bluuebunny/crossref_metadata_2025_split huggingface dataset:
LINCS gene expression signatures analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targetingeIF4G1
Authors: Hu Sai , Zhou Pingkun , Liu Xiaodan , Yin Xiaoyao , Xie Dafei , Huang Bo , Guan Hua 
Published: April 2020

AbstractRadioresistance represents the predominant cause for radiotherapy failure and disease progression, resulting in increased breast cancer mortality. Through gene expression signatures analyses of Library of Integrated Network-Based Cellular Signatures (LINCS) and Gene Expression Omnibus (GEO), the present study aimed to identify potential candidate radiosensitizers from known drugs systematically. The similarity of integrated gene expression signatures between irradiatedeIF4G1-silenced breast cancer cells and known drugs was measured by enrichment scores. Drugs with positive enrichment scores were selected as potential radiosensitizers. The radiosensitizing effects of the candidate radiosensitizers were analyzed in breast cancer cells (MCF-7, MX-1, and MDA-MB-231) by CCK-8 assays and colony-forming capability after exposure to ionizing radiation. Cell apoptosis was detected by flow cytometry. Expressions ofeIF4G1and a series of DNA damage response proteins were analyzed by Western blot assays. Bosutinib was proposed to be a promising radiosensitizer as its administration markedly reduced the dosages of both the drug and ionizing radiation and was associated with fewer adverse drug reactions. The combined treatment with ionizing radiation and bosutinib significantly increased the cells killing potency in all three cell lines as compared to ionizing radiation or bosutinib alone. MX-1 cells were revealed to be the most sensitive to both ionizing radiation and bosutinib among the three cell lines. Bosutinib noticeably downregulated the expression ofeIF4G1in a dose-dependent manner and also reduced the expression of DNA damage response proteins (includingATM,XRCC4,ATRIP, andGADD45a). Moreover,eIF4G1could be a key target of bosutinib through which it regulates DNA damage induced by ionizing radiation. Thus, taken together, bosutinib may serve as a potential candidate radiosensitizer for breast cancer therapy.
The DMCdrive: practical 3D-printable micro-drive system for reliable chronic multi-tetrode recording and optogenetic application in freely behaving rodents
Authors: Kim Hoseok , Brünner Hans Sperup , Carlén Marie 
Published: April 2020

AbstractElectrophysiological recording and optogenetic control of neuronal activity in behaving animals have been integral to the elucidation of how neurons and circuits modulate network activity in the encoding and causation of behavior. However, most current electrophysiological methods require substantial economical investments and prior expertise. Further, the inclusion of optogenetics with electrophysiological recordings in freely moving animals remains a general challenge. Expansion of the technological repertoire across laboratories, research institutes, and countries, demands open access to high-quality devices that can be built with little or no prior expertise from easily accessible parts of low cost. We here present a very affordable, truly easy-to-assemble micro-drive for electrophysiology in combination with optogenetics in freely moving mice and rats. The DMCdrive is particularly suited for reliable long-term recordings of neurons and network activities, and simplify optical tagging and manipulation of neurons in the recorded brain region. The highly functional and practical drive design has been optimized for accurate tetrode movement in brain tissue, and remarkably reduced build time. We provide a complete overview of the drive design, its assembly and use, and proof-of-principle demonstration of long-term recordings paired with cell-type-specific optogenetic manipulations in the prefrontal cortex (PFC) of freely moving transgenic mice and rats.
Tapestry: validate and edit small eukaryotic genome assemblies with long reads
Authors: Davey John W. , Davis Seth J. , Mottram Jeremy C. , Ashton Peter D. 
Published: April 2020

AbstractSummarySmall eukaryotic genome assemblies based on long reads are often close to complete, but still require validation and editing. Tapestry produces an interactive report which can be used to validate, sort and filter the contigs in a raw genome assembly, taking into account GC content, telomeres, read depths, contig alignments and read alignments. The report can be shared with collaborators and included as supplemental material in publications.AvailabilitySource code is freely available athttps://github.com/johnomics/tapestry. Package is freely available in Bioconda (https://anaconda.org/bioconda/tapestry).Contactjohn.davey@york.ac.uk
Use of a highly specific kinase inhibitor for rapid, simple and precise synchronization ofPlasmodium falciparumandPlasmodium knowlesiasexual stage parasites
Authors: Ressurreição Margarida , Thomas James A. , Nofal Stephanie D. , Flueck Christian , Moon Robert W. , Baker David A. , van Ooij Christiaan 
Published: April 2020

