bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular determinants of β-arrestin coupling to formoterol-bound β1-adrenoceptor
Authors: Lee Yang , Warne Tony , Nehmé Rony , Pandey Shubhi , Dwivedi-Agnihotri Hemlata , Edwards Patricia C. , García-Nafría Javier , Leslie Andrew G.W. , Shukla Arun K. , Tate Christopher G. 
Published: April 2020

ABSTRACTThe β1-adrenoceptor (β1AR) is a G protein-coupled receptor (GPCR) activated by the hormone noradrenaline, resulting in the coupling of the heterotrimeric G protein Gs1. G protein-mediated signalling is terminated by phosphorylation of the receptor C-terminus and coupling of β-arrestin 1 (βarr1, also known as arrestin-2), which displaces Gsand induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins (biased agonism)3is important in drug development, as the therapeutic effect may arise from only one signalling cascade, whilst the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, we determined the electron cryo-microscopy (cryo-EM) structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G protein mimetic nanobody Nb806. βarr1 couples to β1AR in a distinct manner to how Gscouples to β2AR7, with the finger loop of βarr1 occupying a narrower cleft on the intracellular surface closer to transmembrane helix H7 than the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop in visual arrestin when it couples to rhodopsin8, and its β-turn configuration is reminiscent of the loop in Nb80 that inserts at the same position. β1AR coupled to βarr1 showed significant differences in structure compared to β1AR coupled to Nb80, including an inward movement of extracellular loop 3 (ECL3) and the cytoplasmic ends of H5 and H6. In the orthosteric binding site there was also weakening of interactions between formoterol and the residues Ser2115.42and Ser2155.46, and a reduction in affinity of formoterol for the β1AR-βarr1 complex compared to β1AR coupled to mini-Gs. These differences provide a foundation for the development of small molecules that could bias signalling in the β-adrenoceptors.
Forecasting COVID-19 impact in India using pandemic waves Nonlinear Growth Models
Authors: Kumar Pavan , Singh Ram Kumar , Nanda Chintan , Kalita Himangshu , Patairiya Shashikanta , Sharma Yagya Datt , Rani Meenu , Bhagavathula Akshaya Srikanth 
Published: April 2020

AbstractThe ongoing pandemic of the coronavirus disease 2019 (COVID-19) started in China and devastated a vast majority of countries. In India, COVID-19 cases are steadily increasing since January 30, 2020, and the government-imposed lockdown across the country to curtail community transmission. COVID-19 forecasts have played an important role in capturing the probability of infection and the basic reproduction rate. In this study, we predicted some trajectories of trajectories associated with COVID-19 in the coming days in India using an Auto-regression integrated moving average model (ARIMA) and Richard’s model. By the end of April 2020, the incidence of new cases is predicted to be 5200 (95% CI: 4650 to 6002) through the ARIMA model versus be 6378 (95% CI: 4904 to 7851) Richard model. We estimated that there would be a total of 197 (95% CI: 118 to 277) deaths and drop down in the recovery rates will reach around 501 (95% CI: 245 to 758) by the end of April 2020. These estimates can help to strengthen the implementation of strategies to increase the health system capacity and enactment of social distancing measures all over India.
Identification of a common deletion in the spike protein of SARS-CoV-2
Authors: Liu Zhe , Zheng Huanying , Yuan Runyu , Li Mingyue , Lin Huifang , Peng Jingju , Xiong Qianlin , Sun Jiufeng , Li Baisheng , Wu Jie , Hulswit Ruben J.G. , Bowden Thomas A. , Rambaut Andrew , Loman Nick , Pybus Oliver G , Ke Changwen , Lu Jing 
Published: April 2020

AbstractTwo notable features have been identified in the SARS-CoV-2 genome: (1) the receptor binding domain of SARS-CoV-2; (2) a unique insertion of twelve nucleotide or four amino acids (PRRA) at the S1 and S2 boundary. For the first feature, the similar RBD identified in SARs-like virus from pangolin suggests the RBD in SARS-CoV-2 may already exist in animal host(s) before it transmitted into human. The left puzzle is the history and function of the insertion at S1/S2 boundary, which is uniquely identified in SARS-CoV-2. In this study, we identified two variants from the first Guangdong SARS-CoV-2 cell strain, with deletion mutations on polybasic cleavage site (PRRAR) and its flank sites. More extensive screening indicates the deletion at the flank sites of PRRAR could be detected in 3 of 68 clinical samples and half of 22 in vitro isolated viral strains. These data indicate (1) the deletion of QTQTN, at the flank of polybasic cleavage site, is likely benefit the SARS-CoV-2 replication or infection in vitro but under strong purification selection in vivo since it is rarely identified in clinical samples; (2) there could be a very efficient mechanism for deleting this region from viral genome as the variants losing 23585-23599 is commonly detected after two rounds of cell passage. The mechanistic explanation for this in vitro adaptation and in vivo purification processes (or reverse) that led to such genomic changes in SARS-CoV-2 requires further work. Nonetheless, this study has provided valuable clues to aid further investigation of spike protein function and virus evolution. The deletion mutation identified in vitro isolation should be also noted for current vaccine development.
Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development
Authors: Ellegood J. , Petkova S.P. , Kinman A. , Qiu L.R. , Wade A. , Fernandes D. , Lindenmaier Z. , Crieghton A. , Nutter L. , Nord A.S. , Silverman J.L. , Lerch J.P. 
Published: April 2020

