bluuebunny/crossref_metadata_2025_split huggingface dataset:
A fresh look at an old concept: Home-range estimation in a tidy world
Authors: Signer Johannes , Fieberg John 
Published: August 2020

AbstractA rich set of statistical techniques have been developed over the last several decades to estimate the spatial extent of animal home ranges from telemetry data, and new methods to estimate home ranges continue to be developed.Here we investigate home-range estimation from a computational point of view and aim to provide a general framework for computing home ranges, independent of specific estimators.We show how such a workflow can help make home-range estimation easier and more intuitive, and we provide a series of examples illustrating how different estimators can be compared easily, so that one can perform a sensitivity analysis to determine the degree to which the choice of estimator influences qualitative and quantitative conclusions.By providing a standardized, tidy implementation of home-range estimators, we hope to equip analysts with the tools needed to explore how estimator choice influences answers to biologically meaningful questions.
Protein interaction probability landscapes for yeast replicative aging
Authors: Guo Hao-Bo , Ghafari Mehran , Dang Weiwei , Qin Hong 
Published: August 2020

AbstractWe proposed a novel probability landscape approach to map the systems-level profile changes of gene networks during replicative aging inSaccharomyces cerevisiae. This approach enabled us to apply quasi-potentials, the negative logarithm of the probabilities, to calibrate the elevation of the landscapes with young cells as a reference state. Our approach detected opposite landscape changes based on protein abundances from transcript levels, especially for intra-essential gene interactions. We showed that essential proteins play different roles from hub proteins on the age-dependent landscapes. We verified that hub proteins tend to avoid other hub proteins, but essential proteins are attractive to other essential proteins. Overall, we showed that the probability landscape is promising for inferring network profile change during aging and that the essential hub proteins may play an important role in the uncoupling between protein and transcript levels during replicative aging.
Exploring G and C-quadruplex structures as potential targets against the severe acute respiratory syndrome coronavirus 2
Authors: Belmonte-Reche Efres , Serrano-Chacón Israel , Gonzalez Carlos , Gallo Juan , Bañobre-López Manuel 
Published: August 2020

ABSTRACTIn this paper we report the analysis of the 2019-nCoV genome and related viruses using an upgraded version of the open-source algorithm G4-iM Grinder. This version improves the functionality of the software, including an easy way to determine the potential biological features affected by the candidates found. The quadruplex definitions of the algorithm were optimized for 2019-nCoV. Using a lax quadruplex definition ruleset, which accepts amongst other parameters two residue G- and C-tracks, hundreds of potential quadruplex candidates were discovered. These sequences were evaluated by theirin vitroformation probability, their position in the viral RNA, their uniqueness and their conservation rates (calculated in over three thousand different COVID-19 clinical cases and sequenced at different times and locations during the ongoing pandemic). These results were compared sequentially to otherCoronaviridaemembers, other Group IV (+)ssRNA viruses and the entire realm. Sequences found in common with other species were further analyzed and characterized. Sequences with high scores unique to the 2019-nCoV were studied to investigate the variations amongst similar species. Quadruplex formation of the best candidates was then confirmed experimentally. Using NMR and CD spectroscopy, we found several highly stable RNA quadruplexes that may be suitable theranostic targets against the 2019-nCoV.GRAPHICAL ABSTRACT
Identification and characterization of pleiotropic high-persistence mutations in the beta subunit of the bacterial RNA polymerase
Authors: Ostrer Lev , Ji Yinduo , Khodursky Arkady 
Published: August 2020

