bluuebunny/crossref_metadata_2025_split huggingface dataset:
Premorbid predictors of death at initial presentation of coronary heart disease in the Women’s Health Initiative study
Authors: Chen Ming-Li , Li Jin , Iyer Kruthika R. , Tcheandjieu Catherine , Jimenez Shirin , Salfati Elias Levy Itshak , Gobbo Liana C. Del , Stefanick Marcia L , Desai Manisha , Xue Xiaonan , Assimes Themistocles L 
Published: April 2024

AbstractBackgroundPremorbid health traits that predispose to a fatal initial presentation of coronary heart disease (CHD) remain poorly characterized.MethodsWe followed 148,230 post-menopausal participants in the Women’s Health Initiative for a median of 13.3 years. We ascertained the first occurrence of CHD and performed a joint Cox multivariate regression to identify premorbid predictors for a fatal rather than a non-fatal incident event.ResultsA total of 10,714 incident CHD events including 513 fatal events accrued during follow up. A five-year increase in age, smoking 5 to 34 cigarettes per day, and a standard deviation (SD) increase in the Cornel voltage product on electrocardiography each independently increased the relative risk (RR) of dying from one’s initial presentation of CHD by 46% (95% confidence interval [CI], 35 to 58%), 30% (8 to 51%,), and 17% (7 to 28%), respectively. A high level of recreational physical activity (>1200 metabolic equivalent (MET) minutes per week) reduced one’s relative risk by 32% (12 to 49%). A significant dose-response effect was observed for both physical activity and smoking and the reduction in absolute risk of presenting with fatal CHD associated with a healthy lifestyle was roughly equivalent to the difference in risk observed among women separated in age by approximately 10 years.ConclusionsModifiable factors affect a post-menopausal woman’s risk of dying from her initial presentation of CHD. Our findings may reduce case-fatality rates of CHD by motivating individuals at risk to adopt and/or adhere to established primary prevention strategies.
Utilising activity patterns of a complex biophysical network model to optimise intra-striatal deep brain stimulation
Authors: Spiliotis Konstantinos , Appali Revathi , Fontes Gomes Anna Karina , Payonk Jan Philipp , Adrian Simon , van Rienen Ursula , Starke Jens , Köhling Rüdiger 
Published: April 2024

AbstractIn this study, we develop a large-scale biophysical network model for the isolated striatal body to optimise potential intrastriatal deep brain stimulation applied in, e.g. obsessive-compulsive disorder by using spatiotemporal patterns produced by the network. The model uses modified Hodgkin-Huxley models on small-world connectivity, while the spatial information, i.e. the positions of neurons, is obtained from a detailed human atlas. The model produces neuronal activity patterns segregating healthy from pathological conditions. Three indices were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the mean activity of the ventral striatal area (emerging as a defined community using modularity detection algorithms), and the frequency spectrum of the entire network activity. By minimising the deviation of the aforementioned indices from the normal state, we guide the optimisation of deep brain stimulation parameters regarding position, amplitude and frequency.
Systematic perturbation screens decode regulators of inflammatory macrophage states and identify a role forTNFmRNA m6A modification
Authors: Haag Simone M , Xie Shiqi , Eidenschenk Celine , Fortin Jean-Philippe , Callow Marinella , Costa Mike , Lun Aaron , Cox Chris , Wu Sunny Z , Pradhan Rachana N , Lock Jaclyn , Kuhn Julia A , Holokai Loryn , Thai Minh , Freund Emily , Nissenbaum Ariane , Keir Mary , Bohlen Christopher J , Martin Scott , Geiger-Schuller Kathryn , Hejase Hussein A , Yaspan Brian L , Carlos Sandra Melo , Turley Shannon J , Murthy Aditya 
Published: April 2024

ABSTRACTMacrophages adopt dynamic cell states with distinct effector functions to maintain tissue homeostasis and respond to environmental challenges. During chronic inflammation, macrophage polarization is subverted towards sustained inflammatory states which contribute to disease, but there is limited understanding of the regulatory mechanisms underlying these disease-associated states. Here, we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human monocyte-derived macrophages (hMDMs) to uncover regulatory circuits of inflammatory macrophage states. This process identifies regulators of five distinct inflammatory states associated with key features of macrophage function. Among these, the mRNA m6A writer components emerge as novel inhibitors of a TNFα-driven cell state associated with multiple inflammatory pathologies. Loss of m6A writer components in hMDMs enhancesTNFtranscript stability, thereby elevating macrophage TNFα production. A PheWAS on SNPs predicted to impact m6A installation onTNFrevealed an association with cystic kidney disease, implicating an m6A-mediated regulatory mechanism in human disease. Thus, systematic phenotypic characterization of primary human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.
Control without cause: How covariate control biases our insights into brain architecture and pathology
Authors: Sperber Christoph , Gallucci Laura , Arnold Marcel , Umarova Roza M. 
Published: April 2024

