bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grand Biological Universe: Genome space geometry unravels looking for a single metric is likely to be futile in evolution
Authors: Sun Nan , Yu Hongyu , Ren Ruohan , Zhou Tao , Guan Mengcen , Zhao Leqi , Yau Stephen S.-T. 
Published: July 2023

AbstractUnderstanding the differences between genomic sequences of different lives is crucial for biological classification and phylogeny. Here, we downloaded all the reliable sequences of the seven kingdoms and determined the dimensions of the genome space embedded in the Euclidean space, along with the corresponding Natural Metrics. The concept of the Grand Biological Universe is further proposed. In the grand universe, the convex hulls formed by the universes of seven kingdoms are mutually disjoint, and the convex hulls formed by different biological groups within each kingdom are mutually disjoint. This study provides a novel geometric perspective for studying molecular biology and also offers an accurate way for large-scale sequence comparison in a real-time manner. Most importantly, this study shows that, due to the space-time distortion in the biological genome space similar to Einstein’s theory, it is futile to look for a single metric to measure different biological universes, as previous studies have done.
ZEB1 shapes AML immunological niches suppressing CD8 T-cell activity while fostering Th17 cell expansion
Authors: Bassani Barbara , Simonetti Giorgia , Cancila Valeria , Ciciarello Marilena , Piva Annamaria , Chiodoni Claudia , Lecis Daniele , Gulino Alessandro , Fonzi Eugenio , Botti Laura , Portararo Paola , Costanza Massimo , Schwaller Juerg , Tzankov Alexandar , Ponzoni Maurilio , Ciceri Fabio , Bolli Niccolò , Curti Antonio , Tripodo Claudio , Colombo Mario P. , Sangaletti Sabina 
Published: July 2023

ABSTRACTAcute myeloid leukemia (AML) development and progression is favored by immune suppression directly triggered by leukemia cells. ZEB1 is a key transcription factor in epithelial-to-mesenchymal transition which, we show here, is capable immune regulation in AML. Leukemic cells which had ZEB1 knocked down have reduced engraftment and extramedullary disease when transplanted into immune competent mice due to concomitant activation of CD8 T lymphocytes and reduced expansion of Th17 cells. Differently, in ZEB1 competent AML, IL-17 sustains the development of a pro-invasive and self-maintaining loop inducingMMPsandSOCS2.In humans, AML patients show,in situon bone marrow biopsies, a direct correlation between ZEB1 and Th17 and, in gene expression profile when divided according to the median value ofZEB1expression, a different overall survival and relapse along with the expression of MMPs, SOCS2 and Th17 cells enrichment. Overall, our data shed new light into the role of ZEB1 in AML that entwines both pro-tumoral and immune regulatory capacity in AML blasts.
Epigenetic variation causes heritable variation in complex traits in the molluskBiomphalaria glabrata, vector of the human parasiteSchistosoma mansoni
Authors: Luviano Nelia , Lopez Marie , Gawehns Fleur , Haegeman Bart , Mouginot Pierick , Chaparro Cristian , Arimondo Paola B. , Pujol Benoit , Pouzol Damien , Cosseau Céline , Grunau Christoph 
Published: July 2023

AbstractDNA methylation variation may play a role in phenotypic variation as it can be directly affected by the environment and be inherited. DNA methylation variations were introduced into the parasite vector snailBiomphalaria glabratawith low genetic diversity by chemical treatment in F0 and followed over 3 generations using epigenetic recombinant inbred lines (epiRILs). We observed phenotypic variation in complex traits such as fecundity and susceptibility to infestation bySchistosoma mansoniand DNA methylation differences in F3. Both, increase and decrease of infestation success (up to 100% and down to 20% prevalence in epiRILs and from 86% to 94% in control RILs) indicated variation in complex resistance/compatibility trait. Average prevalence in control RILs was 84±5% but only 68±21 % in epiRILs. Fecundity also changed and was in average 47±7% in control RILs and 59±18% in epiRILs, being 12% higher in epiRILs. We found that the heritabilityh2of the fecundity in the epiRILs was between 0.5 and 0.6 depending on the method used to estimate it. We developed a model for introducing epimutant offspring snails into resident susceptible populations. If genetic assimilation of the resistant phenotype occured in a small fraction of the introduced epimutant snails, we predict that the susceptible phenotype is replaced by the resistant phenotype after 50-70 generations.
Single-cell T cell receptor sequencing of paired tissue and blood samples reveals clonal expansion of CD8+ effector T cells in patients with calcific aortic valve disease
Authors: Bartoli-Leonard Francesca , Chelvanambi Sarvesh , Pham Tan , Turner Mandy E , Blaser Mark C , Caputo Massimo , Aikawa Masanori , Pang Amanda , Muehlschlegel Jochen , Aikawa Elena 
Published: July 2023

