processing activity when paired with multi-UTR gene promoters. We show that transcription factors regulate processing activity of weak polyadenylation sites to control cell type-specific alternative 3′UTR isoform expression of widely expressed genes.
Single-Strand DNA Breaks Cause Replisome Disassembly
Authors: Vrtis Kyle B. , Dewar James M. , Chistol Gheorghe , Wu R. Alex , Graham Thomas G. W. , Walter Johannes C. 
Published: August 2020

SummaryDNA damage impedes replication fork progression and threatens genome stability. Upon encounter with most DNA adducts, the replicative CMG helicase (CDC45-MCM2-7-GINS) stalls or uncouples from the point of synthesis, yet CMG eventually resumes replication. However, little is known about the effect on replication of single-strand breaks or “nicks”, which are abundant in mammalian cells. UsingXenopusegg extracts, we reveal that CMG collision with a nick in the leading strand template generates a blunt-ended double-strand break (DSB). Moreover, CMG, which encircles the leading strand template, “runs off” the end of the DSB. In contrast, CMG collision with a lagging strand nick generates a broken end with a single-stranded overhang. In this setting, CMG translocates beyond the nick on double-stranded DNA and is then actively removed from chromatin by the p97 ATPase. Our results show that nicks are uniquely dangerous DNA lesions that invariably cause replisome disassembly, and they argue that CMG cannot be deposited on dsDNA while cells resolve replication stress.HighlightsThe structures of leading and lagging strand collapsed forks are differentCMG passively “runs off” the broken DNA end during leading strand fork collapseCMG is unloaded from duplex DNA after lag collapse in a p97-dependent mannerNicks are uniquely toxic lesions that cause fork collapse and replisome disassembly
Extracellular matrix and cyclic stretch alter fetal cardiomyocyte proliferation and maturation in a rodent model of heart hypoplasia
Authors: Watson Matthew C. , Williams Corin , Wang Raymond M. , Perreault Luke R. , Sullivan Kelly E. , Stoppel Whitney L. , Black Lauren D. 
Published: August 2020

AbstractBirth defects, particularly those that affect development of the heart, are a leading cause of morbidity and mortality in infants and young children. Babies born with heart hypoplasia (HH) disorders often have a poor prognosis. It remains unclear whether cardiomyocytes from hypoplastic hearts retain the potential to recover growth, although this knowledge would be beneficial for developing therapies for HH disorders. The objective of this study was to determine the proliferation and maturation potential of cardiomyocytes from hypoplastic hearts and whether these behaviors are influenced by biophysical signaling from the extracellular matrix (ECM) and cyclic mechanical stretch. Congenital diaphragmatic hernia (CDH)-associated HH was induced in rat fetuses by maternal exposure to nitrofen. Hearts were isolated from embryonic day 21 nitrofen-treated fetuses positive for CDH (CDH+) and from fetuses without nitrofen administration during gestation. CDH+ hearts were smaller and had decreased myocardial proliferation, along with evidence of decreased maturity compared to healthy hearts. In culture, CDH+ cardiomyocytes remained immature and demonstrated increased proliferative capacity compared to their healthy counterparts. Culture on ECM derived from CDH+ hearts led to a significant reduction in proliferation for both CDH+ and healthy cardiomyocytes. Healthy cardiomyocytes were dosed with exogenous nitrofen to examine whether nitrofen may have an abhorrent effect on the proliferative ability of cardiomyocyte, yet no significant change in proliferation was observed. When subjected to stretch, CDH+ cardiomyocytes underwent lengthening of sarcomeres while healthy cardiomyocyte sarcomeres were unaffected. Taken together, our results suggest that alterations to environmental cues such as ECM and stretch may be important factors in the pathological progression of HH.
UhAVR1, an HR-triggering avirulence effector ofUstilago hordei, is secreted via the ER-Golgi pathway to the cytosol of barley coleoptile cells and contributes to virulence early in infection
Authors: Alonso Ana Priscilla Montenegro , Ali Shawkat , Song Xiao , Linning Rob , Bakkeren Guus 
Published: August 2020

