bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing predictive models to prioritize viral discovery in zoonotic reservoirs
Authors: Becker Daniel J. , Albery Gregory F. , Sjodin Anna R. , Poisot Timothée , Bergner Laura M. , Dallas Tad A. , Eskew Evan A. , Farrell Maxwell J. , Guth Sarah , Han Barbara A. , Simmons Nancy B. , Stock Michiel , Teeling Emma C. , Carlson Colin J. 
Published: May 2020

AbstractDespite global investment in One Health disease surveillance, it remains difficult—and often very costly—to identify and monitor the wildlife reservoirs of novel zoonotic viruses. Statistical models can be used to guide sampling prioritization, but predictions from any given model may be highly uncertain; moreover, systematic model validation is rare, and the drivers of model performance are consequently under-documented. Here, we use bat hosts of betacoronaviruses as a case study for the data-driven process of comparing and validating predictive models of likely reservoir hosts. In the first quarter of 2020, we generated an ensemble of eight statistical models that predict host-virus associations and developed priority sampling recommendations for potential bat reservoirs and potential bridge hosts for SARS-CoV-2. Over more than a year, we tracked the discovery of 40 new bat hosts of betacoronaviruses, validated initial predictions, and dynamically updated our analytic pipeline. We find that ecological trait-based models perform extremely well at predicting these novel hosts, whereas network methods consistently perform roughly as well or worse than expected at random. These findings illustrate the importance of ensembling as a buffer against variation in model quality and highlight the value of including host ecology in predictive models. Our revised models show improved performance and predict over 400 bat species globally that could be undetected hosts of betacoronaviruses. Although 20 species of horseshoe bats (Rhinolophusspp.) are known to be the primary reservoir of SARS-like viruses, we find at least three-fourths of plausible betacoronavirus reservoirs in this bat genus might still be undetected. Our study is the first to demonstrate through systematic validation that machine learning models can help optimize wildlife sampling for undiscovered viruses and illustrates how such approaches are best implemented through a dynamic process of prediction, data collection, validation, and updating.
Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors
Authors: Zhou Jia , Gelot Camille , Pantelidou Constantia , Li Adam , Yücel Hatice , Davis Rachel E. , Farkkila Anniina , Kochupurakkal Bose , Syed Aleem , Shapiro Geoffrey I. , Tainer John A. , Blagg Brian S. J. , Ceccaldi Raphael , D’Andrea Alan D. 
Published: May 2020

AbstractPARP inhibitors (PARPi) have become a new line of therapy for Homologous Recombination (HR)-deficient cancers. However, resistance to PARPi has emerged as a major clinical problem. DNA polymerase theta (POLθ) is synthetic lethal with HR and a druggable target in HR-deficient cancers. Here, we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cellsin vitroandin vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. BRCA-deficient tumor cells and those with acquired PARPi resistance are sensitive to NVBin vitroandin vivo. Increased POLθ expression levels predict NVB sensitivity. The mechanism of NVB-mediated cell death in PARPi resistant cells is the accumulation of toxic RAD51 foci, which also provides a pharmacodynamic biomarker for NVB response. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance.One Sentence SummaryWe identified Novobiocin as a specific POLθ inhibitor that selectively kills naïve and PARPi resistance HR-deficient tumorsin vitroandin vivo.
A synoptic revision ofPohliella(Podostemaceae) with notes onAulea, CipoiaandSaxicolella
Authors: Cheek Martin 
Published: May 2020