AbstractCalcific aortic valve disease (CAVD) is a complex cardiovascular pathology, culminating in aortic stenosis, heart failure and premature mortality, with no comprehensive treatment strategy, except valve replacement. While T cells have been identified within the valve, their contribution to pathogenesis remains unclear. To elucidate the heterogenous phenotype of the immune populations present within patients with CAVD, deep phenotypic screens of paired valve and peripheral blood cells were conducted via flow cytometry (n=20) and immunohistochemistry (n=10). Following identification of a significant population of memory T cells; specifically, CD8+ T cells within the valve, single cell RNA sequencing and paired single T cell receptor sequencing was conducted on a further 4 patients on CD45+ CD3+, CD4+ or CD8+ T cells. Through unsupervised clustering, 7 T cell populations were identified within the blood and 10 identified within the valve. Tissue resident memory (TRM) T cells were detected for the first time within the valve, exhibiting a highly cytotoxic, activated, and terminally differentiated phenotype. This pan-pro-inflammatory signal was differentially identified in T cells originating from the valve, and not observed in the blood, indicative of an adaptive, local not-systemic inflammatory signature in CAVD patients. T cell receptor analysis identified hyperexpanded clones within the CD8+ T cell central memory (TCM) population, with TRMcells comprising the majority of large and medium clonal expansion within the entire T cell population. Clonal interaction network analysis demonstrated the greatest proportion of clones originating from CD8+ T cell effector memory (TEM) and CD4+ naïve / TCMpopulations and ending in the CD8+ TRMand CD8+ TCMclusters, suggesting a clonal expansion and predicted trajectory of T cells towards a tissue resident, cytotoxic environment within the valve. CDR3 epitope predictive analysis identified 7 potential epitope targets, of whichGALNT4andCR1Lhave previously been implicated in a cardiovascular context as mediators of inflammation. Taken together, the data identified T cell sub-populations within the context of CAVD and further predicted possible epitopes responsible for the clonal expansion of the valvular T cells, which may be important for propagating inflammation in CAVD.
From enhancers to genome conformation: complex transcriptional control underlies expression of a single herpesviral gene
Authors: Morgens David W , Gulyas Leah , Rivera-Madera Alejandro , Souza Annabelle S , Glaunsinger Britt A 
Published: July 2023

AbstractComplex transcriptional control is a conserved feature of both eukaryotes and the viruses that infect them. Here, we illustrate this by combining high-density functional genomics, expression profiling, and viral-specific chromosome conformation capture to define with unprecedented detail the transcriptional regulation of a single gene, ORF68, from Kaposi’s sarcoma-associated herpesvirus (KSHV). We first identified seven cis-regulatory regions by densely tiling the ∼154 kb KSHV genome with CRISPRi. A parallel Cas9 nuclease screen indicated that three of these regions act as promoters of genes that regulate ORF68. RNA expression profiling demonstrated that three more of these regions act by either repressing or enhancing other distal viral genes involved in ORF68 transcriptional regulation. Finally, we tracked how the 3D structure of the viral genome changes during its lifecycle, revealing that these enhancing regulatory elements are physically closer to their targets when active, and that disrupting some elements caused large- scale changes to the 3D genome. These data enable us to construct a complete model revealing that the mechanistic diversity of this essential regulatory circuit matches that of human genes.
The Role of Phylogenetic Structure on Canidae Lineage Distribution and Trait Variation across the Globe
Authors:   Geographical patterns of Canidae phylogenetic information, Porto Lucas Marafina Vieira , Machado Arielli Fabricio 
Published: July 2023

