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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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41 records · Page 3Linked to original sources

bioRxiv2026

An M-learner approach for heterogeneous mediation analysis with high-dimensional omics mediators

Causal mediation analysis is widely used to identify biological pathways linking exposures to outcomes, but most methods assume homogeneous mediation effects across individuals. In high-dimensional omics settings, this assumption can mask important heterogeneity driven by demographic, genetic, or environmental factors. We propose the M-high-learner, a flexible framework for detecting heterogeneous mediation effects with high-dimensional mediators. The method identifies mediators with subgroup-specific indirect effects while distinguishing them from null or homogeneous signals and controlling the type I error rate. It is computationally efficient, scalable, and yields interpretable sub-types. Simulation studies show that the proposed approach achieves high power while maintaining accurate error control. Applications to the Framingham Heart Study and the Multi-Ethnic Study of Atherosclerosis reveal that the mediation role of gene expression in sexs effect on high-density lipoprotein varies across subgroups defined by body mass index and age. Our framework provides a practical tool for uncovering heterogeneous biological mechanisms in high-dimensional genomic studies. Author SummaryBiological processes linking risk factors to disease often differ across individuals, but many existing methods assume these processes are the same for everyone. This can hide important differences between groups. We developed a powerful method to identify when these pathways vary across subgroups using large-scale molecular data. Our approach detects differences in how intermediate biological factors contribute to outcomes in populations defined by characteristics such as age and body mass index. Applying our method to population studies, we found that some biological pathways operate differently across groups, suggesting that key mechanisms may be missed when differences are ignored. Our work provides a tool to better understand how disease-related processes vary across individuals, which may support more targeted and personalized approaches to health research.

bioinformatics↗

bioRxiv2026

Immunogen selection and prior immunity shape antibody breadth following immunisation with avian H5 hemagglutinin

Avian influenza A viruses pose a persistent zoonotic threat to humans owing to their expanding host range and high case fatality rates. In particular, viruses from the 2.3.4.4b clade of the H5 subtype have now been detected in over 60 mammalian species, raising serious pandemic concerns. Understanding immune recognition of the H5 hemagglutinin (HA) is therefore critical for effective vaccine design and pandemic preparedness. To understand the breadth of cross-recognition induced by different H5 strains, we selected genetically diverse H5 human isolates from 2003-2023 and assessed neutralising antibody responses elicited by adjuvanted recombinant HA protein-based vaccines in C57BL/6 mice. Neutralisation activity of sera was determined against seven H5 HA variants using pseudotyped viruses and a PR8-reassortant virus in micro-neutralisation assays. Our results showed a wide variety of cross-strain neutralisation across H5 HA antigen variants. The conventional vaccine strain A/Indonesia/05/2005 displayed narrow activity against emerging clade 2.3.4.4b viruses, whereas ancestral variants exhibited cross-neutralisation profiles showing a diversity of breath but with limited potency. Polyvalent H5 HA formulations and nanoparticle-displayed H5 HA platforms substantially broadened cross-neutralisation against diverse H5 strains. To examine the impact of pre-existing immunity on H5 vaccine immunogenicity in mouse models, mice were primed with either seasonal influenza infection or quadrivalent influenza vaccine (QIV) prior to H5 HA immunisation. QIV pre-vaccination, but not prior influenza infection, enhanced subsequent neutralizing responses towards A/Fujian-Sanyuan/21099/2017 (clade 2.3.4.4b) H5. Collectively, our results demonstrate that immunogen selection and prior immunity shape antibody breadth following immunisation with avian A(H5) hemagglutinin.

immunology↗

bioRxiv2026

Microsecond molecular dynamics of SOD1 variants suggest a structural basis for divergent ALS clinical outcomes

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive motor neuron degeneration. Mutations in the SOD1 gene represent the second most common genetic cause of ALS (ALS), and distinct SOD1 missense variants present with markedly different clinical profiles. A4V leads to an aggressive form of the disease (median survival [~]1y), H46R confers a mild, slowly progressive course and I113T exhibits an intermediate phenotype. The molecular basis by which these mutations produce divergent clinical outcomes remains poorly understood. We performed extensive classical molecular dynamics simulations of wild-type SOD1 and the three ALS-associated variants in the apo monomeric state to attempt to investigate the mechanisms behind such phenotypic differences. Structural stability, global compactness, and conformational flexibility, as well as analysis of collective motions between residues and estimation of free energy, were assessed. The H46R, A4V, and I113T variants exhibited distinct dynamic behaviours, highlighting differences in structural stability, local flexibility, and intramolecular interactions. These findings suggest that specific structural regions may contribute differently to protein dysfunction and could represent key elements for understanding the relationship between molecular dynamic properties and the differing clinical severity associated with these variants. Most strikingly, H46R exhibited exceptional structural stability across every analytical level, the lowest global deviation, most attenuated local flexibility, strongest internal dynamic coordination, and the deepest, most confined free energy basins of any system examined. This convergent multi-layered evidence of structural restraint provides a compelling mechanistic basis for the mild and slowly progressive clinical course of H46R ALS, suggesting that enhanced conformational rigidity, rather than bulk destabilisation, is the defining biophysical feature of this variant, and that its pathogenic mechanism operates through a route fundamentally decoupled from the aggregation-driven toxicity that characterises the more aggressive SOD1-ALS mutations.