AbstractInferential analysis of normal or pathological brain imaging data – as in brain mapping or the identification of neurological imaging markers – is often controlled for secondary variables. However, a rationale for covariate control is rarely given and formal criteria to identify appropriate covariates in such complex data are lacking. We investigated the impact and adequacy of covariate control in large-scale imaging data using the example of stroke lesion-deficit mapping. In 183 stroke patients, we evaluated control for age, sex, hypertension, or lesion volume when mapping real or simulated deficits. We found that the impact of covariate control varies and can be strong, but it does not necessarily improve the precision of results. Instead, it systematically shifts results towards the inversed associations between imaging features and the covariate. This effect of covariate control can bias results and, as shown in another experiment, can even create effects out of nothing. The widespread use of covariate control in the statistical analysis of clinical brain imaging data – and, likely, other biological high-dimensional data as well – may not generally improve statistical results, but it may just change them. Therefore, covariate control constitutes a problematic degree of freedom in the analysis of brain imaging data and may often not be justified at all.
Intrinsic Units: Identifying a system’s causal grain
Authors: Marshall William , Findlay Graham , Albantakis Larissa , Tononi Giulio 
Published: April 2024

AbstractIntegrated information theory (IIT) aims to account for the quality and quantity of consciousness in physical terms. According to IIT, a substrate of consciousness must be a system of units that is a maximum of intrinsic, irreducible cause-effect power, quantified by integrated information (φs). Moreover, the grain of each unit must be the one— from micro (finer) to macro (coarser)—that maximizes the system’s intrinsic irreducibility (i.e., maximizesφs). The units that maximizeφsare called the intrinsic units of the system. This work extends the mathematical framework of IIT 4.0 to assess cause-effect power at different grains and thereby determine a system’s intrinsic units. Using simple, simulated systems, we show that the cause-effect power of a system of macro units can be higher than the cause-effect power of the corresponding micro units. Two examples highlight specific kinds of macro units, and how each kind can increase cause-effect power. The implications of the framework are discussed in the broader context of IIT, including how it provides a foundation for tests and inferences about consciousness.
Compliant DNA Origami Nanoactuators as Size-Selective Nanopores
Authors: Yu Ze , Baptist Anna V. , Reinhardt Susanne C. M. , Bertosin Eva , Dekker Cees , Jungmann Ralf , Heuer-Jungemann Amelie , Caneva Sabina 
Published: April 2024

ABSTRACTBiological nanopores crucially control the import and export of biomolecules across lipid membranes in cells. They have found widespread use in biophysics and biotechnology, where their typically narrow, fixed diameters enable selective transport of ions and small molecules as well as DNA and peptides for sequencing applications. Yet, due to their small channel sizes, they preclude the passage of large macromolecules, e.g., therapeutics. Here, we harness the unique combined properties of DNA origami nanotechnology, machine-inspired design, and synthetic biology, to present a structurally reconfigurable DNA origami MechanoPore (MP) that features a lumen that is tuneable in size through molecular triggers. Controllable switching of MPs between three stable states is confirmed by 3D-DNA-PAINT super-resolution imaging and through dye-influx assays, after reconstitution of the large MPs in the membrane of liposomes via an inverted-emulsion cDICE technique. Confocal imaging of transmembrane transport shows size-selective behaviour with adjustable thresholds. Importantly, the conformational changes are fully reversible, attesting to the robust mechanical switching that overcomes pressure from the surrounding lipid molecules. These MPs advance nanopore technology, offering functional nanostructures that can be tuned on-demand – thereby impacting fields as diverse as drug-delivery, biomolecule sorting and sensing, as well as bottom-up synthetic biology.
Changes in SWEET-mediated sugar partitioning affect photosynthesis performance and plant response to drought
Authors: Aubry Emilie , Clément Gilles , Gilbault Elodie , Dinant Sylvie , Le Hir Rozenn 
Published: April 2024

