bluuebunny/crossref_metadata_2025_split huggingface dataset:
BridgePRS: A powerful trans-ancestry Polygenic Risk Score method
Authors: Hoggart Clive , Choi Shing Wan , García-González Judit , Souaiaia Tade , Preuss Michael , O’Reilly Paul 
Published: February 2023

AbstractPolygenic Risk Scores (PRS) have huge potential to contribute to biomedical research and to a future of precision medicine, but to date their calculation relies largely on Europeanancestry GWAS data. This global bias makes most PRS substantially less accurate in individuals of non-European ancestry. Here we presentBridgePRS, a novel Bayesian PRS method that leverages shared genetic effects across ancestries to increase the accuracy of PRS in non-European populations. The performance ofBridgePRSis evaluated in simulated data and real UK Biobank (UKB) data across 19 traits in African, South Asian and East Asian ancestry individuals, using both UKB and Biobank Japan GWAS summary statistics.BridgePRSis compared to the leading alternative,PRS-CSx, and two single-ancestry PRS methods adapted for trans-ancestry prediction. PRS trained in the UK Biobank are then validated out-of-cohort in the independent Mount Sinai (New York) BioMeBiobank. Simulations reveal thatBridgePRSperformance, relative toPRS-CSx, increases as uncertainty increases: with lower heritability, higher polygenicity, greater between-population genetic diversity, and when causal variants are not present in the data. Our simulation results are consistent with real data analyses in whichBridgePRShas better predictive accuracy in African ancestry samples, especially in out-of-cohort prediction (into BioMe), which shows a 60% boost in meanR2compared toPRS-CSx(P= 2×10−6).BridgePRSperforms the full PRS analysis pipeline, is computationally efficient, and is a powerful method for deriving PRS in diverse and under-represented ancestry populations.
SICKO: Systematic Imaging ofCaenorhabditisKilling Organisms
Authors: Espejo Luis S. , Freitas Samuel , Hofschneider Vanessa , Chang Leah , Antenor Angelo , Balsa Jonah , Haskins Anne , DeNicola Destiny , Dang Hope , Hamming Sage , Kelser Delaney , Sutphin George L. 
Published: February 2023

AbstractCaenorhabditis elegansare an important model system for research on host-microbe interaction. Their rapid life cycle, short lifespan, and transparent body structure allow simple quantification of microbial load and the influence of microbial exposure on host survival.C. eleganshost-microbe interaction studies typically examine group survival and infection severity at fixed timepoints. Here we present an imaging pipeline, Systematic Imaging ofCaenorhabditisKilling Organisms (SICKO), that allows longitudinal characterization of microbes colonizing isolatedC. elegans, enabling dynamic tracking of tissue colonization and host survival in the same animals. Using SICKO, we show thatEscherichia coliorPseudomonas aeruginosagut colonization dramatically shortensC. eleganslifespan and that immunodeficient animals lackingpmk-1are more susceptible to colonization but display similar colony growth relative to wild type. SICKO opens new avenues for detailed research into bacterial pathogenesis, the benefits of probiotics, and the role of the microbiome in host health.
Domestic dogs maintain positive clinical, nutritional, and hematological health outcomes when fed a commercial plant-based diet for a year
Authors: Linde Annika , Lahiff Maureen , Krantz Adam , Sharp Nathan , Ng Theros T. , Melgarejo Tonatiuh 
Published: February 2023