genomics↗

bioRxiv2026

Layer 5 anterior cingulate cortical neurons engage dorsolateral periaqueductal gray excitatory neurons to facilitate the affective component of pain

Pain is a conscious perceptual experience characterized by its aversive quality and consequent motivation to quench pain perception. The anterior cingulate cortex (ACC) critically contributes to the emotional dimension of pain. In both humans and rodents, ACC neural activity increases during acute and chronic pain, whereas ACC lesioning or excitability reduction decreases emotional reactivity during pain. However, the ACC is connected to many brain regions and is engaged during experiences beyond pain. Thus, it remains unclear through which circuit mechanisms the ACC shapes pain experience, and how specific those circuits are to nociception. Here, we show that excitatory input from the ACC to the dorsolateral periaqueductal gray (dlPAG) facilitates the affective-motivational dimension of pain. We first examined ACC[->]dlPAG connectivity using histology, optogenetics, and electrophysiology. We found that the axons of layer 5 ACC neurons terminate in the dlPAG and monosynaptically excite Slc17a6+ (VGLUT2-expressing) dlPAG neurons. Second, we genetically targeted ACC[->]dlPAG neurons with viral vectors to express the inhibitory DREADD hM4Di and then exposed the animals to an array of pain tests. We found that, across acute and chronic pain states, inhibition of the ACC[->]dlPAG pathway reduced affective-motivational but not reflexive pain behaviors. Third, we used fiber photometry to record neural calcium activity in the ACC in behaving mice and found that ACC[->]dlPAG neurons are engaged during a broad array of aversive experiences, rather than exclusively during pain, and exhibit task-specific activity patterns. Collectively, these results uncover the direct contribution of ACC[->]dlPAG neural activity to pain unpleasantness and the necessity of this pathway for generating aversive behavioral responses in general, rather than specifically for encoding the unpleasant quality of noxious stimuli.

neuroscience↗

bioRxiv2026

Magnesium induces iron starvation and metabolic rewiring to support the viability of cell envelope mutants and antibiotic-stressed cells

Magnesium supplementation permits deletion of otherwise essential genes involved in cell envelope biogenesis in the Gram-positive model bacterium Bacillus subtilis. Yet, the specific underlying mechanism has remained elusive. To address this key knowledge gap, we made use of a mutant lacking ezrA and gpsB. Deletion of both of these genes involved in cell wall synthesis leads to severe growth inhibition which is ameliorated by magnesium addition. Our results indicate that, in the absence of magnesium, this mutant contains elevated levels of labile iron, is impaired in activating the oxidative stress response, and displays extreme sensitivity to iron and manganese intoxication. Intriguingly, we find that an ezrA single deletion, but not gpsB, exhibits heightened susceptibility to excess iron and manganese. This observation allowed us to investigate the source of toxicity and how EzrA may support metal homeostasis. Our data suggests that the major contributor of ROS is the electron transport system involved in cellular respiration. Both genetic and chemical means to reprogram the cells in favor of fermentation alleviate the metal toxicity in cells lacking ezrA. Collectively, our data shows that magnesium limits iron availability and redirects metabolism towards pathways that are preferred during iron scarcity. Consequently, these mechanisms result in reduced ROS production and oxidative stress mitigation. This explains why magnesium supplementation may render essential genes dispensable. In support of this model, we find that addition of magnesium helps cells to circumvent lysis typically caused by the treatment of an antibiotic that disrupts cell wall synthesis. Taken together, our results suggest that unmitigated oxidative stress fueled by labile iron is likely responsible for the detrimental effects of specific gene disruptions and certain antibiotic treatments. By reducing the pool of free iron and reprogramming cellular metabolism, magnesium mitigates oxidative damage and protects cells from ROS-mediated death.

microbiology↗