bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitor screening of Spike variants reveals the heterogeneity of neutralizing antibodies to COVID-19 infection and vaccination
Authors: Zhang Xiaomei , Zheng Mei , Liang Te , Zhou Haijian , Wang Hongye , Zhang Jiahui , Ren Jing , Peng Huoying , Li Siping , Bian Haodong , Wei Chundi , Yin Shangqi , He Chaonan , Han Ying , Li Minghui , Hou Xuexin , Zhang Jie , Xie Liangzhi , Lv Jing , Kan Biao , Wang Yajie , Yu Xiaobo 
Published: May 2021

AbstractMutations of the coronavirus responsible for coronavirus disease 2019 (COVID-19) could impede drug development and reduce the efficacy of COVID-19 vaccines. Here, we developed a multiplexed Spike-ACE2 Inhibitor Screening (mSAIS) assay that can measure the neutralizing effect of antibodies across numerous variants of the coronavirus’s Spike (S) protein simultaneously. By screening purified antibodies and serum from convalescent COVID-19 patients and vaccinees against 72 S variants with the mSAIS assay, we identified new S mutations that are sensitive and resistant to neutralization. Serum from both infected and vaccinated groups with a high titer of neutralizing antibodies (NAbs) displayed a broader capacity to neutralize S variants than serum with low titer NAbs. These data were validated using serum from a large vaccinated cohort (n=104) with a tiled S peptide microarray. In addition, similar results were obtained using a SARS-CoV-2 pseudovirus neutralization assay specific for wild-type S and four prevalent S variants (D614G, B.1.1.7, B.1.351, P.1), thus demonstrating that high antibody diversity is associated with high NAb titers. Our results demonstrate the utility of the mSAIS platform in screening NAbs. Moreover, we show that heterogeneous antibody populations provide a more protective effect against S variants, which may help direct COVID-19 vaccine and drug development.HighlightsDeveloped a high throughput assay to screen the neutralizing effect of antibodies across multiple SARS-CoV-2 Spike variants simultaneously.Characterized the heterogeneity of neutralizing antibodies produced in response to COVID-19 infection and vaccination.Demonstrated the capacity of Spike variants neutralization is associated with the diversity of anti-Spike antibodies.
Novel deterministic epidemic model considering mass vaccination and lockdown against coronavirus disease 2019 spread in Israel: A numerical study
Authors: Utamura Motoaki , Koizumi Makoto , Kirikami Seiichi 
Published: May 2021

AbstractWhy public health intervention by the Israeli government against coronavirus disease 2019 spread has been successful while the majority of other countries are still coping with it? To give a quantitative answer, a simple numerical epidemic model is prepared to simulate the entire trend of various infection-related variables considering the 1st and 2nd vaccination campaigns against the alpha variant and simultaneous lockdown. This model is an extension of our previously published deterministic physical model, i.e. Apparent Time Lag Model, which aims at predicting an entire trend of variables in a single epidemic. The time series data of both vaccine dose ratio and lockdown period are employed in the model. Predictions have been compared with observed data in terms of daily new cases, isolated people, infections at large and effective reproductive number, and, further, the model is verified. Moreover, parameter survey calculations for several scenarios have clarified the synergy effects of vaccination and lockdown. In particular, the key element of Israel’s success has been suggested to lie in a high-dose vaccination rate that prevents the onset of a rebound in daily new cases on the rescission of the lockdown.
Early Anakinra Treatment for COVID-19 Guided by Urokinase Plasminogen Receptor
Authors: Kyriazopoulou Evdoxia , Poulakou Garyfallia , Milionis Haralampos , Metallidis Simeon , Adamis Georgios , Tsiakos Konstantinos , Fragkou Archontoula , Rapti Aggeliki , Damoulari Christina , Fantoni Massimo , Kalomenidis Ioannis , Chrysos Georgios , Angheben Andrea , Kainis Ilias , Alexiou Zoi , Castelli Francesco , Serino Francesco Saverio , Bakakos Petros , Nicastri Emanuele , Tzavara Vassiliki , Kostis Evangelos , Dagna Lorenzo , Koufargyris Panagiotis , Dimakou Katerina , Tzatzagou Glykeria , Chini Maria , Bassetti Matteo , Katrini Konstantina , Kotsis Vasileios , Tsoukalas George , Selmi Carlo , Bliziotis Ioannis , Samarkos Michael , Doumas Michael , Ktena Sofia , Masgala Aikaterini , Papanikolaou Ilias , Argyraki Aikaterini , Cardellino Chiara Simona , Katsigianni Eleni-Ioanna , Giannitsioti Efthymia , Cingolani Antonella , Akinosoglou Karolina , Liatsis-Douvitsas Orestis , Symbardi Styliani , Mouktaroudi Maria , Ippolito Giuseppe , Florou Eleni , Kotsaki Antigone , Netea Mihai G. , Eugen-Olsen Jesper , Kyprianou Miltiades , Panagopoulos Periklis , Dalekos George N. , Giamarellos-Bourboulis Evangelos J. 
Published: May 2021

