bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating cytokine levels and 5-year vascular recurrence after stroke: a multicenter prospective cohort study
Authors: Zhang Lanyue , Antabi Mohamad Ali , Mattar Jana , Bounkari Omar El , Fang Rong , Waegemann Karin , Bode Felix J. , Stösser Sebastian , Hermann Peter , Liman Thomas G. , Nolte Christian H. , Ikenberg Benno , Bernkopf Kathleen , Glanz Wenzel , Janowitz Daniel , Spottke Annika , Görtler Michael , Wunderlich Silke , Zerr Inga , Petzold Gabor C. , Endres Matthias , Bernhagen Jürgen , Dichgans Martin , Georgakis Marios K. 
Published: January 2025

AbstractBackgroundAnti-inflammatory therapies are tested in randomized trials for secondary stroke prevention. Detecting inflammatory biomarkers that predict vascular recurrence could optimize patient selection for these trials.MethodsIn a multicenter prospective cohort study, we measured plasma levels of 22 inflammatory cytokines in 486 acute stroke patients (median age 68 years, 34% female, median 3 days post-stroke onset). Patients were followed for over 5 years through telephone and in-person interviews to record the occurrence of the following outcomes: (1) recurrent stroke or transient ischemic attack (TIA; primary outcome); (2) a composite of recurrent vascular events (stroke, TIA, acute coronary syndrome, hospital admission due to heart failure, and death; secondary outcome). Associations between cytokine levels and these outcomes were analyzed using Cox proportional hazards models adjusted for demographic and vascular risk factors.ResultsDuring the 5-year follow-up period, 59 patients (12.1%) experienced recurrent stroke or TIA, and 118 (24.3%) experienced recurrent vascular events. After adjustments for demographic and vascular risk factors, and correction for multiple comparisons, higher plasma levels of CD62E (adjusted Hazard Ratio [aHR] per SD increment: 1.595, 95%CI, 1.186–2.145) and MIF (aHR: 1.581, 95%CI, 1.186–2.107) in the acute phase after stroke were statistically significantly associated with increased risk of recurrent stroke or TIA. The associations followed a dose-response pattern across quartiles of CD62E and MIF levels. Adding baseline CD62E and MIF levels to models including age, sex, vascular risk factors, and baseline C-reactive protein (CRP) levels led to significant improvements in the prediction of 5-year risk of recurrent stroke or TIA (ΔC-index 0.039 to 0.050).ConclusionsAmong stroke patients, higher baseline levels of CD62E and MIF improved prediction of 5-year risk of recurrent stroke or TIA on top of vascular risk factors and CRP levels. Whether assessment of these cytokines could improve patient selection for secondary prevention trials of anti-inflammatory treatments, should be explored in future studies.
Improving the Safety ofN,N-Dimethylacetamide (DMA) as a Potential Treatment for Preterm Birth in a Pregnant Mouse Model Using a Vaginal Nanoformulation
Authors: Mir Asad , Acosta Teeshavi , Concheiro-Guisan Marta , Yellon Steven M. , Patel Ketan , Reznik Sandra E. 
Published: January 2025

AbstractVaginal administration and the uterine first pass effect allow for preferential delivery of drugs to the reproductive tract. Dimethylacetamide has previously been shown to delay preterm birth in a pregnant mouse model when given intraperitoneally but the effectiveness of a vaginal nanoformulation of dimethylacetamide has yet to be tested. The purpose of this study was to compare the two formulations of dimethylacetamide for efficacy in rescuing pups from preterm birth in an inflammation-induced mouse model, effects on the maternal fetal interface, and pharmacokinetic profiles in maternal plasma. Timed pregnant CD1 mice were given a 1.56 mg/kg intraperitoneal dose of lipopolysaccharide followed by 3 doses of either vaginal dimethylacetamide or intraperitoneal dimethylacetamide. Mice were monitored for 48 hours and times of deliveries were recorded. Additionally, CD1 mice in late gestation were given a single dose of either vaginal or intraperitoneal dimethylacetamide and blood was drawn at 3 different time points following administration. Vaginal administration of dimethylacetamide had similar efficacy in delaying inflammation induced preterm birth as intraperitoneal administration but resulted in lower concentrations in the systemic circulation and decreased effects on the maternal fetal interface. Vaginal nanoformulations should be explored for their potential therapeutic value for the delay of preterm birth.
N,N-dimethylacetamide blocks inflammation-induced preterm birth and remediates maternal systemic immune responses
Authors: Reznik Sandra E. , Kashou Alexander , Ward Daylan , Yellon Steve M. 
Published: January 2025

