Biology subjects

Schmidt, R.

Publications and source records attributed to Schmidt, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Intermittent water stress favors microbial generalists that better help wheat under drought

Microorganisms can improve plant resistance to drought through various mechanisms such as the production of plant hormones, osmolytes, antioxidants, and exopolysaccharides. It is, however, unclear how previous exposure to water stress affects the functional capacity of the soil microbial community to help plants resist drought. We compared two soils that had either a continuous or intermittent water stress history for almost forty years. We grew wheat in these soils and subjected it to a water stress, after which we collected the rhizosphere soil and shotgun sequenced its metagenome. Wheat growing in the soil with an intermittent water stress history maintained a higher fresh biomass when subjected to water stress. Genes related to resistance to drought were more abundant in the metagenome and more prevalent, diversified, and redundant in the metagenome assembled genomes of the soil with an intermittent water stress history as compared to the soil with a continuous water stress history. We suggest that an intermittent water stress history selects for generalists that are adapted to both low and replete water contents, and that these generalists harbor a larger repertoire of genes beneficial for life under water stress.

microbiology↗

bioRxiv2023

Genomic structures and regulation patterns at HPV integration sites in cervical cancer

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

genomics↗

bioRxiv2023

Uncovering the Environmental Conditions Required for Phyllachora maydis Infection and Tar Spot Development on Corn in the United States for Use as Predictive Models for Future Epidemics

Phyllachora maydis is a fungal pathogen causing tar spot of corn (Zea mays L.), a new and emerging, yield-limiting disease in the United States. Since being first reported in Illinois and Indiana in 2015, P. maydis can now be found across much of the corn growing of the United States. Knowledge of the epidemiology of P. maydis is limited but could be useful in developing tar spot prediction tools. The research presented here aims to elucidate the environmental conditions necessary for the development of tar spot in the field and the creation of predictive models to anticipate future tar spot epidemics. Extended periods (30-day windowpanes) of moderate ambient temperature were most significant for explaining the development of tar spot. Shorter periods (14- to 21-day windowpanes) of moisture (relative humidity, dew point, number of hours with predicted leaf wetness) were negatively correlated with tar spot development. These weather variables were used to develop multiple logistic regression models, an ensembled model, and two machine learning models for the prediction of tar spot development. This work has improved the understanding of P. maydis epidemiology and provided the foundation for the development of a predictive tool for anticipating future tar spot epidemics.

plant biology↗

bioRxiv2023

T helper cells exhibit a dynamic and reversible 3'UTR landscape.

3 untranslated regions (3UTRs) are critical elements of messenger RNAs, as they contain binding sites for RNA-binding proteins (RBP) and microRNAs that affect various aspects of the RNA life cycle including transcript stability and cellular localisation. In response to T cell receptor activation, T cells undergo massive expansion during the effector phase of the immune response and dynamically modify their 3UTRs. Whether this serves to directly regulate the abundance of specific mRNAs or is a secondary effect of proliferation remains unclear. To study 3UTR dynamics in T helper cells we investigated division-dependent alternative polyadenylation (APA). We generated 3 end UTR sequencing data from naive, activated, memory and regulatory CD4+ T cells. 3UTR length changes were estimated using a non-negative matrix factorization approach and were compared with those inferred from long-read PacBio sequencing. We found that APA events were transient and reverted after effector phase expansion. Using an orthogonal bulk RNAseq dataset, we did not find evidence of APA association with differential gene expression or transcript usage, indicating that APA has only a marginal effect on transcript abundance. 3UTR sequence analysis revealed conserved binding sites for T cell-relevant microRNAs and RBPs in the alternative 3UTRs. These results indicate that polyA site usage could play an important role in the control of cell fate decisions and homeostasis.

immunology↗

bioRxiv2022

Modular Pooled Discovery of Synthetic Knockin Sequences to Program Durable Cell Therapies