ABSTRACTAimUnderstanding the spatial structuring of ecological communities requires us to consider the interplay between evolutionary history and environmental factors. In this study, we investigated the influence of Canidae phylogenetic structure on the distribution and trait patterns of lineages across the planet.LocationAmericas, Africa, Eurasia.Time period12 million years ago – present.Major taxa studiedCanidae.MethodsUsing distribution data and phylogenetic information for 37 Canidae species, we employed phylogenetic fuzzy-weighting to compare assemblages based on their phylogenetic similarity.ResultsOur results revealed distinct global patterns of body size, body mass, range size, habitat type, and evolutionary distinctiveness among lineages. We also identified the shared contributions of phylogenetic structure and temperature to trait variation using variance partitioning analysis. The PCPS axes highlighted the influence of phylogenetic relationships on Canidae assemblages, particularly in South America.Main conclusionsNotably, the study challenges the applicability of Bergmann’s and Rapoport’s rules in explaining canids’ sizes and range sizes geographic variation across continents, emphasizing the importance of phylogenetic information. The unique diversification history of Canidae in South America and Africa and their diverse environmental conditions likely contribute to the observed trait patterns that make both continents so distinguished when compared to N. America and Eurasia. Our findings underscore the need to incorporate phylogenetic information in models assessing trait variation across geographic scales for unbiased estimations.
Conserved and repetitive motifs in an intrinsically disordered protein drive α-carboxysome assembly
Authors: Turnšek Julia B. , Oltrogge Luke M. , Savage David F. 
Published: July 2023

AbstractAll photosynthetic bacteria and some chemoautotrophic bacteria fix CO2into sugars in specialized proteinaceous compartments called carboxysomes. Carboxysomes enclose the enzymes Rubisco and carbonic anhydrase inside a layer of shell proteins to increase the CO2concentration for efficient carbon fixation by Rubisco. In the α-carboxysome lineage, a disordered and highly repetitive protein named CsoS2 is essential for carboxysome formation and function. Without it, the bacteria are unable to fix enough carbon to grow in air. How a protein lacking structure serves as the architectural scaffold for such a vital cellular compartment remains unknown. In this study, we identify key residues in CsoS2 that are necessary for building functional α-carboxysomesin vivo. These highly conserved and repetitive residues, VTG and Y, contribute to the interaction between CsoS2 and shell proteins. We also demonstratein vitroreconstitution of the α-carboxysome into spherical condensates with CsoS2, Rubisco, and shell proteins, and show the utility of reconstitution as a biochemical tool to study carboxysome biogenesis. The precise self-assembly of thousands of proteins is crucial for carboxysome formation, and understanding this process could enable their use in alternative biological hosts or industrial processes as effective tools to fix carbon.
The Fraser complex interconnects tissue layers to support basal epidermis and osteoblast integrated morphogenesis underlying fin skeletal patterning
Authors: Robbins Amy E. , Horst Samuel G. , Lewis Victor M. , Stewart Scott , Stankunas Kryn 
Published: July 2023