ABSTRACTBackgroundIn a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure.MethodsIn the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints.ResultsAnakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.010). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (hazard ratio: 0.45; P: 0.045). Hospital stay was shorter.ConclusionsEarly start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia.(Sponsored by the Hellenic Institute for the Study of SepsisClinicalTrials.govidentifier,NCT04680949)
Microsimulation of SARS-CoV-2 Transmission in Society
Authors: Green Anthony Roland , Keep Daniel , Piper Ian 
Published: May 2021

AbstractThe outbreak of the pandemic disease, COVID-19, has shown that the approaches by different countries has resulted in a range of infection rates through their societies. This has arisen from the varying personal behaviour and tactical use of lockdown strategies within each country. We report the use of microsimulation of a simulated community in Australia, using a discrete infection model within a community of residences, places of work and recreation to demonstrate the applicability of this method to both the current pandemic and to infection more generally. Simulations without any societal intervention on infection spread provided base simulations that could be compared with social and societal controls in the future and which were compared with the initial doubling times of country outbreaks across the world. Different population sizes were represented in some simulations and in other simulations the effects of either social distancing or the use of facial masks as personal behaviours was investigated within the community. Good agreement is found between the initial doubling times for several countries and the simulations that suggests that modelling infection as a collection of individual infections provides an alternative to current epidemiological models. The variation of the basic reproductive number, R0, with time and population size, suggests that one of the fundamentals assumptions in SIR type models is wrong, but varies according to the properties of the population being modelled. Investigation of the infection spread shows that the number of super-spreaders varies with the size of the population and occurs through contacts in clubs, supermarkets, schools and theatres where the source of infection is an employee and where there are high numbers of contacts. The simulations of individual control show that the benefits of social distancing or wearing masks is only fully realised where there is considerable compliance within society to these measures.
Genome-wide association study revealed loci linked to post-drought recovery and traits related to persistence of smooth bromegrass (Bromus inermis)
Authors: Saeidnia Fatemeh , Majidi Mohammad Mahdi , Mirlohi Aghafakhr 
Published: May 2021