Chronic stimulation can cause T cell dysfunction and limit efficacy of cellular immunotherapies. CRISPR screens have nominated gene targets for engineered T cells, but improved methods are required to compare large numbers of synthetic knockin sequences to reprogram cell functions. Here, we developed Modular Pooled Knockin Screening (ModPoKI), an adaptable platform for modular construction of DNA knockin libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors. Over 20 ModPoKI screens across human TCR and CAR T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct to enhance long-term T cell fitness and anti-cancer function in vitro and in vivo. ModPoKIs modularity allowed us to generate a [~]10,000-member library of TF combinations. Non-viral knockin of a combined BATF-TFAP4 polycistronic construct further enhanced function in vivo. ModPoKI facilitates discovery of complex gene constructs to program cellular functions. HighlightsO_LIModular pooled knockins of hundreds of TF and surface receptor constructs combined with different antigen receptors C_LIO_LIChronic stimulation screens discover programs to improve T cell persistence C_LIO_LICombinatorial knockin screens with [~]10,000 transcription factor combinations C_LIO_LIBATF-TFAP4 dual knockin construct improves CAR T cell function in vitro and in vivo C_LI

immunology↗

bioRxiv2022

Assessment of 3D MINFLUX data for quantitative structural biology in cells revisited

Prakash and Curd provide a re-analysis1 of individual datasets taken from our report2 demonstrating MINFLUX 3D imaging in cells. Their evaluation confirms the unique localization precision provided by MINFLUX2,3 featuring a standard deviation of {sigma} = 1-3 nm. We appreciate their confirmation and also welcome the opportunity to clarify their remaining points. The hitherto almost unconceivable 3D localization precision attained by MINFLUX is likely to hold the key to an all-optical dynamical structural biology.

biophysics↗

bioRxiv2022

Two modes of mid-frontal theta suggest a role in conflict and error processing

Mid-frontal theta increases during scenarios when conflicts are successfully resolved. Often considered as a generic signal of cognitive control, its temporal nature has hardly been investigated. Using advanced spatiotemporal techniques, we uncover that mid-frontal theta occurs as a transient oscillation or "event" at single trials with their timing reflecting computationally distinct modes. Single-trial analyses of electrophysiological data from participants performing the Flanker (N = 28) and Simon task (N = 18) were used to probe the relationship between theta and metrics of response conflict. We specifically investigated "partial errors", in which a small burst of muscle activity in the incorrect response effector occurred, quickly followed by a correction. We found that transient theta events in single trials could be categorized into two distinct theta modes based on their relative timing to different task events. Theta events from the first mode occurred briefly after the task stimulus and might reflect conflict-related processing of the stimulus. In contrast, theta events from the second mode were more likely to occur around the time partial errors were committed, suggesting they were elicited by a potential upcoming error. Importantly, in trials in which a full error was committed, this "error-related theta" occurred too late with respect to the onset of the erroneous muscle response, supporting a role of theta also in error correction. We conclude that different modes of transient mid-frontal theta can be adopted in single trials not only to process stimulus conflict, but also to correct erroneous responses.

neuroscience↗

bioRxiv2022

Frequent co-regulation of splicing and polyadenylation by RNA-binding proteins inferred with MAPP

Maturation of eukaryotic pre-mRNAs via splicing, 3 end cleavage and polyadenylation is modulated across cell types and conditions by a variety of RNA-binding proteins (RBPs). Although over 1500 proteins are associated with RNAs in human cells, their binding motifs, targets and functions still remain to be elucidated, especially in the complex environment of human tissues and in the context of diseases. To overcome the lack of methods for systematic and automated detection of sequence motif-guided changes in pre-mRNA processing based on RNA sequencing (RNA-seq) data we have developed MAPP (Motif Activity on Pre-mRNA Processing). We demonstrate MAPPs functionality by applying it to RNA-seq data from 284 RBP knock-down experiments in the ENCODE project, from which MAPP not only infers position-dependent impact profiles of known regulators, but also reveals RBPs that modulate both the inclusion of cassette exons and the poly(A) site choice. Among these, the Polypyrimidine Tract Binding Protein 1 (PTBP1) has a similar activity in glioblastoma samples. This highlights the ability of MAPP to unveil global regulators of mRNA processing under physiological and pathological conditions.

