bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Convalescent Plasma Therapy among Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Single-Center Experience
Authors: Mesina Flordeluna Z. , Mangahas Claudette G. , Gatchalian Ellen M. , Ariola-Ramos Mary Sheila , Torres Rosalio P. 
Published: February 2021

ABSTRACTCOVID-19 Disease has strained our healthcare system. Convalescent plasma has been used to treat emerging infectious diseases -Influenza A/B, SARS-CoV, Ebola virus and now SARS-CoV 2.OBJECTIVEThis study aims to determine the outcome and clinical course of COVID-19 patients who received convalescent plasma transfusion at Cardinal Santos Medical Center.METHODSThis is a retrospective cohort analytical study of 75 patients who received convalescent plasma.RESULTSMedian time from admission to CP transfusion was 3 days. Majority of patients received additional therapies including dexamethasone (100%); Remdesivir (95%); antibiotics (100%), tocilizumab (65%); hemoperfusion (88%) or combination of these. Among the survivors, the median LOS was 15 days while non-survivors have a median LOS of 6 days. One patient (1.33%) had mild transfusion reaction. Four patients (5.33%) developed DVT despite anti-coagulation. There was improvement in the inflammatory markers (LDH pvalue 0.04, CRP pvalue 0.00, Ferritin pvalue 0.0001). There was improvement in the pulmonary parameters -increase in mean PaO2, mean SaO2, and mean PFR; and decrease in mean FiO2 and mean RR post-treatment. Median LOS is 14 days for the CP group vs 11 days for the non-CP group. Mortality rate among the CP group is 25.33% while the non-CP group was 26.67%. LOS and mortality rate did not reach statistical significance.CONCLUSIONSThere was no significant difference in mortality and length of hospital stay in patients given CP vs controls. CP might have a role in the improvement of inflammatory markers and pulmonary status.
Effectiveness of Influenza Vaccines in the HIVE household cohort over 8 years: is there evidence of indirect protection?
Authors: Malosh Ryan E. , Petrie Joshua G. , Callear Amy , Truscon Rachel , Johnson Emileigh , Evans Richard , Bazzi Latifa , Cheng Caroline , Thompson Mark S. , Martin Emily T. , Monto Arnold S. 
Published: February 2021

AbstractBackgroundThe evidence that influenza vaccination programs regularly provide protection to unvaccinated individuals (i.e. indirect effects) of a community is lacking. We sought to determine the direct, indirect, and total effects of influenza vaccine in the Household Influenza Vaccine Evaluation (HIVE) cohort.MethodsUsing longitudinal data from the HIVE cohort from 2010-11 through 2017-18, we estimated direct, indirect, and total influenza vaccine effectiveness (VE) and the incidence rate ratio of influenza virus infection using adjusted mixed-effect Poisson regression models. Total effectiveness was determined through comparison of vaccinated members of full or partially vaccinated households to unvaccinated individuals in completely unvaccinated households.ResultsThe pooled, direct VE against any influenza was 30.2% (14.0-43.4). Direct VE was higher for influenza A/H1N1 43.9% (3.9 to 63.5) and B 46.7% (17.2 to 57.5) than A/H3N2 31.7% (10.5 to 47.8); and was higher for young children 42.4% (10.1 to 63.0) than adults 18.6% (−6.3 to 37.7). Influenza incidence was highest in completely unvaccinated households (10.6 per 100 person-seasons) and lower at all other levels of household vaccine coverage. We found little evidence of indirect VE after adjusting for potential confounders. Total VET was 56.4% (30.1-72.9) in low coverage, 43.2% (19.5-59.9) in moderate coverage, and 33.0% (12.1 to 49.0) in fully vaccinated households.ConclusionInfluenza vaccines may have a benefit above and beyond the direct effect but that effect in this study was small. While there may be exceptions, the goal of global vaccine recommendations should remain focused on provision of documented, direct protection to those vaccinated.
kmtricks: Efficient and flexible construction of Bloom filters for large sequencing data collections
Authors: Lemane Téo , Medvedev Paul , Chikhi Rayan , Peterlongo Pierre 
Published: February 2021

