Biology subjects

de Jong, J.

Publications and source records attributed to de Jong, J..

12 recordsLinked to original sources

bioRxiv2026

Endothelial gain of PIEZO/TRPV mechanosensors drives cavernous malformations

Vascular disease often begins as a failure to read mechanical force. Cerebral cavernous malformations (CCMs) are leaky, brain-invading capillary clusters that cause stroke and seizures and arise from endothelial loss of the CCM complex. They form exclusively in low-flow vessels but existing models cannot explain this selectivity. We previously established that CCM-mutant endothelium inverts its adhesive balance, weakening cell-cell junctions while building matrix-degrading adhesions. The mechanosensors imposing this switch are unknown. Here we show that the mechanosensitive Ca2+ channels PIEZO1, TRPV2 and TRPV4 are overexpressed in the endothelium of CCM lesions in a 42-patient cohort, and that lesion volume scales with their expression level. Mechanistically, PIEZO1 partners with TRPV4 to destabilise cell-cell junctions and with TRPV2 to reinforce cell-matrix adhesions; silencing TRPV4 restores junctional integrity and abolishes KLF4 induction, whereas silencing TRPV2 or inhibition with tranilast abolishes matrix degradation and invasion. In vivo, trpv4 knockdown or inhibition with GSK2798745 restores atrioventricular canal morphogenesis in ccm2-mutant zebrafish. Gain of mechanosensory channel function is thus a causal step in CCM pathogenesis, upstream of the KLF program. Combined therapeutic targeting of TRPV2 and TRPV4 with inhibitors validated in humans offers a route to therapy.

cell biology↗

bioRxiv2026

Briefer than brief - uncovering the true temporal resolution of the visual system

The temporal resolution of vision is seriously limited. However, the response to a very brief flash, called the impulse response, is already quite sluggish at the earliest stages of vision, potentially obscuring the true temporal resolution of the rest of the visual system. Faster monitors that produce briefer flashes are subject to diminishing returns because, by definition, they cannot elicit responses that are any briefer than the impulse response. Here, taking inspiration from previous attempts, we develop a novel technique for presenting flashes that elicit 'briefer-than-brief' visual responses. Using a simple deconvolution technique, we reverse-engineer the visual response and estimate the form that the stimulus should take to elicit the response that a faster visual system would produce to a normal flash. Using psychophysics on human observers, we demonstrate that these 'briefer-than-brief' (BTB) flashes partially bypass the temporal limits presumably imposed by the early visual system using two paradigms: one that requires temporal segregation and one that requires temporal integration of sequential flashes. With BTB flashes, human observers successfully isolated two successive flashes at shorter intervals than with conventional flashes, improving temporal resolution by around 16%. We found that BTB stimuli not only improved temporal resolution, but also induced poorer performance on tasks requiring temporal integration, suggesting that the visual responses elicited by BTB flashes overlap less in time due to their briefer duration. In sum, our findings suggest that, using reverse-engineered stimuli, we can alleviate a temporal bottleneck that probably originates from the earliest stages of vision. In doing so, we allow higher visual areas to operate at a higher temporal resolution than previously thought possible.

neuroscience↗

bioRxiv2026

Image-based Disease-wide Association Study via Self-supervised Learning links Abdominal MRI Features to 158 Diseases

