bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques
Authors: Guehl Nicolas J. , Ramos-Torres Karla M. , Linnman Clas , Moon Sung-Hyun , Dhaynaut Maeva , Wilks Moses Q. , Han Paul K. , Ma Chao , Neelamegam Ramesh , Zhou Yu-Peng , Popko Brian , Correia John A. , Reich Daniel S. , Fakhri Georges El , Herscovitch Peter , Normandin Marc D. , Brugarolas Pedro 
Published: April 2020

ABSTRACTDemyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop newin vivoimaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+channel PET tracer [18F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [18F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [18F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [18F]3F4AP for the focal brain injury was higher than [18F]FDG, [11C]PiB and [11C]PBR28, and compared favorably to currently used MRI methods.
Lisen&Curate: A platform to facilitate knowledge tools for curation of regulation of transcription initiation in bacteria
Authors: Méndez-Cruz Carlos-Francisco , Díaz-Rodríguez Martín , Guadarrama-García Francisco , Lithgow-Serrano Oscar , Gama-Castro Socorro , Solano-Lira Hilda , Rinaldi Fabio , Collado-Vides Julio 
Published: April 2020

ABSTRACTThe amount of published papers in biomedical research makes it rather impossible for a researcher to keep up to date. This is where machine processing of scientific publications could contribute to facilitate the access to knowledge. How to make use of text mining capabilities and still preserve the high quality of manual curation, is the challenge we focused on. Here we present the Lisen&Curate system designed to enable current and future NLP capabilities within a curation environment interface used in curation of literature on the regulation of transcription initiation in bacteria. The current version extracts regulatory interactions with the corresponding sentences for curators to confirm or reject accelerating their curation. It also uses an embedded metrics of sentence similarity offering the curator an alternative mechanism of navigating through semantically similar sentences within a given paper as well as across papers of a pre-defined corpus of publications pertinent to the task. We show results of the use of the system to curate literature inE. colias well as literature inSalmonella. A major advantage of the system is to save as part of the curation work, the precise link for every curated piece of knowledge with the corresponding specific sentence(s) in the curated publication supporting it. We discuss future directions of this type of curation infrastructure.
Developmental Divergence of Sensory Stimulus Representation in Cortical Interneurons
Authors: Kastli Rahel , Vighagen Rasmus , van der Bourg Alexander , Argunsah Ali Ozgur , Iqbal Asim , Voigt Fabian F. , Kirschenbaum Daniel , Aguzzi Adriano , Helmchen Fritjof , Karayannis Theofanis 
Published: April 2020

AbstractTwo inhibitory cell types involved in modulating barrel cortex activity and perception during active whisking in adult mice, are the VIP+and SST+interneurons. Here we identify a developmental transition point of structural and functional rearrangements onto these interneuron types around the start of active sensation at P14. Using in vivo two-photon Ca2+imaging, we find that before P14, both interneuron types respond stronger to a multi-whisker stimulus, whereas after P14 their responses diverge, with VIP+cells losing their multi-whisker preference and SST+neurons enhancing theirs. Rabies virus tracings followed by tissue clearing, as well as photostimulation-coupled electrophysiology reveal that SST+cells receive higher cross-barrel inputs compared to VIP+at both time points. In addition, we also uncover that whereas prior to P14 both cell types receive direct input from the sensory thalamus, after P14 VIP+cells show reduced inputs and SST+cells largely shift to motor-related thalamic nuclei.
Reference-based QUantification Of gene Dispensability (QUOD)
Authors: Sielemann Katharina , Weisshaar Bernd , Pucker Boas 
Published: April 2020

AbstractBackgroundDispensability of genes in a phylogenetic lineage, e.g. a species, genus, or higher-level clade, is gaining relevance as most genome sequencing projects move to a pangenome level. Most analyses classify genes as core genes, which are present in all investigated individual genomes, and dispensable genes, which only occur in a single or a few investigated genomes. The binary classification as ‘core’ or ‘dispensable’ is often based on arbitrary cutoffs of presence/absence in the analysed genomes. Even when extended to ‘conditionally dispensable’, this concept still requires the assignment of genes to distinct groups.ResultsHere, we present a new method which overcomes this distinct classification by quantifying gene dispensability and present a dedicated tool for reference-based QUantification Of gene Dispensability (QUOD). As a proof of concept, sequence data of 966 Arabidopsis thaliana accessions (Ath-966) were processed to calculate a gene-specific dispensability score for each gene based on normalised coverage in read mappings. We validated this score by comparison of highly conserved Benchmarking Universal Single Copy Orthologs (BUSCOs) to all other genes. The average scores of BUSCOs were significantly lower than the scores of non-BUSCOs. Analysis of variation demonstrated lower variation values between replicates of a single accession than between iteratively, randomly selected accessions from the whole dataset Ath-966. Functional investigations revealed defense and antimicrobial response genes among the genes with high-dispensability scores.ConclusionsInstead of classifying a gene as core or dispensable, QUOD assigns a dispensability score to each gene. Hence, QUOD facilitates the identification of candidate dispensable genes, associated with high dispensability scores, which often underlie lineage-specific adaptation to varying environmental conditions.
Oculomotor inhibition precedes temporally expected auditory targets
Authors: Abeles Dekel , Amit Roy , Tal-Perry Noam , Carrasco Marisa , Yuval-Greenberg Shlomit 
Published: April 2020