AbstractThe common excipient, N,N-dimethylacetamide (DMA), prevents imminent endotoxin-induced preterm birth in mice. The present study hypothesized that DMA forestalls preterm birth to term (defined as day 18.5 or later) by attenuating bacterial endotoxin lipopolysaccharide (LPS)–induced maternal systemic inflammatory responses and cervix remodeling. Accordingly, LPS (i.p.) on day 15 postbreeding stimulated preterm delivery within 24 h while mice treated with DMA 2 h preceding and 9 h following LPS administration remained pregnant, comparable to saline and DMA controls, to deliver viable pups at term. Irrespective of LPS or DMA+LPS treatment, maternal plasma pro- and anti-inflammatory cytokines on day 15.5 (12 h post-LPS) increased 10-fold compared to baseline concentrations in controls. On day 16 of pregnancy, plasma concentrations of G-CSF and TNFα were reduced in the prepartum LPS+DMA group compared to those in postpartum mice given LPS. By day 18 of pregnancy, all cytokines returned to baseline - equivalent to low systemic levels throughout the study in saline and DMA controls that gave birth at term. In addition, maternal plasma progesterone declined within 12 h in prepartum LPS-treated mice to postpartum concentrations on day 16. Although a similar transient decrease occurred by 12 h in DMA+LPS mice, plasma progesterone returned to baseline concentrations in controls. Contemporaneously, the progression of prepartum cervix remodeling leading to preterm delivery was acutely forestalled by DMA without impeding birth at term. These findings support the hypothesis that DMA not only prevents inflammation-driven preterm birth, but rescues pregnancy for birth to occur at term. The results raise the possibility that maternal signals can forecast risk of preterm birth while selective suppression of systemic inflammation can mitigate adverse pregnancy outcomes.SummaryDMA rescues pregnancy from inflammation-induced preterm birth through a progesterone-independent mechanism that involves multiple proinflammatory cytokines in maternal circulation.Supported by NIH Grant 1R16GM145586 and the Ines Mandl Research Foundation
GLUT5 armouring enhances adoptive T cell therapy anti-tumour activity under glucose-limiting conditions
Authors: Page Robert , Martinez Olivier , Larcombe-Young Daniel , Bugallo-Blanco Eva , Papa Sophie , Perucha Esperanza 
Published: January 2025

AbstractCancer immunotherapy with engineered T cells has become a standard treatment for certain hematologic cancers. However, clinical trial outcomes for solid tumours are significantly lagging. A primary challenge in solid tumours is the lack of essential metabolites in the tumour microenvironment, such as glucose, due to poor vascularization and competition with tumour cells. To address this, we modified T cells to use fructose as an alternative energy source by introducing ectopic GLUT5 expression. We show that “GLUT5-armored” T cells, engineered with either chimeric antigen receptors (CARs) or an ectopic T cell receptor (TCR), achieve enhanced anti-tumour activity in low-glucose environments in bothin vitroandin vivomodels. This straightforward modification is compatible with current clinical approaches and may improve the efficacy of T cell therapies for solid tumours.Graphical Abstract
Evolution of species’ range and niche in changing environments
Authors: Polechová Jitka 
Published: January 2025