Medical images contain rich phenotypic information that is often not fully captured by manual clinical assessment. Here, we present a systematic framework for extracting such information and conducting image-based disease-wide association studies (iDWAS) using self-supervised learning (SSL). We applied this framework to abdominal MRI data from the UK Biobank and evaluated associations between MRI-derived features and 562 diseases. Features were learned using a VICReg-based SSL model and tested for disease associations using logistic regression models. We identified 158 diseases that were significantly associated with the MRI-derived features, including the ones which are not directly linked to abdominal anatomy. Focusing on Metabolic dysfunction-associated steatohepatitis (MASH), we showed that the MRI-derived features captured disease-relevant information and separated MASH cases from controls better than established biomarkers such as PDFF and Iron-cT1. These findings highlight the ability of SSL to uncover clinically meaningful signals from routine imaging data. The proposed framework is broadly applicable to other imaging datasets and modalities, enabling more systematic approaches to incidental and early disease detection. The trained model and analysis pipeline are publicly available at https://github.com/srm2022/iDWAS. BackgroundMedical images, often analyzed manually by clinicians, contain valuable information that may not be fully captured by the human eye. Machine Learning (ML) has demonstrated significant potential in extracting this information, allowing us to enhance our understanding of underlying pathologies. We present a systematic framework for extracting such information and performing image-based disease-wide association studies (iDWAS) using self-supervised learning. We then applied the framework to abdominal Magnetic Resonance Imaging (MRI) from UK Biobank (UKB) and investigated the associations between MRI-derived features and 562 diseases. Finally, we delved deeper into the observed associations for Metabolic dysfunction-associated steatohepatitis (MASH), a prevalent yet underdiagnosed condition with a high unmet need for non-invasive diagnostic tools. MethodsWe extracted features from MRI images using VICReg-based self-supervised learning and modeled the associations of the extracted features with 562 diseases using logistic regression. Using the likelihood ratio (LR) test, we then assessed how much additional variance can be explained by the MRI-derived features relative to the variance explained by a null model including only common confounders such as age, gender, and BMI. ResultsOf these 562 diseases, we identified 158 diseases to be significantly associated with the MRI-derived features. While many of them (e.g. MASH) are known to primarily emerge in the abdomen, others (e.g. neuropsychiatric diseases) are not. Taking MASH as a use-case and adjusting for MASH-specific confounding, we then showed that our MRI-derived features captured additional MASH-relevant information compared to standard MRI-derived biomarkers of liver health such as proton density fat fraction (PDFF) and iron-corrected T1 (Iron-cT1). The trained SSL model and analysis pipeline are available at https://github.com/srm2022/iDWAS. ConclusionsOur results illustrate (1) how MRIs from one organ of the body can inform about the diseases primarily rooted in other organs of the body, reflecting patients overall health status, and (2) how SSL can extract more information relevant for specific diseases compared to current state-of-the-art biomarkers. Our framework can be applied to other MRI datasets as well as other imaging modalities with minimal adjustment, providing opportunities for the development of more systematic approaches to incidental diagnosing, i.e. (early) detection of diseases falling outside the scope of the original imaging procedure.

bioinformatics↗

bioRxiv2026

Neural acceleration drives adaptations in working memory encoding speed

Humans and non-human animals adaptively boost their encoding speed when they expect limited sensory exposure time, so that they can capture essential information before it is gone. However, it is unclear how the brain implements this crucial adaptation. Using multivariate pattern analysis of human EEG data, we found that an accelerated neural code underlies adaptations in visual working memory encoding speed.

neuroscience↗

bioRxiv2026

Serial dependence in duration perception reveals reliability-weighted updating of the prior

Bayesian theories of perception propose that perceptual estimates result from the integration of prior beliefs ("priors") with sensory input ("likelihood"), weighted by their reliability. While Bayesian theories assume that priors are continuously updated over time, empirical evidence for such reliability-weighted updating modulating sequential percepts remains lacking. Here, we leverage a behavioral phenomenon called serial dependence--in which perceptual judgments are attracted toward previous stimuli--to test a central prediction of Bayesian theories: that perceptual estimates are sequentially updated according to the reliability of successive stimuli. We used a duration reproduction task in which the reliability of perceived duration was manipulated via signal-to-noise ratio by embedding stimuli in dynamic white noise. Consistent with the prediction of Bayesian theories, serial dependence in perceived duration was enhanced by increased reliability of previous stimuli and attenuated by increased reliability of current stimuli. Computational modeling revealed that changes in sensory noise (i.e., the width of the likelihood) can account for the reliability-dependent modulation of serial dependence. These findings provide empirical evidence for reliability-weighted updating, supporting a central prediction of Bayesian theories that prior information and sensory input are iteratively integrated to calibrate perceptual estimates.

neuroscience↗

bioRxiv2025

A global survey of intramolecular isopeptide bonds

Many protein domains harbour covalent intramolecular bonds that enhance their stability and resistance to thermal, mechanical and proteolytic insults. Intramolecular isopeptide bonds represent one such covalent interaction, yet their distribution across protein domains and organisms has been largely unexplored. Here, we sought to address this by employing a large-scale prediction of intramolecular isopeptide bonds in the AlphaFold database using the structural template-based software Isopeptor. Our findings reveal an extensive phyletic distribution in surface proteins resembling fibrillar adhesins and pilins. All identified intramolecular isopeptide bonds are found in two structurally distinct folds, CnaA-like or CnaB-like, from a relatively small set of related Pfam families, including ten novel families that we predict to contain intramolecular isopeptide bonds. One CnaA-like domain of unknown function, DUF11 (renamed here to "CLIPPER") is broadly distributed in cell-surface proteins from Gram-positive bacteria, Gram-negative bacteria, and archaea, and is structurally and biophysically characterised in this work. Using X-ray crystallography, we resolve a CLIPPER domain from a Gram-negative fibrillar adhesin that contains an intramolecular isopeptide bond and further demonstrate that it imparts thermostability and resistance to proteolysis. Our findings demonstrate the extensive distribution of intramolecular isopeptide bond-containing protein domains in nature, and structurally resolve the previously cryptic CLIPPER domain.