ABSTRACTObjectiveDomestic dogs can maintain health on complete and well-balanced canine plant-based nutrition (K9PBN). Novel insight on health outcomes in dogs consuming K9PBN is of relevance to veterinary professionals and consumers given a growing interest in non-traditional dog foods with perceived health benefits, while considering potential safety concerns. We aimed to investigate nutritional equivalence by measuring clinical health outcomes in adult dogs fed K9PBN over twelve months compared to a meat-based diet at baseline.AnimalsFifteen clinically healthy adult dogs living in households in Los Angeles County, California.ProceduresProspective cohort study evaluating clinical, hematological, and nutritional parameters in dogs at 0, 6, and 12 months, including complete blood count (CBC), blood chemistry, cardiac biomarkers, plasma amino acids, and serum vitamin concentrations.ResultsClinically healthy, client-owned, adult dogs maintain health, based on physical exams, CBC, serum chemistry, plasma amino acids, serum vitamins, and cardiac biomarkers combined with client-reported observations, when fed commercial K9PBN over a twelve-month period.Clinical RelevanceThis study is the most comprehensive and longest known K9PBN investigation to date. It provides clinically important evidence-based nutrition data and new knowledge on outcomes in clinically healthy dogs who maintain health without consumption of animal-derived ingredients. Also, it is of major relevance to One Health paradigms since ingredients produced independent of industrial food animal production are both more sustainable and help to circumvent ethical dilemmas for maintenance of health in domestic dogs.
Molecular control of endurance training adaptation in mouse skeletal muscle
Authors: Furrer Regula , Heim Barbara , Schmid Svenia , Nordström Karl J.V. , Dilbaz Sedat , Ritz Danilo , Adak Volkan , Steurer Stefan A. , Walter Jörn , Handschin Christoph 
Published: February 2023

SUMMARYSkeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. While morphological changes in endurance-trained muscles are well-described, the molecular underpinnings of training adaptation are poorly understood. We aimed at defining the molecular signature of a trained muscle and unraveling the training statusdependent responses to an acute bout of exercise. Our results reveal that even though at baseline, the transcriptomes of trained and untrained muscles are very similar, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part mediated by epigenetic modifications. Second, proteomic changes were elicited by different transcriptional modalities. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that defines muscle plasticity in training.HIGHLIGHTSVery few persistent transcriptional events define the trained muscle.The training status determines the acute exercise response.Epigenetic changes shape the transcriptional specification of trained muscle.Absence of the key regulator PGC-1α causes suboptimal training adaptations.
rphenoscate: An R package for semantic-aware evolutionary analyses of anatomical traits
Authors: Porto Diego S. , Tarasov Sergei , Charpentier Caleb , Lapp Hilmar , Balhoff James P. , Vision Todd J. , Dahdul Wasila M. , Mabee Paula M. , Uyeda Josef 
Published: February 2023

AbstractOrganismal anatomy is a complex hierarchical system of interconnected anatomical entities often producing dependencies among multiple morphological characters. Ontologies provide a formalized and computable framework for representing and incorporating prior biological knowledge about anatomical dependencies in models of trait evolution. Further, ontologies offer new opportunities for assembling and working with semantic representations of morphological data.In this work we present a new R package—rphenoscate—that enables incorporating ontological knowledge in evolutionary analyses and exploring semantic patterns of morphological data. In conjunction withrphenoscapeit also allows for assembling synthetic phylogenetic character matrices from semantic phenotypes of morphological data. We showcase the new package functionalities with three data sets from bees and fishes.We demonstrate that ontology knowledge can be employed to automatically set up ontologyinformed evolutionary models that account for trait dependencies in the context of stochastic character mapping. We also demonstrate how ontology annotations can be explored to interrogate patterns of morphological evolution. Finally, we demonstrate that synthetic character matrices assembled from semantic phenotypes retain most of the phylogenetic information of the original data set.Ontologies will become an increasingly important tool not only for enabling prior anatomical knowledge to be integrated into phylogenetic methods but also to make morphological data FAIR compliant—a critical component of the ongoing ‘phenomics’ revolution. Our new package offers key advancements toward this goal.
Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions
Authors: Schöpf Julia , Uhrig Sebastian , Heilig Christoph E. , Lee Kwang-Seok , Walther Tatjana , Carazzato Alexander , Dobberkau Anna Maria , Weichenhan Dieter , Plass Christoph , Hartmann Mark , Diwan Gaurav D. , Carrero Zunamys , Ball Claudia R. , Hohl Tobias , Kindler Thomas , Rudolph-Hähnel Patricia , Nilsson Anna , Øra Ingrid , Imle Roland , Banito Ana , Russell Robert B. , Jones Barbara C. , Lipka Daniel B. , Glimm Hanno , Hübschmann Daniel , Hartmann Wolfgang , Fröhling Stefan , Scholl Claudia 
Published: February 2023