AbstractSugars, produced through photosynthesis, are at the core of all organic compounds synthesized and used for plant growth and response to environmental changes. Their production, transport, and utilization are highly regulated and integrated throughout the plant life cycle. The maintenance of sugar partitioning between the different subcellular compartments and between cells is important in adjusting the photosynthesis performance and response to abiotic constraints. Here, we investigated, in Arabidopsis, the consequences of the disruption of four genes coding for SWEET sugar transporters (SWEET11, SWEET12, SWEET16, and SWEET17) on plant photosynthesis and response to drought. Our results show that mutations in bothSWEET11andSWEET12genes lead to an increase of cytosolic sugars in mesophyll cells and phloem parenchyma cells, which impacts several photosynthesis-related parameters. Further, our results suggest that in theswt11swt12double mutant, the sucrose-induced feedback mechanism on stomatal closure is poorly efficient. On the other hand, changes in fructose partitioning in mesophyll and vascular cells, measured in theswt16swt17double mutant, positively impact gas exchanges, probably through an increased starch synthesis together with higher vacuolar sugar storage. Finally, we propose that the impaired sugar partitioning, rather than the total amount of sugar observed in the quadruple mutant, is responsible for the enhanced sensitivity upon drought. This work highlights the importance of considering SWEET-mediated sugar partitioning rather than global sugar content in photosynthesis performance and plant response to drought. Such knowledge will pave the way to design new strategies to maintain plant productivity in a challenging environment.
Legumain is a paracrine regulator of osteoblast differentiation and mediates the inhibitory effect of TGF-β1 on osteoblast maturation
Authors: Forbord Karl Martin , Lunde Ngoc Nguyen , Bosnjak Tatjana , Johansen Harald Thidemann , Solberg Rigmor , Jafari Abbas 
Published: April 2024

1.AbstractTransforming growth factor-beta 1 (TGF-β1) is a critical regulator of skeletal homeostasis and has diverse promoting effects on osteoblastogenesis. However, the mechanisms behind the intriguing inhibitory effect of TGF-β1 on osteoblast maturation are not fully understood. Here, we demonstrate a novel mechanism by which TGF-β1 modulates osteoblast maturation through lysosomal protease legumain. We observed that presence of TGF-β1 in osteogenic cultures of human bone marrow derived mesenchymal stromal (stem) cells enhanced legumain activity and secretion, in-spite of decreased legumain mRNA expression, suggesting post-transcriptional regulation. We further showed that osteogenic cells internalize and activate prolegumain, associated with inhibited osteoblast maturation, revealing legumain as a paracrine regulator of osteoblast maturation. Interestingly, TGF-β1 treatment exacerbated legumain internalization and activity, and showed an additive effect on legumain-induced inhibition of osteoblast maturation. Importantly, legumain inhibition abolished the inhibitory effect of TGF-β1 on osteoblast maturation. Our findings reveal that TGF-β1 inhibits osteoblast maturation through stimulating secretion and activity of endogenous legumain, as well as increasing the internalization and activation of extracellular legumain. Therefore, our study provides a deeper understanding of the complex regulation of osteoblastogenesis and unveils a novel TGF-β1-legumain axis in regulation of osteoblast maturation and offer novel insights for possible therapeutic interventions related to bone diseases associated with aberrant TGF-β1 signaling.
In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function
Authors: Meurant Sébastien , Amato Ilario , Mauclet Lorris , Dieu Marc , Chevrollier Arnaud , Ledoux Benjamin , Caruso Marino , Lenaers Guy , Arnould Thierry , Renard Patricia 
Published: April 2024

ABSTRACTMitochondrial DNA depletion syndromes are severe genetic disorders associated with mutations in a variety of genes includingMPV17,encoding a protein of the inner mitochondrial membrane with an unclear function. In this study, using BioID technology, we identified MPV17 interacting partners among which proteins from the MICOS complex. However, MPV17 knockout did not impact mitochondrial ultrastructure, but led to increased mitochondria-derived vesicles formation and altered mitochondrial permeability transition pore. Furthermore, MPV17 KO cells exhibited higher mitochondrial calcium levels and reactive oxygen species, leading to mtDNA degradation, a phenomenon prevented by blocking mitochondrial calcium entry or treating cells with antioxidant. We thus propose a function for MPV17 as a potential additional member of the mitochondrial permeability transition pore, whereas in the absence of the protein, the build-up of calcium inside the mitochondria would lead to mtDNA degradation caused by increased oxidative damages.
Temporally controlled nervous system-to-gut signaling bidirectionally regulates longevity inC. elegans
Authors: Xu Lingxiu , Han Chengxuan , Chun Lei , Xu X.Z. Shawn , Liu Jianfeng 
Published: April 2024

AbstractThe nervous system modulates aging by secreting signaling molecules to cell-nonautonomously regulate the physiological state of distal tissues such as the gut. However, the underlying mechanisms are not well understood. Here, usingC. elegansas a model, we identified two distinct neuroendocrine signaling circuits through which motor neurons signal the gut in early life to shorten lifespan but in mid-late life to extend lifespan. Both circuits employ the same neurotransmitter acetylcholine (ACh), while recruiting two different gut ACh receptors ACR-6 and GAR-3 to regulate the transcription factor DAF-16 and HSF-1 in early and mid-late life, respectively. Strikingly, the gut expression of ACR-6 is restricted to early life, whereas that of GAR-3 is confined to mid-late life, providing a potential mechanism for the temporal control of the two circuits. These results identify a novel mechanism that empowers the nervous system to bidirectionally regulate longevity by differentially signaling the gut at different life stages.
TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate
Authors: Meng Michelle Y , Paine Luke W , Sagnat David , Bello Ivana , Oldroyd Sophie , Javid Farideh , Harper Matthew T , Hockley James RF , Smith Ewan St. J , Owens Róisín M , Alric Laurent , Buscail Etienne , Welsh Fraser , Vergnolle Nathalie , Bulmer David C 
Published: April 2024