ABSTRACTDuring the course of the asexual erythrocytic stage of development,Plasmodiumspp. parasites undergo a series of morphological changes and induce alterations in the host cell. At the end of this stage, the parasites exit the host cell, after which the progeny invade a new host cell. These processes are rapid and occur in a time-dependent manner. Of particular importance, egress and invasion of erythrocytes by the parasite are difficult to capture in an unsynchronized culture, or even a culture that has been synchronized to within hours. Therefore, precise synchronization of parasite cultures is of paramount importance for the investigation of these processes. Here we describe a method for synchronizingPlasmodium falciparumandPlasmodium knowlesiasexual blood stage parasites with ML10, a highly specific inhibitor of the cGMP-dependent protein kinase (PKG) that arrests parasite growth approximately 15 minutes prior to egress. This inhibitor allows parasite cultures to be synchronized to within minutes, with a simple wash step. Furthermore, we show that parasites remain viable for several hours after becoming arrested by the compound and that ML10 has advantages over the previously used PKG inhibitor Compound 2. Here, we demonstrate that ML10 is an invaluable tool for the study ofPlasmodium spp. asexual blood stage biology and for the routine synchronization ofP. falciparumandP. knowlesicultures.
Consensus transcriptional regulatory networks of coronavirus-infected human cells
Authors: Ochsner Scott A , Pillich Rudolf T , McKenna Neil J 
Published: April 2020

AbstractEstablishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of CoV infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family target genes encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.
Zika viral proteome analysis reveals an epitope cluster within NS3 helicase as a potential vaccine candidate: anin silicostudy
Authors: Haque Md Tangigul , Shah Md Nur Ahad , Paul Shatabdi , Khan Md Kawsar , Barua Payal 
Published: April 2020

AbstractZika virus (ZIKV), a mosquito-borne flavivirus, is now an emerging global public health concern. Currently, the pathogenicity, genetic diversity and the consequences of ZIKV infection are little known but a protective vaccine against ZIKV is an urgency. In this study, we have taken an immunoinformatics based approach to predict epitope cluster region in the whole proteome (3423 amino acids) of ZIKV. We have operated a range of bioinformatics algorithms to determine the epitopes of CD8+ cytotoxic T-cell (CTL), CD4+ helper T-cell (THL) and B cell. We have predicted an epitope cluster of 23 contiguous amino acids (region 1989-2011, WLEARMLLDNIYLQDGLIASLYR) residing on the protein NS3 helicase in ZIKV proteome. This epitope cluster contains fourteen CD4+ (THL) epitopes and six CD8+ (CTL) epitopes. The cluster region predicted to provide 93.86% population coverage worldwide. Finally, we have validated the epitopes by analysing their binding efficiency (binding energy within −4.7 to −6.9 kcal/mol) with specific HLA alleles. Based on our immunoinformatics analysis, we propose the peptide WLEARMLLDNIYLQDGLIASLYR as a new peptide vaccine candidate against Zika virus for further validation.
Introductions and early spread of SARS-CoV-2 in France
Authors: Gámbaro Fabiana , Behillil Sylvie , Baidaliuk Artem , Donati Flora , Albert Mélanie , Alexandru Andreea , Vanpeene Maud , Bizard Méline , Brisebarre Angela , Barbet Marion , Derrar Fawzi , van der Werf Sylvie , Enouf Vincent , Simon-Loriere Etienne 
Published: April 2020

AbstractFollowing the emergence of coronavirus disease (COVID-19) in Wuhan, China in December 2019, specific COVID-19 surveillance was launched in France on January 10, 2020. Two weeks later, the first three imported cases of COVID-19 into Europe were diagnosed in France. We sequenced 97 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from samples collected between January 24 and March 24, 2020 from infected patients in France. Phylogenetic analysis identified several early independent SARS-CoV-2 introductions without local transmission, highlighting the efficacy of the measures taken to prevent virus spread from symptomatic cases. In parallel, our genomic data reveals the later predominant circulation of a major clade in many French regions, and implies local circulation of the virus in undocumented infections prior to the wave of COVID-19 cases. This study emphasizes the importance of continuous and geographically broad genomic sequencing and calls for further efforts with inclusion of asymptomatic infections.
TAPBPR Promotes Antigen Loading on MHC-I Molecules Using a Peptide Trap
Authors: McShan Andrew C. , Devlin Christine A. , Morozov Giora I. , Overall Sarah A. , Moschidi Danai , Akella Neha , Procko Erik , Sgourakis Nikolaos G. 
Published: April 2020

