bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preeclampsia prediction with maternal and paternal polygenic risk scores: the TMM BirThree Cohort Study
Authors: Ohseto Hisashi , Ishikuro Mami , Obara Taku , Narita Akira , Takahashi Ippei , Shinoda Genki , Noda Aoi , Murakami Keiko , Orui Masatsugu , Iwama Noriyuki , Kikuya Masahiro , Metoki Hirohito , Sugawara Junichi , Tamiya Gen , Kuriyama Shinichi 
Published: February 2024

AbstractBackgroundGenomic information from pregnant women and their husbands may provide effective biomarkers for preeclampsia. This study investigated how parental polygenic risk scores (PRSs) for blood pressure (BP) and preeclampsia are associated with preeclampsia onset and evaluated predictive performances of PRSs with clinical predictive variables.MethodsIn the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, participants were genotyped using either Affymetrix Axiom Japonica Array v2 (further divided into two cohorts—the PRS training cohort and the internal-validation cohort—at a ratio of 1:2) or Japonica Array NEO (external-validation cohort). PRSs were calculated for systolic BP (SBP), diastolic BP (DBP), and preeclampsia. Associations between PRSs and preeclampsia, including preeclampsia superimposed on chronic hypertension, were examined using logistic regression analysis; prediction models were developed using a competing-risks approach with clinical predictive variables and PRSs.ResultsIn total, 19,836 participants were included. Hyperparameters for PRS calculation were optimized for 3,384 participants in the training cohort. In internal- and external-validation cohorts, 357 of 6,768 (5.3%) and 269 of 9,684 (2.8%) participants developed preeclampsia, respectively. Preeclampsia onset was significantly associated with maternal PRSs for SBP and DBP in internal- and external-validation cohorts and with paternal PRSs for SBP and DBP only in the external-validation cohort. Maternal PRSs for DBP calculated using “LDpred2” most improved prediction models. Maternal PRSs for DBP provided additional predictive information on clinical predictive variables. Paternal PRSs for DBP improved prediction models in the internal-validation cohort.ConclusionsParental PRS, along with clinical predictive variables, is potentially useful for predicting preeclampsia.
Interactions in abnormal synergies between the upper and lower extremities in various phases of stroke: A cohort study
Authors: Kim Dongwon , Ko Sung-Hwa , Han Junhee , Kim Young-Taek , Kim Yun-Hee , Chang Won Hyuk , Shin Yong-Il 
Published: February 2024

ABSTRACTObjectiveThe flexion synergy and extension synergy are a representative consequence of a stroke and appear in the upper extremity and lower extremity. Since the ipsilesional corticospinal tract (CST) is the most influential neural pathway for both extremities in motor execution, damage by a stroke to this tract could lead to similar motor pathological features (e.g., abnormal synergies) in both extremities. However less attention has been paid to the inter-limb correlations in the flexion synergy and extension synergy across different recovery phases of a stroke.MethodsIn this study, we used results of the Fugl-Meyer assessment (FMA) to characterize those correlations in a total of 512 participants with hemiparesis post stroke from the acute phase to 1 year. The FMA provides indirect indicators of the degrees of the flexion synergy and extension synergy post stroke.ResultsWe found that generally, strong inter-limb correlations (r>0.65 with all p-values<0.0001) between the flexion synergy and extension synergy appeared in the acute-to-subacute phase (<90 days). But correlations of lower-extremity extension synergy with upper-extremity flexion synergy and extension synergy decreased (down to r=0.38) around 360 days after stroke (p<0.05).InterpretationThese results suggest that the preferential use of alternative neural pathways after damage by a stroke to the CST enhances inter-limb correlations between the flexion synergy and extension, however a recovery of the CST or/and the functional fragmentation (remodeling) of the alternative neural substrates in the chronic phase contribute to diversity in neural pathways in motor execution, eventually leading to reduced inter-limb correlations.
Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis
Authors: Wei Jessica , Moon Jeonghyeon , Yasumizu Yoshiaki , Zhang Le , Radassi Khadir , Buitrago-Pocasangre Nicholas , Deerhake M. Elizabeth , Strauli Nicholas , Chan Alan , Herman Ann , Pedotte Rosetta , Raposo Catarina , Tackenberg Björn , Yim Isaiah , Pappalardo Jenna , Longbrake Erin E. , Sumida Tomokazu S. , Axisa Pierre-Paul , Hafler David A. 
Published: February 2024

AbstractMultiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven “in vivo perturbation” modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16+monocytes increased in frequency post-B cell depletion. In addition, we observed increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion also induced changes in peripheral CD4+T cell populations, including increases in the frequency of TIGIT+regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4+T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.
An iPSC-derived bio-inspired scaffold modelling the structure and the effects of extracellular matrix in cardiac fibrosis
Authors: Niro Francesco , Fernandes Soraia , Cassani Marco , Apostolico Monica , La Cruz Jorge Oliver-De , Sousa Daniel Pereira- , Pagliari Stefania , Vinarsky Vladimir , Zdráhal Zbyněk , Potesil David , Pustka Vaclav , Pompilio Giulio , Sommariva Elena , Rovina Davide , Maione Angela Serena , Bersanini Luca , Becker Malin , Rasponi Marco , Forte Giancarlo 
Published: February 2024

AbstractCardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the differentiation of cardiac fibroblasts (cFbs) into myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictivein vitromodels of heart fibrosis has so far hampered the search for innovative treatments. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (α−SMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblastsin vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere alignment, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis.
Metagenomic, metabolomic, and lipidomic shifts associated with fecal microbiota transplantation for recurrentClostridioides difficileinfection
Authors: McMillan Arthur S , Zhang Guozhi , Dougherty Michael K , McGill Sarah K , Gulati Ajay S , Baker Erin S , Theriot Casey M 
Published: February 2024

SummaryRecurrentC. difficileinfection (rCDI) is an urgent public health threat for which the last resort and lifesaving treatment is a fecal microbiota transplant (FMT). However, the exact mechanisms which mediate a successful FMT are not well understood. Here we use longitudinal stool samples collected from patients undergoing FMT to evaluate changes in the microbiome, metabolome, and lipidome after successful FMTs. We show changes in the abundance of many lipids, specifically acylcarnitines and bile acids, in response to FMT. These changes correlate with Enterobacteriaceae, which encode carnitine metabolism genes, and Lachnospiraceae, which encode bile salt hydrolases andbaiAgenes. LC-IMS-MS revealed a shift from microbial conjugation of primary bile acids pre-FMT to secondary bile acids post-FMT. Here we define the structural and functional changes in successful FMTs. This information will help guide targeted Live Biotherapeutic Product development for the treatment of rCDI and other intestinal diseases.
Protein property prediction based on local environment by 3D equivariant convolutional neural networks
Authors: Chen He , Cheng Yifan , Dong Jianqiang , Mao Jie , Wang Xin , Gao Yuan , Li Yuchao , Wang Chengzhi , Wu Qiong 
Published: February 2024

AbstractPredicting the properties of proteins is an important procedure in protein engineering. It determines the subspace of mutations for protein modifications, which is critical to the success of the project, but heavily relies on the knowledge and experience of scientists. In this study, we propose a novel deep 3D-CNN model, Eq3DCNN, specifically designed for local environment-related tasks in protein engineering. Eq3DCNN uses basic atom descriptors and their coordinates as inputs, utilizing customized data augmentations to enhance its training efficiency. To make the Eq3DCNN extracted features with more generalization capability, we incorporated a rotation equivariant module to get rotation invariant features. Using cross-validations with different data splitting strategies and under the scenarios of zero-shot predictions, we demonstrate that Eq3DCNN outperformed other 3D-CNN models in stability predictions, and also well-preformed on other prediction tasks, such as the binding pocket and the secondary structure predictions. Our results also identified the key factors that contribute to the model’s accuracy and the scope of its applications. These findings may help scientists in designing better mutation experiments and increasing the success rate in protein engineering.
Interpretable Drug Response Prediction through Molecule Structure-aware and Knowledge-Guided Visible Neural Network
Authors: Xie Jiancong , Zhang Zhe , Li Youyou , Rao Jiahua , Yang Yuedong 
Published: February 2024

AbstractPrecise prediction of anti-cancer drug responses has become a crucial obstruction in anti-cancer drug design and clinical applications. In recent years, various deep learning methods have been applied to drug response prediction and become more accurate. However, they are still criticized as being non-transparent. To offer reliable drug response prediction in real-world applications, there is still a pressing demand to develop a model with high predictive performance as well as interpretability. In this study, we propose DrugVNN, an end-to-end interpretable drug response prediction framework, which extracts gene features of cell lines through a knowledge-guided visible neural network (VNN), and learns drug representation through a node-edge communicative message passing network (CMPNN). Additionally, between these two networks, a novel drug-aware gene attention gate is designed to direct the drug representation to VNN to simulate the effects of drugs. By evaluating on the GDSC dataset, DrugVNN achieved state-of-the-art performance. Moreover, DrugVNN can identify active genes and relevant signaling pathways for specific drug-cell line pairs with supporting evidence in the literature, implying the interpretability of our model.
Traditional uses and pharmacological activities ofTetracera alnifolia(Wild) Drake
Authors: Camara A.K. , Baldé E.S. , Diallo M.S.T. , Camara M.K. , Bah T.V. , Condé M. , Soumah A. , Kamano K. , Tietjen I. , Baldé A.M. 
Published: February 2024

