bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-BIRW: a network-based algorithm for drug repurposing
Authors: Ferraro Luigi 
Published: September 2020

AbstractThis paper is based onComputational Biologywith an eye towards medicine. In fact our aim is to identify new indications for existing drugs with a computational approach usingSystems Biology, in order to speed up the market entry, avoiding some phases of drug development (for example toxicity tests) and with a lower cost.The method that we will discuss exploits the concept ofRandom Walkin a heterogeneous network, formed by a drug-drug and disease-disease similarity and known drug-disease associations. This is done by combining different types of data in order to connect more effectively two drugs or two diseases with a similarity score. At the end we integrate the known associations between drugs and diseases with the purpose of finding similarity values of new couples.
Error-related cognitive control and behavioural adaptation mechanisms in the context of motor functioning and anxiety
Authors: Topor Marta , Opitz Bertram , Leonard Hayley C. 
Published: September 2020

AbstractPrevious research suggests that there is an interaction between cognitive and motor processes. This has been investigated throughout development and in different conditions related to motor impairment. The current study addressed a gap in the literature by investigating this interaction in the general population of healthy adults with different profiles of motor proficiency by focusing on error-related cognitive control and behavioural adaptation mechanisms. In addition, the impact of these processes was assessed in terms of experienced anxiety. Forty healthy adults were divided into high and low motor proficiency groups based on an assessment of their motor skills. Using electroencephalography (EEG) during a flanker task, error-related negativity (ERN) was measured as the neural indicator of cognitive control. Post-error slowing (PES) was measured to represent behavioural adaptation. Participants also completed an anxiety assessment questionnaire. Participants in the high motor proficiency group achieved better task accuracy and showed relatively enhanced cognitive control through increased ERN. Contrastingly, individuals in the lower motor proficiency group achieved poorer accuracy whilst showing some evidence of compensation through increased PES. Anxiety was found to be associated with motor functioning, but the study could not provide evidence that this was related to cognitive or behavioural control mechanisms. The interaction between cognitive and motor processes observed in this study is unique for healthy and sub-clinical populations and provides a baseline for the interpretation of similar investigations in individuals with motor disorders.
Sense organ formation and identity are controlled by divergent mechanisms in insects
Authors: Klann Marleen , Schacht Magdalena Ines , Benton Matthew Alan , Stollewerk Angelika 
Published: September 2020

AbstractInsects and other arthropods utilise external sensory structures for mechanosensory, olfactory and gustatory reception. These sense organs have characteristic shapes related to their function, and in many cases are distributed in a fixed pattern so that they are identifiable individually. InDrosophila melanogaster, the identity of sense organs is regulated by specific combinations of transcription factors. In other arthropods, however, sense organ subtypes cannot be linked to the same code of gene expression. This raises the questions of how sense organ diversity has evolved in arthropods, and if theD. melanogastersubtype identity principle is representative for insects. To address these questions, we analyse sense organ development in another insect, the flour beetleTribolium castaneum.We show that in contrast toD. melanogaster,T. castaneumsense organs cannot be categorised based on their requirement for individual or combinations of the conserved sense organ transcription factors such ascutandpox-neuroand members of the Achaete-Scute (Tc ASH,Tc asense) and Atonal family (Tc atonal,Tc cato,Tc amos). Rather, these genes are required for the specification of sense organ precursors and the development and differentiation of sensory cell types in diverse external sensilla. Based on our findings and past research, we present an evolutionary scenario suggesting that sensory organs have diversified from a default state through subsequent recruitment of sensory genes to the different sense organ specification processes. A specific role for genes in subtype identity has evolved as a secondary effect of the function of these genes in individual or subsets of sense organs, which can largely not be aligned with morphological or functional categories.
Genomic divergence and differential gene expression between crustacean ecotypes across a marine thermal gradient
Authors: Emami-Khoyi Arsalan , Knapp Ingrid S. , Monsanto Daniela M. , van Vuuren Bettine Jansen , Toonen Robert J. , Teske Peter R. 
Published: September 2020