AbstractOne of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and genes that regulate chromatin modify and control events regulating the formation of neural connections. AT-Rich Interactive Domain 1B(ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. For this work, a novel preclinical mouse model ofArid1bdeficiency was created and molecularly validated to characterize and define neuroanatomical, behavioural and transcriptional phenotypes. Brains of adultArid1b+/-mice had a smaller cerebellum along with a larger hippocampus and corpus callosum. In addition, a notable sex dependence was observed throughout development; males had an early emergence of the neuroanatomical phenotype around postnatal day 7, whereas females had a delayed emergence of the phenotype around postnatal day 40. Behavioural assays relevant to NDD were conducted during neonatal development and adulthood to evaluate general health, anxiety-like, motor, cognitive, and social behaviours inArid1b+/-mice. During neonatal development,Arid1b+/-mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults,Arid1b+/-mice showed low motor skills in open field exploration and normal three chambered approach.Arid1b+/-mice had learning and memory deficits in novel object recognition but surprisingly not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. This study represents a full investigation ofArid1b+/-haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.
Perceptual decisions and oculomotor responses rely on temporally distinct streams of evidence
Authors: Lisi Matteo , Morgan Michael J. , Solomon Joshua A. 
Published: April 2020

AbstractPerceptual decisions often require the integration of noisy sensory evidence over time. This process is formalized with sequential sampling models, where evidence is accumulated up to a decision threshold before a choice is made. Although intuition suggests that decision formation must precede the preparation of a motor response (i.e., the action used to communicate the choice), neurophysiological findings have suggested that these two processes might be one and the same. To test this idea, we developed a reverse-correlation protocol in which the visual stimuli that influence decisions can be distinguished from those guiding motor responses. In three experiments, we found that the temporal weighting function of oculomotor responses did not overlap with the relatively early weighting function of stimulus properties having an impact on decision formation. These results support a timeline in which perceptual decisions are formed, at least in part, prior to the preparation of a motor response.
Virus-host interactome and proteomic survey of PMBCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis
Authors: Li Jingjiao , Guo Mingquan , Tian Xiaoxu , Liu Chengrong , Wang Xin , Yang Xing , Wu Ping , Xiao Zixuan , Qu Yafei , Yin Yue , Fu Joyce , Zhu Zhaoqin , Liu Zhenshan , Peng Chao , Zhu Tongyu , Liang Qiming 
Published: April 2020

ABSTRACTThe ongoing coronavirus disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a global public health concern due to relatively easy person-to-person transmission and the current lack of effective antiviral therapy. However, the exact molecular mechanisms of SARS-CoV-2 pathogenesis remain largely unknown. We exploited an integrated proteomics approach to systematically investigate intra-viral and virus-host interactomes for the identification of unrealized SARS-CoV-2 host targets and participation of cellular proteins in the response to viral infection using peripheral blood mononuclear cells (PBMCs) isolated from COVID-19 patients. Using this approach, we elucidated 251 host proteins targeted by SARS-CoV-2 and more than 200 host proteins that are significantly perturbed in COVID-19 derived PBMCs. From the interactome, we further identified that non-structural protein nsp9 and nsp10 interact with NKRF, a NF-КB repressor, and may precipitate the strong IL-8/IL-6 mediated chemotaxis of neutrophils and overexuberant host inflammatory response observed in COVID-19 patients. Our integrative study not only presents a systematic examination of SARS-CoV-2-induced perturbation of host targets and cellular networks to reflect disease etiology, but also reveals insights into the mechanisms by which SARS-CoV-2 triggers cytokine storms and represents a powerful resource in the quest for therapeutic intervention.
Cell cycle abnormality is a cellular phenotype in OCD
Authors: Manjappa Pravallika , Balachander Srinivas , Naaz Safoora , Nadella Ravi Kumar , Shukla Tulika , Paul Pradip , Purushottam Meera , Reddy YC Janardhan , Jain Sanjeev , Viswanath Biju , Sud Reeteka 
Published: April 2020