AbstractIndividual bacteria can escape killing by bactericidal antibiotics by becoming dormant. Such cells, also known as persisters, naturally occur in bacterial populations at a low frequency. Here we present the finding that antibiotic-resistance mutations in therpoBgene, encoding the beta subunit of RNA polymerase, increase the frequency of persisters by orders of magnitude. Furthermore, we show that: i) the persistent state depends on the (p)ppGpp transcriptional program and not on (p)ppGpp itself; ii) the high persistence (hip) is associated with increased populational heterogeneity in transcription; iii) indole overproduction, caused by transcriptional changes in thehipmutants, explains 50-80% of thehipphenotype. We report that the analogousrpoBmutations occur frequently in clinical isolates ofAcinetobacter baumannii, Mycobacterium tuberculosis and Staphylococcus aureus, and we demonstrate that one of thoserpoBmutations causes high persistence in MRSA. We also show that the RpoB-associatedhipphenotype can be reversed by inhibiting protein synthesis.ImportancePersistence is an inevitable consequence of antibiotic usage. Although persistence is not a genetically heritable trait, here we demonstrate for the first time that antibiotic resistance, which is heritable, can promote persistence formation. Our finding that resistance to one antibiotic, rifampicin, can boost persistence to other antibiotics, such as ciprofloxacin and ampicillin, may help explain why certain chronic infections are particularly recalcitrant to antibiotic therapies. Out results also emphasize the need to assess the effects of combination antibiotic therapies on persistence.
Single cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium
Authors: Kirkwood PM , Gibson DA , Smith JR , Wilson-Kanamori JR , Kelepouri O , Esnal-Zufiaurre A , Dobie R , Henderson NC , Saunders PTK 
Published: August 2020

AbstractThe endometrium is a dynamic tissue that exhibits remarkable resilience to repeated episodes of differentiation, breakdown, regeneration and remodelling. Endometrial physiology relies on a complex interplay between the stromal and epithelial compartments with the former containing a mixture of fibroblasts, vascular and immune cells. There is evidence for rare populations of putative mesenchymal progenitor cells located in the perivascular niche of human endometrium, but the existence of an equivalent cell population in mouse is unclear.In the current study we used thePdgfrb-BAC-eGFP transgenic reporter mouse in combination with bulk and single cell RNA sequencing (scRNAseq) to redefine the endometrial mesenchyme. Contrary to previous reports we show that CD146 is expressed in both PDGFRβ+ perivascular cells as well as CD31+ endothelial cells. Bulk RNAseq revealed cells in the perivascular niche which express high levels ofPdgfrbas well as genes previously identified in pericytes and/or vascular smooth muscle cells (Acta2, Myh11, Olfr78, Cspg4, Rgs4, Rgs5, Kcnj8, Abcc9). scRNAseq identified five subpopulations of cells including closely related pericytes/vascular smooth muscle cells and three subpopulations of fibroblasts. All three fibroblast populations were PDGFRα+/CD34+ but were distinct in their expression ofSpon2/Angptl7(fibroblast 1),Smoc2/Rgs2(fibroblast 2) andClec3b/Col14a1/Mmp3(fibroblast 3), with potential functions in regulation of immune responses, response to wounding and organisation of extracellular matrix respectively.In conclusion, these data are the first to provide a single cell atlas of the mesenchymal cell landscape in mouse endometrium. By identifying novel markers for subpopulations of mesenchymal cells we can use mouse models investigate their contribution to endometrial function, compare with other tissues and apply these findings to further our understanding of human endometrium.HighlightsGFP expression in the mouse endometrium, under the control of thePdgfrbpromoter, is restricted to two cell populations based on the intensity of GFP with GFPbrightcells close to the vasculatureSingle cell RNAseq identified five subpopulations of GFP+ mesenchymal cells: pericytes, vascular smooth muscle cells (vSMC) and three closely related but distinct populations of fibroblastsBioinformatics revealed that pericytes and vSMC share functions associated with the circulatory system, actin-filament process and cell adhesion, and an apparent role for pericytes in smooth muscle cell migration and response to interferonsComparisons between the fibroblast subpopulations suggest distinct roles in regulation of immune response, response to wound healing and collagen organisation.Graphical Abstract
SARS-CoV-2 infection dynamics in lungs of African green monkeys
Authors: Speranza Emily , Williamson Brandi N. , Feldmann Friederike , Sturdevant Gail L. , Pérez-Pérez Lizzette , Mead-White Kimberly , Smith Brian J. , Lovaglio Jamie , Martens Craig , Munster Vincent J. , Okumura Atsushi , Shaia Carl , Feldmann Heinz , Best Sonja M. , de Wit Emmie 
Published: August 2020