AbstractWhat determines the limits to adaptation and to a species’ range is a fundamental question, especially relevant in the context of current rapid environmental change. Yet, to date, no predictive theory incorporates the feedback between ecology and evolution while accounting for the evolution of genetic variance under selection, mutation, dispersal, and genetic drift. This study outlines a comprehensive theory showing that under joint evolutionary and population dynamics, the limits of adaptation are fundamentally determined by the three measurable parameters: i) the effective environmental gradient, ii) the effective rate of temporal change, and iii) the neighbourhood size, which represents the local population size accessible via dispersal. Dispersal across heterogeneous environments supports higher local genetic variance, facilitating adaptation to a faster temporal change. However, local diversity is depleted by genetic drift, which is measured by the inverse of neighbourhood size. Extending earlier predictions in stable environments, I use scaling arguments to derive a generalized expansion threshold – a tipping point where adaptation fails and the species’ range can no longer expand. Beyond this threshold, species’ ranges also tend to fragment, particularly when temporal change incurs a high fitness cost. The onset of fragmentation is rapid and associated with a loss of genetic variance. The theory not only identifies new phenomena but also establishes a fundamental relationship between these core measurable parameters. It provides a predictive framework for understanding species’ range and niche limits while advancing the theoretical foundations for assessing population resilience of spatially structured populations under unprecedented environmental change.
Reflection Knockoffs via Householder Reflection: Applications in Proteomics and Genetic Fine Mapping
Authors: Guan Yongtao , Levy Daniel 
Published: January 2025

AbstractWe present a novel knockoff construction method, and demonstrate its superior performance in two applications: identifying proteomic signatures of age and genetic fine mapping. Both applications involve datasets of highly correlated features, but they differ in the abundance of driver associations. Our primary contribution is the invention of the reflection knockoff, which is constructed from mirror images – obtained via Householder reflection – of the original features. The reflection knockoff substantially outperforms Fixed-X and Model-X knockoffs in feature selection, particularly when features are highly correlated. Our secondary contribution is a simple method to aggregate multiple sets of identically distributed knockoff statistics to improve the consistency of knockoff filters. In the study of proteomic signatures of age, single feature tests showed overly abundant proteomic association with age. However, knockoff filters using reflection knockoffs and aggregation revealed that a majority of these associations are hitchhikers. When applied to genetic fine mapping, knockoff filters using reflection knockoffs and aggregation outperform a state-of-the-art method. We discuss a promising application of reflection knockoffs: sharing genetic data without raising concerns about privacy and regulatory violations.
The inflammasome adaptor protein ASC triggers immunometabolic dysregulation induced by dysbiosis during obesity
Authors: Martinez-Garcia JJ , Rodríguez S , Guijarro A , Quevedo-Romero I , Mateo SV , Molina-López C , Hurtado-Navarro L , Baroja-Mazo A , Pelegrín P 
Published: January 2025

AbstractThe innate immune system oversees the response to danger signals. One of the most complexes organs that develops this response is the gut, which is extremely sensitive to the microbial changes in response to high saturated fat diets (HFD), leaving the space to be colonised by opportunistic bacteria, and triggering the innate immune response. Different evidence suggests the potential of the inflammasome in diet-induced inflammation, but little is known about its impact on the gut immunometabolic dysregulation. In this work, we report that the inflammasome adaptor apoptosis speck-like protein with a caspase activation domain (ASC) is essential for the development of obesity and insulin resistance during a high-fat diet (HFD). In ASC-deficient mice (Pycard-/-), lower weight gain and improved glucose tolerance were observed in comparison to wild type mice. Therefore, the absence of ASC reduces intestinal permeability and improves the benefitial effects of the gut microbiota, decreasing dysbiosis, making the intestinal environment healthier. Additionally,Pycard-/-mice presented an enhanced glycolysis and aerobic metabolism, contributing to reduced inflammation, fat accumulation in the liver and improved hepatic metabolic function. Developing therapies targeting ASC could be beneficial to treat obesity, type II diabetes, and metabolism-associated liver diseases.
Quantifying the organization and dynamics ofM. smegmatismorphology from Long-Term Time-Lapse Atomic Force Microscopy
Authors: Soubrier Clément , Madzvamuse Anotida , Eskandarian Haig Alexander , Dao Duc Khanh 
Published: January 2025