AbstractAbnormal indices of cell cycle regulation have been reported in multiple psychiatric disorders. Though reports specific to obsessive compulsive disorder (OCD) are scant, numerous studies have highlighted partly common underlying biology in psychiatric disorders, cell cycle regulation being one such process. In this study, we therefore aimed to explore cell cycle in OCD. To the best of our knowledge, this is the first study to investigate these effects in OCD. We also evaluated the effect of in vitro fluoxetine, commonly used serotonin reuptake inhibitor (SRI) in OCD patients, on cell cycle regulation. The effects of both disease (OCD) and treatment (SRI) were assessed using lymphoblastoid cell lines (LCLs), derived from OCD patients and healthy controls, as a model system. LCLs were treated with 10μM of fluoxetine for 24 hours, and the percentage of cells in each phase of the cell cycle was determined by flow cytometry. We observed a lower proportion of cells in the G2/M phase in OCD cases than controls. The findings suggest that cell cycle dysregulation could be peripheral cellular phenotype for OCD. Among cases, all of whom had been systematically characterized for SRI treatment response, LCLs from non-responders to SRI treatment had a lower proportion of cells in G2/M phase than responders.
Comparing performance of deep convolutional neural network with orthopaedic surgeons on identification of total hip prosthesis design from plain radiographs
Authors: Borjali Alireza , Chen Antonia F. , Bedair Hany S. , Melnic Christopher M. , Muratoglu Orhun K. , Morid Mohammad A. , Varadarajan Kartik M. 
Published: April 2020

ABSTRACTA crucial step in preoperative planning for a revision total hip replacement (THR) surgery is accurate identification of failed implant design, especially if one or more well-fixed/functioning components are to be retained. Manual identification of the implant design from preoperative radiographic images can be time-consuming and inaccurate, which can ultimately lead to increased operating room time, more complex surgery, and increased healthcare costs. No automated system has been developed to accurately and efficiently identify THR implant designs. In this study, we present a novel, fully automatic and interpretable approach to identify the design of nine different THR femoral implants from plain radiographs using deep convolutional neural network (CNN). We also compared the CNN’s performance with three board-certified and fellowship trained orthopaedic surgeons. The CNN achieved on-par accuracy with the orthopaedic surgeons while being significantly faster. The need for additional training data for less distinct designs was also highlighted. Such CNN can be used to automatically identify the design of a failed THR femoral implant preoperatively in just a fraction of a second, saving time and improving identification accuracy.
A hybrid cytcmaturation system enhances the bioelectrical performance of engineeredEscherichia coliby improving the rate-limiting step
Authors: Su Lin , Fukushima Tatsuya , Ajo-Franklin Caroline M. 
Published: April 2020

ABSTRACTBioelectronic devices can use electron flux to enable communication between biotic components and abiotic electrodes. We have modifiedEscherichia colito electrically interact with electrodes by expressing the cytochromecfromShewanella oneidensisMR-1. However, we observe inefficient electrical performance, which we hypothesize is due to the limited compatibility of theE. colicytochromecmaturation (Ccm) systems with MR-1 cytochromec. Here we test whether the bioelectronic performance ofE. colican be improved by constructing hybrid Ccm systems containing protein domains from bothE. coliandS. oneidensisMR-1. The hybrid CcmH increased cytochromecexpression by increasing the abundance of CymA 60%, while only slightly changing the abundance of the other cytochromesc. Electrochemical measurements showed that the overall current from the hybridccmstrain increased 121% relative to the wildtypeccmstrain, with an electron flux per cell of 12.3 ± 0.3 fA·cell-1. Additionally, the hybridccmstrain doubled its electrical response with the addition of exogenous flavin, and quantitative analysis of this demonstrates CymA is the rate-limiting step in this electron conduit. These results demonstrate that this hybrid Ccm system can enhance the bioelectrical performance of the cytcexpressingE. coli, allowing the construction of more efficient bioelectronic devices.
Precursor intensity-based label-free quantification software tools for proteomic and multiomic analysis within the Galaxy Platform
Authors: Mehta Subina , Easterly Caleb , Sajulga Ray , Millikin Robert J. , Argentini Andrea , Eguinoa Ignacio , Martens Lennart , Shortreed Michael R. , Smith Lloyd M. , McGowan Thomas , Kumar Praveen , Johnson James E. , Griffin Timothy J. , Jagtap Pratik 
Published: April 2020

