bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic history and forensic characteristics of Sherpa highlanders on the Tibetan Plateau inferred from high-resolution genome-wide InDels and SNPs
Authors: Wang Mengge , Du Weian , Tang Renkuan , Liu Yan , Zou Xing , Yuan Didi , Wang Zheng , Liu Jing , Guo Jianxin , Yang Xiaomin , Chen Jing , Yang Meiqing , Zhang Xianpeng , Wei Lan-Hai , Yuan Haibing , Yeh Hui-Yuan , Wang Chuan-Chao , Liu Chao , He Guanglin 
Published: June 2021

AbstractSherpa people, one of the high-altitude hypoxic adaptive populations, mainly reside in Nepal and the southern Tibet Autonomous Region. The genetic origin and detailed evolutionary profiles of Sherpas remain to be further explored and comprehensively characterized. Here we analyzed the newly-generated InDel genotype data from 628 Dingjie Sherpa people by merging with 4222 worldwide InDel profiles and collected genome-wide SNP data (approximately 600K SNPs) from 3324 individuals in 382 modern and ancient populations to explore and reconstruct the fine-scale genetic structure of Sherpas and their relationships with nearby modern and ancient East Asians based on the shared alleles and haplotypes. The forensic parameters of 57 autosomal InDels (A-InDels) included in our used new-generation InDel amplification system showed that this updated InDel panel is informative and polymorphic in Sherpas, suggesting that it can be used as the supplementary tool for forensic personal identification and parentage testing in the highland East Asians. Descriptive findings from the PCA, ADMIXTURE and TreeMix-based phylogeny suggested that Sherpas showed excess allele sharing with neighboring Tibeto-Burman Tibetans. Furthermore, patterns of allele sharing in f-statistics demonstrated that Sherpa people had a different evolutionary history compared with their neighbors from Nepal (Newar and Gurung) but showed genetic similarity with 2700-year-old Chokhopani and modern Tibet Tibetans. QpAdm/qpGraph-based admixture sources and models further showed that Sherpa, core Tibetans and Chokhopani formed one clade which could be fitted as having the main ancestry from late Neolithic Qijia millet farmers and other deep ancestries from early Asians. Chromosome painting profiles and shared IBD fragments inferred from FineStructure and ChromoPainter not only confirmed the abovementioned genomic affinity patterns but also revealed the fine-scale microstructures among Sino-Tibetan speakers. Finally, natural-selection signals revealed via iHS, nSL, and iHH12 showed signatures associated with disease susceptibility in Sherpa people. Generally, we provided the comprehensive landscape of admixture and evolutionary history of Sherpa people based on the shared alleles and haplotypes from the low-density forensic markers and high-density genome-wide SNP data. The more detailed genetic landscape of Sherpa people should be further confirmed and characterized via ancient genomes or single-molecule real-time sequencing technology.
Sex-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning in healthy individuals
Authors: Koch Elise , Nyberg Lars , Lundquist Anders , Pudas Sara , Adolfsson Rolf , Kauppi Karolina 
Published: June 2021

AbstractPolygenic risk for schizophrenia has been associated with lower cognitive ability and age-related cognitive change in healthy individuals. Despite well-established neuropsychological sex differences in schizophrenia patients, genetic studies on sex differences in schizophrenia in relation to cognitive phenotypes are scarce. Here, we investigated whether the effect of a polygenic risk score (PRS) for schizophrenia on childhood, midlife and late life cognitive function in healthy individuals is modified by sex, and if PRS is linked to accelerated cognitive decline. Using a longitudinal data set from healthy individuals aged 25-100 years (N = 1,459) spanning a 25-year period, we found that PRS was associated with lower cognitive ability (episodic memory, semantic memory, visuospatial ability), but not with accelerated cognitive decline. A significant interaction effect between sex and PRS was seen on cognitive task performance, and sex-stratified analyses showed that the effect of PRS was male-specific. In a sub-sample, we observed a male-specific effect of the PRS on school performance at age 12 (N = 496). Our findings of sex-specific effects of schizophrenia genetics on cognitive functioning across the life-span indicate that the effects of underlying disease genetics on cognitive functioning is dependent on biological processes that differ between the sexes.
Local temporal Rac1-GTP nadirs and peaks restrict cell protrusions and retractions
Authors: Hu Jianjiang , Gong Xiaowei , Strömblad Staffan 
Published: June 2021