ABSTRACTFraser Syndrome is a rare, multisystemic autosomal recessive disorder characterized by disrupted epithelial-mesenchymal associations upon loss of Fraser Complex genes. Disease manifestation and affected organs are highly variable. Digit malformations such as syndactyly are common but of unclear developmental origins. We explored if zebrafishfraser extracellular matrix complex subunit 1 (fras1)mutants model Fraser Syndrome-associated appendicular skeleton patterning defects. Approximately 10% offras1mutants survive to adulthood, displaying striking and varied fin abnormalities, including endochondral bone fusions, ectopic cartilage, and disrupted caudal fin symmetry. The fins of survivingfras1mutants frequently have fewer and unbranched bony rays.fras1mutant fins regenerate to their original size but with exacerbated ray branching and fin symmetry defects. Single cell RNA-Seq analysis,in situhybridizations, and antibody staining show specific Fraser complex expression in the basal epidermis during regenerative outgrowth. Fras1 and Fraser Complex component Frem2 accumulate along the basal side of distal-most basal epidermal cells. Greatly reduced and mislocalized Frem2 accompanies loss of Fras1 infras1mutants. The Sonic hedgehog signaling between distal basal epidermis and adjacent mesenchymal pre-osteoblasts that promotes ray branching persists upon Fraser Complex loss. However,fras1mutant regenerating fins exhibit extensive sub-epidermal blistering associated with a disorganized basal epidermis and adjacent pre-osteoblasts. We propose Fraser Complex-supported tissue layer adhesion enables robust integrated tissue morphogenesis involving the basal epidermis and osteoblasts. Further, we establish zebrafish fin development and regeneration as an accessible model to explore mechanisms of Fraser Syndrome-associated digit defects and Fraser Complex function at epithelial-mesenchymal interfaces.
Multi-Omic Graph Diagnosis (MOGDx) : A data integration tool to perform classification tasks for heterogeneous diseases
Authors: Ryan Barry , Marioni Riccardo E. , Simpson T. Ian 
Published: July 2023

AbstractHeterogeneity in human diseases presents challenges in diagnosis and treatments due to the broad range of manifestations and symptoms. With the rapid development of labelled multi-omic data, integrative machine learning methods have achieved breakthroughs in treatments by redefining these diseases at a more granular level. These approaches often have limitations in scalability, oversimplification, and handling of missing data. In this study, we introduce Multi-Omic Graph Diagnosis (MOGDx), a flexible command line tool for the integration of multi-omic data to perform classification tasks for heterogeneous diseases. MOGDx is a network integrative method that combines patient similarity networks with a reduced vector representation of genomic data. The reduced vector is derived from the shared latent embedding of a multi-modal encoder and the combined network is fed into a graph convolutional network for classification. The multi-modal encoder and graph convolutional network are trained simultaneously making a fully supervised pipeline. MOGDx was evaluated on three datasets from the cancer genome atlas for breast invasive carcinoma, kidney cancer, and low grade glioma. MOGDx demonstrated state-of-the-art performance and an ability to identify relevant multi-omic markers in each task. It did so while integrating more genomic measures with greater patient coverage compared to other network integrative methods. MOGDx is available to download fromhttps://github.com/biomedicalinformaticsgroup/MOGDx. Overall, MOGDx is a promising tool for integrating multi-omic data, classifying heterogeneous diseases, and interpreting genomic markers.
Performance of ChatGPT on Chinese National Medical Licensing Examinations: A Five-Year Examination Evaluation Study for Physicians, Pharmacists and Nurses
Authors: Zong Hui , Li Jiakun , Wu Erman , Wu Rongrong , Lu Junyu , Shen Bairong 
Published: July 2023

