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Results for “cell biology”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

The mitochondrial RNA extrusion-induced innate immunity is regulated by N6-methyladenosine machinery

Mitochondrial RNA (mtRNA) released into the cytosol functions as a damage associated molecular pattern that activates pattern-recognition receptor (PRR)-mediated inflammation, yet its release mechanisms and cytoplasmic fate remain poorly understood. Here we report that chemical Abt-373-treatment and Vesicular stomatitis virus (VSV) infection induce mtRNA extrusion through Bax/Bak and VDAC1 channels, accompanied by mtDNA release. Extruded mtRNA in A549 cells activates multiple cytosolic PRRs, including RIG-I, MDA5, TLR3/7/8, and PKR, each contributing differentially to the innate immune signaling. Analysis of GEO datasets and methylated RNA immunoprecipitation (MeRIP) assays further reveals that mtRNA carries methyladenosine (m6A) modification. m6A machinery proteins are involved in the cytoplasmic retention time of mtRNA and its interaction with RIG-I, thereby modulating mtRNA-induced innate immunity. Thus, our work establishes in vitro models of mtRNA extrusion, and highlights m6A-dependent modulation as a potential therapeutic target for mtRNA-driven inflammation.

immunology↗

bioRxiv2026

Dynamical Regimes in Rejuvenation

Biological aging is accompanied by systematic changes in epigenetic modifications and chromatin organization. The reversal of the effects of aging, rejuvenation, is experimentally achieved by the transient induction of factors that modify these marks in cells and organisms. Here, we show that key features of rejuvenation experiments emerge from the biophysical interplay between dynamic epigenetic marks and the three-dimensional conformation of chromatin. Using a minimal field theory and molecular dynamics simulations, we show that the system responds in three distinct temporal regimes. The intermediary regime fulfills necessary conditions for successful rejuvenation. In this regime, the system spends time near a separatrix, allowing for high epigenetic plasticity, while memory retained in the chromatin conformation enables restoration of the original epigenetic correlations. Analysis of sequencing data further supports the predicted coupling between chromatin compaction and epigenetic correlations. Our results provide a physical explanation for how rejuvenation may remodel age-associated epigenetic states without irreversibly erasing cellular identity. We identify a general mechanism by which memory stored in a slow structural variable permits reversible remodeling of a faster internal state.

biophysics↗

bioRxiv2026

Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.

neuroscience↗

bioRxiv2026

Designing antimicrobials with programmable mechanism and safety

Antimicrobial peptides (AMPs) are a promising solution to antimicrobial resistance, yet generative models for their design cannot control the physicochemical properties and motifs that shape activity and selectivity. Here, we present OmegAMP, a conditional diffusion framework controlling net charge, mean hydrophobicity, and sequence length, supporting de novo, analog, and motif-guided design. Across 204 wet-lab characterized peptides, de novo generation yielded antimicrobials with broad activity against multidrug-resistant Gram-negative isolates. Analog generation converted six inactive prototypes into antimicrobials, with the prototype determining each analog's membrane-disruption mode and mammalian-cell safety. Motif-guided analog generation preserved lipopolysaccharide engagement of active prototypes, and a redesigned non-antimicrobial leucine zipper acquired antimicrobial activity while retaining DNA-perturbing character in vitro. In murine skin and thigh infection models, leads reduced bacterial burden, with a motif-guided DNA-perturbing lead matching the fluoroquinolone control systemically. OmegAMP opens a programmable route to new peptide antibiotics whose mechanism and safety follow from the chosen prototype.

bioinformatics↗

bioRxiv2026

Temozolomide Induces Aberrant RNA Alkylation and Widespread Translational Repression

