bluuebunny/crossref_metadata_2025_split huggingface dataset:
All-atom molecular dynamics simulations of synaptic vesicle fusion I: a glimpse at the primed state
Authors: Rizo Josep , Sari Levent , Qi Yifei , Im Wonpil , Lin Milo M. 
Published: December 2021

AbstractSynaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to synaptotagmin-1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of synaptotagmin-1 and/or complexin-1. Our results help visualize potential states of the release machinery en route to fusion, and suggest mechanistic features that may control the speed of release. In particular, the simulations suggest that the primed state contains almost fully assembled trans-SNARE complexes bound to the synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration where interactions of the C2B domain with the plasma membrane orient complexin-1 toward the vesicle, avoiding premature membrane merger but keeping the system ready for fast fusion upon Ca2+ influx.
Symphonizing pileup and full-alignment for deep learning-based long-read variant calling
Authors: Zheng Zhenxian , Li Shumin , Su Junhao , Leung Amy Wing-Sze , Lam Tak-Wah , Luo Ruibang 
Published: December 2021

AbstractDeep learning-based variant callers are becoming the standard and have achieved superior SNP calling performance using long reads. In this paper, we present Clair3, which leveraged the best of two major method categories: pile-up calling handles most variant candidates with speed, and full-alignment tackles complicated candidates to maximize precision and recall. Clair3 ran faster than any of the other state-of-the-art variant callers and performed the best, especially at lower coverage.
The influence of saccades on yaw gaze stabilization in fly flight
Authors: Davis Brock A. , Mongeau Jean-Michel 
Published: December 2021

AbstractIn a way analogous to human vision, the fruit flyD. melanogasterand many other flying insects generate smooth and saccadic movements to stabilize and shift their gaze in flight, respectively. It has been hypothesized that this combination of continuous and discrete movements benefits both flight stability and performance, particularly at high frequencies or visual motion speeds [1]. Here we develop a hybrid control system model to explore the effects of saccades on the yaw gaze stabilization reflex ofD. melanogaster. Inspired from experimental studies, the model includes a first order plant, a Proportional-Integral (PI) continuous controller, and a saccadic reset system that fires based on the integrated error of the continuous controller. We explore the gain, delay and switching threshold parameter space to quantify the optimum regions for yaw stability and performance. We show that the addition of saccades to a continuous controller provides benefits to both stability and performance across a range of visual motion speeds. Our model suggests thatDrosophilaoperates near its optimal switching threshold for its experimental gain set. We also show that based on experimental data,D. melanogasteroperates in a region that trades off performance and stability. This trade-off increases flight robustness, which could facilitate compensation for internal perturbations such as wing damage.
Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges
Authors: Roy Sourav , Ghosh Prithwi , Bandyopadhyay Abhirup , Basu Sankar 
Published: December 2021

AbstractThe COVID-19 origin debate has greatly been influenced by Genome comparison studies of late, revealing the seemingly sudden emergence of the Furin-Like Cleavage Site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCSSpike) containing its 681PRRAR685 motif, absent in other related respiratory viruses. Being the rate-limiting (i.e., the slowest) step, the host Furin cleavage is instrumental in the abrupt increase in transmissibility in COVID-19, compared to earlier onsets of respiratory viral diseases. In such a context, the current paper entraps a ’disorder-to-order transition’ of the FLCSSpike (concomitant to an entropy arrest) upon binding to Furin. The interaction clearly seems to be optimized for a more efficient proteolytic cleavage in SARS-CoV-2. The study further shows the formation of dynamically interchangeable and persistent networks of salt-bridges at the Spike–Furin interface in SARS-CoV-2 involving the three arginines (R682, R683, R685) of the FLCSSpike with several anionic residues (E230, E236, D259, D264, D306) coming from Furin, strategically distributed around its catalytic triad. Multiplicity and structural degeneracy of plausible salt-bridge network archetypes seems the other key characteristic features of the Spike–Furin binding in SARS-CoV-2 allowing the system to breathe – a trademark of protein disorder transitions. Interestingly, with respect to the homologous interaction in SARS-CoV (2002/2003) taken as a baseline, the Spike–Furin binding events generally in the coronavirus lineage seems to have a preference for ionic bond formation, even with lesser number of cationic residues at their potentially polybasic FLCSSpike patches. The interaction energies are suggestive of a characteristic metastabilities attributed to Spike–Furin interactions generally to the coronavirus lineage – which appears to be favorable for proteolytic cleavages targeted at flexible protein loops. T he current findings not only offer novel mechanistic insights into the coronavirus molecular pathology and evolution but also add substantially to the existing theories of proteolytic cleavages.
Microtubule plus-end regulation by centriolar cap proteins
Authors: Ogunmolu Funso E. , Moradi Shoeib , Volkov Vladimir A. , van Hoorn Chris , Wu Jingchao , Andrea Nemo , Hua Shasha , Jiang Kai , Vakonakis Ioannis , Potočnjak Mia , Herzog Franz , Gigant Benoît , Gudimchuk Nikita , Stecker Kelly E. , Dogterom Marileen , Steinmetz Michel O. , Akhmanova Anna 
Published: December 2021