systems biology↗

bioRxiv2021

Endoplasmic reticulum oxidoreductin (ERO) provides resilience against reductive stress and hypoxic conditions by mediating luminal redox dynamics

Oxidative protein folding in the endoplasmic reticulum (ER) depends on the coordinated action of protein disulfide isomerases and ER oxidoreductins (EROs). Strict dependence of ERO activity on molecular oxygen as the final electron acceptor implies that oxidative protein folding and other ER processes are severely compromised under hypoxia. While many key players involved in oxidative protein folding are known, our understanding of how redox homeostasis in the ER is maintained and how EROs, the Cys residues of nascent proteins, and the luminal glutathione redox buffer interact is limited. Here, we isolated viable ero1 ero2 double mutants largely deficient in ERO activity, which rendered the mutants highly sensitive to reductive stress and hypoxia. To elucidate the specific redox dynamics in the ER lumen in vivo, we expressed the glutathione redox potential (EGSH) sensor Grx1-roGFP2iL-HDEL with a midpoint potential of -240 mV in the ER of Arabidopsis plants. We found EGSH values of -241 mV in wild-type plants, which is less oxidizing than previously estimated. In the ero1 ero2 mutants, luminal EGSH was reduced further to -253 mV. Recovery to reductive ER stress, as induced by acute exposure to dithiothreitol, was delayed in ero1 ero2 mutants. The characteristic signature of EGSH dynamics in the ER lumen triggered by hypoxia was affected in the ero1 ero2 mutant reflecting a disrupted balance of reductive and oxidizing inputs, including nascent polypeptides and glutathione entry. The ER redox dynamics can now be dissected in vivo, revealing a central role of EROs as major redox integrators to promote luminal redox homeostasis. One sentence summaryDynamic monitoring the ER luminal glutathione redox potential highlights the role of EROs in defining redox conditions and the interplay between different redox inputs during hypoxia and reductive stress.

plant biology↗

bioRxiv2021

Investigating the genetic and environmental basis of head micromovements during MRI

IntroductionHead motion during magnetic resonance imaging is heritable. Further, it shares phenotypical and genetic variance with body mass index (BMI) and impulsivity. Yet, to what extent this trait is related to single genetic variants and physiological or behavioral features is unknown. We investigated the genetic basis of head motion in a meta-analysis of genome-wide association studies. Further, we tested whether physiological or psychological measures, such as respiratory rate or impulsivity, mediated the relationship between BMI and head motion. MethodsWe conducted a genome-wide association meta-analysis for mean and maximal framewise head displacement (FD) in seven population neuroimaging cohorts (UK Biobank, LIFE-Adult, Rotterdam Study cohort 1-3, Austrian Stroke Prevention Family Study, Study of Health in Pomerania; total N = 35.109). We performed a pre-registered analysis to test whether respiratory rate, respiratory volume, self-reported impulsivity and heart rate mediated the relationship between BMI and mean FD in LIFE-Adult. ResultsNo variant reached genome-wide significance for neither mean nor maximal FD. Neither physiological nor psychological measures mediated the relationship between BMI and head motion. ConclusionBased on these findings from a large meta-GWAS and pre-registered follow-up study, we conclude that the previously reported genetic correlation between BMI and head motion relies on polygenic variation, and that neither psychological nor simple physiological parameters explain a substantial amount of variance in the association of BMI and head motion. Future imaging studies should thus rigorously control for head motion at acquisition and during preprocessing.

neuroscience↗

bioRxiv2021

Visualization of bacterial type 3 secretion system components down the molecular level by MINFLUX nanoscopy

Type 3 secretion systems (T3SS) are essential virulence factors of numerous bacterial pathogens and inject effector proteins into host cells. The needle-like T3SS machinery consists of more than 20 components, has a length of around 100 nm and a diameter of up to 30 nm according to EM studies. Its intrabacterial components are highly dynamic and in permanent exchange with other bacterial structures. Therefore, a temporally and spatially resolved visualization of the T3SS using fluorescence microscopy techniques has been challenging. In the present study, novel labeling strategies were combined with super-resolution microscopy such as STED, STORM and MINFLUX. MINFLUX nanoscopy allowed to visualize components of the T3SS machinery such as the dynamic sorting platform component YscL and the extrabacterial pore protein YopD at unprecedented resolutions. The presented results represent the basis for an in depth investigation of T3SS structure and function and therefore gain new insights into the infection process of human pathogens in order to develop novel treatment and prevention strategies.

