bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-Scale Analysis of Circulating Amino Acids and Adipose Gene Expression in Relation to Abdominal Obesity
Authors: Ina Maltais-Payette , Jinchu Vijay , Marie-Michelle Simon , Corbeil Jacques , Brière Francis , Elin Grundberg , André Tchernof 
Published: November 2020

ABSTRACTBackgroundCirculating level of the amino acid glutamate is associated with central fat accumulation, yet the pathophysiology of this relationship remains unknown. We aimed to: i) refine and validate the association between circulating glutamate and abdominal obesity in a large population-based twin cohort; and ii) investigate whether transcriptomic profiles in adipose tissue could provide insight into biological mechanisms underlying the association.MethodsFirst, in a cohort of 4,665 individuals from the TwinsUK resource, we identified individuals with abdominal obesity and compared prevalence of the latter across circulating glutamate quintiles. Second, we used transcriptomic signatures generated from adipose tissue, both subcutaneous and visceral, to investigate associations with circulating glutamate levels.ResultsIndividuals in the top circulating glutamate quintile had a 7-fold higher prevalence of abdominal obesity compared to those in the bottom quintile. The adipose tissue transcriptomic analyses identifiedGLUL, encoding Glutamate-Ammonia Ligase, as being associated with circulating glutamate and abdominal obesity, with pronounced signatures in the visceral depot.ConclusionCirculating glutamate is positively associated with the prevalence of abdominal obesity which relates to dysregulated GLUL expression specifically in visceral adipose tissue.
Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge
Authors: Douguet Laetitia , dit Hreich Serena Janho , Benzaquen Jonathan , Seguin Laetitia , Juhel Thierry , Dezitter Xavier , Duranton Christophe , Ryffel Bernhard , Kanellopoulos Jean , Delarasse Cecile , Renault Nicolas , Furman Christophe , Homerin Germain , Féral Chloé , Cherfils-Vicini Julien , Millet Régis , Adriouch Sahil , Ghinet Alina , Hofman Paul , Vouret-Craviari Valérie 
Published: November 2020

ABSTRACTOnly a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.
Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms
Authors: Lindholm Malene E , Jimenez-Morales David , Zhu Han , Seo Kinya , Amar David , Zhao Chunli , Raja Archana , Madhvani Roshni , Espenel Cedric , Sutton Shirley , Caleshu Colleen , Berry Gerald J , Motonaga Kara S. , Dunn Kyla , Platt Julia , Ashley Euan A , Wheeler Matthew T 
Published: November 2020

AbstractAlpha-actinin 2 (ACTN2) anchors actin within cardiac sarcomeres. The mechanisms linkingACTN2mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novelACTN2mutations to reveal insights into the physiological function of ACTN2. Patient-derived iPSC-cardiomyocytes harboring ACTN2 protein-truncating variants were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc structure. In homozygous stop-gain cells, affinity-purification mass spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, two sarcolemma-associated proteins, that may lead to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing. Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance ofACTN2truncation as causative of disease.
Genomic Resources of Broomcorn Millet: Demonstration and Application of a High-throughput BAC Mapping Pipeline
Authors: Xu Wei , Liang Mengjie , Yang Xue , Wang Hao , Luo Meizhong 
Published: November 2020

AbstractBackgroundWith high-efficient water-use and drought tolerance, broomcorn millet has emerged as a candidate for food security. To promote its research process for molecular breeding and functional research, a comprehensive genome resource is of great importance.ResultsHerein, we constructed a BAC library for broomcorn millet, generated BAC end sequences based on the clone-array pooled shotgun sequencing strategy and Illumina sequencing technology, and integrated BAC clones into genome by a novel pipeline for BAC end profiling. The BAC library is consisted of 76,023 clones with an average insert length of 123.48 Kb, covering about 9.9-fold of the 850 Mb genome. Of 9,216 clones tested using our pipeline, 8,262 clones were mapped on the broomcorn millet cultivar longmi4 genome. These mapped clones covered 308 of the 829 gaps left by the genome. To our knowledge, this is the only BAC resource for broomcorn millet.ConclusionsWe constructed a high-quality BAC libraray for broomcorn millet and designed a novel pipeline for BAC end profiling. BAC clones can be browsed and obtained from our website (http://eightstarsbio.com/gresource/JBrowse-1.16.5/index.html). The high-quality BAC clones mapped on genome in this study will provide a powerful genomic resource for genome gap filling, complex segment sequencing, FISH, functional research, and genetic engineering of broomcorn millet.
Spatio-temporal mRNA dynamics in the early zebrafish embryo
Authors: Holler Karoline , Neuschulz Anika , Drewe-Boß Philipp , Mintcheva Janita , Spanjaard Bastiaan , Arsiè Roberto , Ohler Uwe , Landthaler Markus , Junker Jan Philipp 
Published: November 2020