AbstractWhen indexing large collections of short-read sequencing data, a common operation that has now been implemented in several tools (Sequence Bloom Trees and variants, BIGSI, ..) is to construct a collection of Bloom filters, one per sample. Each Bloom filter is used to represent a set of k-mers which approximates the desired set of all the non-erroneous k-mers present in the sample. However, this approximation is imperfect, especially in the case of metagenomics data. Erroneous but abundant k-mers are wrongly included, and non-erroneous but low-abundant ones are wrongly discarded. We proposekmtricks, a novel approach for generating Bloom filters from terabase-sized collections of sequencing data. Our main contributions are 1/ an efficient method for jointly counting k-mers across multiple samples, including a streamlined Bloom filter construction by directly counting, partitioning and sorting hashes instead of k-mers, which is approximately four times faster than state-of-the-art tools; 2/ a novel technique that takes advantage of joint counting to preserve low-abundant k-mers present in several samples, improving the recovery of non-erroneous k-mers. Our experiments highlight that this technique preserves around 8x more k-mers than the usual yet crude filtering of low-abundance k-mers in a large metagenomics dataset.Availabilityhttps://github.com/tlemane/kmtricksFundingThe work was funded by IPL Inria Neuromarkers, ANR Inception (ANR-16-CONV-0005), ANR Prairie (ANR-19-P3IA-0001), ANR SeqDigger (ANR-19-CE45-0008).
N-Terminal finger stabilizes the reversible feline drug GC376 in SARS-CoV-2 Mpro
Authors: Arutyunova Elena , Khan Muhammad Bashir , Fischer Conrad , Lu Jimmy , Lamer Tess , Vuong Wayne , van Belkum Marco J. , McKay Ryan T. , Tyrrell D. Lorne , Vederas John C. , Young Howard S. , Lemieux M. Joanne 
Published: February 2021

AbstractThe main protease (Mpro, also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug’s properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar Kivalues with the Mprofrom both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 Mpro. The comparison of a new X-ray crystal structure of Mprofrom SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 Mpro, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the Mpro, which facilitates coordination of the drug’s P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.
Single cell transcriptome mapping identifies a local innate B cell population driving local antibody production and chronic rejection after lung transplantation
Authors: Smirnova Natalia F. , Riemondy Kent , Collins Susan , Patel Kapil N. , Cool Carlyne , Koenigshoff Melanie , Sharma Nirmal S. , Eickelberg Oliver 
Published: February 2021

AbstractBronchiolitis obliterans syndrome (BOS) due to chronic rejection is the main reason for poor outcomes after lung transplantation (LTx). We and others have recently identified B cells as major contributors to BOS after LTx. The extent of B cell heterogeneity, however, as well as those B cell populations that determine chronic rejection of the lung, remain entirely unclear. Here, we provide a map of cell population heterogeneity and their gene expression patterns during chronic rejection after orthotopic LTx in mice. Out of a total of 14 major comprehensive cell clusters, corresponding to 11 known major cell subpopulations,Mzb1-expressing plasma cells (PCs) were the most prominently increased cell population in lungs with BOS.Scgb1a1-expressing bronchial epithelial cells were depleted, whileCd14-expressing monocytes andPdgfra-expressing fibroblasts were enriched in BOS grafts. These findings were validated in two different cohorts of human BOS after LTx. MZB1-IgG-double positive PCs infiltrated the airways of patients with BOS, while they were absent from healthy lungs. IgG, but not IgA, IgD, IgE or IgM, were significantly increased in bronchoalveolar lavage from BOS patients, compared with LTx patients who did not develop BOS. Pseudotime and trajectory analysis revealed that aBhlhe41,Cxcr3, Itgb1-triple positive-B cell subset, also expressing classical markers of the innate-like B-1 B cell population, served as the progenitor pool forMzb1+ PCs. This progenitor B cell subset accounted for the increase in IgG2cexpression and production in BOS lung grafts. Importantly,Aicda−/−mice, which lack all isotypes of Ig (except IgM) were protected from the onset of BOS after LTx. In summary, we provide a detailed atlas of cell population changes of chronic rejection after LTx. We have identified IgG-positive PCs and their progenitors – an innate B cell subpopulation characterized by a specific subset of markers - as the major source of local antibody production and a major contributor to both mouse and human BOS after LTx.
Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1, a novel oncogene in AML
Authors: Nicosia Luciano , Boffo Francesca Ludovica , Ceccacci Elena , Pallavicini Isabella , Bedin Fabio , Massignani Enrico , Ravasio Roberto , Minucci Saverio , Bonaldi Tiziana 
Published: February 2021

AbstractThe histone de-methylase LSD1 is over-expressed in haematological tumours and has emerged as a promising target for anti-cancer treatment, so that several LSD1 inhibitors are under development and testing, in pre-clinical and clinical settings. However, the complete understanding of their complex mechanism of action is still unreached. Here, we unravelled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the down-regulation of the chromatin protein GSE1. Analysis of the phenotypic effects of GSE1 depletion in NB4 cells showed a strong decrease of cell viabilityin vitroand of tumour growthin vivo. Mechanistically, we found that a set of genes associated with immune response and cytokine signalling pathways are up-regulated by LSD1 inhibitors through GSE1 protein reduction and that LSD1 and GSE1 co-localise at promoters of a subset of these genes at the basal state, enforcing their transcriptional silencing. Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights on GSE1 as a novel therapeutic target for AML.
Gene duplication to the Y chromosome in Trinidadian Guppies
Authors: Lin Yuying , Darolti Iulia , Furman Benjamin L. S. , Almeida Pedro , Sandkam Benjamin A. , Breden Felix , Wright Alison E. , Mank Judith E. 
Published: February 2021