AbstractBackgroundLarge language models like ChatGPT have revolutionized the field of natural language processing with their capability to comprehend and generate textual content, showing great potential to play a role in medical education.ObjectiveThis study aimed to quantitatively evaluate and comprehensively analysis the performance of ChatGPT on three types of national medical examinations in China, including National Medical Licensing Examination (NMLE), National Pharmacist Licensing Examination (NPLE), and National Nurse Licensing Examination (NNLE).MethodsWe collected questions from Chinese NLMLE, NPLE and NNLE from year 2017 to 2021. In NMLE and NPLE, each exam consists of 4 units, while in NNLE, each exam consists of 2 units. The questions with figures, tables or chemical structure were manually identified and excluded by clinician. We applied direct instruction strategy via multiple prompts to force ChatGPT to generate the clear answer with the capability to distinguish between single-choice and multiple-choice questions.ResultsChatGPT failed to pass the threshold score (0.6) in any of the three types of examinations over the five years. Specifically, in the NMLE, the highest recorded score was 0.5467, which was attained in both 2018 and 2021. In the NPLE, the highest score was 0.5599 in 2017. In the NNLE, the most impressive result was shown in 2017, with a score of 0.5897, which is also the highest score in our entire evaluation. ChatGPT’s performance showed no significant difference in different units, but significant difference in different question types. ChatGPT performed well in a range of subject areas, including clinical epidemiology, human parasitology, and dermatology, as well as in various medical topics such as molecules, health management and prevention, diagnosis and screening.ConclusionsThese results indicate ChatGPT failed the NMLE, NPLE and NNLE in China, spanning from year 2017 to 2021. but show great potential of large language models in medical education. In the future high-quality medical data will be required to improve the performance.
Calcium and Integrin-binding protein 2 (CIB2) controls force sensitivity of the mechanotransducer channels in cochlear outer hair cells
Authors: Aristizábal-Ramírez Isabel , Dragich Abigail K. , Giese Arnaud P.J. , Sofia Zuluaga-Osorio K. , Watkins Julie , Davies Garett K. , Hadi Shadan E. , Riazuddin Saima , Vander Kooi Craig W. , Ahmed Zubair M. , Frolenkov Gregory I. 
Published: July 2023

SUMMARYCalcium and Integrin-Binding Protein 2 (CIB2) is an essential subunit of the mechano-electrical transduction (MET) complex in mammalian auditory hair cells. CIB2 binds to pore-forming subunits of the MET channel, TMC1/2 and is required for their transport and/or retention at the tips of mechanosensory stereocilia. Since genetic ablation of CIB2 results in complete loss of MET currents, the exact role of CIB2 in the MET complex remains elusive. Here, we generated a new mouse strain with deafness-causing p.R186W mutation inCib2and recorded small but still measurable MET currents in the cochlear outer hair cells. We found that R186W variant causes increase of the resting open probability of MET channels, steeper MET current dependence on hair bundle deflection (I-X curve), loss of fast adaptation, and increased leftward shifts of I-X curves upon hair cell depolarization. Combined with AlphaFold2 prediction that R186W disrupts one of the multiple interacting sites between CIB2 and TMC1/2, our data suggest that CIB2 mechanically constraints TMC1/2 conformations to ensure proper force sensitivity and dynamic range of the MET channels. Using a custom piezo-driven stiff probe deflecting the hair bundles in less than 10 µs, we also found that R186W variant slows down the activation of MET channels. This phenomenon, however, is unlikely to be due to direct effect on MET channels, since we also observed R186W-evoked disruption of the electron-dense material at the tips of mechanotransducing stereocilia and the loss of membrane-shaping BAIAP2L2 protein from the same location. We concluded that R186W variant of CIB2 disrupts force sensitivity of the MET channels and force transmission to these channels.
Spatial organization and function of RNA molecules within phase-separated condensates are controlled by Dnd1
Authors: Westerich Kim Joana , Tarbashevich Katsiaryna , Schick Jan , Gupta Antra , Zhu Mingzhao , Hull Kenneth , Romo Daniel , Zeuschner Dagmar , Goudarzi Mohammad , Gross-Thebing Theresa , Raz Erez 
Published: July 2023

SUMMARYGerm granules, condensates of phase-separated RNA and protein, are organelles essential for germline development in different organisms The patterning of the granules and its relevance for germ cell fate are not fully understood. Combining three-dimensionalin vivostructural and functional analyses, we study the dynamic spatial organization of molecules within zebrafish germ granules. We find that localization of RNA molecules to the periphery of the granules, where ribosomes are localized depends on translational activity at this location. In addition, we find that the vertebrate-specific Dead end (Dnd1) protein is essential fornanos3RNA localization at the condensates’ periphery. Accordingly, in the absence of Dnd1, or when translation is inhibited,nanos3RNA translocates into the granule interior, away from the ribosomes, a process that is correlated with loss of germ cell fate. These findings highlight the relevance of sub-granule compartmentalization for posttranscriptional control, and its importance for preserving germ cell totipotency.