SummaryEarly stages of embryogenesis depend heavily on subcellular localization and transport of maternally deposited mRNA. However, systematic analysis of these processes is currently hindered by a lack of spatio-temporal information in single-cell RNA sequencing. Here, we combined spatially-resolved transcriptomics and single-cell RNA labeling to study the spatio-temporal dynamics of the transcriptome during the first few hours of zebrafish development. We measured spatial localization of mRNA molecules with sub-single-cell resolution at the one-cell stage, which allowed us to identify a class of mRNAs that are specifically localized at an extraembryonic position, the vegetal pole. Furthermore, we established a method for high-throughput single-cell RNA labeling in early zebrafish embryos, which enabled us to follow the fate of individual maternal transcripts until gastrulation. This approach revealed that many localized transcripts are specifically transported to the primordial germ cells. Finally, we acquired spatial transcriptomes of two xenopus species, and we compared evolutionary conservation of localized genes as well as enriched sequence motifs. In summary, we established sub-single-cell spatial transcriptomics and single-cell RNA labeling to reveal principles of mRNA localization in early vertebrate development.
Fast Vesicle Fusion Mediated by Hydrophobic Dipeptides
Authors: Wei C. , Pohorille A. 
Published: November 2020

AbstractTo understand the transition from inanimate matter to life, we studied a process that directly couples simple metabolism to evolution via natural selection, demonstrated experimentally by Adamala and Szostak (Nat. Chem. 2013, 5, 495–501). In this process, dipeptides synthesized inside precursors of cells promote absorption of fatty acid micelles to vesicles inducing their preferential growth and division at the expense of other vesicles. The process is explained on the basis of coarse-grained molecular dynamics simulations, each extending for tens of microseconds, carried out to model fusion between a micelle and a membrane, both made of fatty acids in the absence and presence of hydrophobic dipeptides. In all systems with dipeptides, but not in their absence, fusion events were observed. They involve the formation of a stalk made by hydrophobic chains from the micelle and the membrane, similar to that postulated for vesicle-vesicle fusion. The emergence of a stalk is facilitated by transient clusters of dipeptides, side chains of which formed hydrophobic patches at the membrane surface. Committor probability calculations indicate that the size of a patch is a suitable reaction coordinate and allow for identifying the transition state for fusion. Free energy barrier to fusion is greatly reduced in the presence of dipeptides to only 4-5 kcal/mol, depending of the hydrophobicity of side chains. The mechanism of mediated fusion, which is expected to apply to other small peptides and hydrophobic molecules, provides a robust means by which a nascent metabolism can confer evolutionary advantage to precursors of cells.SignificanceWe study fusion of micelles and vesicles in the presence and absence of hydrophobic dipeptides by way of molecular dynamics simulations and demonstrate the spontaneous formation of a hydrophobic stalk that has been also long postulated as the key process in vesicle-vesicle fusion but shown only in forced simulations. We show that fusion is facilitated by clusters of dipeptides that form hydrophobic patches at the membrane surface. In order to understand the transition from inanimate matter to life, we explain and generalize experimental findings that hydrophobic dipeptides synthesized inside precursors of cells promote absorption of fatty acid micelles to vesicles inducing their preferential growth and division, thus providing cells endowed with such metabolism with evolutionary advantage.
AI-Driven Multiscale Simulations Illuminate Mechanisms of SARS-CoV-2 Spike Dynamics
Authors: Casalino Lorenzo , Dommer Abigail , Gaieb Zied , Barros Emilia P. , Sztain Terra , Ahn Surl-Hee , Trifan Anda , Brace Alexander , Bogetti Anthony , Ma Heng , Lee Hyungro , Turilli Matteo , Khalid Syma , Chong Lillian , Simmerling Carlos , Hardy David J. , Maia Julio D. C. , Phillips James C. , Kurth Thorsten , Stern Abraham , Huang Lei , McCalpin John , Tatineni Mahidhar , Gibbs Tom , Stone John E. , Jha Shantenu , Ramanathan Arvind , Amaro Rommie E. 
Published: November 2020