AbstractEnvironmental gradients between marine biogeographical provinces separate distinct faunal communities; in the absence of absolute dispersal barriers numerous species nonetheless occur on either side of such boundaries. While the regional populations of such widespread species tend to be morphologically indistinguishable from each other, genetic evidence suggests that they represent unique ecotypes, and likely even cryptic species, that may be uniquely adapted to their local environment. Here, we explored genomic divergence in four sympatric southern African decapod crustaceans whose ranges span the boundary between the cool-temperate west coast (south-eastern Atlantic) and the warm-temperate south coast (south-western Indian Ocean) near the southern tip of the African continent. Using genome-wide data, we found that all four species comprise distinct west- and south coast ecotypes, with molecular dating suggesting divergence during the Pleistocene. Using transcriptomic data from one of the decapod crustaceans, we further found a clear difference in gene expression profiles between the west- and south coast ecotypes. This was particularly clear in the individual from the south coast, which experienced a ‘transcriptomic shock’ at low temperatures that are more typical of the west coast and may explain their absence from that coastline. Our results shed new light on the processes involved in driving genomic divergence and incipient speciation.
The kinesin-8 member Kif19 alters microtubule dynamics, suppresses cell adhesion, and promotes cancer cell invasion
Authors: Eisenberg Samuel C. , Dey Abhinav , Birnbaum Rayna , Sharp David J. 
Published: September 2020

AbstractMetastasis is one of the deadliest aspects of cancer. Initial Metastatic spread is dependent on the detachment and dissemination of cells from a parent tumor, and invasion into the surrounding tissue. In this study, we characterize the kinesin-8 member Kif19 as a promoter of cancer cell invasion that suppresses cell-cell adherens junctions and cell-matrix focal adhesions. Initial analysis of publicly available cancer patient data sets demonstrated that Kif19 expression correlates with worse overall survival probability in several cancers and that Kif19 expression is increased in metastases of colorectal and breast carcinoma compared to the primary tumor. Depletion of Kif19 from two human cancer cell lines (DMS53 and MDA-MB-231) did not alter viability, but decreased the cells’ ability to invade a Matrigel matrix by half and impaired the invasion of spheroids into a primary cell monolayer. Ectopically expressed Kif19 localized to, and partially depolymerized, microtubules in the cell periphery. However, Kif19 depletion increased microtubule dynamicity and sensitivity to pharmacological depolymerization without altering total microtubule polymer levels. These data indicate that Kif19 can both depolymerize and stabilize microtubules. Given this activity, we then studied Kif19’s effect on focal adhesions and adherens junctions, which are both regulated by microtubule dynamics. Kif19 knockdown increased the proportion of cell surface area covered by Vinculin focal adhesions. Further, Kif19 depletion increased whole cell E-cadherin expression and the accumulation of E-cadherin at cell-cell adherens junctions. Conversely, ectopic overexpression of full-length Kif19 led to proportionally smaller focal adhesions and impaired E-cadherin accumulation at cell-cell junctions. Our current hypothesis is that aberrant Kif19 expression in cancer alters focal adhesion dynamics and suppresses E-cadherin expression, which enhance cell invasiveness. Further, we propose that these changes in cell adhesion are due to modification of peripheral microtubule dynamics by Kif19, potentially through disruption of local rho GTPase activity.
De novo virus inference and host prediction from metagenome using CRISPR spacers
Authors: Sugimoto Ryota , Nishimura Luca , Thanh Phuong Nguyen , Ito Jumpei , Parrish Nicholas F. , Mori Hiroshi , Kurokawa Ken , Nakaoka Hirofumi , Inoue Ituro 
Published: September 2020