ABSTRACTSaxicolellaEngl., an African genus of the waterfall specialist plant family Podostemaceae, was shown to be polyphyletic as currently delimited. One clade, sampled from species in Ghana, is sister to AmericanCeratolacis(Tul.)Wedd.,PodostemumMichx. and all Old World Podostemoideae (podostemoids). The second clade, sampled from Cameroonian material, was embedded within the major clade of African podostemoids. In this paper the generic nomenclature applied toSaxicolellasensu lato (Saxicolella, PohliellaEngl., AuleaLebrun & Stork nom. inval.), is reviewed and the morphological support for the two clades and their correct generic names is determined.Pohliellais shown to be the correct name for the first clade (based onPohliella laciniataEngl., Cameroon) and a synoptic treatment of its three published species is given, one of which is extinct, and two are threatened. However, a fourth, unpublished species exists. The new combinationsPohliella submersa(J.B.Hall) Cheek andPohliella amicorum(J.B. Hall) Cheek are made for the two published Ghanaian species. The recently described New World genusCipoiaC.T. Philbrick, Novelo & Irgang is revealed as being morphologically identical toPohliella, but in view of the geographical disjunction, confirmation from molecular evidence is awaited before its two species are also transferred toPohliella. The correct name for the second clade, embedded in African podostemoids, isSaxicolella(sensu stricto), now with two known species,Saxicolella nanaEngl. (type ofSaxicolella,Cameroon) andSaxicolella flabellata(G.Taylor) C. Cusset (Nigeria).
Characterization and Functional Annotation of Uncharacterized ABC Transporter ATP-Binding Protein Rv0986 ofMycobacterium tuberculosis(Strain ATCC 25618 / H37Rv)
Authors: Mohammad Saikat Abu Saim 
Published: May 2020

AbstractThe most significant ancient infectious disease tuberculosis is causes by a human pathogen,Mycobacterium tuberculosis(MTB). Amazingly, tuberculosis (TB) has become one of the major causes of human death worldwide. The protein Rv0986 is associated with the ATP-binding cassette domain of the transporters involved in the export of lipoprotein and macrolide, and cell division protein, therefore, related to mycobacterial infection. But the protein Rv0986 is not yet explored. As a result, identification, characterization, and functional annotation of uncharacterized protein Rv0986 were predicted where the structure modeling was generated by using Modeller, Phyre2, and Swiss Model with the structural quality assessment by Ramachandran Plot (PROCHECK), Verify 3d, and Swiss-Model Interactive Workplace as well. Z-scores obtained from Prosa-web were also applied for overall 3D model quality. This in-silico method will uncover the significance of undiscovered uncharacterized protein Rv0986 present in MTB, and indeed it can accelerate the way to enrich our knowledge in the pathogenesis and drug-targeting opportunity against infection by MTB.
Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice
Authors: Miller Richard A. , Harrison David E. , Allison David B. , Bogue Molly , Diaz Vivian , Fernandez Elizabeth , Galecki Andrzej , Garvey W. Timothy , Kumar Navasuja , Javors Martin A. , Ladiges Warren C. , Macchiarini Francesca , Nelson James , Reifsnyder Peter , Rosenthal Nadia A. , Salmon Adam B. , Smith Daniel L. , Snyder Jessica M. , Lombard David B. , Strong Randy 
Published: May 2020

AbstractCanagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e. slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
Experimental evidence of memory-based foraging decisions in a large wild mammal
Authors: Ranc Nathan , Moorcroft Paul R. , Ossi Federico , Cagnacci Francesca 
Published: May 2020

AbstractMany animals restrict their movements to a characteristic home range. This pattern of constrained space-use is thought to result from the foraging benefits of memorizing the locations and quality of heterogeneously distributed resources. However, due to the confounding effects of sensory perception, the role of memory in home range movement behavior lacks unequivocal evidence in the wild. Here, we analyze the foraging decisions of a large mammal during a field resource manipulation experiment designed to disentangle the effects of memory and perception. Using a cognitive movement model, we demonstrate that roe deer (Capreolus capreolus) rely on memory, not perception, to track the spatio-temporal dynamics of resources within their home range. Our findings show a memory-based spatial transition model parametrized with experimental data can successfully be used to quantify cognitive processes and to predict how animals respond to resource heterogeneity in space and time.
Direct digital sensing of protein biomarkers in solution
Authors: Krainer Georg , Saar Kadi L. , Arter William E. , Welsh Timothy J. , Czekalska Magdalena A. , Jacquat Raphaël P.B. , Peter Quentin , Traberg Walther C. , Pujari Arvind , Jayaram Akhila K. , Challa Pavankumar , Taylor Christopher G. , van der Linden Lize-Mari , Franzmann Titus , Owens Roisin M. , Alberti Simon , Klenerman David , Knowles Tuomas P.J. 
Published: May 2020