AbstractSpatiotemporal coordination of the GTP-binding activity of Rac1 and RhoA initiates and reinforces cell membrane protrusions and retractions during cell migration1–7. However, while protrusions and retractions form cycles that cells use to efficiently probe their microenvironment8–10, the control of their finite lifetime remains unclear. To examine if Rac1 or RhoA may also control protrusion and retraction lifetimes, we here define the relation of their spatiotemporal GTP-binding levels to key protrusion and retraction events, as well as to cell-ECM mechanical forces in fibrosarcoma cells grown on collagen of physiologically relevant stiffness. We identified temporal Rac1-GTP nadirs and peaks at the maximal edge velocity of local membrane protrusions and retractions, respectively, followed by declined edge velocity. Moreover, increased local Rac1-GTP consistently preceded increased cell-ECM traction force. This suggests that Rac1-GTP nadirs and peaks may restrain the lifetime of protrusions and retractions, possibly involving the regulation of local traction forces. Functional testing by optogenetics validated this notion, since local Rac1-GTP elevation applied early in the process prolonged protrusions and restrained retractions, while local Rac1-GTP inhibition acted in reverse. Optogenetics also defined Rac1-GTP as a promotor of local traction force. Together, we show that Rac1 plays a fundamental role in restricting the size and durability of protrusions and retractions, plausibly in part through controlling traction forces.
LSD induces increased signalling entropy in rats’ prefrontal cortex
Authors: Savino Aurora , Nichols Charles D. 
Published: June 2021

AbstractPsychedelic drugs are gaining attention from the scientific community as potential new compounds for the treatment of psychiatric diseases such as mood and substance use disorders. The 5-HT2A receptor has been identified as the main molecular target, and early studies pointed to an effect on the expression of neuroplasticity genes. Analysing RNA-seq data from the prefrontal cortex of rats chronically treated with lysergic acid diethylamide (LSD), we describe the psychedelic-induced rewiring of gene co-expression networks, which become less centralized but more complex, with an overall increase in signalling entropy, typical of highly plastic systems. Intriguingly, signalling entropy mirrors, at the molecular level, the increased brain entropy reported through neuroimaging studies in human, suggesting the underlying mechanisms of higher-order phenomena. Moreover, from the analysis of network topology we identify potential transcriptional regulators and imply different cell types in psychedelics’ activity.
Panel Informativity Optimizer (PIO): an R package to improve cancer NGS panel informativity
Authors: Alcazer Vincent , Sujobert Pierre 
Published: June 2021

ABSTRACTMutation detection by next generation sequencing (NGS) is routinely used for cancer diagnosis. Selecting an optimal set of genes for a given cancer is not trivial as it has to optimize informativity (i.e. the number of patients with at least one mutation in the panel), while minimizing panel length in order to reduce sequencing costs and increase sensitivity. We propose herein Panel Informativity Optimizer (PIO), an open-source software developed as an R package with a user-friendly graphical interface to help optimize cancer NGS panel informativity. Using patient-level mutational data from either private datasets or preloaded dataset of 91 independent cohort from 31 different cancer type, PIO selects an optimal set of genomic intervals to maximize informativity and panel size in a given cancer type. Different options are offered such as the definition of genomic intervals at the gene or exon level, and the use of optimization strategy at the patient or patient per kilobase level. PIO can also propose an optimal set of genomic intervals to increase informativity of custom panels. A panel tester function is also available for panel benchmarking. Using public databases, as well as data from real-life settings, we demonstrate that PIO allows panel size reduction of up to 1000kb, and accurately predicts the performance of custom or commercial panels. PIO is available online at https://vincentalcazer.shinyapps.io/Panel_informativity_optimizer/ or can be set on a locale machine from https://github.com/VincentAlcazer/PIO.
Entamoeba histolytica adaption to auranofin: a phenotypic and multi-omics characterization
Authors: Shaulov Yana , Sarid Lotem , Trebicz-Geffen Meirav , Ankri Serge 
Published: June 2021