AbstractEye movements are inhibited prior to the onset of temporally-predictable visual targets. This oculomotor inhibition effect could be considered a marker for the formation of temporal expectations and the allocation of temporal attention in the visual domain. Here we show that eye movements are also inhibited before predictable auditory targets. In two experiments, we manipulate the period between a cue and an auditory target to be either predictable or unpredictable. The findings show that although there is no perceptual gain from avoiding gaze-shifts in this procedure, saccades and blinks are inhibited prior to predictable relative to unpredictable auditory targets. These findings show that oculomotor inhibition occurs prior auditory targets. This link between auditory expectation and oculomotor behavior, in combination with the results of our parallel study in the tactile domain, reveals a multimodal perception action coupling, which has a central role in temporal expectations.
Synaptic plasticity induced by differential manipulation of tonic and phasic motoneurons in Drosophila
Authors: Aponte-Santiago Nicole A. , Ormerod Kiel G. , Akbergenova Yulia , Littleton J. Troy 
Published: April 2020

AbstractStructural and functional plasticity induced by neuronal competition is a common feature of developing nervous systems. However, the rules governing how postsynaptic cells differentiate between presynaptic inputs are unclear. In this study we characterized synaptic interactions following manipulations of Ib tonic or Is phasic glutamatergic motoneurons that co-innervate postsynaptic muscles at Drosophila neuromuscular junctions (NMJs). After identifying drivers for each neuronal subtype, we performed ablation or genetic manipulations to alter neuronal activity and examined the effects on synaptic innervation and function. Ablation of either Ib or Is resulted in decreased muscle response, with some functional compensation occurring in the tonic Ib input when Is was missing. In contrast, the phasic Is terminal failed to show functional or structural changes following loss of the co-innervating Ib input. Decreasing the activity of the Ib or Is neuron with tetanus toxin light chain resulted in structural changes in muscle innervation. Decreased Ib activity resulted in reduced active zone (AZ) number and decreased postsynaptic subsynaptic reticulum (SSR) volume, with the emergence of filopodial-like protrusions from synaptic boutons of the Ib input. Decreased Is activity did not induce structural changes at its own synapses, but the co-innervating Ib motoneuron increased the number of synaptic boutons and AZs it formed. These findings indicate tonic and phasic neurons respond independently to changes in activity, with either functional or structural alterations in the tonic motoneuron occurring following ablation or reduced activity of the co-innervating phasic input, respectively.Significance StatementBoth invertebrate and vertebrate nervous systems display synaptic plasticity in response to behavioral experiences, indicating underlying mechanisms emerged early in evolution. How specific neuronal classes innervating the same postsynaptic target display distinct types of plasticity is unclear. Here, we examined if Drosophila tonic Ib and phasic Is motoneurons display competitive or cooperative interactions during innervation of the same muscle, or compensatory changes when the output of one motoneuron is altered. We established a system to differentially manipulate the motoneurons and examined the effects of cell-type specific changes to one of the inputs. Our findings indicate Ib and Is motoneurons respond differently to activity mismatch or loss of the co-innervating input, with the tonic subclass responding robustly compared to phasic motoneurons.
Integrative profiling of early host chromatin accessibility responses in human neutrophils with sensitive pathogen detection
Authors: Ram-Mohan Nikhil , Thair Simone A. , Litzenburger Ulrike M. , Cogill Steven , Andini Nadya , Yang Xi , Chang Howard Y. , Yang Samuel 
Published: April 2020

AbstractSepsis is a leading cause of death globally where neutrophils respond to pathogens via tightly regulated antimicrobial effectors. Combining early neutrophilic responses and pathogen detection may reveal insights for disease recognition. We performed ATAC-seq of human neutrophils challenged with six toll-like receptor ligands and two organisms; and RNA-seq afterEscherichia coli(EC) exposure for 1 and 4 hours along with ATAC-seq. ATAC-seq of neurophils retains more pathogenic DNA reads than standard library preparation methods. Only a fraction of differential chromatin regions overlap between challenges. Shared signatures exist for ligands but rest are unique in position, function, and challenge. Epigenomic changes are plastic, only ∼500 are shared by EC challenges over time, resulting in varied differential genes and associated processes. We also identify three classes of chromatin mediated gene regulation based on their relative locations. These and transcription factor footprinting reveal timely and challenge specific mechanisms of transcriptional regulation in neutrophils.
Pervasive generation of non-canonical subgenomic RNAs by SARS-CoV-2
Authors: Nomburg Jason , Meyerson Matthew , DeCaprio James A. 
Published: April 2020