AbstractViruses are the most numerous biological entity, existing in all environments and infecting all cellular organisms. Compared with cellular life, the evolution and origin of viruses are poorly understood; viruses are enormously diverse and most lack sequence similarity to cellular genes. To uncover viral sequences without relying on either reference viral sequences from databases or marker genes known to characterize specific viral taxa, we developed an analysis pipeline for virus inference based on clustered regularly interspaced short palindromic repeats (CRISPR). CRISPR is a prokaryotic nucleic acid restriction system that stores memory of previous exposure. Our protocol can infer viral sequences targeted by CRISPR and predict their hosts using unassembled short-read metagenomic sequencing data. Analysing human gut metagenomic data, we extracted 11,391 terminally redundant CRISPR-targeted sequences which are likely complete circular genomes of viruses or plasmids. The sequences include 257 complete crAssphage family genomes, 11 genomes larger than 200 kilobases, 766 genomes ofMicroviridaespecies, 114 genomes ofInoviridaespecies and many entirely novel genomes of unknown taxa. We predicted the host(s) of approximately 70% of discovered genomes by linking protospacers to taxonomically assigned CRISPR direct repeats. These results support that our protocol is efficient for de novo inference of viral genomes and host prediction. In addition, we investigated the origin of the diversity-generating retroelement (DGR) locus of the crAssphage family. Phylogenetic analysis and gene locus comparisons indicate that DGR is orthologous in human gut crAssphages and shares a common ancestor with baboon-derived crAssphage; however, the locus has likely been lost in multiple lineages recently.
Improvements to the ARTIC multiplex PCR method for SARS-CoV-2 genome sequencing using nanopore
Authors: Tyson John R , James Phillip , Stoddart David , Sparks Natalie , Wickenhagen Arthur , Hall Grant , Choi Ji Hyun , Lapointe Hope , Kamelian Kimia , Smith Andrew D , Prystajecky Natalie , Goodfellow Ian , Wilson Sam J , Harrigan Richard , Snutch Terrance P , Loman Nicholas J , Quick Joshua 
Published: September 2020

AbstractGenome sequencing has been widely deployed to study the evolution of SARS-CoV-2 with more than 90,000 genome sequences uploaded to the GISAID database. We published a method for SARS-CoV-2 genome sequencing (https://www.protocols.io/view/ncov-2019-sequencing-protocol-bbmuik6w) online on January 22, 2020. This approach has rapidly become the most popular method for sequencing SARS-CoV-2 due to its simplicity and cost-effectiveness. Here we present improvements to the original protocol: i) an updated primer scheme with 22 additional primers to improve genome coverage, ii) a streamlined library preparation workflow which improves demultiplexing rate for up to 96 samples and reduces hands-on time by several hours and iii) cost savings which bring the reagent cost down to £10 per sample making it practical for individual labs to sequence thousands of SARS-CoV-2 genomes to support national and international genomic epidemiology efforts.
Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition
Authors: Ogden Tom E.H. , Yang Ji-Chun , Schimpl Marianne , Easton Laura E. , Underwood Elizabeth , Rawlins Philip B. , McCauley Michael M. , Langelier Marie-France , Pascal John M. , Embrey Kevin J. , Neuhaus David 
Published: September 2020

ABSTRACTPARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of DNA single-strand breaks by PARP-1’s F1 and F2 domainsviaa process of further domain assembly to activation of the catalytic domain (CAT); synthesis and attachment of poly(ADP-ribose) (PAR) chains to protein sidechains then signals for assembly of DNA repair components. A key component in transmission of the allosteric signal is the HD subdomain of CAT, which alone bridges between the assembled DNA-binding domains and the active site in the ART subdomain of CAT. Here we present a study of isolated CAT domain from human PARP-1, using NMR-based dynamics experiments to analyse WT apo-protein as well as a set of inhibitor complexes (with veliparib, olaparib, talazoparib and EB-47) and point mutants (L713F, L765A and L765F), together with new crystal structures of the free CAT domain and inhibitor complexes. Variations in both dynamics and structures amongst these species point to a model for full-length PARP-1 activation where first DNA binding and then substrate interaction successively destabilise the folded structure of the HD subdomain to the point where its steric blockade of the active site is released and PAR synthesis can proceed.
Unsupervised clustering analysis of SARS-Cov-2 population structure reveals six major subtypes at early stage across the world
Authors: Li Yawei , Liu Qingyun , Zeng Zexian , Luo Yuan 
Published: September 2020

AbstractIdentifying the population structure of the newly emerged coronavirus SARS-CoV-2 has significant potential to inform public health management and diagnosis. As SARS-CoV-2 sequencing data accrued, grouping them into clusters is important for organizing the landscape of the population structure of the virus. Due to the limited prior information on the newly emerged coronavirus, we utilized four different clustering algorithms to group 16,873 SARS-CoV-2 strains, which automatically enables the identification of spatial structure for SARS-CoV-2. A total of six distinct genomic clusters were identified using mutation profiles as input features. Comparison of the clustering results reveals that the four algorithms produced highly consistent results, but the state-of-the-art unsupervised deep learning clustering algorithm performed best and produced the smallest intra-cluster pairwise genetic distances. The varied proportions of the six clusters within different continents revealed specific geographical distributions. In particular, our analysis found that Oceania was the only continent on which the strains were dispersively distributed into six clusters. In summary, this study provides a concrete framework for the use of clustering methods to study the global population structure of SARS-CoV-2. In addition, clustering methods can be used for future studies of variant population structures in specific regions of these fast-growing viruses.
Mutagenesis of the Orco Odorant Receptor Co-receptor Impairs Olfactory Function in the Malaria VectorAnopheles coluzzii
Authors: Sun Huahua , Liu Feng , Ye Zi , Baker Adam , Zwiebel Laurence J. 
Published: September 2020