Temozolomide (TMZ) is a frontline alkylating chemotherapy, yet its direct impact on RNA modification and global translation dynamics remains poorly understood. Here, we demonstrate that TMZ induces pervasive RNA alkylation causing severe translational impairment. TMZ directly deposits aberrant methyl groups onto single-stranded mRNA in vitro, creating physical lesions that lower translational efficiency. In glioblastoma cells, acute TMZ exposure triggers a rapid, widespread accumulation of m7G on cellular RNAs, leading to the significant attenuation of global protein synthesis. Nanopore direct RNA sequencing identified distinct guanine-specific error signatures and sequence context preferences associated with TMZ-induced damage. Using a quantitative yeast spike-in ribosome profiling strategy, we mapped this translational repression at transcript-level, revealing a global downregulation of translational efficiency. This widespread repression disproportionately targets highly interconnected networks essential for cellular proliferation, specifically chromosome organization. We show that the severity of this translational repression is driven by a transcript's coding guanine density, stability and translation initiation speed. Together, our findings suggest that TMZ-induced alkylation targets stable, highly translated, guanine-rich transcripts. This establishes aberrant RNA methylation and subsequent translational arrest as a potential mechanism of temozolomide cytotoxicity.

biochemistry↗

bioRxiv2026

Identification of a pan-orthoebolavirus-reactive antibody from an rVSV-EBOV vaccinated individual

Orthoebolaviruses such as Ebola virus (EBOV), Sudan virus (SUDV) and Bundibugyo virus (BDBV) can cause severe disease with high case-fatality rates. While licensed EBOV vaccines and therapeutic antibodies protect against EBOV infection, no single monoclonal antibody currently provides broad protection across multiple orthoebolaviruses. Here, we analyzed the humoral immune response of an rVSV-EBOV vaccinee to identify pan-orthoebolavirus-neutralizing antibodies. Using BDBV- and SUDV-glycoproteins for single B cell-sorting, we identified B10, which neutralized authentic EBOV and SUDV, with potent activity against SUDV compared with established cross-reactive antibodies. Structural analysis mapped antibody B10 binding to the pan-orthoebolavirus conserved GP2-stalk/HR2 region, associated with asymmetric trimer destabilization and spike opening. In vivo, B10 showed significant prophylactic efficacy in an EBOV mouse model and partial protection with antiviral activity in a SUDV mouse model. Together, these findings demonstrate that rVSV-EBOV vaccination induced the development of a broadly orthoebolavirus-neutralizing antibody that holds exeptional therapeutic potential.

immunology↗

bioRxiv2026

Basophilic Erythroblast Emerges as the Key Turning Point in Polycythemia Vera

Abstract Polycythemia vera (PV) is a rare, chronic myeloproliferative neoplasm driven by the JAK2V617F mutation and characterized by uncontrolled erythroid proliferation. Although the mutation arises in hematopoietic stem cells, the differentiation stage at which its transcriptional consequences first become biologically meaningful has remained undefined. Using a multi-layer transcriptomics integration approach that combined differential gene expression, NicheNet ligand-receptor analysis, pseudotime trajectory inference, and CNV profiling on scRNA seq data, alongside bulk transcriptome validation, we identified basophilic erythroblasts as the critical transition point at which JAK2V617F shifts from a genomically present but transcriptionally silent state to an actively trajectory-altering and treatment-responsive disease driver. Differential expression revealed a qualitatively distinct disease signature at this stage, including ERFE-mediated iron dysregulation, MAP2K2-driven RAS/MAPK co-activation, and epigenetic reprogramming. NicheNet showed the establishment of a TGF{beta} superfamily and chemokine-driven niche-remodeling axis, and pseudotime analysis demonstrated that basophilic erythroblasts are the first erythroid population to exhibit condition-dependent trajectory divergence, whereas earlier progenitors showed none despite carrying the mutation. Interferon- treatment showed its broadest counterresponse at this stage but declined sharply thereafter, identifying basophilic erythroblasts as both the principal therapeutic target and the point of maximum vulnerability in PV.

bioinformatics↗

bioRxiv2026

Synaptic adhesion molecule signaling is activated and organized by tyrosine phosphorylation-induced biomolecular condensate formation