SummaryDetailed knowledge about the dynamics of SARS-CoV-2 infection is important for unraveling the viral and host factors that contribute to COVID-19 pathogenesis. Old-World nonhuman primates recapitulate mild-moderate COVID-19 cases, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with SARS-CoV-2 or inactivated virus to study the dynamics of virus replication throughout the respiratory tract. RNA sequencing of single cells from the lungs and mediastinal lymph nodes allowed a high-resolution analysis of virus replication and host responses over time. Viral replication was mainly localized to the lower respiratory tract, with evidence of replication in the pneumocytes. Macrophages were found to play a role in initiating a pro-inflammatory state in the lungs, while also interacting with infected pneumocytes. Our dataset provides a detailed view of changes in host and virus replication dynamics over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.
SARS-CoV-2 Quasispecies provides insight into its genetic dynamics during infection
Authors: Sun Fengming , Wang Xiuhua , Tan Shun , Dan Yunjie , Lu Yanqiu , Zhang Juan , Xu Junli , Tan Zhaoxia , Xiang Xiaomei , Zhou Yi , He Weiwei , Wan Xing , Zhang Wei , Chen Yaokai , Tan Wenting , Deng Guohong 
Published: August 2020

AbstractA novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has been pandemic worldwide. The genetic dynamics of quasispecies afford RNA viruses a great fitness on cell tropism and host range. However, no quasispecies data of SARS-CoV-2 have been reported yet. To explore quasispecies haplotypes and its transmission characteristics, we carried out single-molecule real-time (SMRT) sequencing of the full-length of SARS-CoV-2 spike gene within 14 RNA samples from 2 infection clusters, covering first-to third-generation infected-patients. We observed a special quasispecies structure of SARS-CoV-2 (modeled as ‘One-King’): one dominant haplotype (mean abundance ~70.15%) followed by numerous minor haplotypes (mean abundance < 0.10%). We not only discovered a novel dominant haplotype of F1040but also realized that minor quasispecies were also worthy of attention. Notably, some minor haplotypes (like F1040and currently pandemic one G614) could potentially reveal adaptive and converse into the dominant one. However, minor haplotypes exhibited a high transmission bottleneck (~6% could be stably transmitted), and the new adaptive/dominant haplotypes were likely originated from genetic variations within a host rather than transmission. The evolutionary rate was estimated as 2.68-3.86 × 10−3per site per year, which was larger than the estimation at consensus genome level. The ‘One-King’ model and conversion event expanded our understanding of the genetic dynamics of SARS-CoV-2, and explained the incomprehensible phenomenon at the consensus genome level, such as limited cumulative mutations and low evolutionary rate. Moreover, our findings suggested the epidemic strains may be multi-host origin and future traceability would face huge difficulties.
rMVP: A Memory-efficient, Visualization-enhanced, and Parallel-accelerated tool for Genome-Wide Association Study
Authors: Yin Lilin , Zhang Haohao , Tang Zhenshuang , Xu Jingya , Yin Dong , Zhang Zhiwu , Yuan Xiaohui , Zhu Mengjin , Zhao Shuhong , Li Xinyun , Liu Xiaolei 
Published: August 2020

AbstractAlong with the development of high-throughout sequencing technologies, both sample size and number of SNPs are increasing rapidly in Genome-Wide Association Studies (GWAS) and the associated computation is more challenging than ever. Here we present a Memory-efficient, Visualization-enhanced, and Parallel-accelerated R package called “rMVP” to address the need for improved GWAS computation. rMVP can: (1) effectively process large GWAS data; (2) rapidly evaluate population structure; (3) efficiently estimate variance components by EMMAX, FaST-LMM, and HE regression algorithms; (4) implement parallel-accelerated association tests of markers using GLM, MLM, and FarmCPU methods; (5) compute fast with a globally efficient design in the GWAS processes; and (6) generate various visualizations of GWAS related information. Accelerated by block matrix multiplication strategy and multiple threads, the association test methods embedded in rMVP are approximately 5-20 times faster than PLINK, GEMMA, and FarmCPU_pkg. rMVP is freely available athttps://github.com/xiaolei-lab/rMVP.
A Multi-pronged Screening Approach Targeting Inhibition of ETV6 PNT Domain Polymerization
Authors: Gerak Chloe A. N. , Zhang Si Miao , Balgi Aruna D. , Sadowski Ivan J. , Sessions Richard B. , McIntosh Lawrence P. , Roberge Michel 
Published: August 2020