AbstractAuranofin (AF), an antirheumatic agent, targets mammalian thioredoxin reductase (TrxR), an important enzyme controlling redox homeostasisis, AF is also very effective against a diversity of pathogenic bacteria and protozoan parasites. Here, we report about the resistance of the parasite Entamoeba histolytica to 2 μM of AF that has been acquired by gradual exposure of the parasite to increasing amount of the drug. AF adapted E.histolytica trophozoites (AFAT) has an impaired growth, cytopathic activity and they are more sensitive to oxidative stress (OS), nitrosative stress (NS) and metronidazole (MTZ) than wild type (WT) trophozoites. Integrated transcriptomics and redoxomics analyses showed that many upregulated genes in AFAT, including genes encoding for dehydrogenase and cytoskeletal proteins, have their product oxidized in wild type trophozoites exposed to AF (acute AF trophozoites) but not in AFAT. We also showed that the level of reactive oxygen species (ROS) and oxidized proteins (OXs) in AFAT is lower than that of acute AF trophozoites. Overexpression of E.histolytica TrxR (EhTrxR) did not protect the parasite against AF which suggests that EhTrxR is not central is the mechanism of adaptation to AF.
A live-cell marker to visualize the dynamics of stable microtubules
Authors: Jansen Klara I. , Burute Mithila , Kapitein Lukas C. 
Published: June 2021

AbstractThe microtubule (MT) cytoskeleton underlies processes such as intracellular transport and cell division. Immunolabeling for post-translational modifications of tubulin has revealed the presence of different MT subsets, which are believed to differ in stability and function. Whereas dynamic MTs can readily be studied using live-cell plus-end markers, the dynamics of stable MTs have remained obscure due to a lack of tools to directly visualize these MTs in living cells. Here, we present a live-cell marker to visualize stable MTs and explore their dynamics. We demonstrate that a rigor mutant of kinesin-1 binds selectively to acetylated MTs without affecting MT organization and organelle transport. These MTs are long-lived, do not depolymerize upon nocadozale-treatment or laser-based severing, and display rich dynamics, including undulation, looping and sliding. This marker will help to explore how different MT subsets contribute to cellular organization and transport.
SARS-CoV-2 neutralising antibodies in Dogs and Cats in the United Kingdom
Authors: Smith Shirley L. , Anderson Enyia. R. , Cansado-Utrilla Cintia , Prince Tessa , Farrell Sean , Brant Bethaney , Smyth Stephen , Noble Peter-John M. , Pinchbeck Gina L. , Marshall Nikki , Roberts Larry , Hughes Grant L. , Radford Alan D. , Patterson Edward I. 
Published: June 2021

AbstractCompanion animals are susceptible to SARS-CoV-2 infection and sporadic cases of pet infections have occurred in the United Kingdom. Here we present the first large-scale serological survey of SARS-CoV-2 neutralising antibodies in dogs and cats in the UK. Results are reported for 688 sera (454 canine, 234 feline) collected by a large veterinary diagnostic laboratory for routine haematology during three time periods; pre-COVID-19 (January 2020), during the first wave of UK human infections (April-May 2020) and during the second wave of UK human infections (September 2020-February 2021). Both pre-COVID-19 sera and those from the first wave tested negative. However, in sera collected during the second wave, 1.4% (n=4) of dogs and 2.2% (n=2) cats tested positive for neutralising antibodies. The low numbers of animals testing positive suggests pet animals are unlikely to be a major reservoir for human infection in the UK. However, continued surveillance of in-contact susceptible animals should be performed as part of ongoing population health surveillance initiatives.
How Communication Pathways Bridge Local and Global Conformations in an IgG4 Antibody: a Molecular Dynamics Study
Authors: Tarenzi Thomas , Rigoli Marta , Potestio Raffaello 
Published: June 2021