bioinformatics↗

bioRxiv2023

Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth

Force-driven cellular interactions are known to play a critical role in cancer cell invasion, but have remained largely unexplored in the context of vascular abnormalities, partly due to a lack of suitable genetic and cellular models. One such vascular abnormality, cerebral cavernous malformation (CCM) is characterized by leaky, tumor-like vessels in the brain, where CCM mutant cells recruit wild-type cells from the surrounding endothelium to form mosaic lesions and promote lesion growth; however the mechanisms underlying this recruitment remain poorly understood. Here, we use 3D traction force microscopy in a in-vitro model of early angiogenic invasion to reveal that hyper-angiogenic CCM2-silenced endothelial cells enhance angiogenic invasion of neighboring wild-type cells through force and extracellular matrix-guided mechanisms. We show that mechanically hyperactive CCM2-silenced tips guide wild-type cells by exerting and transmitting pulling forces and by leaving degraded paths in the matrix as cues promoting invasion in a ROCKs-dependent manner. This transmission of forces is associated with a reinforcement of {beta}1 integrin-dependent adhesive sites and actin cytoskeleton in the wild-type followers. We also show that during this process wild-type cells are reprogrammed into stalk cells through activation of matrisome and DNA replication programs, eventually leading to cell proliferation. These observations unveil a novel vascular lesion growth mechanism where CCM2 mutants hijack the function of wild-type cells to fuel CCM lesion growth. By integrating biophysical computational methodologies to quantify cellular forces with advanced molecular techniques, we provide new insights in the etiology of vascular malformations, and open up avenues to study the role of cell mechanics in tissue heterogeneity and disease progression.

bioengineering↗

bioRxiv2023

Dietary cystine restriction increases the proliferative capacity of the small intestine of mice

Over 88 million people are currently estimated to have adopted towards a vegan or vegetarian diet. Cysteine is a semi-essential amino acid, which availability is largely dependent on dietary intake of meat, eggs and whole grains. Vegan/vegetarian diets are therefore inherently low in cysteine concentrations. Sufficient uptake of cysteine is crucial, as it serves as substrate for protein synthesis and conversion to taurine and glutathione. In this study, we therefore investigate the effect of low dietary cystine, the oxidized derivative of cysteine, on intestinal epithelial layer function. Mice (8/group) received a high fat diet with normal or low cystine concentration for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels after 2 weeks. Stem cell markers as well as the proliferation marker Ki67 were increased upon cystine restriction in the small intestine. In line with this, gene set enrichment analysis indicated enrichment of Wnt signaling in the small intestine of mice on the low cystine diet, indicative of proliferative cells. Increased proliferation was absent in the colon. In the colon, dietary cystine restriction results in an increase in goblet cells, but no significant changes in the thickness of the mucus barrier or in its protective capacity. Also the microbiome was not changed upon dietary restriction. In conclusion, we show that cystine restriction for two weeks does not seem to induce any systemic effects. The increased proliferative capacity and number of goblet cells observed in the intestine may be the effect of starting epithelial damage or a reaction of the epithelium to start enlarging the absorptive capacity.

molecular biology↗

bioRxiv2022

The effects of gamma-aminobutyric acid (GABA) on working memory and attention: A randomized, double-blind, placebo-controlled, crossover trial

Background{gamma}-aminobutyric acid (GABA) is a primary inhibitory neurotransmitter that plays a significant role in the central nervous system. Studies on both animals and humans show it has the pharmacological potential for reducing the impact of cognitive disorders, as well as enhancing cognitive functions and mood. However, its specific effects on human attention and working memory have not yet been extensively studied. AimsIn this randomised, double-blind, placebo-controlled, and crossover trial, we aimed to test whether the administration of 800 mg GABA, dissolved in a drink, acutely affected visual working memory maintenance, as well as temporal and spatial attention in healthy adults. MethodsThe participants were 32 young adults (16 females and 16 males). Working memory recall precision, spatial attention and temporal attention were measured by a delayed match-to-sample task, a visual search task, and a speeded rapid serial visual presentation task, respectively. Participants completed two experimental sessions (GABA and Placebo) in randomized and counterbalanced order. In each session, forty-five minutes after administration of the drink, they completed the all three of the aforementioned cognitive tasks. ResultsLinear mixed model analysis results showed that GABA increased visual search time, compared to the placebo, but did not affect visual search accuracy, temporal attention, nor visual working memory precision. ConclusionsThe results suggest that GABA increases visual search time but does not affect temporal attention and memory, and that previously reported effects on cognition might rely on other functions.