ABSTRACTWe develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. We use this workflow to investigate the mechanisms of infectivity of the SARS-CoV-2 spike protein, the main viral infection machinery. Our workflow enables more efficient investigation of spike dynamics in a variety of complex environments, including within a complete SARS-CoV-2 viral envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. We present several novel scientific discoveries, including the elucidation of the spike’s full glycan shield, the role of spike glycans in modulating the infectivity of the virus, and the characterization of the flexible interactions between the spike and the human ACE2 receptor. We also demonstrate how AI can accelerate conformational sampling across different systems and pave the way for the future application of such methods to additional studies in SARS-CoV-2 and other molecular systems.ACM Reference FormatLorenzo Casalino1†, Abigail Dommer1†, Zied Gaieb1†, Emilia P. Barros1, Terra Sztain1, Surl-Hee Ahn1, Anda Trifan2,3, Alexander Brace2, Anthony Bogetti4, Heng Ma2, Hyungro Lee5, Matteo Turilli5, Syma Khalid6, Lillian Chong4, Carlos Simmerling7, David J. Hardy3, Julio D. C. Maia3, James C. Phillips3, Thorsten Kurth8, Abraham Stern8, Lei Huang9, John McCalpin9, Mahidhar Tatineni10, Tom Gibbs8, John E. Stone3, Shantenu Jha5, Arvind Ramanathan2∗, Rommie E. Amaro1∗. 2020. AI-Driven Multiscale Simulations Illuminate Mechanisms of SARS-CoV-2 Spike Dynamics. In Supercomputing ’20: International Conference for High Performance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages. https://doi.org/finalDOI
Null effects of levodopa on reward- and error-based motor adaptation, savings, and anterograde interference
Authors: Palidis Dimitrios J. , McGregor Heather R. , Vo Andrew , MacDonald Penny A. , Gribble Paul L. 
Published: November 2020

AbstractDopamine signaling is thought to mediate reward-based learning. We tested for a role of dopamine in motor adaptation by administering the dopamine precursor levodopa to healthy participants in two experiments involving reaching movements. Levodopa has been shown to impair reward-based learning in cognitive tasks. Thus, we hypothesized that levodopa would selectively impair aspects of motor adaptation that depend on reinforcement of rewarding actions.In the first experiment, participants performed two separate tasks in which adaptation was driven either by visual error-based feedback of the hand position or binary reward feedback. We used EEG to measure event-related potentials evoked by task feedback. We hypothesized that levodopa would specifically diminish adaptation and the neural responses to feedback in the reward learning task. However, levodopa did not affect motor adaptation in either task nor did it diminish event-related potentials elicited by reward outcomes.In the second experiment, participants learned to compensate for mechanical force field perturbations applied to the hand during reaching. Previous exposure to a particular force field can result in savings during subsequent adaptation to the same force field or interference during adaptation to an opposite force field. We hypothesized that levodopa would diminish savings and anterograde interference, as previous work suggests that these phenomena result from a reinforcement learning process. However, we found no reliable effects of levodopa.These results suggest that reward-based motor adaptation, savings, and interference may not depend on the same dopaminergic mechanisms that have been shown to be disrupted by levodopa during various cognitive tasks.New and NoteworthyMotor adaptation relies on multiple processes including reinforcement of successful actions. Cognitive reinforcement learning is impaired by levodopa-induced disruption of dopamine function. We administered levodopa to healthy adults who participated in multiple motor adaptation tasks. We found no effects of levodopa on any component of motor adaptation. This suggests that motor adaptation may not depend on the same dopaminergic mechanisms as cognitive forms or reinforcement learning that have been shown to be impaired by levodopa.
SeRenDIP-CE: Sequence-based Interface Prediction for Conformational Epitopes
Authors: Hou Qingzhen , Stringer Bas , Waury Katharina , Capel Henriette , Haydarlou Reza , Abeln Sanne , Heringa Jaap , Feenstra K. Anton 
Published: November 2020

AbstractMotivationAntibodies play an important role in clinical research and biotechnology, with their specificity determined by the interaction with the antigen’s epitope region, as a special type of protein-protein interaction (PPI) interface. The ubiquitous availability of sequence data, allows us to predicting epitopes from sequence in order to focus time-consuming wet-lab experiments onto the most promising epitope regions. Here, we extend our previously developed sequence-based predictors for homodimer and heterodimer PPI interfaces to predict epitope residues that have the potential to bind an antibody.ResultsWe collected and curated a high quality epitope dataset from the SAbDaB database. Our generic PPI heterodimer predictor obtained an AUC-ROC of 0.666 when evaluated on the epitope test set. We then trained a random forest model specifically on the epitope dataset, reaching AUC 0.694. Further training on the combined heterodimer and epitope datasets, improves our final predictor to AUC 0.703 on the epitope test set. This is better than the best state-of-the-art sequence-based epitope predictor BepiPred-2.0. On one solved antibody-antigen structure of the COVID19 virus spike RNA binding domain, our predictor reaches AUC 0.778. We added the SeRenDIP-CE Conformational Epitope predictors to our webserver, which is simple to use and only requires a single antigen sequence as input, which will help make the method immediately applicable in a wide range of biomedical and biomolecular research.AvailabilityWebserver, source code and datasets are available atwww.ibi.vu.nl/programs/serendipwww/Contactk.a.feenstra@vu.nl
Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists
Authors: Stahl Edward L. , Bohn Laura M. 
Published: November 2020