AbstractBackgroundSARS-CoV-2, a positive-sense RNA virus in the familyCoronaviridae, has caused a worldwide pandemic of coronavirus disease 2019 or COVID-19 Coronaviruses generate a tiered series of subgenomic RNAs (sgRNAs) through a process involving homology between transcriptional regulatory sequences (TRS) located after the leader sequence in the 5’ UTR (the TRS-L) and TRS’ located near the start of structural and accessory proteins (TRS-B) near the 3’ end of the genome. In addition to the canonical sgRNAs generated by SARS-CoV-2, non-canonical sgRNAs (nc-sgRNAs) have been reported. However, the consistency of these nc-sgRNAs across viral isolates and infection conditions is unknown. The comprehensive definition of SARS-CoV-2 RNA products is a key step in understanding SARS-CoV-2 pathogenesis.MethodsHere, we report an integrative analysis of eight independent SARS-CoV-2 transcriptomes generated using three sequencing strategies, five host systems, and seven viral isolates. Read-mapping to the SARS-CoV-2 genome was used to determine the 5’ and 3’ coordinates of all identified junctions in viral RNAs identified in these samples.ResultsUsing junctional abundances, we show nc-sgRNAs make up as much as 33% of total sgRNAsin vitro, are largely consistent in abundance across independent transcriptomes, and increase in abundance over time duringin vitroinfection. By assessing the homology between sequences flanking the 5’ and 3’ junction points, we show that nc-sgRNAs are not associated with TRS-like homology. By incorporating read coverage information, we find strong evidence for subgenomic RNAs that contain only 5’ regions of ORF1a. Finally, we show that non-canonical junctions change the landscape of viral open reading frames.ConclusionsWe identify canonical and non-canonical junctions in SARS-CoV-2 sgRNAs and show that these RNA products are consistently generated across many independent viral isolates and sequencing approaches. These analyses highlight the diverse transcriptional activity of SARS-CoV-2 and offer important insights into SARS-CoV-2 biology.
Sialylation of Asparagine 612 inhibits Aconitase activity during mouse sperm capacitation; A possible mechanism for the switch from oxidative phosphorylation to glycolysis
Authors: Villaverde Ana Izabel Silva Balbin , Ogle Rachel , Lewis Peter , Hetherington Louise , Carbone Vince , Velkov Tony , Netherton Jacob , Baker Mark A. 
Published: April 2020

AbstractAfter ejaculation, mammalian spermatozoa must undergo a process known as capacitation in order to successfully fertilize the oocyte. Several post-translational modifications occur during capacitation, including sialylation, which despite being limited to a few proteins, seems to be essential for proper sperm-oocyte interaction. Regardless of its importance, to date, no single study has ever identified nor quantified which glycoproteins bearing terminal sialic acid (Sia) are altered during capacitation. Here we characterize sialylation during mouse sperm capacitation. Using tandem mass spectrometry coupled with liquid chromatography (LC-MS/MS), we found 142 non-reductant peptides, with 9 of them showing potential modifications on their sialylated oligosaccharides during capacitation. As such, N-linked sialoglycopeptides from C4b-binding protein, endothelial lipase (EL), serine proteases 39 and 52, testis-expressed protein 101 and zonadhesin were reduced following capacitation. In contrast, mitochondrial aconitate hydratase (aconitase; ACO2) was the only protein to show an increase in Sia content during capacitation. Interestingly, while the loss of Sia within EL (N62) was accompanied by a reduction in its phospholipase A1activity, the increase of sialylation in the ACO2 (N612) also resulted in a decrease of the activity of this TCA cycle enzyme. The latter was confirmed by N612D recombinant protein with both His and GFP tag, in which the N612D mutant had no activity compared to WT when protein. Computer modelling show that N612 sits atop the catalytic site of ACO2. The introduction of sialic acid causes a large confirmation change in the alpha helix, essentially, distorting the active site, leading to complete loss of function. These findings suggest that the switch from oxidative phosphorylation, over to glycolysis that occurs during capacitation may come about through sialylation of ACO2.
Histone loaders CAF1 and HIRA restrict Epstein-Barr virus B-cell lytic reactivation
Authors: Zhang Yuchen , Jiang Chang , Trudeau Stephen J. , Narita Yohei , Zhao Bo , Teng Mingxiang , Guo Rui , Gewurz Benjamin E 
Published: April 2020