AbstractAssociation analysis has been proved as a powerful tool for genetic dissection of complex traits. This study was conducted to identify marker–trait associations for recovery, persistence, and as well as finding stable associations. In this study, a diverse panel of polycross derived progenies of smooth bromegrass was phenotyped under normal and water stress, during three consecutive years. Association analysis was performed between nine important agronomic traits along with three seasonal growth activity indices based on 535 SRAP markers. Population structure analysis identified five main subpopulations possessing significant genetic differences. Association analysis using mixed linear mode1 identified 339 and 233 marker-trait associations under normal and water stress environments, respectively. Some of these markers were associated with more than one trait; which can be attributed to pleiotropic effects or to a number of tightly linked genes affecting several traits. If the effectiveness of these markers in genetic control of these traits is validated, they could be potentially used for initiation of marker-assisted selection and targeted trait introgression of smooth bromegrass under normal and water stress environments.HighlightIn this study, stable marker-trait associations (MTAs) between years and moisture regimes (normal and water stress environments) were identified in a diverse panel of polycross derived progenies of smooth bromegrass.
Structure-based design of stabilized recombinant influenza neuraminidase tetramers
Authors: Ellis Daniel , Lederhofer Julia , Acton Oliver J. , Tsybovsky Yaroslav , Kephart Sally , Yap Christina , Gillespie Rebecca A. , Creanga Adrian , Stephens Tyler , Pettie Deleah , Murphy Michael , Borst Andrew J. , Park Young-Jun , Lee Kelly K. , Graham Barney S. , Veesler David , King Neil P. , Kanekiyo Masaru 
Published: May 2021

AbstractInfluenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across all non-bat subtypes adopt various tetrameric conformations, including a previously unreported “open” state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We used homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the “closed” state. In addition to improving thermal stability, conformational stabilization improved affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. The stabilized NA proteins can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, as well as a roadmap towards structure-based discovery of NA-directed therapeutics and vaccines.
Synaptic targets of photoreceptors specialized to detect color and skylight polarization in Drosophila
Authors: Kind Emil , Longden Kit D. , Nern Aljoscha , Zhao Arthur , Sancer Gizem , Flynn Miriam , Laughland Connor , Gezahegn Bruck , Ludwig Henrique , Thomson Alex , Obrusnik Tessa , Alarcón Paula G. , Dionne Heather , Bock Davi D. , Rubin Gerald M. , Reiser Michael B. , Wernet Mathias F. 
Published: May 2021

AbstractColor and polarization provide complementary information about the world and are detected by specialized photoreceptors. However, the downstream neural circuits that process these distinct modalities are incompletely understood in any animal. Using electron microscopy, we have systematically reconstructed the synaptic targets of the photoreceptors specialized to detect color and skylight polarization in Drosophila, and we have used light microscopy to confirm many of our findings. We identified known and novel downstream targets that are selective for different wavelengths or polarized light, and followed their projections to other areas in the optic lobes and the central brain. Our results revealed many synapses along the photoreceptor axons between brain regions, new pathways in the optic lobes, and spatially segregated projections to central brain regions. Strikingly, photoreceptors in the polarization-sensitive dorsal rim area target fewer cell types, and lack strong connections to the lobula, a neuropil involved in color processing. Our reconstruction identifies shared wiring and modality-specific specializations for color and polarization vision, and provides a comprehensive view of the first steps of the pathways processing color and polarized light inputs.
Transcriptome analysis provides genome annotation and expression profiles in the central nervous system ofLymnaea stagnalisat different ages
Authors: Rosato Martina , Hoelscher Brittany , Lin Zhenguo , Agwu Chidera , Xu Fenglian 
Published: May 2021

AbstractMolecular studies of the freshwater snailLymnaea stagnalis, a unique model organism for neurobiology research, has been severely hindered by the lack of sufficient genomic information. As part of our ongoing effort studyingL. stagnalisneuronal growth and connectivity at various developmental stages, we provide the first age-specific transcriptome analysis and gene annotation of young, adult, and oldL. stagnaliscentral nervous system (CNS). RNA sequencing using Illumina NovaSeq 6000 platform produced 56-69 millions of 150 bp paired-end reads, and 74% of these reads were mapped to the draft genome ofL. stagnalis. We provide gene annotations for 32,288 coding sequences with a minimum of 100 codons, contributing to the largest number of annotated genes for theL. stagnalisgenome to date. Lastly, transcriptomic analyses reveal age-specific differentially expressed genes and enriched pathways in young, adult, and old CNS. These datasets represent the largest and most updatedL. stagnalisCNS transcriptomes.
Tafazzin regulates the function of lipopolysaccharide activated B lymphocytes in mice
Authors: Zegallai Hana M. , Abu-El-Rub Ejlal , Cole Laura K. , Field Jared , Mejia Edgard M. , Gordon Joseph W. , Marshall Aaron J. , Hatch Grant M. 
Published: May 2021