microbiology↗

bioRxiv2021

ERM-1 phosphorylation and NRFL-1 redundantly control lumen formation in the C. elegans intestine

Reorganization of the plasma membrane and underlying actin cytoskeleton into specialized domains is essential for the functioning of most polarized cells in animals. Proteins of the ezrin-radixin-moesin (ERM) and Na+/H+ exchanger 3 regulating factor (NHERF) family are conserved regulators of cortical specialization. ERM proteins function as membrane-actin linkers and as molecular scaffolds that organize the distribution of proteins at the membrane. NHERF proteins are PDZ-domain containing adapters that can bind to ERM proteins and extend their scaffolding capability. Here, we investigate how ERM and NHERF proteins function in regulating intestinal lumen formation in the nematode Caenorhabditis elegans. C. elegans has single ERM and NHERF family proteins, termed ERM-1 and NRFL-1, and ERM-1 was previously shown to be critical for intestinal lumen formation. Using CRISPR/Cas9-generated nrfl-1 alleles we demonstrate that NRFL-1 localizes at the intestinal microvilli, and that this localization is depended on an interaction with ERM-1. However, nrfl-1 loss of function mutants are viable and do not show defect in intestinal development. Interestingly, combining nrfl-1 loss with erm-1 mutants that either block or mimic phosphorylation of a regulatory C-terminal threonine causes severe defects in intestinal lumen formation. These defects are not observed in the phosphorylation mutants alone, and resemble the effects of strong erm-1 loss of function. The loss of NRFL-1 did not affect the localization or activity of ERM-1. Together, these data indicate that ERM-1 and NRFL-1 function together in intestinal lumen formation in C. elegans. We postulate that the functioning of ERM-1 in this tissue involves actin-binding activities that are regulated by the C-terminal threonine residue and the organization of apical domain composition through NRFL-1.

cell biology↗

bioRxiv2021

Characterization of the composition and functioning of the Crumbs complex in C. elegans

The apical domain of epithelial cells can acquire a diverse array of morphologies and functions, which is critical for the function of epithelial tissues. The Crumbs proteins are evolutionary conserved transmembrane proteins with essential roles in promoting apical domain formation in epithelial cells. The short intracellular tail of Crumbs proteins interacts with a variety of proteins, including the scaffolding protein Pals1 (protein associated with LIN7, Stardust in Drosophila). Pals1 in turn binds to a second scaffolding protein termed PATJ (Pals1-associated tight junction protein), to form the core Crumbs/Pals1/PATJ Crumbs complex. While essential roles in epithelial organization have been shown for Crumbs proteins in Drosophila and mammalian systems, the three Caenorhabditis elegans crumbs genes are dispensable for epithelial polarization and animal development. Moreover, the presence and functioning of orthologs of Pals1 and PATJ has not been investigated. Here, we identify MAGU-2 and MPZ-1 as the C. elegans orthologs of Pals1 and PATJ, respectively. We show that MAGU-2 interacts with all three Crumbs proteins as well as MPZ-1, and localizes to the apical membrane domain in a Crumbs-dependent fashion. Similar to crumbs mutants, a magu-2 null mutant shows no developmental or epithelial polarity defects. Finally, we show that overexpression of the Crumbs proteins EAT-20 or CRB-3 in the C. elegans intestine can lead to apical membrane expansion. Our results shed light into the composition of the C. elegans Crumbs complex and indicate that the role of Crumbs proteins in promoting apical domain formation is conserved.