AbstractThe affinity of an antibody for its antigen is primarily determined by the specific sequence and structural arrangement of the complementarity-determining regions (CDRs). Recently, however, evidence has accumulated that points toward a nontrivial relation between the CDR and distal sites on the antibody structure: variations in the binding strengths have been observed upon mutating amino acids separated from the paratope by several nanometers, thus suggesting the existence of a communication network within antibodies whose extension and relevance might be deeper than insofar expected. In this work, we test this hypothesis by means of molecular dynamics (MD) simulations of the IgG4 monoclonal antibody pembrolizumab, an approved drug that targets the programmed cell death protein 1 (PD-1). The molecule is simulated in both the apo and holo states, totalling 4μsof MD trajectory. The analysis of these simulations shows that the bound antibody explores a restricted range of conformations with respect to the apo one, and that the global conformation of the molecule correlates with that of the CDR; a pivotal role in this relationship is played by the relatively short hinge, which mechanically couples Fab and Fc domains. These results support the hypothesis that pembrolizumab behaves as a complex machinery, with a multi-scale hierarchy of global and local conformational changes that communicate with one another. The analysis pipeline developed in this work is general, and it can help shed further light on the mechanistic aspects of antibody function.SynopsisAntigen binding restricts the conformational variability of the therapeutic antibody pembrolizumab in an interplay between the paratope and hinge region, mediated by a full-scale interaction network.Graphical TOC Entry
A rare natural lipid induces neuroglobin expression to prevent amyloid oligomers toxicity and retinal neurodegeneration
Authors: Oamen Henry Patrick , Romero Nathaly Romero , Knuckles Philip , Saarikangas Juha , Dong Yuhong , Caudron Fabrice 
Published: June 2021

AbstractMost neurodegenerative diseases such as Alzheimer’s disease are proteinopathies linked to the toxicity of amyloid oligomers. Treatments to delay or cure these diseases are lacking. Using budding yeast, we report that the natural lipid tripentadecanoin induces expression of the nitric oxide oxidoreductase Yhb1 to prevent the formation of protein aggregates during aging and extends replicative lifespan. In mammals, tripentadecanoin induces expression of the Yhb1 orthologue, neuroglobin, to protect neurons against amyloid toxicity. Tripentadecanoin also rescues photoreceptors in a mouse model of retinal degeneration and retinal ganglion cells in a Rhesus monkey model of optic atrophy. Together, we propose that tripentadecanoin affects p-bodies to induce neuroglobin expression and offers a potential treatment for proteinopathies and retinal neurodegeneration.One Sentence SummaryThe natural lipid tripentadecanoin is cytoprotective against amyloid oligomer toxicity and retinal neurodegeneration by inducing YHBI/neuroglobin expression in yeast and mammals.
Designing BH3-mimetic Peptide Inhibitors for the Viral Bcl-2 Homologs A179L and BHRF1: Importance of long-range electrostatic interactions
Authors: Reddy C. Narendra , Sankararamakrishnan Ramasubbu 
Published: June 2021

AbstractViruses have evolved strategies to prevent apoptosis of infected cells at early stages of infection. The viral proteins (vBcl-2s) from specific viral genes adopt a helical fold that is structurally similar to that of mammalian anti-apoptotic Bcl-2 proteins and exhibit little sequence similarity. Hence vBcl-2 homologs are attractive targets to prevent viral infection. However, very few studies have focused on developing inhibitors for vBcl-2 homologs. In this study, we have considered two vBcl-2 homologs, A179L from African swine fever virus and BHRF1 from Epstein-Barr virus. We generated two sets of 8000 randomized BH3-like sequences from eight wild-type pro-apoptotic BH3 peptides. During this process, the four conserved hydrophobic residues and an Asp residue were retained at their respective positions and all other positions were substituted randomly without any bias. We constructed 8000 structures each for A179L and BHRF1 in complex with BH3-like sequences. Histograms of interaction energies calculated between the peptide and the protein resulted in negatively skewed distributions. The BH3-like peptides with high helical propensities selected from the negative tail of respective interaction energy distributions exhibited more favorable interactions with A179L and BHRF1 and they are rich in basic residues. Molecular dynamics studies and electrostatic potential maps further revealed that both acidic and basic residues favorably interact with A179L while only basic residues have the most favorable interactions with BHRF1. As in mammalian homologs, the role of long range interactions and non-hotspot residues have to be taken into account while designing specific BH3-mimetic inhibitors for vBcl-2 homologs.
A Bayesian Multivariate Mixture Model for Spatial Transcriptomics Data
Authors: Allen Carter , Chang Yuzhou , Neelon Brian , Chang Won , Kim Hang J. , Li Zihai , Ma Qin , Chung Dongjun 
Published: June 2021