ABSTRACTLinking clinical multi-omics analyses with mechanistic studies provides opportunities to explore the pathogenesis of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective systemic therapies. All tumors exhibited outlier expression of the ALK receptor tyrosine kinase, which was partly accompanied by intragenic deletions and aberrant splicing, resulting in truncated ALK variants that were oncogenic and sensitive to ALK inhibitors. Additional recurrent alterations included CKDN2A/MTAP co-deletions, providing a rationale for therapies targeting CDK4/6 and PRMT5. Functional studies showed that FUS-TFCP2 blocks myogenic differentiation and induces transcription of ALK and a truncated form of TERT through binding outside their regular promoters. Furthermore, FUS-TFCP2 inhibited DNA double-strand break repair. Consistent with this, and unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibited marked genomic instability and signs of defective homologous recombination. DNA methylation profiling indicated a close relationship with undifferentiated sarcomas rather than rhabdomyosarcoma. Finally, we identified patients in whom overt disease was preceded by benign lesions carrying TFCP2 fusions, providing insight into stepwise sarcomagenesis and suggesting new approaches to early detection and interception.SIGNIFICANCEMost rare cancers are poorly understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. This study illustrates the potential of linking precision oncology programs with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers that could improve the clinical management of such diseases.
Scorpionfish BPI is highly active against multiple drug-resistantPseudomonas aeruginosaisolates from cystic fibrosis patients
Authors: Holzinger Jonas M. , Toelge Martina , Werner Maren , Ederer Katharina U. , Siegmund Heiko , Peterhoff David , Blaas Stefan , Gisch Nicolas , Brochhausen-Delius Christoph , Gessner André , Bülow Sigrid 
Published: February 2023

SummaryChronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context,Pseudomonas aeruginosa(Pa) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of CF patients produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA) thereby neutralizing its bactericidal function. In accordance with literature, we describe that 54.3% of a total of 46 CF patients expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfishSebastes schlegelii(scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towardsPaLPS, and was bactericidal against MDRPaderived from CF patients at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDRPainfections, especially in the presence of BPI-ANCA.
Determination of oligomeric organization of membrane proteins from native membranes at nanoscale-spatial and single-molecule resolution
Authors: Walker Gerard , Brown Caroline , Ge Xiangyu , Kumar Shailesh , Muzumdar Mandar D. , Gupta Kallol , Bhattacharyya Moitrayee 
Published: February 2023

AbstractThe oligomeric organization of membrane proteins in native cell membranes is a critical regulator of their function. High-resolution quantitative measurements of oligomeric assemblies and how they change under different conditions are indispensable to the understanding of membrane protein biology. We report a single-molecule imaging technique (Native-nanoBleach) to determine the oligomeric distribution of membrane proteins directly from native membranes at an effective spatial resolution of ∼10 nm. We achieved this by capturing target membrane proteins in “native nanodiscs” with their proximal native membrane environment using amphipathic copolymers. We established this method using structurally and functionally diverse membrane proteins with well-established stoichiometries. We then applied Native-nanoBleach to quantify the oligomerization status of a receptor tyrosine kinase (TrkA) and a small GTPase (KRas) under conditions of growth-factor binding or oncogenic mutations, respectively. Native-nanoBleach provides a sensitive, single-molecule platform to quantify membrane protein oligomeric distributions in native membranes at an unprecedented spatial resolution.
Atomistic molecular insight on Angiotensin-(1-7) interpeptide interactions
Authors: Chi L. América , Asgharpour Somayeh , Blanco-Rodríguez Rodolfo , Martínez-Archundia Marlet 
Published: February 2023