AbstractChaperones tapasin and TAP-binding protein related (TAPBPR) perform the important functions of stabilizing nascent MHC-I molecules (chaperoning) and selecting high affinity peptides in the MHC-I groove (editing). While X-ray and cryo-EM snapshots of MHC-I in complex with TAPBPR and tapasin, respectively, have provided important insights into the peptide-deficient MHC-I groove structure, the molecular mechanism through which these chaperones influence the selection of specific amino acid sequences remains incompletely characterized. Of particular importance is a 16 residue loop in TAPBPR (corresponding to 11 residues in tapasin), which has been proposed to actively compete with incoming peptides by forming direct contacts in the F-pocket of the empty MHC-I groove. Using a deep mutational scanning functional analysis of TAPBPR, we find that important residues for the chaperoning activity are located on the major interaction surfaces with nascent MHC-I molecules, excluding the loop. However, interactions with properly conformed molecules toward peptide editing are influenced by loop mutations, in an MHC-I allele- and peptide-dependent manner. Detailed biophysical characterization by ITC, FP and NMR reveals that the loop does not interact with the peptide-deficient MHC-I groove to compete with incoming peptides, but instead promotes peptide loading by acting as a kinetic trap. Our results suggest that the longer loop of TAPBPR lowers the affinity threshold for peptide selection, to promote loading within subcellular compartments of reduced peptide concentration and to prevent disassembly of high affinity peptide-MHC-I complexes that are transiently interrogated by TAPBPR during editing.
Homeostatic control of meiotic G2/prophase checkpoint function by Pch2 and Hop1
Authors: Raina Vivek B. , Vader Gerben 
Published: April 2020

SummaryCheckpoints cascades coordinate cell cycle progression with essential chromosomal processes. During meiotic G2/prophase, recombination and chromosome synapsis are monitored by what are considered distinct checkpoints [1–3]. In budding yeast, the AAA+ ATPase Pch2 is thought to specifically promote cell cycle delay in response to synapsis defects [4–6]. However, unperturbedpch2Δcells are delayed in meiotic G2/prophase [6], suggesting paradoxical roles for Pch2 in cell cycle progression. Here, we provide insight into the checkpoint roles of Pch2 and its connection to Hop1, a HORMA domain-containing client protein. Contrary to current understanding, we find that the Pch2-Hop1 module is crucial for checkpoint function in response to both recombination and synapsis defects, thus revealing a shared meiotic checkpoint cascade. Meiotic checkpoint responses are transduced by DNA break-dependent phosphorylation of Hop1 [7, 8]. Based on our data and on the effect of Pch2 on HORMA topology [9–11], we propose that Pch2 promotes checkpoint proficiency by catalyzing the availability of signaling-competent Hop1. Conversely, we demonstrate that Pch2 can act as a checkpoint silencer, also in the face of persistent DNA repair defects. We establish a framework in which Pch2 and Hop1 form a homeostatic module that governs general meiotic checkpoint function. We show that this module can - depending on the cellular context - fuel or extinguish meiotic checkpoint function, which explains the contradictory roles of Pch2 in cell cycle control. Within the meiotic checkpoint, the Pch2-Hop1 module thus operates analogous to the Pch2/TRIP13-Mad2 module in the spindle assembly checkpoint that monitors chromosome segregation [12–16].
Identification and Characterization of Fbxl22, a novel skeletal muscle atrophy-promoting E3 ubiquitin ligase
Authors: Hughes David C. , Baehr Leslie M. , Driscoll Julia R. , Lynch Sarah A. , Waddell David S. , Bodine Sue C. 
Published: April 2020

AbstractMuscle-specific E3 ubiquitin ligases have been identified in muscle atrophy-inducing conditions. The purpose of the current study was to explore the functional role of Fbxl22, and a newly identified splice variant (Fbxl22-193), in skeletal muscle homeostasis and neurogenic muscle atrophy. In mouse C2C12muscle cells, promoter fragments of the Fbxl22 gene were cloned and fused with the secreted alkaline phosphatase reporter gene to assess the transcriptional regulation of Fbxl22. The tibialis anterior muscles of male C57/BL6 mice (12-16 weeks old) were electroporated with expression plasmids containing the cDNA of two Fbxl22 splice variants and tissues collected after 7, 14 and 28 days. Gastrocnemius muscles of wild type and MuRF1 knockout mice were electroporated with an Fbxl22 RNAi or empty plasmid, denervated three days post-transfection, and tissues collected 7 days post-denervation. The full-length gene and novel splice variant are transcriptionally induced early (after 3 days) during neurogenic muscle atrophy. In vivo overexpression of Fbxl22 isoforms in mouse skeletal muscle lead to evidence of myopathy/atrophy suggesting that both are involved in the process of neurogenic muscle atrophy. Knockdown of Fbxl22 in MuRF1 KO muscles resulted in significant additive muscle sparing at 7 days of denervation. Targeting two E3 ubiquitin ligases appears to have a strong additive effect on protecting muscle mass loss with denervation and these findings have important implications in the development of therapeutic strategies to treat muscle atrophy.
Transient and layer-specific reduction in neocortical PV inhibition during sensory association learning
Authors: Kuljis Dika A. , Park Eunsol , Myal Stephanie E. , Clopath Claudia , Barth Alison L. 
Published: April 2020