AbstractB lymphocytes are responsible for humoral immunity and play a key role in the immune response. Optimal mitochondrial function is required to support B cell activity during activation. We examined how deficiency of tafazzin, a cardiolipin remodeling enzyme required for mitochondrial function, alters the metabolic activity of B cells and their response to activation by lipopolysaccharide in mice. B cells were isolated from 3 month old wild type or tafazzin knockdown mice and incubated for up to 72 h with lipopolysaccharide and cell proliferation, expression of cell surface markers, secretion of antibodies and chemokines, proteasome and immunoproteasome activities, and metabolic function determined. In addition, proteomic analysis was performed to identify altered levels of proteins involved in survival, immunogenic, proteasomal and mitochondrial processes. Compared to wild type lipopolysaccharide activated B cells, lipopolysaccharide activated tafazzin knockdown B cells exhibited significantly reduced proliferation, lowered expression of cluster of differentiation 86 and cluster of differentiation 69 surface markers, reduced secretion of immunoglobulin M antibody, reduced secretion of keratinocytes-derived chemokine and macrophage-inflammatory protein-2, reduced proteasome and immunoproteasome activities, and reduced mitochondrial respiration and glycolysis. Proteomic analysis revealed significant alterations in key protein targets that regulate cell survival, immunogenicity, proteasomal processing and mitochondrial function consistent with the findings of the above functional studies. The results indicate that the cardiolipin transacylase enzyme tafazzin plays a key role in regulating mouse B cell function and metabolic activity during activation.
Pan-cancer HLA Gene-mediated Tumor Immunogenicity and Immune Evasion
Authors: Gong Xutong , Karchin Rachel 
Published: May 2021

AbstractHuman Leukocyte Antigen (HLA) expression contributes to the activation of anti-tumor immunity through interactions with T cell receptors. However, pan-cancer HLA-mediated immunogenicity and immunoediting mechanisms has not been systematically studied. In a retrospective analysis of 33 tumor types from the Cancer Genome Atlas, we uncovered HLA class I and class II differential expression, which outperformed traditional clinical metrics in predicting patient survival. We also characterized the distribution of HLA supertypes across cancers and showed that patients with high HLA allelic diversity and gene expression had better prognosis. Immune microenvironments with varied survival outcomes could be predicted using a neural network model trained on HLA expression data. Furthermore, we identified a subset of tumors which upregulated HLA class I but not class II genes and exploited HLA-mediated escape strategies. Our results suggest the potential of using HLA expression data to predict patient prognosis. Taken together, we emphasize the crucial role of HLA upregulation in shaping prolonged anti-tumor immunity.SynopsisIn a retrospective analysis of 11080 patients of 33 TCGA cancer types, we showed HLA class I and class II differential expression shape various immune microenvironments and tumor immunoediting mechanisms, predicting tumor immunogenicity and patient survival.
A Cre-dependent massively parallel reporter assay allows for cell-type specific assessment of the functional effects of non-coding elementsin vivo
Authors: Lagunas Tomas , Plassmeyer Stephen P. , Fischer Anthony D. , Friedman Ryan Z. , Rieger Michael A. , Selmanovic Din , Sarafinovska Simona , Lucero Alessandra F. Aguilar , An Joon-Yong , Sanders Stephan J. , Cohen Barak A. , Dougherty Joseph D. 
Published: May 2021