AbstractThe rod shapedMycobacterium smegmatisdisplays complex cell surface morphology, characterized by wave-form cell surface features and driven by asymmetric growth dynamics. To systematically analyze these morphological variations, we developed a comprehensive computational pipeline for automated processing of Long-Term Time-Lapse Atomic Force Microscopy (LTTL-AFM) images ofM. smegmatiscells cultured in axenic conditions of growth and stress. Upon running the pipeline to produce large enough datasets of single cell height profiles, we identify and statistically study key features that govern cell surface morphology: We confirm thatM. smegmatiscells undergo bi-phasic, asymmetric pole growth with constant elongation rate at the old pole and a shift in the rate of elongation after a lag phase at the new pole. Stable wave-form cell surface peaks and troughs propagate along the long axis of the cell, which emerge as a result of polar elongation. Backtracking in time from cell division, we detect that division-site selection occurs at the wave-trough nearest mid-cell. To reproduce the fundamental cell features observed, we introduced a reaction-diffusion mathematical model on an evolving one-dimensional surface. Our simulations indicate that the dynamic manifestation of wave-form cell surface morphology inM. smegmatiscan be explained by the interaction of as few as two “chemical species”, providing a plausible theoretical basis for how molecular determinants may functionally control wave-form morphology in pole-growing bacteria.
ATAC-seq as a versatile tool to portray genomes and epigenomes
Authors: Toumi Islem , Lecam Laurent , Roux Pierre-François 
Published: January 2025

ABSTRACTAssay for transposase-accessible chromatin using sequencing (ATAC-seq) is a cornerstone for epigenomic profiling, yet its potential for genomic characterization remains poorly explored. Here, we systematically benchmarked bulk ATAC-seq against whole-genome sequencing (WGS) to assess its capacity for detecting small variants, copy number variations (CNVs), telomeric content, and mitochondrial mutations. Using paired datasets from six melanoma cell lines, we demonstrated that ATAC-seq achieves reasonable precision in SNP detection, robustly profiles CNVs in the nuclear genome, and effectively quantifies mitochondrial genetic burden, with strong concordance to WGS at classical sequencing depths. Notably, we present the first systematic evaluation of telomeric length by ATAC-seq, revealing its untapped potential for studying cellular aging and genome stability. By bridging genomic and epigenomic insights into a single genome-wide approach, bulk ATAC-seq emerges as a cost-effective and versatile tool poised to transform cancer and aging research and advance clinical diagnostics through its integrative capabilities.
Ciliopathy-associated protein, CEP290, is required for ciliary necklace and outer segment membrane formation in retinal photoreceptors
Authors: Moye Abigail R. , Robichaux Michael A. , Agosto Melina A. , Rivolta Carlo , Moulin Alexandre P. , Wensel Theodore G. 
Published: January 2025

AbstractThe most common genetic cause of the childhood blinding disease Leber Congenital Amaurosis is mutation of the ciliopathy geneCEP290. Though studied extensively, the photoreceptor-specific roles of CEP290 remain unclear. Using advanced microscopy techniques, we investigated the sub-ciliary localization of CEP290 and its role in mouse photoreceptors during development. CEP290 was found throughout the connecting cilium between the microtubules and membrane, with nine-fold symmetry. In the absence of CEP290 ciliogenesis occurs, but the connecting cilium membrane is aberrant, and sub-structures, such as the ciliary necklace and Y-links, are defective or absent throughout the mid to distal connecting cilium. Transition zone proteins AHI1 and NPHP1 were abnormally restricted to the proximal connecting cilium in the absence of CEP290, while others like NPHP8 and CEP89 were unaffected. Although outer segment disc formation is inhibited in CEP290 mutant retina, we observed large numbers of extracellular vesicles. These results suggest roles for CEP290 in ciliary membrane structure, outer segment disc formation and photoreceptor-specific spatial distribution of a subset of transition zone proteins, which collectively lead to failure of outer segment formation and photoreceptor degeneration.
A putative ecocline inKlebsiella pneumoniae
Authors: Liu Siqi , Svensson Sarah L. , Falush Daniel 
Published: January 2025

AbstractAre quantitative traits important for bacteriology? The quantitative trait models used in animal and plant genetics assume that the trait takes continuous values and is influenced by many variants circulating in the population, each of which acts approximately independently. Amongst the many continuous-valued bacterial traits such as cell size or antibiotic minimum inhibitory concentration, we do not know of any for which these assumptions have been validated. We propose that such traits can be identified if they are the targets of selection and this selection structures overall genetic variation of the species. The phylogenetic trees of global strain collections ofKlebsiella pneumoniae(KP) have a “backbone”, which has not been explained. We propose that this backbone reflects a genome-wide component of variation, which is well-captured by Principal Components Analysis (PCA) applied to diverse KP genomes. We show that this structure can be recapitulated in simulations of diversifying selection on a quantitative trait and cannot be explained by neutral models. An implication is that variation in KP forms an ecocline – i.e. a cline generated by natural selection rather than geography but the trait underlying the cline, if it exists, remains to be determined.
H3K4 methylation-promoted transcriptional memory ensures faithful zygotic genome activation and embryonic development
Authors: Oak Meghana S. , Stock Marco , Mezes Matthias , Straub Tobias , Hynes-Allen Antony M. , van den Ameele Jelle , Forne Ignasi , Ettinger Andreas , Imhof Axel , Scialdone Antonio , Hörmanseder Eva 
Published: January 2025