AbstractThe basidiomyceteUstilago hordei(Uh) causes covered smut disease of barley and oats. Virulence effectors that aid the infection process and support the pathogen’s lifestyle have been described for this fungus. Genetically, six avirulence genes are known and one codes for UhAVR1, the only proven avirulence effector identified in smut pathogens to date that triggers complete immunity in barley cultivars carrying the resistance geneRuh1. A prerequisite for resistance breeding is understanding the host targets and molecular function of UhAVR1. Analysis of this effector upon natural infection of barley coleoptiles using teliospores showed that UhAVR1 is expressed during the early stages of fungal infection where it leads to HR triggering in resistant cultivars or performs its virulence function in susceptible cultivars. Fungal secretion of UhAVR1 is directed by its signal peptide and occurs via the BrefeldinA-sensitive ER-Golgi pathway, both in cell culture away from its host, and during barley interaction. Transient expression of this effector in barley and a heterologous host,Nicotiana benthamiana(Nb), supports a cytosolic localization. Delivery of UhAVR1 via foxtail mosaic virus,Pseudomonasspecies orAgrobacterium-mediatedsuppression of cell inducers in barley andNbsupport a role in the suppression of a common component(s) of ETI and PTI which is conserved in both plant systems.
Evaluation of the Safety of Percutaneous Electrical Stimulation of the Phrenic and Femoral Nerves in a Chronic Porcine Model: A GLP Study
Authors: O’Mahony John , Dingfelder Carlus , Polyakov Igor , Jocewicz Trace , Mischke Jennifer 
Published: August 2020

ABSTRACTPurposeDiaphragm pacing has been proposed as a method to prevent ventilator-induced diaphragm dysfunction (VIDD) during mechanical ventilation (MV). The present study assessed the safety of lead deployment and control of diaphragm inspiratory work in synchrony with MV utilizing percutaneous electrical phrenic nerve stimulation (PEPNS) in a sedated and ventilated porcine model.MethodsThe ability to safely place PEPNS four-electrode leads near the femoral nerve using ultrasound visualization and electrical stimulation to guide lead placement using a through the needle (TTN) approach was assessed for 4 animals. The feasibility of using the PEPNS system to activate the diaphragm in synchrony with inspiration within a desired target Work of Breathing (WOB) between 0.3 and 0.7 joules/L over eight hours was tested using three of the four animals with the fourth used as a control. The ability to control WOB during inspiration was assessed for flow and pressure-controlled breaths using a flow and pressure sensor attached to the wye, the connector joining the inspiratory and expiratory limbs to the endotracheal tube. Overall health (moribundity) was assessed at baseline and throughout the study until Day 30 for the surviving animals. Gross pathology and histopathological studies were performed on the femoral nerves and diaphragm muscle tissue following termination of the animals at Day 30.ResultsThe lower bound estimate of the proportion of successful stimulation within the desired level of WOB was 95.1%, achieving the study endpoint. Triggering synchrony was statistically significant at <88ms (p<0.0001) with WOB able to be maintained between 0.3 and 0.7 joules/L. There was no evidence of tissue or nerve damage nor impact on overall animal health associated with lead placement or electrical stimulation.ConclusionThe PEPNS leads were found to be safe for their intended use and the PEPNS system met preestablished study endpoints for synchrony and stimulation efficacy.
UFold: Fast and Accurate RNA Secondary Structure Prediction with Deep Learning
Authors: Fu Laiyi , Cao Yingxin , Wu Jie , Peng Qinke , Nie Qing , Xie Xiaohui 
Published: August 2020

AbstractMotivationFor many RNA molecules, the secondary structure is essential for the correct function of the RNA. Predicting RNA secondary structure from nucleotide sequences is a long-standing problem in genomics, but the prediction performance has reached a plateau over time. Traditional RNA secondary structure prediction algorithms are primarily based on thermodynamic models through free energy minimization, which imposes strong prior assumptions and is slow to run.ResultsHere we propose a deep learning-based method, called UFold, for RNA secondary structure prediction, trained directly on annotated data without any thermodynamic assumptions. UFold improves substantially upon previous models, with approximately 10~30% improvement over traditional thermodynamic models and 14% improvement over other learning-based methods. It achieves an F1 score of 0.91 on base pair prediction accuracy on an RNA structure prediction benchmark dataset. UFold is also fast with an inference time about 160ms per sequence up to 1600bp length. We provide an online web server that implements UFold for RNA structure prediction and is made freely available.AvailabilityAn online web server running UFold is available athttps://ufold.ics.uci.edu. Code is available athttps://github.com/uci-cbcl/UFold.Contactxhx@uci.edu
Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site
Authors: Hazlewood Jessamine E. , Dumenil Troy , Le Thuy T. , Slonchak Andrii , Kazakoff Stephen H. , Patch Ann-Marie , Gray Lesley-Ann , Howley Paul M. , Liu Liang , Hayball John D. , Yan Kexin , Rawle Daniel J. , Prow Natalie A. , Suhrbier Andreas 
Published: August 2020