AbstractETV6 is an ETS family transcriptional repressor for which head-to-tail polymerization of its PNT domain facilitates cooperative binding to DNA by its ETS domain. Chromosomal translocations frequently fuse the ETV6 PNT domain to one of several protein tyrosine kinases. The resulting chimeric oncoproteins undergo ligand-independent self-association, autophosphorylation, and aberrant stimulation of downstream signaling pathways leading to a variety of cancers. Currently, no small molecules inhibitors of ETV6 PNT domain polymerization are known and no assays targeting PNT domain polymerization have been described. In this study, we developed complementary experimental and computational approaches for identifying such inhibitory compounds. One mammalian cellular approach utilized a mutant PNT domain heterodimer system covalently attached to splitGaussialuciferase fragments. In this protein fragment complementation assay, inhibition of PNT domain heterodimerization reduces luminescence. A yeast assay took advantage of activation of the reporterHIS3gene upon heterodimerization of mutant PNT domains fused to DNA-binding and transactivation domains. In this two-hybrid screen, inhibition of PNT domain heterodimerization prevents cell growth in medium lacking histidine. The Bristol University Docking Engine (BUDE) was used to identify virtual ligands from the ZINC8 library predicted to bind the PNT domain polymerization interfaces. Over 75 hits from these three assays were tested by NMR spectroscopy for binding to the purified ETV6 PNT domain. Although none were found to bind, lessons learned from this study may facilitate future approaches for developing therapeutics that act against ETV6 oncoproteins by disrupting PNT domain polymerization.
Niche-derived soluble DLK1 promotes glioma stemness and growth
Authors: Grassi Elisa S. , Jeannot Pauline , Pantazopoulou Vasiliki , Berg Tracy J. , Pietras Alexander 
Published: August 2020

AbstractTumor cell behaviors associated with aggressive tumor growth such as proliferation, therapeutic resistance, and stemness are regulated in part by soluble factors derived from the tumor microenvironment. Tumor-associated astrocytes represent a major component of the glioma tumor microenvironment, and astrocytes have an active role in maintenance of normal neural stem cells in the stem cell niche, in part via secretion of soluble Delta-like Non-Canonical Notch Ligand 1 (DLK1). We found that astrocytes, when exposed to stresses of the tumor microenvironment such as hypoxia or ionizing radiation (IR), increased secretion of soluble DLK1. Tumor-associated astrocytes in a glioma mouse model expressed DLK1 in perinecrotic (hypoxic) and perivascular tumor areas. Glioma cells exposed to recombinant DLK1 displayed increased proliferation, enhanced sphere and colony formation abilities, and increased levels of stem cell marker genes. Mechanistically, DLK1-mediated effects on glioma cells involved increased and prolonged stabilization of Hypoxia-Inducible Factor 2alpha (HIF-2alpha), and inhibition of HIF-2alpha activity abolished effects of DLK1 in hypoxia. Forced expression of soluble DLK1 resulted in more aggressive tumor growth and shortened survival in a genetically engineered mouse model of glioma. Together, our data support DLK1 as a soluble mediator of glioma aggressiveness derived from the tumor microenvironment.Graphical abstractHighlightsAstrocytes secrete DLK1 after exposure to hypoxia or irradiationSoluble DLK1 promotes stemness in glioma, in part by increasing HIF-2alpha stabilization.High levels of soluble DLK1 are associated with tumor aggressiveness and lethality.
Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli
Authors: Terrén Iñigo , Orrantia Ane , Mosteiro Alba , Vitallé Joana , Zenarruzabeitia Olatz , Borrego Francisco 
Published: August 2020