ABSTRACTEthnopharmacological relevanceTetracera alnifolia(Wild) Drake, is well used in traditional Guinean medicine for the treatment of infectious skin diseases. The present aim was to contribute to the valorization ofTetracera alnifolialeaves, focused on ethnomedical, biological and phytochemical investigations.Materials and methodswe conducted an ethnomedical survey across several markets of the city of Conakry to identify 39 healers. Chloroform, methanol, dichloromethane, and aqueous extracts were tested for activities against protozoa, bacteria, fungi, HIV, and SARS-CoV-2.Resultsthe traditional healers indicated thatT. alnifoliais used in the treatment of more than 15 pathologies includingFassa(marasmus/malnutrition),Soukhou kouyé(white discharge in women), andTèmou bankhi(sexual weakness in men). Leaves were the most used part. The modes of preparation included decoction and powder. Data from biological activities identicatied good activities of the methanolic extract againstLeishmania infantum(MIC = 8.11 μg / ml) and a moderate activity onTrypanosoma brucei(MIC = 28.15 μg / ml) andStaphylococcus aureus(MIC = 29.91 μg / ml), while dichloromethane extracts acted on live SARS-CoV-2 replication with up to 53.4% inhibition at 50 μg/mL.Conclusionthese results explain at least in part the traditional use ofT. alnifolia
Modified histone peptides uniquely tune the material properties of HP1α condensates
Authors: Deshpande Priyasha , Prentice Emily , Vidal Ceballos Alfredo , Casaccia Patrizia , Elbaum-Garfinkle Shana 
Published: February 2024

AbstractBiomolecular condensates have emerged as a powerful new paradigm in cell biology with broad implications to human health and disease, particularly in the nucleus where phase separation is thought to underly elements of chromatin organization and regulation. Specifically, it has been recently reported that phase separation of heterochromatin protein 1alpha (HP1α) with DNA contributes to the formation of condensed chromatin states. HP1α localization to heterochromatic regions is mediated by its binding to specific repressive marks on the tail of histone H3, such as trimethylated lysine 9 on histone H3 (H3K9me3). However, whether epigenetic marks play an active role in modulating the material properties of HP1α and dictating emergent functions of its condensates, remains only partially understood. Here, we leverage a reductionist system, comprised of modified and unmodified histone H3 peptides, HP1α and DNA to examine the contribution of specific epigenetic marks to phase behavior of HP1α. We show that the presence of histone peptides bearing the repressive H3K9me3 is compatible with HP1α condensates, while peptides containing unmodified residues or bearing the transcriptional activation mark H3K4me3 are incompatible with HP1α phase separation. In addition, inspired by the decreased ratio of nuclear H3K9me3 to HP1α detected in cells exposed to uniaxial strain, using fluorescence microscopy and rheological approaches we demonstrate that H3K9me3 histone peptides modulate the dynamics and network properties of HP1α condensates in a concentration dependent manner. These data suggest that HP1α-DNA condensates are viscoelastic materials, whose properties may provide an explanation for the dynamic behavior of heterochromatin in cells in response to mechanostimulation.Statement of significanceThe organization of genomic information in eukaryotic cells necessitates compartmentalization into functional domains allowing for the expression of cell identity-specific genes, while repressing genes related to alternative fates. Heterochromatin hosts these transcriptionally silent regions of the genome - which ensure the stability of cell identity -and is characterized by repressive histone marks (H3K9m3) and other specialized proteins (HP1a), recently shown to phase separate with DNA. We show that HP1a forms condensates with DNA which persist in the presence of H3K9me3 peptides. The viscoelastic nature of these condensates depend on H3K9me3:HP1 ratios, which are modulated by mechanical strain in cells. Thus, phase separation may explain the dynamic behavior of heterochromatin in cells, in response to mechanostimulation.
Association between mitochondrial DNA copy number and production traits in pigs
Authors: Molinero Eduard , Pena Ramona N. , Estany Joan , Ros-Freixedes Roger 
Published: February 2024