developmental biology↗

bioRxiv2021

Transient beta modulates decision thresholds during human action-stopping

Action-stopping in humans involves bursts of beta oscillations in prefrontal-basal ganglia regions. To determine the functional role of these beta bursts we took advantage of the Race Model framework describing action-stopping. We incorporated beta bursts in three race model variants, each implementing a different functional contribution of beta to action-stopping. In these variants, we hypothesized that a transient increase in beta could 1) modulate decision thresholds, 2) change stop accumulation rates, or 3) promote the interaction between the Stop and the Go process. We then tested the model predictions using EEG recordings in humans performing a Stop-signal task. We found that the model variant in which beta increased decision thresholds for a brief period of time best explained the empirical data. The model parameters fitted to the empirical data indicated that beta bursts involve a stronger decision threshold modulation for the Go process than for the Stop process. This suggests that prefrontal beta influences stopping by temporarily holding the response from execution. Our study further suggests that human action-stopping could be multi-staged with the beta acting as a pause, increasing the response threshold for the Stop process to modulate behavior successfully. Our novel approach of introducing transient oscillations into the race model and testing against human neurophysiological data allowed us to discover potential mechanisms of prefrontal beta, possibly generalizing its role in situations requiring executive control over actions.

neuroscience↗

bioRxiv2021

Resolving the molecular architecture of the photoreceptor active zone by MINFLUX nanoscopy

Cells assemble macromolecular complexes into scaffoldings that serve as substrates for catalytic processes. Years of molecular neurobiology indicate that neurotransmission depends on such optimization strategies, yet the molecular topography of the presynaptic Active Zone (AZ) where transmitter is released upon synaptic vesicle (SV) fusion remains to be visualized. Therefore, we implemented MINFLUX optical nanoscopy to resolve the AZ of rod photoreceptors. To facilitate MINFLUX nanoscopy of the AZ, we developed and verified an immobilization technique, we name Heat Assisted Rapid Dehydration (HARD). Here fresh retinal slices are directly stamped onto glass coverslips yielding a single layer of rod AZs. These AZs exhibited excellent labeling efficiency and minimal signal redundancy in the Z-direction. Our data indicate that the SV release site is a molecular complex of bassoon-Rab3-binding molecule 2 (RIM2)-ubMunc13-2-CAST. The complexes are serially duplicated longitudinally, and reflected in register along the axis of symmetry of the synaptic ribbon. One sentence summaryStructural motifs formed by active zone proteins at the photoreceptor synapse.

neuroscience↗

bioRxiv2021

CRISPR activation and interference screens in primary human T cells decode cytokine regulation

The pathways that regulate cytokine responses in T cells are disrupted in autoimmunity, immune deficiencies, and cancer, and include immunotherapy targets. Systematic discovery of cytokine regulators requires both loss-of-function and gain-of-function studies, which have been challenging in primary human cells. We now have accomplished genome-wide pooled CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) screens in primary human T cells to map gene networks controlling Interleukin-2 and Interferon-{gamma} production. Arrayed CRISPRa confirmed key hits and enabled multiplexed T cell secretome characterization, revealing reshaped cytokine responses driven by individual regulators. CRISPRa uncovered genes not canonically expressed in T cells, including the transcription factor FOXQ1, whose overexpression promoted the expression of most cytokines, while selectively dampening T helper 2 (Th2) cytokines. Paired CRISPRa and CRISPRi screens reveal signaling components that tune critical immune cell functions, which could inform design of future immunotherapies.

immunology↗

bioRxiv2021

Caenorhabditis elegans LET-413 Scribble is essential in the epidermis for growth, viability, and directional outgrowth of epithelial seam cells

The conserved adapter protein Scribble (Scrib) plays essential roles in a variety of cellular processes, including polarity establishment, proliferation, and directed cell migration. While the mechanisms through which Scrib promotes epithelial polarity are beginning to be unraveled, its roles in other cellular processes including cell migration remain enigmatic. In C. elegans, the Scrib ortholog LET-413 is essential for apical-basal polarization and junction formation in embryonic epithelia. However, whether LET-413 is required for postembryonic development or plays a role in migratory events is not known. Here, we use inducible protein degradation to investigate the functioning of LET-413 in larval epithelia. We find that LET-413 is essential in the epidermal epithelium for growth, viability, and junction maintenance. In addition, we identify a novel role for LET-413 in the polarized outgrowth of the epidermal seam cells. These stem cell-like epithelial cells extend anterior and posterior directed apical protrusions in each larval stage to reconnect to their neighbors. We show that the role of LET-413 in seam cell outgrowth is mediated at least in part by the junctional component DLG-1 discs large, which appears to restrict protrusive activity to the apical domain. Finally, we demonstrate that the Rho-family GTPases CED-10 Rac and CDC-42 can regulate seam cell outgrowth and may also function downstream of LET-413. Our data uncover multiple essential functions for LET-413 in larval development and shed new light on the regulation of polarized outgrowth of the seam cells.