AbstractCentrioles are microtubule-based organelles required for the formation of centrosomes and cilia. Centriolar microtubules, unlike their cytosolic counterparts, grow very slowly and are very stable. The complex of centriolar proteins CP110 and CEP97 forms a cap that stabilizes the distal centriole end and prevents its over-elongation. Here, we used in vitro reconstitution assays to show that whereas CEP97 does not interact with microtubules directly, CP110 specifically binds microtubule plus ends, potently blocks their growth and induces microtubule pausing. Cryo-electron tomography indicated that CP110 binds to the luminal side of microtubule plus ends and reduces protofilament peeling. Furthermore, CP110 directly interacts with another centriole biogenesis factor, CPAP/SAS- 4, which tracks growing microtubule plus ends, slows down their growth and prevents catastrophes. CP110 and CPAP synergize in inhibiting plus-end growth, and this synergy depends on their direct binding. Together, our data reveal a molecular mechanism controlling centriolar microtubule plus- end dynamics and centriole biogenesis.
Loss ofGrin2aCauses a Transient Delay in the Electrophysiological Maturation of Hippocampal Parvalbumin Interneurons: A Possible Mechanism for Transient Seizure Burden in Patients with NullGRIN2AVariants
Authors: Camp Chad R. , Vlachos Anna , Klöckner Chiara , Krey Ilona , Banke Tue G. , Shariatzadeh Nima , Ruggiero Sarah M , Galer Peter , Park Kristen L. , Caccavano Adam , Kimmel Sarah , Yuan Xiaoqing , Yuan Hongjie , Helbig Ingo , Benke Tim A. , Lemke Johannes R. , Pelkey Kenneth A. , McBain Chris J. , Traynelis Stephen F. 
Published: December 2021

AbstractN-methyl-D-aspartate receptors (NMDARs) comprise a family of ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (encoded by theGRIN1gene) and two GluN2 subunits (encoded by theGRIN2A-GRIN2Dgenes). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within theGRIN2Agene, which encodes the GluN2A subunit. Here, we show that unlike missenseGRIN2Avariants, individuals affected with disease-associated nullGRIN2Avariants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. To explore this new clinical finding at that circuit and cellular level, we conducted studies usingGrin2a+/-andGrin2a-/-mice at various stages during neurodevelopment. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of bothGrin2a+/-andGrin2a-/-mice. These alterations in somatic spiking are not due to global upregulation otherGRINgenes (includingGrin2b) nor can they be attributed to perturbations in the intrinsic excitability or action-potential firing properties of CA1 pyramidal cells. Deeper evaluation of the developing CA1 circuit led us to uncover age- andGrin2agene dosing-dependent transient delays in the electrophysiological maturation programs of PV interneurons. Overall, we report thatGrin2a+/+mice reach electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, withGrin2a+/-mice not reaching electrophysiological maturation until preadolescence, andGrin2a-/-not reaching electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure burden in disease-associated nullGRIN2Apatients.
Identification of ER/SR resident proteins as biomarkers for ER/SR calcium depletion in skeletal muscle cells
Authors: Greer Lacey K. , Meilleur Katherine G. , Harvey Brandon K. , Wires Emily S. 
Published: December 2021