The precise formation of synapses ensures the proper wiring and function of nervous systems. Specific synapse formation is controlled by synaptic adhesion molecules, which link pre- and post-synaptic cells. Despite this central role, details of how adhesion molecules organize and signal intracellularly to build core synaptic structures are limited. Here, we identify multiple tyrosine phosphorylation sites on the cytoplasmic tail of the C. elegans SYG-1 synaptic adhesion molecule that are critical to initiate presynapse formation. We determine that SRC-1 and SRC-2 tyrosine kinases are redundantly responsible for SYG-1 phosphorylation and are consequently critical for presynapse assembly. The phosphorylated population of SYG-1 localizes in clusters within a larger SYG-1 pool and these clusters mark sites of presynaptic active zone assembly. Reconstitution of SYG-1 clusters in vitro with SH2-domain adapters and WSP-1 reveals a dynamic biomolecular condensate-forming system. Blocking phosphotyrosine adapters and condensate formation in vivo results in the loss of SYG-1 clusters, defective presynapse formation, and compromised neurotransmission. We conclude that phosphorylation of a subpopulation of synaptic adhesion molecules activates and organizes them into condensate-based clusters to initiate presynapse formation.

neuroscience↗

bioRxiv2026

GABAB Receptors Gate Sex-Specific Synaptic Plasticity in the Nucleus Accumbens

Excitatory synaptic plasticity within the nucleus accumbens (NAc) drives motivated behaviors, and dysregulation is implicated in several psychiatric disorders marked by impaired reward processing. The NAc integrates glutamatergic input, which conveys information about reward, context, and behavioral goals, with local GABAergic signaling that regulates excitatory transmission and medium spiny neuron (MSNs) output. However, little is known regarding GABA-dependent modulation of activity-dependent excitatory synaptic plasticity. Here, we investigated GABAB receptor (GABABR) regulation of plasticity at hippocampus (Hipp)-NAc synapses, at which plasticity is a key mediator of reward-related behaviors. Using whole-cell electrophysiological recordings in mouse brain slices, we found that pharmacological inhibition of GABABRs converts long-term potentiation (LTP) into long-term depression (LTD) selectively in females, identifying a sex-specific role for GABABRs in modulating long-term plasticity of Hipp-MSN synapses. This LTD required mGluR5 activation and estrogen receptor alpha (ER) in both D1- and D2-expressing MSN subtypes, while only D1-MSNs suggested that LTD was expressed presynaptically through a CB1 receptor-dependent mechanism. Notably, GABABR inhibition did not alter basal synaptic transmission, indicating a specific role for these receptors in gating plasticity beyond regulation of basal excitatory drive. Together, these findings identify a novel, sex-specific mechanism by which GABABRs control the direction of synaptic plasticity.

neuroscience↗

bioRxiv2026

Neural spiketrains and population vectors entangle neural representations

Neural recordings are usually analyzed by comparing neural spiketrains or comparing time bins (population vectors). If multiple variables drive the neural activity these comparisons will be affected by all of them. Our aim is to disentangle these different latent variables or covariates that drive neural activity and reveal their structure and geometry. The central idea of the paper is that a matrix is disentangled when its rows and columns are local on each other, a condition we call bidirectional locality. In such a matrix, rows and columns encode the same geometry and they respond to only one localized part of it. This suggests finding bidirectional local matrices in a given data matrix, from which we can recover the geometry of the covariates driving it in a straightforward way. We present two ways of doing just this. The first method, coherent projections, works by finding non-negative projections of the neural data matrix (neurons by time bins) that are bidirectionally local. The second method, clumps, works by finding dense submatrices of the neural data matrix, that each identify a local region of one covariate. We apply these methods to two neural datasets, showing that they can separate grid cell modules and reveal a movement-driven low-dimensional structure in the motor cortex.