AbstractFor mass spectrometry-based peptide and protein quantification, label-free quantification (LFQ) based on precursor mass peak (MS1) intensities is considered reliable due to its dynamic range, reproducibility, and accuracy. In LFQ workflows, protein abundance changes are inferred from peptide-level information, including microbial peptides (for metaproteomics) and peptides carrying post-translational modifications (for proteomics) and/or variant sequences (for proteogenomics). Multi-omics studies (such as proteogenomics and metaproteomics) rely on peptide detection and quantification to identify and quantify peptides that map to unique proteoforms and metaproteins. The Galaxy for proteomics (Galaxy-P) platform has proven useful for the development of accessible workflows to identify proteins in these complex multi-omic studies. However, proteomics workflows within the Galaxy platform have lacked well-tested label-free quantification tools.In this study, our main goals were to evaluate two recently published open-source LFQ tools and to implement them within the Galaxy platform, enabling their easy integration with established workflows. These two tools, moFF and FlashLFQ, were selected based on their described peptide quantification capabilities and amenability to Galaxy implementation. Through rigorous testing and communication with the tools’ developers, we gained insights into the software features necessary for maximizing the performance of each tool. Software features evaluated included: a) match-between-runs (MBR); b) using both Thermo .raw and HUPO standards .mzML file formats as input for improved quantification; c) use of containers and/or conda packages; d) parameters needed for analyzing large input datasets; and e) optimization and validation of software performance. This work 1) establishes a process for software implementation, optimization and validation within Galaxy; and 2) makes powerful new tools for LFQ available which should prove highly useful for a variety of proteomics and multi-omics applications employing the Galaxy platform.
Discovery of a hidden transient state in all bromodomain families
Authors: Raich Lluís , Meier Katharina , Günther Judith , Christ Clara D. , Noé Frank , Olsson Simon 
Published: April 2020

ABSTRACTBromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These post-translational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly understood, hampering the rational design of potent and selective inhibitors. Here we combine extensive molecular dynamics simulations, Markov state modeling and structural data to reveal a novel and transiently formed state that is conserved across all BD families. It involves the breaking of two backbone hydrogen bonds that anchor the ZA-loop with the αAhelix, opening a cryptic pocket that partially occludes the one associated with histone binding. Our results suggest that this novel state is an allosteric regulatory switch for BDs, potentially related to a recently unveiled BD-DNA binding mode.
Modelling the spatial crosstalk between two biochemical signals explains wood formation dynamics and tree-ring structure
Authors: Hartmann Félix P. , Rathgeber Cyrille B. K. , Badel Eric , Fournier Meriem , Moulia Bruno 
Published: April 2020

AbstractIn conifers, xylogenesis produces during a growing season a very characteristic tree-ring structure: large thin-walled earlywood cells followed by narrow thick-walled latewood cells. Although many factors influence the dynamics of differentiation and the final dimensions of xylem cells, the associated patterns of variation remain very stable from one year to the next. While radial growth is characterised by an S-shaped curve, the widths of xylem differentiation zones exhibit characteristic skewed bell-shaped curves. These elements suggest a strong internal control of xylogenesis. It has long been hypothesised that much of this regulation relies on a morphogenetic gradient of auxin. However, recent modelling works have shown that while this hypothesis could account for the dynamics of stem radial growth and the zonation of the developing xylem, it failed to reproduce the characteristic tree-ring structure. Here we investigated the hypothesis of a regulation by a crosstalk between auxin and a second biochemical signal, using dynamical modelling. We found that, in conifers, such a crosstalk is sufficient to simulate the characteristic features of wood formation dynamics, as well as the resulting tree-ring structure. In this model, auxin controls cell enlargement rates while another signal (e.g., cytokinin, TDIF) drives cell division and auxin polar transport.HighlightA dynamical model proves that two interacting signals (auxin, plus a cytokinin or the TDIF peptide) can drive wood formation dynamics and tree-ring structure development in conifers.
Feminisation of complex traits inDrosophila melanogastervia female-limited X chromosome evolution
Authors: Lund-Hansen Katrine K. , Abbott Jessica K. , Morrow Edward H. 
Published: April 2020

AbstractA handful of studies have investigated sexually antagonistic constraints on obtaining sex-specific fitness optima, though exclusively through male-genome-limited evolution experiments. In this paper, we established a female-limited X chromosome evolution experiment, where we used an X chromosome balancer to enforce the inheritance of the X chromosome through the matriline, thus removing exposure to male selective constraints. This approach eliminates the effects of sexually antagonistic selection on the X chromosome, permitting evolution towards a single sex-specific optimum. After multiple generations of selection, we found strong evidence that body size and development time had moved towards a female-specific optimum, whereas reproductive fitness and locomotion activity remained unchanged. The changes in body size and development time are consistent with previous results, and suggest that the X chromosome is enriched for sexually antagonistic genetic variation controlling these traits. The lack of change in reproductive fitness and locomotion activity could be due to a number of mutually non-exclusive explanations, including a lack of sexually antagonistic variance on the X chromosome or confounding effects of the use of the balancer chromosome. This study is the first to employ female-genome-limited selection and adds to the understanding of the complexity of sexually antagonistic genetic variation.