ABSTRACTDifferences in allele frequencies at autosomal genes between males and females in a population can result from two scenarios. Unresolved sexual conflict over survival produces allelic differentiation between the sexes. However, given the substantial mortality costs required to produce allelic differences between males and females at each generation, it remains unclear how many loci within the genome experience significant sexual conflict over survival. Alternatively, recent studies have shown that similarity between autosomal and Y sequence, arising from duplication onto the Y, can create perceived allelic differences, and this represents potentially resolved sexual conflict. However, Y duplications are most likely in species with large non-recombining regions, in part because they simply represent larger targets for duplications. We assessed the genomes of 120 wild-caught guppies, which experience extensive predation- and pathogen-induced mortality and have a relatively small ancestral Y chromosome. We identified seven autosomal genes that show allelic differences between male and female adults. Five of these genes show clear evidence of whole or partial gene duplication to the Y chromosome, suggesting that the male-specific region of the guppy Y chromosome, although relatively small, may nonetheless act as a hotspot for the resolution of sexual conflict. The remaining two genes show evidence of partial homology to the Y. Overall, our findings suggest that the guppy genome experiences a very low level of unresolved sexual conflict over survival, and instead the Y chromosome, despite its small ancestral size and recent origin, acts as a major mechanism of conflict resolution.
Identification of common key genes and pathways between Covid-19 and lung cancer by using protein-protein interaction network analysis
Authors: Nan Kang Soon , Karuppanan Kalimuthu , Kumar Suresh 
Published: February 2021

AbstractCOVID-19 is indeed an infection that is caused by a recently found coronavirus group, a type of virus proven to cause human respiratory diseases. The high mortality rate was observed in patients who had pre-existing health conditions like cancer. However, the molecular mechanism of SARS-CoV-2 infection in lung cancer patients was not discovered yet at the pathway level. This study was about determining the common key genes of COVID-19 and lung cancer through network analysis. The hub genes associated with COVID-19 and lung cancer were identified through Protein-Protein interaction analysis. The hub genes are ALB, CXCL8, FGF2, IL6, INS, MMP2, MMP9, PTGS2, STAT3 and VEGFA. Through gene enrichment, it is identified both COVID-19 and lung cancer have a common pathway in EGFR tyrosine kinase inhibitor resistance, IL-17 signalling pathway, AGE-RAGE signalling pathway in diabetic complications, HIF-1 signalling pathway and pathways in cancer.
N-terminal extensions strengthen hydrophobic inter-subunit interactions between HU’s C-terminal domains to frustrate heterodimer formation
Authors: Arora Kanika , Thakur Bhishem , Mrigwani Arpita , Guptasarma Purnananda 
Published: February 2021

AbstractHU is a nucleoid-associated protein (NAP) that helps bacterial chromosomal DNA to remain compact.Escherichia colicontains two homologs of HU that are ~ 70 % identical: HU-A and HU-B. The early log phase, late log phase, and stationary phase ofE. coligrowth are reported to be dominated, respectively, by HU-AA homodimers, HU-BB homo-dimers, and HU-AB heterodimers. Here, we show that the formation of HU-AB heterodimers occurs to a much lower degree in HU chains that have a displaced N-terminus, whether through addition of an N-terminal affinity (polyhistidine) tag, or fusion of a fluorescent protein. A combination of mass spectrometry, spectroscopy, chromatography, and electrophoresis (exploring glutaraldehyde crosslinking of subunits) was used to study the mixing, co-expression, unfolding and refolding of HU-AA and HU-BB homodimers. The data suggests that, in HU polypeptides with N-terminal extension, whereas inter-subunit contacts between the alpha helical N-terminal domains (NTDs) undergo facile unfolding and dissociation, inter-subunit contacts between the beta sheet- and IDR-dominated C-terminal domains (CTDs) fail to do so, due to persistence of hydrophobic inter-subunit interactions between two beta sheets. This persistence causes HU to remain nominally dimeric even after substantive unfolding, and frustrates subunit exchange and heterodimer formation.
FRET-based screening in HEK293T identifies p38 MAPK and PKC inhibition as therapeutic targets for α-synuclein aggregation
Authors: Svanbergsson Alexander , Ek Fredrik , Martinsson Isak , Rodo Jordi , Liu Di , Brandi Edoardo , Haikal Caroline , Torres-Garcia Laura , Li Wen , Gouras Gunnar , Olsson Roger , Björklund Tomas , Li Jia-Yi 
Published: February 2021

AbstractAggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the induced pathology’s traits similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic intervention. High-throughput screening (HTS) of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α- synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. Our findings highlight the value HTS brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds.
Sucrose synthase activity is not required for cellulose biosynthesis in Arabidopsis
Authors: Wang Wei , Viljamaa Sonja , Hodek Ondrej , Moritz Thomas , Niittylä Totte 
Published: February 2021

AbstractBiosynthesis of plant cell walls requires UDP-glucose as the substrate for cellulose biosynthesis, and as an intermediate for the synthesis of other matrix polysaccharides. The sucrose cleaving enzyme sucrose synthase (SUS) is thought to have a central role in UDP-glucose biosynthesis, and a long held and much debated hypothesis postulates that SUS is required to supply UDP-glucose to cellulose biosynthesis. To investigate the role of SUS in cellulose biosynthesis ofArabidopsis thalianawe characterized mutants in which four, or all six ArabidopsisSUSgenes were disrupted. Thesesusmutants showed no growth phenotypes, vascular tissue cell wall defects or changes in cellulose content. Moreover, the UDP-glucose content of rosette leaves of the sextuplesusmutants was increased by approximately 20% compared to wild type. It can thus be concluded that cellulose biosynthesis is able to employ alternative UDP-glucose biosynthesis pathway(s), and thereby the model of SUS requirement for cellulose biosynthesis in Arabidopsis can be refuted.
Rapid sequence evolution driven by transposable elements at a virulence locus in a fungal wheat pathogen
Authors: Singh Nikhil Kumar , Badet Thomas , Abraham Leen , Croll Daniel 
Published: February 2021

AbstractBackground: Plant pathogens cause substantial crop losses in agriculture production and threaten food security. Plants evolved the ability to recognize virulence factors and pathogens have repeatedly escaped recognition due rapid evolutionary change at pathogen virulence loci (i.e.effector genes). The presence of transposable elements (TEs) in close physical proximity of effector genes can have important consequences for gene regulation and sequence evolution. Species-wide investigations of effector gene loci remain rare hindering our ability to predict pathogen evolvability.Results: Here, we performed genome-wide association studies (GWAS) on a highly polymorphic mapping population of 120 isolates ofZymoseptoria tritici, the most damaging pathogen of wheat in Europe. We identified a major locus underlying significant variation in reproductive success of the pathogen and damage caused on the wheat cultivar Claro. The most strongly associated locus is intergenic and flanked by genes encoding a predicted effector and a serine type protease, respectively. The center of the locus contained a highly dynamic region consisting of multiple families of TEs. Based on a large global collection of assembled genomes, we show that the virulence locus has undergone substantial recent sequence evolution. Large insertion and deletion events generated length variation between the flanking genes by a factor of seven (5-35 kb). The locus showed also strong signatures of genomic defenses against TEs (i.e.RIP) contributing to the rapid diversification of the locus.Conclusions: In conjunction, our work highlights the power of combining GWAS and population-scale genome analyses to investigate major effect loci in pathogens.
Advanced Complexity and Plasticity of Neural Activity in Reciprocally Connected Human Cerebral Organoids
Authors: Osaki Tatsuya , Ikeuchi Yoshiho 
Published: February 2021

AbstractMacroscopic axonal connections in the human brain distribute information and neuronal activity across the brain. Although brain organoid technologies have recently provided novel avenues to investigate human brain function by replicating small neuronal networks of the brainin vitro, functionality of the macroscopic connections between distant regions has not been investigated with organoids. Here, we describe the neural activity of human cerebral organoids reciprocally connected by a bundle of axons. The connected organoids produced significantly more intense and complex oscillatory activity than conventional cerebral organoids. Optogenetic manipulations revealed that the connected organoids could respond to external stimuli and maintain the elevated frequency of neuronal activity for a short term, indicating that the connected organoids exhibit plasticity as a neuronal network. Our findings highlight functional importance of inter-regional connections and suggest that connected organoids can be used as a powerful tool for investigating the development and functions of macroscopic circuits in the human brain. can allow researchers to develop and test compounds to modulate activity ofin vitroneuronal network models in unprecedented ways.
The role of network connectivity on epileptiform activity
Authors: Giacopelli Giuseppe , Tegolo Domenico , Migliore Michele 
Published: February 2021

AbstractA number of potentially important mechanisms have been identified as key players to generate epileptiform activity, such as genetic mutations, activity-dependent alteration of synaptic functions, and functional network reorganization at the macroscopic level. Here we study how network connectivity at cellular level can affect the onset of epileptiform activity, using computational model networks with different wiring properties. The model suggests that networks connected as in real brain circuits are more resistant to generate seizure-like activity. The results suggest new experimentally testable predictions on the cellular network connectivity in epileptic individuals, and highlight the importance of using the appropriate network connectivity to investigate epileptiform activity with computational models.