neuroscience↗

bioRxiv2022

Adaptive Encoding Speed in Working Memory

Humans can adapt when complex patterns unfold at a faster or slower pace, for instance when remembering a grocery list that is dictated at an increasingly fast pace. Integrating information over such timescales crucially depends on working memory, but although recent findings have shown that working memory capacity can be flexibly adapted, such adaptations have not yet been demonstrated for encoding speed. In a series of experiments, we found that young adults encoded at a faster rate when they were adapted to overall and recent rate of incoming information. Interestingly, our participants were unable to use explicit cues to speed up encoding, even though these cues were objectively more informative than statistical information. Our findings suggest that adaptive tuning of encoding speed in working memory is a fundamental but largely implicit mechanism underlying our ability to keep up with the pace of our surroundings. Significance StatementHumans can store information very quickly. For instance, when we hear someone speak twice as fast as normal, we can still follow quite well. How is this possible? We hypothesized that when humans expect limited time to store a piece of information (e.g. when listening to a sped-up podcast) they would ideally store that information more quickly before its gone. Indeed, we found that young adults encoded more information per second when they implicitly expect that they have little time to do so. However, they were unable to use explicit cues about how much time they have. It seems that young adults can, at least implicitly, tune the pace at which they store information.

neuroscience↗

bioRxiv2021

Quality control strategies for brain MRI segmentation and parcellation: practical approaches and recommendations - insights from The Maastricht Study

BackgroundQuality control of brain segmentation is a fundamental step to ensure data quality. Manual quality control is the current gold standard, despite unfeasible in large neuroimaging samples. Several options for automated quality control have been proposed, providing potential time efficient and reproducible alternatives. However, those have never been compared side to side, which prevents to reach consensus in the appropriate QC strategy to use. This study aims to elucidate the changes manual editing of brain segmentations produce in morphological estimates, and to analyze and compare the effects of different quality control strategies in the reduction of the measurement error. MethodsWe used structural MR images from 259 participants of The Maastricht Study. Morphological estimates were automatically extracted using FreeSurfer 6.0. A subsample of the brain segmentations with inaccuracies was manually edited, and morphological estimates were compared before and after editing. In parallel, 11 quality control strategies were applied to the full sample. Those included: a manual strategy, manual-QC, in which images were visually inspected and manually edited; five automated strategies where outliers were excluded based on the tools MRIQC and Qoala-T, and the metrics morphological global measures, Euler numbers and Contrast-to-Noise ratio; and five semi-automated strategies, were the outliers detected through the mentioned tools and metrics were not excluded, but visually inspected and manually edited. We used a regression of morphological brain measures against age as a test case to compare the changes in relative unexplained variance that each quality control strategy produces, using the reduction of relative unexplained variance as a measure of increase in quality. ResultsManually editing brain surfaces produced changes particularly high in subcortical brain volumes and moderate in cortical surface area, thickness and hippocampal volumes. The exclusion of outliers based on Euler numbers yielded a larger reduction of relative unexplained variance for measurements of cortical area, subcortical volumes and hippocampal subfields, while manual editing of brain segmentations performed best for cortical thickness. MRIQC produced a lower, but consistent for all types of measures, reduction in relative unexplained variance. Unexpectedly, the exclusion of outliers based on global morphological measures produced an increase of relative unexplained variance, potentially removing more morphological information than noise from the sample. ConclusionOverall, the automatic exclusion of outliers based on Euler numbers or MRIQC are reliable and time efficient quality control strategies that can be applied in large neuroimaging cohorts.

neuroscience↗

bioRxiv2020

Advanced in silico validation framework forthree-dimensional Traction Force Microscopy andapplication to an in vitro model of sproutingangiogenesis

In the last decade, cellular forces in three-dimensional hydrogels that mimic the extracellular matrix have been calculated by means of Traction Force Microscopy (TFM). However, characterizing the accuracy limits of a traction recovery method is critical to avoid obscuring physiological information due to traction recovery errors. So far, 3D TFM algorithms have only been validated using simplified cell geometries, bypassing image processing steps or arbitrarily simulating focal adhesions. Moreover, it is still uncertain which of the two common traction recovery methods, i.e., forward and inverse, is more robust against the inherent challenges of 3D TFM. In this work, we established an advanced in silico validation framework that is applicable to any 3D TFM experimental setup and that can be used to correctly couple the experimental and computational aspects of 3D TFM. Advancements relate to the simultaneous incorporation of complex cell geometries, simulation of microscopy images of varying bead densities and different focal adhesion sizes and distributions. By measuring the traction recovery error with respect to ground truth solutions, we found that while highest traction recovery errors occur for cases with sparse and small focal adhesions, our implementation of the inverse method improves two-fold the accuracy with respect to the forward method (average error of 23% vs. 50%). This advantage was further supported by recovering cellular tractions around angiogenic sprouts in an in vitro model of angiogenesis. The inverse method recovered more realistic traction patterns than the forward method, showing higher traction peaks and a clearer pulling pattern at the sprout protrusion tips.

bioengineering↗