AbstractThe detection of proteins is of central importance to biomolecular analysis and diagnostics, yet fundamental limitations due to the surface-based nature of most sensing approaches persist, and limited improvements have been designed to integrate multimodal information beyond concentration measurements. Here we present a single-molecule microfluidic sensing platform for digital protein biomarker detection in solution, termed digital immunosensor assay (DigitISA). DigitISA is based on microchip electrophoretic separation combined with single-molecule detection and enables absolute number–concentrations quantification of proteins in a single, solution-phase step. Applying DigitISA to a range of targets including amyloid aggregates, exosomes, and biomolecular condensates, we demonstrate that the assay provides information beyond stoichiometric interactions, and enables characterization of immunochemistry, binding affinity, and protein biomarker abundance. Together, DigitISA constitutes a new experimental paradigm for the digital sensing of protein biomarkers, and enables analyses of targets that would otherwise be hard or impossible to address by conventional immuno-sensing techniques.
Endothelial CXCL12 regulates neovascularization during tissue repair and tumor progression
Authors: Maan Zeshaan N. , Hu Michael S. , Rennert Robert , Barrera Janos A. , Duscher Dominik , Januszyk Michael , Whittam Alexander , Padmanabhan Jagannath , Vial Nicholas , Ho Natalie , Fischer Lauren H. , Riegler Johannes , Wu Joseph C. , Longaker Michael T. , Gurtner Geoffrey C. 
Published: May 2020

AbstractCXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1 [SDF-1]), primarily known for its role in embryogenesis and hematopoiesis, has also been implicated in tumor biology and neovascularization. However, its specific role and mechanism of action remain poorly understood. We previously demonstrated that CXCL12 expression is Hypoxia-Inducible Factor (HIF)-1 responsive. Here we use a conditional CXCL12 knockout mouse to show that endothelial-specific deletion of CXCL12 (eKO) does not affect embryogenesis, but reduces the survival of ischemic tissue, altering tissue repair and tumor progression. Loss of vascular endothelial CXCL12 disrupts endothelial – fibroblast crosstalk necessary for stromal growth and vascularization. Single-cell gene expression analysis in combination with a parabiosis model reveals a specific population of non-inflammatory circulating cells, defined by genes regulating neovascularization, which is recruited by endothelial CXCL12. These findings indicate an essential role for endothelial CXCL12 expression during the adult neovascular response in tissue injury and tumor progression.
Astrocytic glutamate uptake coordinates experience-dependent, eye-specific refinement in developing visual cortex
Authors: Sipe Grayson , Petravicz Jeremy , Rikhye Rajeev , Garcia Rodrigo , Mellios Nikolaos , Sur Mriganka 
Published: May 2020