AbstractBackground and PurposeAbdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. While the vanilloid transient receptor potential 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon-projecting sensory neurons suggests that non-neuronal cells may also contribute to TRPV4-mediated nociceptor stimulation.Experimental ApproachChanges in murine colonic afferent activity were examined usingex vivoelectrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assay from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca2+imaging when cultured alone or co-cultured with colonic mucosal cells.Key ResultsThe TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removal of the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pre-treatment with purinoreceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co-cultured with colonic mucosal cells produced a marked increase in intracellular Ca2+to GSK1016790A compared to neurons cultured alone.Conclusions and ImplicationsOur data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics.Bullet Point SummaryWhat is already known?Activation of TRPV4 causes visceral hypersensitivity via the stimulation of colonic afferents.What does this study add?TRPV4-mediated colonic afferent activation is dependent on mucosal release of ATP and glutamate.What is the clinical significance?Mucosal TRPV4-mediated colonic afferent activation provides a gut restricted target for treating abdominal pain.
Discordance between phylogenomic datasets in aphids: who is telling the truth?
Authors: Jousselin Emmanuelle , Coeur d’acier Armelle , Clamens Anne-Laure , Galan Maxime , Cruaud Corinne , Barbe Valérie , Manzano-Marin Alejandro 
Published: April 2024

AbstractAphids (Hemiptera: Aphididae) are intensively studied due to their significance as pests and their captivating biological traits. Despite this considerable research interest, the evolutionary history of this insect family is poorly understood. Recent phylogenomic analyses have produced conflicting topologies, particularly at deep nodes, complicating our understanding of aphid trait evolution. In this work, we aimed to produce new data to unravel the backbone phylogeny of aphids. We sequenced partial and whole mitochondrial genomes from 87 species that were added to 31 published mitochondria. We additionally sequenced 42 nuclear loci across 95 aphid species and sourced 146 genes from 12 new and 61 published genomes from the primary aphid obligate endosymbiont, Buchnera aphidicola. We obtain data from these three sources for a subset of 51 aphid species, facilitating a comparative analysis of their phylogenetic signals. Our analyses confirm the monophyly of subfamilies, validating current taxonomic classifications, except for Eriosomatinae and Calaphidinae. However, relationships between subfamilies remain contentious in both mitochondrial and nuclear phylogenies. The topologies obtained withBuchneraappear fully resolved but exhibit some discordance with host phylogenies at deep evolutionary scales and conflict with views on the evolution of aphid morphology. We discuss alternative hypotheses for these discrepancies. Finally, the paucity of phylogenetic information at deep phylogenetic scales may stem from an initial rapid radiation. Though challenging to establish, this scenario may inherently hinder resolution in aphid phylogenetics.
KMAP: Kmer Manifold Approximation and Projection for visualizing DNA sequences
Authors: Fu Chengbo , Niskanen Einari A. , Wei Gong-Hong , Yang Zhirong , Sanvicente-García Marta , Güell Marc , Cheng Lu 
Published: April 2024

ABSTRACTIdentifying and illustrating patterns in DNA sequences is a crucial task in various biological data analyses. In this task, patterns are often represented by sets of kmers, the fundamental building blocks of DNA sequences. To visually unveil these patterns, we could project each kmer onto a point in two-dimensional (2D) space. However, this projection poses challenges due to the high-dimensional nature of kmers and their unique mathematical properties. Here, we established a mathematical system to address the peculiarities of the kmer manifold. Leveraging this kmer manifold theory, we developed a statistical method named KMAP for detecting kmer patterns and visualizing them in 2D space. We applied KMAP to three distinct datasets to showcase its utility. KMAP achieved a comparable performance to the classical method MEME, with approximately 90% similarity in motif discovery from HT-SELEX data. In the analysis of H3K27ac ChIP-seq data from Ewing Sarcoma (EWS), we found that BACH1, OTX2 and ERG1 might affect EWS prognosis by binding to promoter and enhancer regions across the genome. We also found that FLI1 bound to the enhancer regions after ETV6 degradation, which showed the competitive binding between ETV6 and FLI1. Moreover, KMAP identified four prevalent patterns in gene editing data of the AAVS1 locus, aligning with findings reported in the literature. These applications underscore that KMAP could be a valuable tool across various biological contexts. KMAP is freely available at:https://github.com/chengl7-lab/kmap.