neuroscience↗

bioRxiv2026

Melanin Suppresses Aβ Aggregation and Toxicity

The aggregation of amyloid-{beta} (A{beta}) peptides into insoluble deposits is a characteristic hallmark of Alzheimer's disease (AD) and related neurodegenerative disorders. While AD is the most common cause of dementia, there are currently no disease-modifying treatments which are both affordable and adverse-free. In this study, we report that melanin, a pigment which is commonly found in nature and is abundant in parts of the human brain, suppresses the aggregation of the 42-amino acid A{beta} variant (A{beta}42). Using biophysical and biochemical techniques, we show that melanin delays A{beta}42 aggregation while also reducing the amount of A{beta}42 that converts into aggregates. Using thioflavin T assays paired with chemical kinetics, we characterised the melanin-induced inhibition of A{beta}42 aggregation in vitro. Using MALDI-MS, we elucidate the molecular basis of this effect by showing that melanin prevents A{beta}42 dimerisation. We then demonstrate that melanin also reverts the aggregation process by dissolving pre-formed A{beta}42 fibrils. Finally, we show that melanin reduces A{beta}42 aggregation and rescues A{beta}42 toxicity in an SH-SY5Y neuroblastoma cell model. Our study shows that melanin disrupts the aggregation and cytotoxicity of A{beta}42, and suggests that compounds derived from human metabolites may offer promising avenues to combat amyloid formation.

biophysics↗

bioRxiv2026

A transcriptomic and spatial map of serotonin autoreceptor expression in Drosophila

Serotonin is an evolutionarily ancient neurotransmitter that modulates an array of behaviors such as mood, sleep, and appetite across species. Serotonin acts primarily by binding to serotonin receptors, which are expressed in post-synaptic neurons (heteroreceptors) and serotonergic neurons themselves (autoreceptors). Serotonin autoreceptors modulate serotonergic tone, the foundational principles of which have been excellently demonstrated in vertebrate and invertebrate models. However, many aspects of the mechanisms and contexts in which this modulation occurs are still unclear. Drosophila melanogaster is a powerful model organism that can provide unique insights into autoreceptor function by the ability to perform precise spatial and temporal genetic manipulation with structural and functional readouts / behaviors of serotonin systems. However, a systematic characterization of serotonin autoreceptor expression in Drosophila has not been conducted. Here we use single-cell sequencing and genetic labeling to show that all five serotonin receptors are expressed in serotonergic neurons and map their expression at both the larval and adult stages of development. This is the first evidence of 5-HT2A and 5-HT7 expression in serotonergic neurons in any organism. Moreover, the unique combinations of autoreceptor expression in specific neuronal clusters will aid in the development of novel hypotheses for autoreceptor function, and demonstrates the utility of Drosophila as a model organism to study the function of serotonin autoreceptors.

neuroscience↗

bioRxiv2026

Using sequence-to-function models to interpret archaic hominin introgression

Understanding the functional impact of archaic hominin introgression remains challenging due to the poor representation of global introgression in publicly available genomics resources. Sequence-to-function models can predict the effects of any possible variant in the human genome and may fill this gap. Here, we used AlphaGenome to predict the effects of 144,139 introgressed SNPs segregating in present-day individuals of Papuan genetic ancestry. AlphaGenome's chromatin accessibility predictions recapitulate experimentally observed effects, but gene expression performs no better than chance. Predictions correlate more strongly with an independent reporter assay of single-variant activity than with the same variants' effects in live cells, indicating that AlphaGenome captures the regulatory potential of individual variants more reliably. Predictions carry tissue specificity, allowing us to predict specific tissues potentially impacted by introgressed haplotypes. We identify genes, including JAK1 and TAB2, that are associated with haplotypes that contain an excess of variants predicted by AlphaGenome to have large impacts on chromatin accessibility. Finally, we highlight the challenges and limitations associated with using sequence-to-function models for introgressed variant effect prediction, and show that while AlphaGenome's chromatin accessibility predictions can aid in prioritising candidate functional regions, expression predictions and the assignment of variants to target genes remain as open challenges.