AbstractMosquitoes rely heavily on their olfactory systems for host seeking, selection of oviposition sites, and avoiding predators and other environmental dangers. Of these behaviors, the preferential selection of a human blood-meal host drives the vectorial capacity of anthropophilic femaleAnopheles coluzziimosquitoes. Olfactory receptor neurons (ORNs) are dispersed across several appendages on the head and express an obligate odorant receptor co-receptor (Orco) coupled with a “tuning” odorant receptor (OR) to form heteromeric, odor-gated ion channels in the membrane of these neurons. To examine the mechanistic and functional contributions of Orco/OR complexes to the chemosensory processes ofAn. coluzzii, we utilized CRISPR/Cas9 gene editing to create a line of homozygous, Orco-knockout, mutant mosquitoes. As expected,orco-/-ORNs across both adult and larval stages ofAn. coluzziidisplay significantly lower background activity and lack nearly all odor-evoked responses. In addition, blood-meal-seeking, adult female,orco- /-mutant mosquitoes exhibit severely reduced attraction to human- and non-human-derived odors while gravid females are significantly less responsive to established oviposition attractants. These results reinforce observations in other insects that Orco is crucial in maintaining the activity of ORNs. In that light, it significantly influences a range of olfactory-driven behaviors central to the anthropophilic host preference that is critical to the vectorial capacity ofAn. coluzziias a primary vector for human malaria.
Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals
Authors: Stanzick Kira J , Li Yong , Gorski Mathias , Wuttke Matthias , Pattaro Cristian , Köttgen Anna , Stark Klaus J , Heid Iris M , Winkler Thomas W 
Published: September 2020

ABSTRACTChronic kidney disease (CKD) has a complex genetic underpinning. Genome-wide association studies (GWAS) of CKD-defining glomerular filtration rate (GFR) have identified hundreds of loci, but prioritization of variants and genes is challenging. To expand and refine GWAS discovery, we meta-analyzed GWAS data for creatinine-based estimated GFR (eGFRcrea) from the Chronic Kidney Disease Genetics Consortium (CKDGen, n=765,348, trans-ethnic) and UK Biobank (UKB, n=436,581, Europeans). The results (i) extend the number of eGFRcrea loci (424 loci; 201 novel; 8.9% eGFRcrea variance explained by 634 independent signals); (ii) improve fine-mapping resolution (138 99% credible sets with ≤5 variants, 44 single-variant sets); (iii) ascertain likely kidney function relevance for 343 loci (consistent association with alternative biomarkers); and (iv) highlight 34 genes with strong evidence by a systematic Gene PrioritiSation (GPS). We provide a sortable, searchable and customizable GPS tool to navigate through thein silicofunctional evidence and select relevant targets for functional investigations.
Hydrogen-deuterium exchange reveals a dynamic DNA binding map of Replication Protein A
Authors: Ahmad Faiz , Patterson Angela , Deveryshetty Jaigeeth , Mattice Jenna , Pokhrel Nilisha , Bothner Brian , Antony Edwin 
Published: September 2020