ABSTRACTThe uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two-photon microscopy, immunohistochemistry and slice electrophysiology. We find that though eye-specific thalamic axonal segregation is intact, binocular refinement in the primary visual cortex is disrupted. Eye-specific responses to visual stimuli in GLT1 HET mice show altered binocular matching, with abnormally high responses to ipsilateral compared to contralateral eye stimulation and a greater mismatch between preferred orientation selectivity of ipsilateral and contralateral eye responses. Furthermore, the balance of excitation and inhibition in cortical circuits is dysregulated with an increase in somatostatin positive interneurons, decrease in parvalbumin positive interneurons, and increase in dendritic spine density in the basal dendrites of layer 2/3 excitatory neurons. Monocular deprivation induces atypical ocular dominance plasticity in GLT1 HET mice, with an unusual depression of ipsilateral open eye responses; however, this change in ipsilateral responses correlates well with an upregulation of GLT1 protein following monocular deprivation. These results demonstrate that a key function of astrocytic GLT1 function during development is the experience-dependent refinement of ipsilateral eye inputs relative to contralateral eye inputs in visual cortex.SIGNIFICANCEWe show that astrocytic glutamate uptake via the transporter GLT1 is necessary for activity-dependent regulation of cortical inputs. Dysregulation of GLT1 expression and function leads to a disruption of binocular refinement and matching in visual cortex. Inputs from the ipsilateral eye are stronger, and monocular deprivation, which upregulates GLT1 expression in a homeostatic fashion, causes a paradoxical reduction of ipsilateral, non-deprived eye, responses. These results provide new evidence for the importance of glutamate transport in cortical development, function, and plasticity.
The novel Coronavirus enigma: Phylogeny and mutation analyses of SARS-CoV-2 viruses circulating in India during early 2020
Authors: Banerjee Anindita , Sarkar Rakesh , Mitra Suvrotoa , Lo Mahadeb , Dutta Shanta , Chawla-Sarkar Mamta 
Published: May 2020

AbstractBackgroundThis is a comprehensive analysis of 46 Indian SARS-CoV-2 genome sequences available from the NCBI and GISAID repository during early 2020. Evolutionary dynamics, gene-specific phylogeny and emergence of the novel co-evolving mutations in nine structural and non-structural genes among circulating SARS-CoV-2 strains in ten states of India have been assessed.Materials and methods46 SARS-CoV-2 nucleotide sequences submitted from India were downloaded from the GISAID (39/46) or from NCBI (7/46) database. Phylogenetic study and analyses of mutation were based on the nine structural and non-structural genes of SARS-CoV-2 strains. Secondary structure of RdRP/NSP12 protein was predicted with respect to the novel A97V mutation.ResultsPhylogenetic analyses revealed the evolution of “genome-type clusters” and adaptive selection of “L” type SARS-CoV-2 strains with genetic closeness to the bat SARS-like coronaviruses than pangolin or MERS-CoVs. With regards to the novel co-evolving mutations, 2 groups are seen to circulate in India at present: the “major group” (52.2%) and the “minor group” (30.4%), harboring four and five co-existing mutations, respectively. The “major group” mutations fall in the A2a clade. All the minor group mutations, except 11083G>T (L37F, NSP6) were unique to the Indian isolates.ConclusionThe study highlights rapidly evolving SARS-CoV-2 virus and co-circulation of multiple clades and sub-clades, driving this pandemic worldwide. This comprehensive study is a potential resource for monitoring the novel mutations in the viral genome, changes in viral pathogenesis, for designing vaccines and other therapeutics.
A Multi-Objective Genetic Algorithm to Find Active Modules in Multiplex Biological Networks
Authors: Novoa-del-Toro Elva-María , Mezura-Montes Efrén , Vignes Matthieu , Magdinier Frédérique , Tichit Laurent , Baudot Anaïs 
Published: May 2020

AbstractThe identification of subnetworks of interest - or active modules - by integrating biological networks with molecular profiles is a key resource to inform on the processes perturbed in different cellular conditions. We here propose MOGAMUN, a Multi-Objective Genetic Algorithm to identify active modules in multiplex biological networks. MOGAMUN optimizes both the density of interactions and the scores of the nodes (e.g., their differential expression).We compare MOGAMUN with state-of-the-art methods, representative of different algorithms dedicated to the identification of active modules in single networks. MOGAMUN identifies dense and high-scoring modules that are also easier to interpret. In addition, to our knowledge, MOGAMUN is the first method able to use multiplex networks. Multiplex networks are composed of different layers of physical and functional relationships between genes and proteins. Each layer is associated to its own meaning, topology, and biases; the multiplex framework allows exploiting this diversity of biological networks.We applied MOGAMUN to identify cellular processes perturbed in Facio-Scapulo-Humeral muscular Dystrophy, by integrating RNA-seq expression data with a multiplex biological network. We identified different active modules of interest, thereby providing new angles for investigating the pathomechanisms of this disease.AvailabilityMOGAMUN is available athttps://github.com/elvanov/MOGAMUN.Contactelva.novoa@inserm.fr,anais.baudot@univ-amu.fr
Multi-metrics assessment of dynamic cerebral autoregulation in middle and posterior cerebral arteries in young fit women
Authors: Labrecque Lawrence , Drapeau Audrey , Rahimaly Kevan , Imhoff Sarah , Billaut François , Brassard Patrice 
Published: May 2020