AbstractAngiotensin-(1-7) is an endogenous peptide with vaso-protective, anti-oxidant, and anti-inflammatory effects which has been proposed as a potential therapeutic agent in a wide range of clinical conditions. Angiotensin-(1-7) presents a pH-dependent physical instability in aqueous solutions; however, it still lacks a proper atomistic study that provides insights into this behavior and its potential implications. Hence, we studied the formation of early Angiotensin-(1-7) oligomeric aggregates in an aqueous environment under acidic and neutral conditions; physiological and high ionic strength; and high and low peptide concentrations using all-atom Molecular Dynamics simulations. Our main findings are: 1) at acidic pH, there is a poor level of Angiotensin-(1-7) clustering, while, 2) at neutral pH, peptides aggregate in a unique cluster, in good trend with experimental physical instability reports and 3) an increase in salt concentration at acidic pH gives place to aggregation similar to the case at neutral pH. Our results open the route for the modulation of Angiotensin-(1-7) aggregation through a combination of salt concentration and pH conditions. Our protocol (MD + cluster analysis + amino acids interaction map analysis) is general and could be applied to other peptides to study the inter-peptide interaction mechanisms.
Anticipating change: the impact of simulated seasonal heterogeneity on heat tolerances along a latitudinal cline
Authors: Lush Jared , Sgrò Carla M. , Hall Matthew D. 
Published: February 2023

AbstractAn understanding of thermal limits and variation across geographic regions is central to predicting how any population may respond to scenarios of global change. Latitudinal clines, in particular, have been used in demonstrating that populations can be locally adapted to their own thermal environment and, as a result, not all populations will be equally impacted by an increase in temperature. But how robust are these signals of thermal adaptation to the other ecological challenges that animals commonly face in the wild? Seasonal changes in population density, food availability, or photoperiod are common ecological challenges that could disrupt patterns of thermal tolerance along a cline if each population differentially used these signals to anticipate future temperatures and adjust their thermal tolerances accordingly. In this study, we aimed to test the robustness of a cline in thermal tolerance to simulated signals of seasonal heterogeneity. Experimental animals were derived from clones of the Australian water flea,Daphnia carinata, sampled from nine populations along a latitudinal transect in eastern Australia. We then factorially combined summer (18h light, 6h dark) and winter (6h light, 18h dark) photoperiods with high (5 million algal cells individual-1day-1) and low (1 million algal cells individual-1day-1) food availabilities, before performing static heat shock assays and recording knockdown times as a measure of thermal tolerance. In general, higher food availably led to an increase in thermal tolerances, with the magnitude of increase varying by clone. In contrast, summer photoperiods led to rank order changes in thermal tolerances, with heat resistance increasing for some clones, and other decreasing for others. Heat resistance, however, still declined along the latitudinal cline, irrespective of the manipulation of seasonal signals, with northern clones always showing greater thermal resistance, and that this was most likely driven by adaptation to winter thermal conditions. While photoperiod and food availability can clearly shape thermal tolerances for specific clones or populations, they are unlikely to be used to anticipate future temperatures, and thus observed clines in heat resistance will remained robust to these forms of seasonal heterogeneity.
Intraperitoneal transfer of wild-type bone marrow cells in theCsf1rknockout rat repopulates resident tissue macrophages without contributing to monocytopoiesis
Authors: Sehgal Anuj , Carter-Cusack Dylan , Keshvari Sahar , Patkar Omkar , Huang Stephen , Summers Kim M. , Hume David A. , Irvine Katharine M. 
Published: February 2023