ABSTRACTReplication Protein A (RPA) binds to single-stranded DNA (ssDNA) and interacts with over three dozen enzymes and serves as a recruitment hub to coordinate most DNA metabolic processes including DNA replication, repair, and recombination. RPA binds ssDNA utilizing six oligosaccharide/oligonucleotide binding (OB) domains within a heterotrimeric complex of RPA70, RPA32 and RPA14 subunits. Based on their DNA binding affinities they are classified as high versus low-affinity DNA binding domains (DBDs). However, recent evidence suggests that the DNA-binding dynamics of DBDs better define their roles. Utilizing hydrogen-deuterium exchange mass spectrometry (HDX-MS) we assessed the contacts and dynamics of the individual domains of human RPA to determine the landscape of conformational changes upon binding to ssDNA. As expected, ssDNA interacts with the major DBDs (A, B, C, and D). However, DBD-A and DBD-B are dynamic and do not show robust DNA-dependent protection. DBD-C displays the most extensive changes in HDX, suggesting a major role in stabilizing RPA on ssDNA. DNA-dependent HDX kinetics are also captured for DBD-D and DBD-E. Slower allosteric changes transpire in the protein-protein interaction domains and the linker regions. We propose a dynamics-based DNA binding model for RPA utilizing a dynamic half and a less-dynamic half.
TEA-seq: a trimodal assay for integrated single cell measurement of transcription, epitopes, and chromatin accessibility
Authors: Swanson Elliott , Lord Cara , Reading Julian , Heubeck Alexander T. , Savage Adam K. , Green Richard , Li Xiao-jun , Torgerson Troy R. , Bumol Thomas F. , Graybuck Lucas T. , Skene Peter J. 
Published: September 2020

AbstractSingle-cell measurements of cellular characteristics have been instrumental in understanding the heterogeneous pathways that drive differentiation, cellular responses to extracellular signals, and human disease states. scATAC-seq has been particularly challenging due to the large size of the human genome and processing artefacts resulting from DNA damage that are an inherent source of background signal. Downstream analysis and integration of scATAC-seq with other single-cell assays is complicated by the lack of clear phenotypic information linking chromatin state and cell type. Using the heterogeneous mixture of cells in human peripheral blood as a test case, we developed a novel scATAC-seq workflow that increases the signal-to-noise ratio and allows simultaneous measurement of cell surface markers: Integrated Cellular Indexing of Chromatin Landscape and Epitopes (ICICLE-seq). We extended this approach using a droplet-based multiomics platform to develop a trimodal assay to simultaneously measureTranscriptomic state (scRNA-seq), cell surfaceEpitopes, and chromatinAccessibility (scATAC-seq) from thousands of single cells, which we term TEA-seq. Together, these multimodal single-cell assays provide a novel toolkit to identify type-specific gene regulation and expression grounded in phenotypically defined cell types.
Diagnosing Cognitive Disorders in Older Adults with Temporal Lobe Epilepsy
Authors: Reyes Anny , Kaestner Erik , Edmonds Emily C. , Macari Anna Christina , Wang Zhong Irene , Drane Daniel L. , Punia Vineet , Busch Robyn M. , Hermann Bruce P. , McDonald Carrie R. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2020

AbstractObjectiveTo characterize the nature and prevalence of cognitive disorders in older adults with temporal lobe epilepsy (TLE) and compare their cognitive profiles to non-epileptic patients with mild cognitive impairment (i.e.,classicMCI; cMCI).MethodsSeventy-eight older patients with TLE, 77 cMCI, and 69 normal aging controls (NAC), all 55-80 years, completed neuropsychological measures of memory, language, executive function and processing speed. An actuarial neuropsychological method designed to diagnose MCI was applied to individual patients to identify older adults with TLE who met diagnostic criteria for MCI (TLE-MCI). A linear classifier was performed to evaluate how well the diagnostic criteria differentiated patients with TLE-MCI from cMCI. In TLE, the contribution of epilepsy-related and vascular risk factors to cognitive impairment was evaluated using multiple regression.ResultsForty-three TLE patients (60%) met criteria for TLE-MCI, demonstrating marked deficits in both memory and language. A classification model between TLE-MCI and cMCI correctly classified 81.1% (90.6% specificity, 61.3% sensitivity) of the cohort based on neuropsychological scores. Whereas TLE-MCI showed greater deficits in language relative to cMCI, patients with cMCI showed greater rapid forgetting on memory measures. Both epilepsy-related risk factors and the presence of leukoaraiosis on MRI contributed to impairment profiles in TLE-MCI.InterpretationApproximately 60% of older adults with TLE meet diagnostic criteria for a cognitive disorder associated with aging (i.e., MCI). The TLE-MCI phenotype may be secondary to an accumulation of epilepsy and vascular risk factors, signal the onset of a neurodegenerative disease, or represent a combination of both factors.