AbstractIndividuals with low orthostatic tolerance show greater decrease in posterior cerebral artery mean blood velocity (PCAvmean). Since young fit women often experience presyncopal symptoms, their posterior cerebral circulation may be prone to greater decreases in PCAvmean, probably explained by an attenuated dynamic cerebral autoregulation (dCA). Regional differences in dCA have never been evaluated in young fit women. We compared dCA in the middle cerebral artery (MCA) and posterior cerebral artery (PCA) in 11 young fit women (25 ± 4y;) in response to a sit-to-stand (5 min sitting followed by 5 min standing) and repeated squat-stand maneuvers performed at 0.05 Hz and 0.10 Hz. The cerebral pressure-flow relationship was characterized using four metrics: 1) percent reduction in blood velocity (BV) per percent reduction in MAP (% BV/% MAP) during initial orthostatic stress (0-15 s after sit-to-stand); 2) onset of the regulatory response (i.e. time delay before an increase in conductance (BV/MAP); 3) rate of regulation (RoR), following sit-to-stand and; 4) transfer function analysis (TFA) of forced MAP oscillations induced by repeated squat-stands. Upon standing, the relative decline in MCAvmeanand PCAvmeanwas similar (−25 ± 9 vs. −30 ± 13%; p=0.29). The onset of the regulatory response (p=0.665), %ΔBV/%ΔMAP (p=0.129) and RoR (p=0.067) were not different between MCA and PCA. In regard to TFA, there was an ANOVA artery effect for gain (p<0.001) and a frequency effect for phase (p<0.001). These findings indicate the absence of regional differences in dCA in young fit women.New findingsWhat is the central question of this study?Are there regional differences in the dynamic cerebral autoregulation in young fit women?What is the main finding and its importance?The key finding of this study is that there are no differences in dynamic cerebral autoregulation between both arteries. These results indicate that dynamic cerebral autoregulation does not seem to be responsible for making the posterior cerebral circulation more vulnerable to transient reduction in blood pressure in young fit women.
An endocrine-hepato-muscular metabolic cycle links skeletal muscle atrophy and hyperglycemia in type 2 diabetes
Authors: Okun Jürgen G. , Rusu Patricia M. , Chan Andrea Y. , Yap Yann W. , Sharkie Thomas , Schumacher Jonas , Schmidt Kathrin V. , Zota Annika , Hille Susanne , Jungmann Andreas , Maggi Ludovico , Lee Young , Blüher Matthias , Herzig Stephan , Heikenwalder Mathias , Müller Oliver , Rose Adam J. 
Published: May 2020

AbstractBoth obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we uncover dysregulated systemic alanine metabolism and hyper-expression of the alanine transaminases (ALT) in the liver of obese/diabetic mice and humans. Hepatocyte-selective silencing of both ALT enzymes revealed a clear role in systemic alanine clearance which related to glycemic control. In obese/diabetic mice, not only did silencing both ALT enzymes retard hyperglycemia, but also reversed skeletal muscle atrophy. This was due to a rescue of depressed skeletal muscle protein synthesis, with a liver-skeletal muscle amino acid metabolic crosstalk exemplified by ex vivo experiments. Mechanistically, chronic liver glucocorticoid and glucagon signaling driven liver alanine catabolism promoted hyperglycemia and skeletal muscle wasting. Taken together, here we reveal an endocrine-hepato-muscular metabolic cycle linking hyperglycemia and skeletal muscle atrophy in type 2 diabetes.