AbstractPoxvirus systems have been extensively used as vaccine vectors. Herein a systems vaccinology analysis of intramuscular injection sites provides detailed insights into host innate immune responses, as well as expression of vector and recombinant immunogen genes, after vaccination with a new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya and Zika virus immunogen mRNA and protein expression was associated with necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. Adjuvant signatures at 12 hours post-vaccination were dominated by TLR3, 4 and 9, STING, MAVS, PKR and the inflammasome. Th1 cytokine signatures were dominated by IFNγ, TNF and IL1β, and chemokine signatures by CCL5 and CXCL12. Multiple signatures associated with dendritic cell stimulation were evident. By day seven, vaccine transcripts were absent, and cell death, neutrophil, macrophage and inflammation annotations had abated. No compelling arthritis signatures were identified. Such innate systems vaccinology approaches should inform refinements in poxvirus-based vector design.
Controlling for effects of confounding variables on machine learning predictions
Authors: Dinga Richard , Schmaal Lianne , Penninx Brenda W.J.H. , Veltman Dick J. , Marquand Andre F. 
Published: August 2020

ABSTRACTMachine learning predictive models are being used in neuroimaging to predict information about the task or stimuli or to identify potentially clinically useful biomarkers. However, the predictions can be driven by confounding variables unrelated to the signal of interest, such as scanner effect or head motion, limiting the clinical usefulness and interpretation of machine learning models. The most common method to control for confounding effects is regressing out the confounding variables separately from each input variable before machine learning modeling. However, we show that this method is insufficient because machine learning models can learn information from the data that cannot be regressed out. Instead of regressing out confounding effects from each input variable, we propose controlling for confounds post-hoc on the level of machine learning predictions. This allows partitioning of the predictive performance into the performance that can be explained by confounds and performance independent of confounds. This approach is flexible and allows for parametric and non-parametric confound adjustment. We show in real and simulated data that this method correctly controls for confounding effects even when traditional input variable adjustment produces false-positive findings.
Chronic stress induces co-ordinated cortical microcircuit cell type transcriptomic changes consistent with altered information processing
Authors: Newton Dwight F. , Oh Hyunjung , Shukla Rammohan , Misquitta Keith , Fee Corey , Banasr Mounira , Sibille Etienne 
Published: August 2020

ABSTRACTMajor depressive disorder (MDD) is associated with altered GABAergic and glutamatergic signalling, suggesting altered excitation-inhibition balance (EIB) in cortical mood- and cognition-regulating brain regions. Information processing in cortical microcircuits involves regulation of pyramidal (PYR) cells by Somatostatin-(SST), Parvalbumin-(PV), and Vasoactive intestinal peptide-(VIP) expressing interneurons. Human and rodent studies suggest that impaired PYR-cell dendritic morphology and decreased SST-cell function may mediate altered EIB in MDD. However, knowledge of co-ordinated changes across microcircuit cell types is virtually absent. We thus investigated the co-ordinated transcriptomic effects of UCMS on microcircuit cell types in the medial prefrontal cortex. C57Bl/6 mice, exposed to unpredictable chronic mild stress (UCMS) or control housing for five weeks were assessed for anxiety- and depressive-like behaviours. Microcircuit cell types were laser-microdissected and processed for RNA-sequencing. UCMS-exposed mice displayed predicted elevated behavioural emotionality. Each microcircuit cell type showed a unique transcriptional signature after UCMS. Pre-synaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed down-regulated post-synaptic gene signatures. At the microcircuit level, we observed a shift from distributed transcriptomic co-ordination across cell types in controls towards UCMS-induced increased co-ordination between PYR-, SST- and PV-cells, and a hub-like role for PYR-cells. Lastly, we identified a microcircuit-wide co-expression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviours. Together, these findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cortical EIB mediated by increased co-ordinated regulation of PYR-cells by SST- and PV-cells.
Assessing Overall Reproducibility for Large-scale High-throughput MRI-based Association Studies
Authors: Jiao Zeyu , Lai Yinglei , Kang Jujiao , Gong Weikang , Ma Liang , Jia Tianye , Xie Chao , Cheng Wei , Heinz Andreas , Desrivières Sylvane , Schumann Gunter ,   IMAGEN Consortium, Sun Fengzhu , Feng Jianfeng 
Published: August 2020