AbstractSensory and motor learning reorganizes neocortical circuitry, particularly manifested in the strength of excitatory synapses. Prior studies suggest reduced inhibition can facilitate glutamatergic synapse plasticity during learning, but the role of specific inhibitory neurons in this process has not been well-documented. Here we investigate whether inhibition from parvalbumin (PV)-expressing neurons is altered in primary somatosensory cortex in mice trained in a whisker-based reward-association task. Anatomical and electrophysiological analyses show PV input to L2/3, but not L5, pyramidal (Pyr) neurons is rapidly suppressed during early stages of sensory training, effects that are reversed after longer training periods. Importantly, sensory stimulation without reward does not alter PV-mediated inhibition. Computational modeling indicates that reduced PV inhibition in L2/3 selectively enables an increase in translaminar recurrent activity, also observed during SAT. PV disinhibition in superficial layers of the neocortex may be one of the earliest changes in learning-dependent rewiring of the cortical column.Impact statementTactile learning is associated with reduced PV inhibition in superficial layers of somatosensory cortex. Modeling studies suggest that PV disinhibition can support prolonged recurrent activity initiated by thalamic input.
Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis
Authors: Wei Xiaoyan , Franke Julia , Ost Mario , Wardelmann Kristina , Börno Stefan , Timmermann Bernd , Meierhofer David , Kleinridders Andre , Klaus Susanne , Stricker Sigmar 
Published: April 2020

AbstractBackgroundNeurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin(NF1).Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients’ mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy is mostly unknown.MethodsTo dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth.ResultsNf1Lbx1and Nf1Myf5animals showed only mild defects in prenatal myogenesis. Nf1Lbx1animals were perinatally lethal, while Nf1Myf5animals survived only up to approx. 25 weeks. A comprehensive phenotypic characterization of Nf1Myf5animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1Myf5muscles, which was concomitant to a fiber type shift from type 2B to type 2A and type 1. Moreover, Nf1Myf5muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1Myf5animals, in line with a drastic reduction of white, but not brown adipose tissue.ConclusionsOur results demonstrate a cell-autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.
Impact of the nucleosome histone core on the structure and dynamics of DNA containing pyrimidine-pyrimidone (6-4) photoproduct
Authors: Matoušková Eva , Bignon Emmanuelle , Claerbout Victor , Dršata Tomáš , Gillet Natacha , Monari Antonio , Dumont Elise , Lankaš Filip 
Published: April 2020

ABSTRACTThe pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion, which constitutes a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with compaction proteins, and notably histones, affects the mechanism of its mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA containing 64-PP lesions within the nucleosome core particle by atomic-resolution molecular dynamics simulations at the multi-microsecond time scale. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, we also show that local DNA flexibility at the damaged site is enhanced, due to imperfect structural adaptation to restraints imposed by the histone core. In particular, if 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.
Leveraging a WGS compression and indexing format with dynamic graph references to call structural variants
Authors: English Adam C. , McCarthy Nils , Flickenger Robert , Maheshwari Surabhi , Meed Lisa , Mangubat Alindrina , Shekar Sri Niranjan 
Published: April 2020

SummaryWe introduce a novel structural variant calling pipeline (BioGraph) that leverages a read compression and indexing format to discover alleles, assess their supporting coverage, and assign useful quality scores. To evaluate BioGraph’s performance, we run five sequencing replicates of the individual HG002 through the BioGraph variant calling pipeline, as well as two other short-read sv-calling pipelines. BioGraph detects the GIAB benchmark SVs at a peak sensitivity of ≈59% compared to ≈42% sensitivity from the other pipelines. The overall precision of BioGraph is lower than other pipelines (≈81% and ≈90%, respectively), however, adjusting for quality score, BioGraph calls were sensitive to a greater number of SV calls given the same false discovery rate compared to the other pipelines. Cumulatively ≈77% of GIAB benchmark SVs are discovered by BioGraph in at least one replicate. After merging discovered calls and running BioGraph Coverage to create a squared-off project-level VCF, we find ≈90% percent of discovered true positive alleles have at least 5x coverage in all replicates, thus increasing per-replicate recall of alleles having at least 1x coverage to ≈76.9%.