SummaryIn the life of a vertebrate embryo, gene expression is initiated for the first time at zygotic genome activation (ZGA). Maternally expressed transcription factors present in the embryo are essential for this process. However, it is unknown if active chromatin modifications established in the gamete are propagated in the embryo as an epigenetic memory to support ZGA and embryonic development. Here, we provide evidence that inXenopus laevis, H3K4 methylation provides an epigenetic memory of active chromatin states. We show that this is required for faithful zygotic genome activation and successful embryonic development. Chromatin configurations of promoters displaying high H3K4me3 intensity and breadth, alongside DNA hypomethylation and increased GC content, are propagated from the gametes to the embryo across multiple cell divisions and a transcriptionally quiescent phase in early development. We show that this transmission of H3K4 methylation is essential for precise zygotic genome activation and expression of key pioneer ZGA transcription factors Pou5f3.2 and Sox3. Finally, we demonstrate that the H3K4 methyltransferases Kmt2b and Cxxc1 ensure transcription-independent propagation of H3K4me3 and proper zygotic gene expression. In summary, our study establishes the role of H3K4 methylation in maintaining memory of active chromatin states inXenopusembryos and reveals its importance for successful embryonic development.
Epigenetic priming of neural progenitors by Notch enhances Sonic hedgehog signaling and establishes gliogenic competence
Authors: Tran Luuli N. , Shinde Ashwini , Schuster Kristen H. , Sabaawy Aiman , Dale Emily , Welch Madalynn J. , Isner Trevor J. , Nunez Sylvia A. , García-Moreno Fernando , Sagerström Charles G. , Appel Bruce H. , Franco Santos J. 
Published: January 2025

ABSTRACTThe remarkable cell diversity of multicellular organisms relies on the ability of multipotent progenitor cells to generate distinct cell types at the right times and locations during embryogenesis. A key question is how progenitors establish competence to respond to the different environmental signals required to produce specific cell types at critical developmental timepoints. We addressed this in the mouse developing forebrain, where neural progenitor cells must switch from producing neurons to making oligodendrocytes in response to increased Sonic Hedgehog (SHH) signaling during late embryogenesis. We show that progenitor responses to SHH are regulated by Notch signaling, thus permitting proper timing of the neuron-oligodendrocyte switch. Notch activity epigenetically primes genes associated with the oligodendrocyte lineage and SHH pathway, enabling amplified transcriptional responses to endogenous SHH and robust oligodendrogenesis. These results reveal a critical role for Notch in facilitating progenitor competence states and influencing cell fate transitions at the epigenetic level.
Conformal duality of the nonlinear Schrödinger equation: Theory and applications to parameter estimation
Authors: Reinhardt David B. , Lee Dean , Schleich Wolfgang P. , Meister Matthias 
Published: January 2025

The nonlinear Schrödinger equation (NLSE) in one spatial dimension has stationary solutions similar to those of the linear Schrödinger equation (LSE) as well as more exotic solutions such as solitary waves and quantum droplets. Here, we present a newly discovered conformal duality which unifies the stationary and time-dependent traveling-wave solutions of the one-dimensional cubic-quintic NLSE, the cubic NLSE and LSE. Any two systems that are classified by the same single number called the cross ratio are related by this symmetry. Notably, the conformal duality can also be adapted in Newtonian mechanics and serves as a powerful tool for investigating physical systems that otherwise cannot be directly accessed in experiments. Further, we show that the conformal symmetry is a valuable resource to substantially improve NLSE parameter estimation from noisy empirical data by introducing an optimization afterburner. The new method therefore has far reaching practical applications for nonlinear physical systems.

Published by the American Physical Society
2025