developmental biology↗

bioRxiv2021

MRI Radiomic Signature of White Matter Hyperintensities Is Associated with Clinical Phenotypes

IntroductionNeuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of describing the texture of conventional images beyond what meets the naked eye, radiomic analyses hold potential for evaluating brain health. We sought to: 1) evaluate this novel approach to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and 2) uncover associations between predictive radiomic features and patients clinical phenotypes. MethodsOur analyses were based on a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images and corresponding deep-learning-generated total brain and WMH segmentation. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with the most stable selected features predictive of WMH burden and then related this signature to clinical variables (age, sex, hypertension (HTN), atrial fibrillation (AF), diabetes mellitus (DM), coronary artery disease (CAD), and history of smoking) using canonical correlation analysis. ResultsRadiomic features were highly predictive of WMH burden (R2=0.855{+/-}0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1-6<.001, p-valueCV7=.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and DM, CV4 by HTN, CV5 by AF and DM, CV6 by CAD, and CV7 by CAD and DM. ConclusionRadiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes. Further research could evaluate radiomics to predict the progression of WMH. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe did a systematic review on PubMed until December 1, 2020, for original articles and reviews in which radiomics were used to characterize stroke or cerebrovascular diseases. Radiomic analyses cover a broad ensemble of high-throughput quantification methods applicable to digitalized medical images that extract high-dimensional data by describing a given region of interest by its size, shape, histogram, and relationship between voxels. We used the search terms "radiomics" or "texture analysis", and "stroke", "cerebrovascular disease", "small vessel disease", or "white matter hyperintensities". Our research identified 24 studies, 18 studying radiomics of stroke lesions and 6 studying cerebrovascular diseases. All the latter six studies were based on MRI (T1-FLAIR, dynamic contrast-enhanced imaging, T1 & T2-FLAIR, T2-FLAIR post-contrast, T2-FLAIR, and T2-TSE images). Four studies were describing small vessel disease, and two were predicting longitudinal progression of WMH. The average sample size was small with 96 patients included (maximum: 204). One study on 141 patients identified 7 T1-FLAIR radiomic features correlated with cardiovascular risk factors (age and hyperlipidemia) using univariate correlations. All studies were monocentric and performed on a single MRI scanner. Added value of this studyTo date and to the best of our knowledge, this is the largest radiomics study performed on cerebrovascular disease or any topic, and one of the very few to include a great diversity of participating sites with diverse clinical MRI scanners. This study is the first one to establish a radiomic signature of WMH and to interpret its relationship with common cardiovascular risk factors. Our findings add to the body of evidence that damage caused by small vessel disease extend beyond the visible white matter hyperintensities, but the added value resides in the detection of that subvisible damage on routinely acquired T2-FLAIR imaging. It also suggests that cardiovascular phenotypes might manifest in distinct textural patterns detectable on conventional clinical-grade T2-FLAIR images. Implications of all the available evidenceAssessing brain structural integrity has implications for treatment selection, follow-up, prognosis, and recovery prediction in stroke patients but also other neurological disease populations. Measuring cerebral parenchymal structural integrity usually requires advanced imaging such as diffusion tensor imaging or functional MRI. Translation of those neuroimaging biomarkers remains uncommon in clinical practice mainly because of their time-consuming and costly acquisition. Our study provides a potential novel solution to assess brains structural integrity applicable to standard, routinely acquired T2-FLAIR imaging. Future research could, for instance, benchmark this radiomics approach against diffusion or functional MRI metrics in the prediction of cognitive or functional outcomes after stroke.

neuroscience↗