AbstractAberrations to endoplasmic/sarcoplasmic reticulum (ER/SR) calcium concentration can result in the departure of endogenous proteins in a phenomenon termed exodosis. Redistribution of the ER/SR proteome can have deleterious effects to cell function and cell viability, often contributing to disease pathogenesis. Many proteins prone to exodosis reside in the ER/SR via an ER retention/retrieval sequence (ERS) and are involved in protein folding, protein modification, and protein trafficking. While the consequences of their extracellular presence have yet to be fully delineated, the proteins that have undergone exodosis may be useful for biomarker development. Skeletal muscle cells rely upon tightly coordinated ER/SR calcium release for muscle contractions, and perturbations to calcium homeostasis can result in myopathies. Ryanodine receptor type-1 (RYR1) is a calcium release channel located in the SR. Mutations to the RYR1 gene can compromise calcium homeostasis leading to a vast range of clinical phenotypes that include hypotonia, myalgia, respiratory insufficiency, ophthalmoplegia, fatigue and malignant hyperthermia (MH). There are currently no FDA approved treatments for RYR1-related myopathies (RYR1-RM). Here we examine the exodosis profile of skeletal muscle cells following ER/SR calcium depletion. Proteomic analysis identified 4,465 extracellular proteins following ER/SR calcium depletion with 1,280 proteins significantly different than vehicle. A total of 54 ERS proteins were identified and 33 ERS proteins significantly increased following ER/SR calcium depletion. Specifically, ERS protein, mesencephalic astrocyte-derived neurotrophic factor (MANF), was elevated following calcium depletion, making it a potential biomarker candidate for human samples. Despite no significant elevation of MANF in plasma levels among healthy volunteers and RYR1-RM individuals, MANF plasma levels positively correlated with age in RYR1-RM individuals, presenting a potential biomarker of disease progression. Selenoprotein N (SEPN1) was also detected only in extracellular samples following ER/SR calcium depletion. This protein is integral to calcium handling and SEPN1 variants have a causal role in SEPN1-related myopathies (SEPN1-RM). Extracellular presence of ER/SR membrane proteins may provide new insight into proteomic alterations extending beyond ERS proteins. Pre-treatment of skeletal muscle cells with bromocriptine, an FDA approved drug recently found to have anti-exodosis effects, curbed exodosis of ER/SR resident proteins. Changes to the extracellular content caused by intracellular calcium dysregulation presents an opportunity for biomarker development and drug discovery.
Unsupervised genome-wide cluster analysis: nucleotide sequences of the omicron variant of SARS-CoV-2 are similar to sequences from early 2020
Authors: Hahn Georg , Lee Sanghun , Prokopenko Dmitry , Novak Tanya , Hecker Julian , Khurana Surender , Baden Lindsey R. , Randolph Adrienne G. , Weiss Scott T. , Lange Christoph 
Published: December 2021

AbstractThe GISAID database contains more than 1,000,000 SARS-CoV-2 genomes, including sequences of the recently discovered SARS-CoV-2 omicron variant and of prior SARS-CoV-2 strains that have been collected from patients around the world since the beginning of the pandemic. We applied unsupervised cluster analysis to the SARS-CoV-2 genomes, assessing their similarity at a genome-wide level based on the Jaccard index and principal component analysis. Our analysis results show that the omicron variant sequences are most similar to sequences that have been submitted early in the pandemic around January 2020. Furthermore, the omicron variants in GISAID are spread across the entire range of the first principal component, suggesting that the strain has been in circulation for some time. This observation supports a long-term infection hypothesis as the omicron strain origin.
SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells
Authors: Nguyen Long C. , Renner David M. , Silva Diane , Yang Dongbo , Parenti Nicholas , Medina Kaeri M. , Nicolaescu Vlad , Gula Haley , Drayman Nir , Valdespino Andrea , Mohamed Adil , Dann Christopher , Wannemo Kristin , Robinson-Mailman Lydia , Gonzalez Alan , Stock Letícia , Cao Mengrui , Qiao Zeyu , Moellering Raymond E. , Tay Savas , Randall Glenn , Beers Michael F. , Rosner Marsha Rich , Oakes Scott A. , Weiss Susan R. 
Published: December 2021

SUMMARYSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.IMPORTANCESARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.
Prolactin action is necessary for parental behavior in male mice
Authors: Smiley Kristina O. , Brown Rosemary S.E. , Grattan David R. 
Published: December 2021