AbstractHomozygous null mutation of the macrophage colony-stimulating factor receptor (Csf1r) gene in rats leads to the loss of most tissue macrophage populations and has pleiotropic impacts on postnatal growth and organ maturation leading to mortality by 8-12 weeks of age. The phenotype of theCsf1rknockout (Csf1rko) can be reversed by intraperitoneal transfer of wild-type bone marrow cells (BMT) at weaning. Here we used aCsf1r-mApple transgenic reporter, which is expressed in neutrophils and B cells as well as monocytes and macrophages, to track the fate of donor-derived cells. Following BMT intoCsf1rrecipients, wild-type mApple+vecells restored IBA1+tissue macrophage populations in every tissue donor-derived cells also completely replaced recipient macrophages in organs such as spleen, lung and liver that were only partly macrophage-deficient in theCsf1rko. However, monocytes, neutrophils and B cells in bone marrow, blood and lymphoid tissues remained of recipient (mApple-ve) origin. An mApple+vecell population expanded in the peritoneal cavity and invaded locally in the mesentery, fat pads, omentum and diaphragm. One week after BMT, distal organs contained foci of mApple+ve, IBA1-veimmature progenitors that appeared to proliferate, migrate and differentiate locally. We conclude that rat bone marrow contains progenitor cells that are able to restore and maintain all tissue macrophage populations in aCsf1rkorat directly without contributing to the bone marrow progenitor or blood monocyte populations.
Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer
Authors: Garioni Michele , Blukacz Lauriane , Nuciforo Sandro , Parmentier Romuald , Roma Luca , Coto-Llerena Mairene , Pueschel Heike , Piscuoglio Salvatore , Vlajnic Tatjana , Stenner Frank , Seifert Hans-Helge , Rentsch Cyrill A. , Bubendorf Lukas , Magnen Clémentine Le 
Published: February 2023

AbstractSarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of the first long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological and phenotypical features of SARC and harbor somatic mutations in genes frequently altered in sarcomatoid tumors such asTP53, RB1, andKRAS. High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and organoids derived from a patient with conventional urothelial carcinoma (UroCa), identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, such as agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts, GR was found to be significantly more expressed, at mRNA and protein level, in SARC as compared to UroCa tumor samples. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.
Enterovirus Evolution Reveals the Mechanism of an RNA-Targeted Antiviral and Determinants of Viral Replication
Authors: Davila-Calderon Jesse , Li Mei-Ling , Penumutchu Srinivasa R. , Haddad Christina , Malcolm Linzy , Hargrove Amanda E. , Brewer Gary , Tolbert Blanton S. 
Published: February 2023

AbstractSelective pressures on positive-strand RNA viruses provide opportunities to establish target site specificity and mechanisms of action of antivirals. Here, Enterovirus-A71 revertant viruses with resistant mutations in the SLII IRES domain (SLIIresist) were selected at low doses of the antiviral DMA-135. The EV-A71 revertant viruses were resistant to DMA-135 at concentrations that robustly inhibit replication of wild-type virus. EV-A71 IRES structures harboring the suppressor mutations induced efficient expression of reporter Luciferase mRNA in the presence of non-cytotoxic doses of DMA-135 whereas DMA-135 dose-dependently inhibited Luciferase expression from the wild-type IRES element. NMR studies indicate that the resistant mutations change the structure of SLII at the bulge loop binding site of DMA-135 and at part of an extended surface recognized by host RNA-binding protein AUF1. Comparisons of biophysical analysis of complexes formed between AUF1, DMA-135, or either SLII or SLIIresistshow that DMA-135 stabilizes a ternary complex with AUF1-SLII but not AUF1-SLIIresist. Further studies demonstrate that the hnRNP A1 protein retains binding affinity for SLIIresist, illustrating that DMA-135 inhibition and viral resistance do not perturb the SLII-hnRNP A1 arm of the regulatory axis. Taken together, this work demonstrates how viral evolution under selective pressures of small molecules can elucidate RNA binding site specificity, mechanisms of action, and provide additional insights into the viral pathways inhibited by the antiviral DMA-135.