AbstractIn a recent report in Science Signaling (DOI: 10.1126/scisignal.aaz3140), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although many of the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that since they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor (GPCR) response in a system, while biased agonism takes into consideration not only intrinsic efficacy, but also potency of an agonist in an assay. Herein, we have re-analyzed the data presented in the published work (DOI: 10.1126/scisignal.aaz3140) (including the recent Erratum: DOI: 10.1126/scisignal.abf9803) to derive intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC50). Based on this reanalysis, the data support the conclusion that biased agonism, favoring G protein signaling, was observed. Moreover, a conservation of rank order intrinsic efficacy was not observed upon comparing responses in each assay, further suggesting that multiple active receptor states were present. These observations agree with prior studies wherein oliceridine, PZM21 and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, the data in the Science Signaling manuscript does provide strong corroborating evidence that G protein signaling bias may be a means to improve opioid analgesia while avoiding certain undesirable side effects.
Discovery of a Promising Susceptibility Factor for Fusarium Head Blight in Wheat
Authors: Chhabra Bhavit , Tiwari Vijay , Gill Bikram S , Dong Yanhong , Rawat Nidhi 
Published: November 2020

AbstractFusarium head blight (FHB) disease of wheat caused byFusariumspp. deteriorates both quantity and quality of the crop. Manipulation of susceptibility factors, the genes facilitating disease development in plants, offers a novel and alternative strategy for enhancing FHB resistance in plants. In this study, a major effect susceptibility gene for FHB was identified on the short arm of chromosome 7A (7AS). Nullisomic-tetrasomic lines for homoeologous group-7 of wheat revealed dosage effect of the gene, with tetrasomic 7A being more susceptible than control Chinese Spring wheat, qualifying it as a bonafide susceptibility factor. The gene locus was conserved in six chromosome 7A inter-varietal wheat substitution lines of diverse origin and a tetraploidTriticum dicoccoidesgenotype. The susceptibility gene was named asSF7ASFHBand mapped on chromosome 7AS to 48.5-50.5 Mb peri-centromeric region between del7AS-3 and del7AS-8. Our results showed that deletion ofSF7ASFHBimparts ~ 50-60% type 2 FHB resistance (against the spread of the fungal pathogen) and its manipulation may lead to enhanced resistance against FHB in wheat.HighlightDiscovery and mapping of a conserved susceptibility factor located on the short arm of wheat chromosome 7A whose deletion makes plants resistant to Fusarium Head Blight.
PCQC: Selecting optimal principal components for identifying clusters with highly imbalanced class sizes in single-cell RNA-seq data
Authors: Burstein David , Fullard John F. , Roussos Panos 
Published: November 2020

AbstractSummaryPrior to identifying clusters in single cell gene expression experiments, selecting the top principal components is a critical step for filtering out noise in the data set. Identifying these top principal components typically focuses on the total variance explained, and principal components that explain small clusters from rare populations will not necessarily capture a large percentage of variance in the data. We present a computationally efficient alternative for identifying the optimal principal components based on the tails of the distribution of variance explained for each observation. We then evaluate the efficacy of our approach in three different single cell RNA-sequencing data sets and find that our method matches, or outperforms, other selection criteria that are typically employed in the literature.Availability and implementationpcqc is written in Python and available atgithub.com/RoussosLab/pcqc
Impacts of water quality onAcroporacoral settlement: The relative importance of substrate quality and light
Authors: Ricardo Gerard F. , Harper Charlotte E. , Negri Andrew P. , Luter Heidi M. , Wahab Muhammad Azmi Abdul , Jones Ross J. 
Published: November 2020

AbstractCoral larval settlement patterns are influenced by a vast array of factors; however, the relative roles of individual factors are rarely tested in isolation, leading to confusion about which are most crucial for settlement. For example, direct effects of light environment are often cited as a major determinate of settlement patterns, yet this has not been demonstrated under environmentally realistic lighting regimes in the absence of confounding factors. Here we apply programmable multispectral lights to create realistic light spectra, while removing correlating (but not obvious) factors that are common in laboratory settlement experiments. Using two common species ofAcropora– key framework builders of the Great Barrier Reef – we find little evidence that light intensity or changes in the spectral profile play a substantial role in larval settlement under most environmentally realistic settings but can under more extreme or artificial settings. We alternatively hypothesise and provide evidence that chronic conditions of light and recent sediment exposures that impact benthic substrates (e.g., crustose coralline algae) preceding settlement have a greater impact, with up to 74% decrease in settlement observed on substrates with prior exposure and poor water quality conditions. Management of water quality conditions that impact the quality of benthic-settlement substrates therefore should present a priority area of focus for improving coral recruitment.