ABSTRACTParental care is critical for successful reproduction in mammals. In comparison to maternal care, the neuroendocrine mechanisms supporting paternal care are less well-studied. Laboratory mice show a mating-induced suppression of infanticide (normally observed in virgins) and onset of paternal behavior. Using this model, we sought to investigate whether the hormone prolactin plays a role in paternal behavior, as it does for maternal behavior. First, using c-fos immunoreactivity in Prlr-IRES-Cre-tdtomato reporter mouse sires, we show that the circuitry activated during paternal interactions contains prolactin-responsive neurons, including the medial preoptic area, bed nucleus of the stria terminalis, and medial amygdala. To evaluate whether prolactin action is required for the establishment and display of paternal behavior, we conditionally deleted the prolactin receptor (Prlr) from 3 distinct cell types: glutamatergic, GABAergic, and CaMKIIα-expressing forebrain neurons. Prlr-deletion from CaMKIIα-expressing forebrain neurons, but not from glutamatergic or GABAergic cells, resulted in a profound effect on paternal behavior, as none of these males completed the pup retrieval task. Finally, although sires do not show an acute increase in circulating prolactin levels in response to pups, pharmacological blockade of prolactin-release at the time of pup exposure resulted in failure to retrieve pups, similar to when the Prlr was deleted from CaMKIIα neurons, with prolactin administration rescuing this behavior. Taken together, our data show that paternal behavior in sires is dependent on basal levels of circulating prolactin acting at the Prlr on CaMKIIα-expressing neurons. These new data in male mice demonstrate that prolactin has a similar action in both sexes to promote parental care.
Gut mélange à trois: fluctuating selection modulated by microbiota, host immune system, and antibiotics
Authors: Barreto Hugo C. , Abreu Beatriz , Gordo Isabel 
Published: December 2021

SUMMARYIron is critical in host-microbe interactions, and its availability is tightly regulated in the mammalian gut. Antibiotics and inflammation can perturb iron availability in the gut, which could alter host-microbe interactions. Here, we show that an adaptive allele of iscR, a major regulator of iron homeostasis of Escherichia coli, is under fluctuating selection in the mouse gut. In vivo competitions in immune-competent, immune-compromised, and germ-free mice reveal that the selective pressure on an iscR mutant E. coli is modulated by the presence of antibiotics, the microbiota, and the immune system. In vitro assays show that iron availability is an important mediator of the iscR allele fitness benefits or costs. We identify Lipocalin-2, a host’s immune protein that prevents bacterial iron acquisition, as a major host mechanism underlying fluctuating selection of iscR. Our results provide a remarkable example of strong fluctuating selection acting on bacterial iron regulation in the mammalian gut.
A review of methodologies for performance evaluation of automated construction processes
Authors: Krishnamoorthi Sundararaman , Raphael Benny 
Published: December 2021

PurposeThe aim of this paper is to synthesize knowledge related to performance evaluation of automated construction processes during the planning and execution phases through a theme-based literature classification. The primary research question that is addressed is “How to quantify the performance improvement in automated construction processes?”Design/methodology/approachA systematic literature review of papers on automated construction was conducted involving three stages-planning, conducting and reporting. In the planning stage, the purpose of the review is established through key research questions. Then, a four-step process is employed consisting of identification, screening, shortlisting and inclusion of papers. For reporting, observations were critically analysed and categorized according to themes.FindingsThe primary conclusion from this study is that the effectiveness of construction processes can only be benchmarked using realistic simulations. Simulations help to pinpoint the root causes of success or failure of projects that are either already completed or under execution. In automated construction, there are many complex interactions between humans and machines; therefore, detailed simulation models are needed for accurate predictions. One key requirement for simulation is the calibration of the models using real data from construction sites.Research limitations/implicationsThis study is based on a review of 169 papers from a database of peer-reviewed journals, within a time span of 50 years.Originality/valueGap in research in the area of performance evaluation of automated construction is brought out. The importance of simulation models calibrated with on-site data within a methodology for performance evaluation is highlighted.
An examination of social media advertising features, brand engagement and purchase intention in the fast food industry
Authors: Hanaysha Jalal Rajeh 
Published: December 2021

PurposeThis study aimed to investigate the impact of social media advertising features (interactivity, perceived relevance, informativeness and entertainment) on brand engagement in the fast food industry. It was also designed to identify the effect of brand engagement on purchase intention.Design/methodology/approachThe data was gathered from 258 customers of fast food restaurants in United Arab Emirates using an online survey. The collected data was analyzed via the partial least square approach (PLS-SEM) to verify the hypotheses and reach at conclusions.FindingsThe findings indicated that social media advertising features have positive effects on brand engagement. In particular, it was found that interactivity, perceived relevance, informativeness and entertainment are positively associated with brand engagement. The results also confirmed that brand engagement has a positive effect on purchase intention.Originality/valueThis study provides a noteworthy contribution to the literature by examining the effect of four unique social media advertising features on consumer engagement. By looking at previous studies, it can also be observed there is a limited empirical research on the effect of perceived relevance and informativeness on brand engagement. It further focuses on covering existing gaps in the literature concerning the effect of brand engagement on purchase intention in the fast food industry setting. This is one of the earlier studies that collectively examined these factors in model; particularly, in fast food industry setting with empirical data from a Middle East country.