Biology subjects

Wessels, M.

Publications and source records attributed to Wessels, M..

5 recordsLinked to original sources

bioRxiv2026

Autologous biopsy-derived co-culture platform for interrogation of intestinal epithelial-T cell crosstalk

Interactions between intraepithelial lymphocytes (IELs) and the intestinal epithelium are central to mucosal homeostasis and disease. However, mechanistic in vitro studies describing their crosstalk in humans are limited by scarceness of primary material and insufficient knowledge about co-culture requirements. Here, we establish an autologous human duodenal IEL-organoid co-culture system encompassing expandable and bankable IEL and organoid protocols, with co-culture conditions that allow viability of both cell types. This system enables successive interrogation of lympho-epithelial interactions starting from minimal biopsy material. Under baseline conditions, CD45CD8CD103TCR{beta} IELs retain tissue-residency and effector features and induce an epithelial interferon response and chemokine production, without overt epithelial apoptosis. IL-15 and IL-21, essential cytokines involved in IEL-activation in intestinal enteropathies like celiac disease, increases granzyme B expression and interferon-{gamma} secretion but do not trigger epithelial cell death. However, enforcing IEL-epithelial contact using an anti-CD3-anti-Ep-CAM bispecific antibody induces epithelial apoptosis accompanied by increased tumor necrosis factor (TNF) and FAS-ligand (FASLG) secretion. These findings validate the platforms ability to resolve non-destructive and cytotoxic lympho-epithelial interaction and provide a tractable system for studying intestinal inflammation and immune-mediated epithelial cell death.

immunology↗

bioRxiv2026

Predicting Gravitational Self-Motion: Falling Down versus Falling Up

Humans have been shown to use an internalized representation or prior of Earth gravity to predict object motion. Often, this is shown using the fact that humans tend to neglect an objects acceleration when predicting its motion. This bias tends to be ameliorated when the acceleration acting on the object is Earth gravity. It is currently unclear whether this prior can also be used when assessing ones self-motion. We immersed two cohorts of 20 seated participants in a virtual environment of a street scene. They experienced simulated self-motion consistent with either flying straight upwards towards the ceiling (ANTI-GRAVITY) or falling downwards towards the ground (GRAVITY). After 0.8 s to 1.4 s of motion, the screen turned blank, and participants pressed a button to indicate when they thought they reached the surface they were moving towards. In Experiment 1, they were instructed to use their eye level as the reference (i.e., when they imagined the floor or ceiling to be aligned with their eyes). In Experiment 2, they used their feet or the top of theirs heads to judge when they had reached the ceiling or floor, respectively. In Experiment 1, no differences between the GRAVITY and ANTI-GRAVITY conditions were found in terms of accuracy or precision, contrary to our hypotheses. In Experiment 2 participants pressed the button significantly later in the ANTI-GRAVITY condition than in the GRAVITY condition, in line with the predictions of the use of a gravity prior, while precision remained unaffected. Speculatively, the instructions in Experiment 1 may have made the experience less ecologically valid and immersive, thus preventing participants from activating the strong gravity prior. Experiment 2 (head/feet as reference), on the other hand, provides convincing evidence for an involvement of this prior in the prediction of self-motion. In sum, the study provides evidence that humans can rely on an internalized representation of Earth gravity when predicting self-motion, at least under ecologically valid task conditions. The absence of effects in Experiment 1 and their presence in Experiment 2 suggest that activation of this gravity prior depends on the framing of the task.

animal behavior and cognition↗

bioRxiv2025

Microbial sedimentary DNA from a cultural landscape disentangles the impacts of humans and nature over the past 13.5 thousand years

Bacteria and archaea are currently under-characterised in palaeoecological studies, despite their ubiquity, high diversity and tight integration with the biotic and abiotic environment and human activity. The complexity of their assemblages, and the difficulties in separating living- from paleo-prokaryotes renders analyses challenging. Here we present an ancient prokaryote metagenomic time-series from a sediment core of Lake Constance, a large and deep perialpine lake from temperate Europe, spanning the last 13,500 years of natural and anthropogenic impact. We mapped DNA to reference genomes and estimated the DNA damage of taxa, which displayed a monotonic relationship with time. By constructing co-abundance networks we recognize major microbial assemblages, containing both ancient and living microbes, that show specific dynamics. Short-term and often low-abundance assemblages are linked to the Pleistocene-Holocene transition, floods and human activities. Noticeably, certain lineages harbouring microbes common in human-impacted environments expanded during the Middle Ages and Modern time. Some abundant taxa that were linked to various freshwater and soil environments persisted through millennia. By extricating various sources and trajectories of change, we demonstrate the power of prokaryotic sedimentary DNA in revealing long-term eco-evolutionary outcomes caused by both nature- and humans.

ecology↗

bioRxiv2024

Biochemical analysis of the endoribonuclease activity of the human mitochondrial topoisomerase 1

The incorporation of ribonucleotides (rNMPs) into the nuclear genome leads to severe genomic instability, including strand breaks and short 2-5 bp deletions at repetitive sequences. Curiously, the detrimental effects of rNMPs are not observed for the human mitochondrial genome (mtDNA) that typically contains several rNMPs per molecule. Given that the nuclear genome instability phenotype is dependent on the activity of the nuclear topoisomerase 1 enzyme (hTop1), and mammalian mitochondria contain a distinct topoisomerase 1 paralog (hTop1mt), we hypothesized that the differential effects of rNMPs on the two genomes may reflect differing properties of the two cellular topoisomerase 1 enzymes. Here, we characterized the endoribonuclease activity of hTop1mt and found it to be less efficient than that of its nuclear counterpart, a finding that was partly explained by its substrate binding properties. While hTop1 and yeast Top1 showed higher affinity for an rNMP-containing substrate and were able to cleave at an rNMP located outside of the consensus cleavage site, hTop1mt showed no preference for rNMPs. As a consequence, hTop1mt was inefficient at producing the short rNMP-dependent deletions that are characteristic of Top1-driven genome instability. These findings help explain the tolerance of rNMPs in the mitochondrial genome.

biochemistry↗

bioRxiv2018

Genetic data and cognitively-defined late-onset Alzheimer’s disease subgroups

Categorizing people with late-onset Alzheimers disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n=4 050, of whom 2 431 had genome-wide single nucleotide polymorphism (SNP) data). We assigned people to cognitively-defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimers disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p<10-5 and odds ratios more extreme than those previously reported for Alzheimers disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had [≥]1 APOE e4 allele than any other subgroup (overall p= 1.5 x 10-27). Across subgroups, there were 33 novel suggestive loci across the genome with p<10-5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively-defined subgroups and nominate novel genetic loci.

genetics↗