AbstractMitochondria are essential organelles in the regulation of cellular energetic metabolism. Mitochondrial DNA copy number (mtDNA_CN) can be used as a proxy for mitochondria number, size, and activity. The aims of our study are to evaluate the effect of mtDNA_CN and mitochondrial haploblocks on production traits in pigs, and to identify the genetic background of this cellular phenotype. We collected performance data of 234 pigs and extracted DNA from skeletal muscle. Whole-genome sequencing data was used to determine mtDNA_CN. We detected positive correlations of muscle mtDNA_CN with backfat thickness at 207 d (+0.14;p-value = 0.07), and negative correlations with carcase loin thickness (–0.14;p-value = 0.03). Pigs with less mtDNA_CN had greater loin thickness (+4.1 mm;p-value = 0.01) and lower backfat thickness (–1.1 mm;p-value = 0.08), which resulted in greater carcase lean percentage (+2.4%;p-value = 0.04) than pigs with high mtDNA_CN. These results support the hypothesis that a reduction of mitochondrial activity is associated with greater feed efficiency. Pork from pigs with less mtDNA_CN may also tend to have lower ultimate pH (correlation: +0.19;p-value < 0.01). We found no association of the most frequent mitochondrial haploblocks with mtDNA_CN or the production traits, but several genomic regions that harbour potential candidate genes with functions related to mitochondrial biogenesis and homeostasis were associated to mtDNA_CN. These regions provide new insights into the genetic background of this cellular phenotype but it is still uncertain if such associations translate into noticeable effects on the production traits.
Atypical landscape of transposable elements in the large genome ofAedes aegypti
Authors: Daron Josquin , Bergman Alexander , Lopez-Maestre Hélène , Lambrechts Louis 
Published: February 2024

AbstractTransposable elements (TEs) contribute significantly to variation in genome size among eukaryotic species, but the factors influencing TE accumulation and diversification are only partially understood. Most of our current knowledge about TE organization, dynamics and evolution derives from investigations in model organisms with a relatively small genome size such asDrosophila melanogasterorArabidopsis thaliana. Whether the observed patterns hold true in larger genomes remains to be determined. The Diptera order is an ideal taxon to address this question, because it includes a forty-year model of TE biology (D. melanogaster) as well as mosquito species with significantly larger genomes. Here, we use a comparative genomics approach to characterize the genomic forces that have shaped the TE content of theAedes aegyptigenome (1.3 Gb) relative to theAnopheles coluzziigenome (300 Mb) and theD. melanogastergenome (180 Mb). Leveraging a newly developed high-quality TE library forAe. aegypti, our results reveal a contrasted pattern of TE organization inAe. aegypticompared toAn. coluzziiandD. melanogaster. Our analyses suggest that the substantial TE fraction observed in theAe. aegyptigenome reflect both a high rate of TE transposition and a low rate of TE elimination. Together, our results indicate that TE organization and evolutionary dynamics in the large genome ofAe. aegyptiare distinct from those of other dipterans with smaller genomes.
Modelling the spatiotemporal dynamics of multispecies population interactions in the context of climate change
Authors: Christou Katerina , Schmucki Reto , Audusseau Hélène 
Published: February 2024

AbstractSpecies interactions are fundamental to the stability and productivity of ecosystems. To improve our capacity to predict and understand how climate change shapes the distribution of species and the dynamics of biotic interactions, we need to develop spatially explicit multi-species models that are built upon species-specific responses to changing conditions.We developed a two-dimensional diffusion-advection-reaction predator-prey model that integrates species-specific responses to heterogeneous landscapes, affecting species dispersal, reproduction and survival rates. We derived conditions for the stability and feasibility of the coexistence steady-state and observed how temperature variation stabilises or destabilises the system.We conducted numerical simulations to explore the effect of predicted extreme temperatures on the spatial dynamics of a parasitoid-butterfly system and their interactions. Applied to four different climatic environments, the numerical approximations demonstrate the asymmetric impact of a warming climate on interacting species. The output density distribution maps highlight the capability of our model to produce interpretable multiscale predictions which can be used to identify and evaluate species vulnerability locally and across their range.By building upon a solid mechanistic understanding of species-specific responses to environmental change, our model can be extended to other species and variables, including environments where the availability of empirical data is limited, and explore the dynamics and distribution of interacting species under different scenarios of environmental change.
Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters
Authors: Dmitrieva Nataliia , Gholami Samira , Alleva Claudia , Carloni Paolo , Alfonso-Prieto Mercedes , Fahlke Christoph 
Published: February 2024

AbstractThe solute carrier 17 (SLC17) family contains anion transporters that accumulate neuro-transmitters in secretory vesicles, remove carboxylated monosaccharides from lysosomes, or extrude organic anions from the kidneys and the liver. We combined classical molecular dynamics simulations, Markov state modeling and hybrid first principles quantum mechani-cal/classical mechanical (QM/MM) simulations with experimental approaches to describe the transport mechanisms of a model bacterial protein, the D-galactonate transporter DgoT, at atomic resolution. We found that protonation of D46 and E133 precedes galactonate binding and that substrate binding induces closure of the extracellular gate, with the conserved R47 coupling substrate binding to transmembrane helix movement. After isomerization to an inward-facing conformation, deprotonation of E133 and subsequent proton transfer from D46 to E133 opens the intracellular gate and permits galactonate dissociation either in its unprotonated form or after proton transfer from E133. After release of the second proton, apo DgoT returns to the outward-facing conformation. Our results provide a framework to understand how various SLC17 transport functions with distinct transport stoichiometries can be attained through subtle variations in proton and substrate binding/unbinding.