AbstractThe function of regulatory elements is highly dependent on the cellular context, and thus for understanding the function of elements associated with psychiatric diseases these would ideally be studied in neurons in a living brain. Massively Parallel Reporter Assays (MPRAs) are molecular genetic tools that enable functional screening of hundreds of predefined sequences in a single experiment. These assays have not yet been adapted to query specific cell typesin vivoin a complex tissue like the mouse brain. Here, using a test-case 3′UTR MPRA library with genomic elements containing variants from ASD patients, we developed a method to achieve reproducible measurements of element effectsin vivoin a cell type-specific manner, using excitatory cortical neurons and striatal medium spiny neurons as test cases. This new technique should enable robust, functional annotation of genetic elements in the cellular contexts most relevant to psychiatric disease.
Characterization of the subunit composition and structure of native adult glycine receptors
Authors: Yu Hailong , Bai Xiao-chen , Wang Weiwei 
Published: May 2021

SUMMARYThe strychnine-sensitive pentameric Glycine Receptor (GlyR) mediates fast inhibitory neurotransmission in the mammalian nervous system. Only heteromeric GlyRs mediate synaptic transmission, since they contain the β subunit that permits clustering at the synapse through its interaction with scaffolding proteins. Here we show that α2 and β subunits assemble with an unexpected 4:1 stoichiometry to produce GlyR with native electrophysiological properties. We determined structures in multiple functional states at 3.6 – 3.8 Å resolutions and show α2β GlyR assembly mechanism. Furthermore, we show that one single β subunit in each GlyR gives rise to the characteristic electrophysiological properties of heteromeric GlyR, while more β subunits renders GlyR non-conductive. A single β subunit ensures a univalent GlyR-scaffold linkage, which means the scaffold alone regulates the cluster properties.
Unsupervised deep learning method for cell segmentation
Authors: Din Nizam Ud , Yu Ji 
Published: May 2021

AbstractAdvances in the artificial neural network have made machine learning techniques increasingly more important in image analysis tasks. Recently, convolutional neural networks (CNN) have been applied to the problem of cell segmentation from microscopy images. However, previous methods used a supervised training paradigm in order to create an accurate segmentation model. This strategy requires a large amount of manually labeled cellular images, in which accurate segmentations at pixel level were produced by human operators. Generating training data is expensive and a major hindrance in the wider adoption of machine learning based methods for cell segmentation. Here we present an alternative strategy that uses unsupervised learning to train CNNs without any human-labeled data. We show that our method is able to produce accurate segmentation models. More importantly, the algorithm is applicable to both fluorescence and bright-field images, requiring no prior knowledge of signal characteristics and requires no tuning of parameters.
Customizing Multifunctional Neural Interfaces through Thermal Drawing Process
Authors: Antonini Marc-Joseph , Sahasrabudhe Atharva , Tabet Anthony , Schwalm Miriam , Rosenfeld Dekel , Garwood Indie , Park Jimin , Loke Gabriel , Khudiyev Tural , Kanik Mehmet , Corbin Nathan , Canales Andres , Jasanoff Alan , Fink Yoel , Anikeeva Polina 
Published: May 2021

AbstractFiber drawing enables scalable fabrication of multifunctional flexible fibers that integrate electrical, optical and microfluidic modalities to record and modulate neural activity. Constraints on thermomechanical properties of materials, however, have prevented integrated drawing of metal electrodes with low-loss polymer waveguides for concurrent electrical recording and optical neuromodulation. Here we introduce two fabrication approaches: (1) an iterative thermal drawing with a soft, low melting temperature (Tm) metal indium, and (2) a metal convergence drawing with traditionally non-drawable high Tmmetal tungsten. Both approaches deliver multifunctional flexible neural interfaces with low-impedance metallic electrodes and low-loss waveguides, capable of recording optically-evoked and spontaneous neural activity in mice over several weeks. We couple these fibers with a light-weight mechanical microdrive (1g) that enables depth-specific interrogation of neural circuits in mice following chronic implantation. Finally, we demonstrate the compatibility of these fibers with magnetic resonance imaging (MRI) and apply them to visualize the delivery of chemical payloads through the integrated channels in real time. Together, these advances expand the domains of application of the fiber-based neural probes in neuroscience and neuroengineering.