AbstractHigh throughput spatial transcriptomics (HST) is a rapidly emerging class of experimental technologies that allow for profiling gene expression in tissue samples at or near single-cell resolution while retaining the spatial location of each sequencing unit within the tissue sample. Through analyzing HST data, we seek to identify sub-populations within a tissue sample that reflect distinct cell types or states. Existing methods either ignore the spatial heterogeneity in gene expression profiles, fail to account for important statistical features such as skewness, or are heuristic network-based clustering methods that lack the inferential benefits of statistical modeling. To address this gap, we develop SPRUCE: a Bayesian spatial multivariate finite mixture model based on multivariate skew-normal distributions, which is capable of identifying distinct cellular sub-populations in HST data. We further implement a novel combination of Pólya–Gamma data augmentation and spatial random effects to infer spatially correlated mixture component membership probabilities without relying on approximate inference techniques. Via a simulation study, we demonstrate the detrimental inferential effects of ignoring skewness or spatial correlation in HST data. Using publicly available human brain HST data, SPRUCE outperforms existing methods in recovering expertly annotated brain layers. Finally, our application of SPRUCE to human breast cancer HST data indicates that SPRUCE can distinguish distinct cell populations within the tumor microenvironment.
Mice are not automatons; subjective experience in premotor circuits guides behavior
Authors: Schreiner Drew C. , Cazares Christian , Renteria Rafael , Gremel Christina M. 
Published: June 2021

SummarySubjective experience is a powerful driver of decision-making and continuously accrues. However, most neurobiological studies constrain analyses to task-related variables and ignore how continuously and individually experienced internal, temporal, and contextual factors influence adaptive behavior during decision-making and the associated neural mechanisms. We show mice rely on learned information about recent and longer-term subjective experience of variables above and beyond prior actions and reward, including checking behavior and the passage of time, to guide self-initiated, self-paced, and self-generated actions. These experiential variables were represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrated this information to bias strategy-level decision-making, and DMS projections used specific aspects of this recent experience to plan upcoming actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.
Automated classification of bat echolocation call recordings with artificial intelligence
Authors: Tabak Michael A. , Murray Kevin L. , Lombardi John A. , Bay Kimberly J. 
Published: June 2021

AbstractAcoustic recorders are commonly used to remotely monitor and collect data on bats (Order Chiroptera). These efforts result in many acoustic recordings that must be classified by a bat biologist with expertise in call classification in order to obtain useful information. The rarity of this expertise and time constraints have prompted efforts to automatically classify bat species in acoustic recordings using a variety of learning methods. There are several software programs available for this purpose, but they are imperfect and the United States Fish and Wildlife Service often recommends that a qualified acoustic analyst review bat call identifications even if using these software programs. We sought to build a model to classify bat species using modern computer vision techniques. We used images of bat echolocation calls (i.e., plots of the pulses) to train deep learning computer vision models that automatically classify bat calls to species. Our model classifies 10 species, five of which are protected under the Endangered Species Act. We evaluated our models using standard model validation procedures, but we also performed two out-of-distribution tests. For the out-of-distribution tests, an entire dataset was withheld from the procedure before splitting the data into training and validation sets. We found that our validation accuracy (93%) and out-of-distribution accuracy (90%) were higher than when we used Kaleidoscope Pro and BCID software (65% and 61% accuracy, respectively) to evaluate the same calls. Our results suggest that our approach is effective at classifying bat species from acoustic recordings, and our trained model will be incorporated into new bat call identification software: WEST-EchoVision.