ABSTRACTNatural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18. These IL-12/15/18-stimulated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have been revealed as a powerful tool in cancer immunotherapy due to their persistence in the host and their increased effector functions. Several studies have shown that NK cells modulate their metabolism in response to cytokine-stimulation and other stimuli, suggesting that there is a link between metabolism and cellular functions. In this paper, we have analyzed metabolic changes associated to IL-12/15/18-stimulation and the relevance of glycolytic pathway for NK cell effector functions. We have found that CIML NK cells are able to retain increased glycolytic machinery seven days after cytokine withdrawal. Furthermore, we found that glycolytic inhibition with 2-DG is stimuli-dependent and that differently affects to distinct effector functions. These findings may have implications in the design of NK cell-based cancer immunotherapies.
Dicer1 promotes Aβ clearance via blocking B2 RNA-mediated repression of apolipoprotein E
Authors: Wang Yan , Lian Meiling , Song Liping , Wu Shengzhou 
Published: August 2020

AbstractMetabolism of β-amyloid is critical for healthy brain. Decreased clearance of β-amyloid is associated with ensued accumulation of amyloid peptide, culminating in formation of senile plaques, a neuropathological hallmark of Alzheimer’s disease(AD). Apolipoprotein E (APOE), a lipoprotein for phospholipid and cholesterol metabolism, is predominantly synthesized by glia in the central nervous system, controlling Aβ aggregation and metabolism. By use of stereotactic injection and a Morris water maze, we found that delivery of Dicer1-expressing adenovirus into the hippocampus of an animal model of AD mice APPswe/PSEN1deltaE9 significantly improved spatial memory. The effect was associated with reduced amyloid peptides in the hippocampus which were analyzed with immunofluorescence and enzyme-linked immunosorbent assay. With western blot, quantitative real-time PCR, fluorescencein situhybridization, and northern blot, Dicer1 overexpression increased apolipoprotein E (APOE) and concomitantly decreased B2 RNA in the hippocampus of the AD mice and in astrocyte cultures whereas transfection of B2 Mm2 RNA decreasedAPOEmRNA and protein levels in astrocyte cultures. Further, human or mouseAPOEmRNA was found containing Alu RNA or its equivalent, B2 Mm2 RNA, locating downstream of its 3’-untranslated region (UTR), respectively. The 3’-UTR or 3’-UTR in conjunction with the downstream Alu/B2 RNA were cloned into a luciferase reporter; with dual-luciferase assay, we found that simultaneous transfection of Dicer1 siRNA or Alu/B2 RNA decreased the corresponding luciferase activities which suggest that Alu RNA mediatedAPOEmRNA degradation. Altogether, Dicer1 expression mediated amyloid peptide clearance by increasing APOE via blocking B2 RNA-mediatedAPOEmRNA degradation.
Characterization of novel pollen-expressed transcripts reveals their potential roles in pollen heat stress response inArabidopsis thaliana
Authors: Rutley Nicholas , Poidevin Laetitia , Doniger Tirza , Tillet Richard , Rath Abhishek , Forment Javier , Luria Gilad , Schlauch Karen , Ferrando Alejandro , Harper Jeffery , Miller Gad 
Published: August 2020

ABSTRACTThe male gametophyte is the most heat-sensitive of all plant tissues. In recent years, long noncoding RNAs (lncRNAs) have emerged as important components of cellular regulatory networks involved in most biological processes, including response to stress. While examining RNAseq datasets of developing and germinatingArabidopsis thalianapollen exposed to heat stress (HS), we identified 66 novel and 246 recently-annotated intergenic expressed loci (XLOCs) of unknown function, with the majority encoding lncRNAs. Comparison to HS in cauline leaves and other RNAseq experiments, indicated 74% of the 312 XLOCs are pollen-specific, and at least 42% are HS-responsive. Phylogenetic analysis revealed 96% of the genes evolved recently inBrassicaceae. We found that 50 genes are putative targets of microRNAs, and that 30% of the XLOCs contain small open reading frames (ORFs) with homology to protein sequences. Finally, RNAseq of ribosome-protected RNA fragments together with predictions of periodic footprint of the ribosome P-sites indicated that 23 of these ORFs are likely to be translated. Our findings indicate that many of the 312 unknown genes might be functional, and play significant role in pollen biology, including the HS response.