AbstractMagnetic Resonance Imaging (MRI) technology has been increasingly used in large-scale association studies. Reproducibility of statistically significant findings generated by MRI-based association studies, especially structural MRI (sMRI) and functional MRI (fMRI), has been recently heavily debated. However, there is still a lack of overall reproducibility assessment for MRI-based association studies. It is also crucial to elucidate the relationship between overall reproducibility and sample size in an experimental design. In this study, we proposed an overall reproducibility index for large-scale high-throughput MRI-based association studies. We performed the overall reproducibility assessments for several recent large sMRI/fMRI databases and observed satisfactory overall reproducibility. Furthermore, we performed the sample size evaluation for the purpose of achieving a desirable overall reproducibility. Additionally, we evaluated the overall reproducibility of GMV changes for UKB vs. PPMI and UKB vs. HCP. We demonstrated that both sample size and some experimental factors play important roles in the overall reproducibility for different experiments. In summary, a systematic assessment of overall reproducibility is fundamental and crucial in the current large-scale high-throughput MRI-based research.
Distinct synaptic and related transcriptional abnormalities in neonatal, childhood and mature autism model of primate: implications for early-age therapeutic intervention
Authors: Watanabe Satoshi , Kurotani Tohru , Oga Tomofumi , Noguchi Jun , Isoda Risa , Nakagami Akiko , Sakai Kazuhisa , Nakagaki Keiko , Sumida Kayo , Hoshino Kohei , Saito Koichi , Miyawaki Izuru , Sekiguchi Masayuki , Wada Keiji , Minamimoto Takafumi , Ichinohe Noritaka 
Published: August 2020

AbstractAutism spectrum disorder (ASD) is a synapse-related disorder that is diagnosed at around 3 years of age. Earlier intervention is desirable for better ASD prognosis; however, there is limited biological literature regarding early-age ASD. This study aimed to assess altered cortical synapses and gene expression in the ASD model marmoset. There were distinct phenotypes in the model animals across the neonate, childhood, and mature stages in the dorsomedial prefrontal cortex (Brodmann area 8b/9). At the neonate stage, synapses were underdeveloped and modulated genes were enriched with synaptogenesis- and ASD-related genes. At the childhood stage, synaptic features and gene expressions associated with experience-dependent circuit remodeling were altered in model animals. At the mature stage, there were synapse overdevelopment and altered gene expression similar to those in human ASD. These early synaptic phenotypes and altered gene expressions could be novel targets of efficient therapy from a young age.
Control and regulation of acetate overflow inEscherichia coli
Authors: Millard Pierre , Enjalbert Brice , Uttenweiler-Joseph Sandrine , Portais Jean-Charles , Létisse Fabien 
Published: August 2020

AbstractOverflow metabolism refers to the production of seemingly wasteful by-products by cells during growth on glucose even when oxygen is abundant. Two theories have been proposed to explain acetate overflow inEscherichia coli– global control of the central metabolism and local control of the acetate pathway – but neither accounts for all observations. Here, we develop a kinetic model ofE. colimetabolism that quantitatively accounts for observed behaviors and successfully predicts the response ofE. colito new perturbations. We reconcile these theories and clarify the origin, control and regulation of the acetate flux. We also find that, in turns, acetate regulates glucose metabolism by coordinating the expression of glycolytic and TCA genes. Acetate should not be considered a wasteful end-product since it is also a co-substrate and a global regulator of glucose metabolism inE. coli. This has broad implications for our understanding of overflow metabolism.
Multiscale pink-beam microCT imaging at the ESRF-ID17 biomedical beamline
Authors: Mittone Alberto , Fardin Luca , Di Lillo Francesca , Fratini Michela , Requardt Herwig , Mauro Anthony , Homs-Regojo Roberto Arturo , Douissard Paul-Antoine , Barbone Giacomo E. , Stroebel Johannes , Romano Mariele , Massimi Lorenzo , Begani-Provinciali Ginevra , Palermo Francesca , Bayat Sam , Cedola Alessia , Coan Paola , Bravin Alberto 
Published: August 2020

Recent trends in hard X-ray micro-computed tomography (microCT) aim at increasing both spatial and temporal resolutions. These challenges require intense photon beams. Filtered synchrotron radiation beams, also referred to as `pink beams', which are emitted by wigglers or bending magnets, meet this need, owing to their broad energy range. In this work, the new microCT station installed at the biomedical beamline ID17 of the European Synchrotron is described and an overview of the preliminary results obtained for different biomedical-imaging applications is given. This new instrument expands the capabilities of the beamline towards sub-micrometre voxel size scale and simultaneous multi-resolution imaging. The current setup allows the acquisition of tomographic datasets more than one order of magnitude faster than with a monochromatic beam configuration.