ABSTRACTEpstein-Barr virus (EBV) infects 95% of adults worldwide and causes infectious mononucleosis. EBV is associated with endemic Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphomas, nasopharyngeal and gastric carcinomas. In these cancers and in most infected B-cells, EBV maintains a state of latency, where nearly 80 lytic cycle antigens are epigenetically suppressed. To gain insights into host epigenetic factors necessary for EBV latency, we recently performed a human genome-wide CRISPR screen that identified the chromatin assembly factor CAF1 as a putative Burkitt latency maintenance factor. CAF1 loads histones H3 and H4 onto newly synthesized host DNA, though its roles in EBV genome chromatin assembly are uncharacterized. Here, we identified that CAF1 depletion triggered lytic reactivation and transforming virion secretion from Burkitt cells, despite strongly also inducing interferon stimulated genes. CAF1 perturbation diminished occupancy of histones 3.1, 3.3 and repressive H3K9me3 and H3K27me3 marks at multiple viral genome lytic cycle regulatory elements. Suggestive of an early role in establishment of latency, EBV strongly upregulated CAF1 expression in newly infected primary human B-cells prior to the first mitosis, and histone 3.1 and 3.3 were loaded on the EBV genome by this timepoint. Knockout of CAF1 subunit CHAF1B impaired establishment of latency in newly EBV-infected Burkitt cells. A non-redundant latency maintenance role was also identified for the DNA synthesis-independent histone 3.3 loader HIRA. Since EBV latency also requires histone chaperones ATRX and DAXX, EBV coopts multiple host histone pathways to maintain latency, and these are potential targets for lytic induction therapeutic approaches.IMPORTANCEEpstein-Barr virus (EBV) was discovered as the first human tumor virus in endemic Burkitt lymphoma, the most common childhood cancer in sub-Saharan Africa. In Burkitt lymphoma and in 200,000 EBV-associated cancers per year, epigenetic mechanisms maintain viral latency, where lytic cycle factors are silenced. This property complicated EBV’s discovery and facilitates tumor immunoevasion. DNA methylation and chromatin-based mechanisms contribute to lytic gene silencing. Here, we identify histone chaperones CAF1 and HIRA, which have key roles in host DNA replication-dependent and replication independent pathways, respectively, are each important for EBV latency. EBV strongly upregulates CAF1 in newly infected B-cells, where viral genomes acquire histone 3.1 and 3.3 variants prior to the first mitosis. Since histone chaperones ATRX and DAXX also function in maintenance of EBV latency, our results suggest that EBV coopts multiple histone pathways to reprogram viral genomes and highlights targets for lytic induction therapeutic strategies.
DNA repair-based classification of melanoma cell lines reveals an effect of mutations in BRAF and NRAS driver genes on DNA repair capacity
Authors: Sauvaigo Sylvie , Benkhiat Manel , Braisaz Florian , Girard Julien , Libert Sarah , Mouret Stéphane , de Fraipont Florence , Aspord Caroline , Bouquet Fanny , Leccia Marie-Thérèse 
Published: April 2020

AbstractMelanoma, the most serious form of skin cancer, frequently involves the dysregulation of key signaling pathways. Treatment strategies presently target the MAPK/ERK pathway, which is overactive in melanomas due in part to BRAF and NRAS mutations, and involve inhibitors against mutated BRAF (vemurafenib or dabrafenib) or MEK kinases (cobimetinib or trametinib), or a combination of the two. Using an established biochip technology, we assessed base excision repair (BER) and nucleotide excision repair (NER) activities in a collection of BRAF mutated (A-375, Colo 829, HT-144, Malme-3M, SK-mel5, SK-mel24 and SK-mel28) and NRAS mutated (M18, MZ2 and SK-mel2) melanoma cell lines, as well as wild-type controls (A7, CHL-1). We evaluated both basal activities (i.e., without treatment) and repair capacities after treatment with vemurafenib or cobimetinib alone, or in combination. Our results indicate that globally the DNA repair capacity of the cell lines was determined by the mutation status of the BRAF and NRAS genes, indicating that the MAPK pathway participates in the regulation of both BER and NER. Treatment of BRAF mutated melanoma cells with vemurafenib alone or the vemurafenib/cobimetinib combination, but not cobimetinib alone, led to reduced DNA repair capacity in about 60% of the BRAF mutated samples, indicating that signaling pathway inhibition can alter DNA repair activity. Upregulation of some DNA repair activities was also observed in several of the treated samples, suggesting activation of compensatory signaling pathways upon treatment. The data collectively indicate that mutations in the BRAF and NRAS genes exert distinct regulatory effects on the excision/synthesis steps of the BER and NER pathways and that targeted pharmacological inactivation of the signaling mechanism can translate into specific consequences in DNA repair capacity. The heterogeneity of the responses reported herein could help define subtypes of melanoma that are associated with resistance to targeted therapies.