genomics↗

bioRxiv2026

Sensory neuron dysfunction and hyperexcitability in dorsal root ganglia at disease onset in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder traditionally characterized by motor neuron degeneration, but emerging evidence indicates sensory system involvement. Despite reports of sensory abnormalities in some patients, the molecular and functional alterations in dorsal root ganglion (DRG) neurons remain insufficiently characterized. We investigated DRG pathology at disease onset in 12-week-old SOD1G93A mice using an integrated transcriptomic, morphological, and electrophysiological approach. RNA sequencing of lumbar DRG identified 35 differentially expressed genes, predominantly upregulated, enriched in oxidative stress-related and phagosome pathways. Comparative analysis with motor neuron transcriptomes revealed distinct gene expression profiles, indicating sensory neuron-specific molecular responses. Immunohistochemistry demonstrated reduced soma diameter in both A- and C-fiber DRG neurons. Nav channel colocalization increased for Nav1.7 in A fibers and Nav1.8 in both fiber types, whereas Nav1.6 was unchanged. Whole-cell patch-clamp recordings showed depolarized resting membrane potential, increased spike amplitude, and enhanced repetitive firing in A-fiber neurons, consistent with hyperexcitability, while C fibers showed no significant functional changes. These findings demonstrate early molecular, structural, and functional alterations in primary sensory neurons in ALS, supporting pathology beyond motor neurons and identifying sensory neuron excitability as a potential therapeutic target.

neuroscience↗

bioRxiv2026

X-inactivation escapee domains are CTCF-cohesin independent chromatin compartments

X-chromosome inactivation involves chromosome-wide gene silencing accompanied by extensive chromatin changes, as well the loss of topologically associating domains. Yet discrete regions of the inactive X chromosome retain activity within localised 3D domains, which contain active genes that variably escape from X inactivation. The transcription factor and architectural protein CTCF has been proposed to be implicated in escape by insulating escape domains or sustaining their topology via cohesin-mediated loop extrusion. Here, we test the role of CTCF and cohesin in escape using acute degron-mediated depletion of CTCF and RAD21 in neural progenitor cells with established escape profiles. Although CTCF occupancy correlates with escape status on the inactive X chromosome, its removal - together with loss of loop extrusion - does not disrupt escapee gene expression, or domain organization, nor does it result in spreading of silencing or activation of genes in cis. Rather, we show that facultative escape regions are self-sustaining compartments of active chromatin enriched in H3K27 acetylation and depleted in H3K27 methylation, with the magnitude of compartment strength scaling up with the degree of transcriptional activity on the inactive X chromosome. These active escapee compartments are propagated independently of CTCF and RAD21-dependent 3D architecture. Our findings identify chromatin compartmentalization as the primary feature of facultative escapee domains.

genetics↗

bioRxiv2026

The interaction between NC(p7)1-55 and p6 may regulate interactions with nucleic acids during assembly through modulation of Gag folding.

We present the solution structures of HIV-1 proteins NC(p7)1-55 corresponding to the full-length NC(p7) and mature p6. The studies were carried in water and, to mimic the membrane, in micellar DPC (Dodecylphosphocholine) conditions. Our results unravel for the first time the structure adopted by the N-terminal amino acids of the free NC(p7)1-55, with the formation of a small helix spanning residues F6 to R10. Our NMR and Fluorescence Anisotropy data disclose an interaction between NC(p7)1-55 and p6 both in water and DPC, with respective Kd of 2.5mM and 370 mM at 23{degrees}C. The interaction is thus strengthened in lipidic conditions. Protein p6 stabilizes the N-terminus of NC(p7)1-55 while increasing at the same time the dynamic of the first zinc finger. Although the entire p6 sequence is involved in the interaction, we show that its C-terminal region is particularly sensitive to the presence of NC(p7)1-55, with a propensity of forming a a helix ranging from amino acids S111 to F116. This study brings experimental evidence of a direct protein-protein interaction between p6 and the N-terminal region of NC(p7)1-55. We further show that such interaction is readily accommodated within the NC(p15) framework and hypothesize that it may facilitate the selective assembly of assembly of the viral genomic RNA (gRNA) in the cell.

biophysics↗

bioRxiv2026

Structures of LolB bound to LolA or lipoprotein resolve the final steps of bacterial lipoprotein trafficking

In Gram-negative bacteria, lipoproteins are structural elements of the outer membrane and essential components of machineries responsible for its construction and maintenance. The Lol system, responsible for the trafficking of lipoproteins from the site of maturation on the inner membrane to the outer membrane, is therefore crucial to the function of the cell envelope and a key target of efforts to find novel antimicrobials. In the final steps of this process, the outer membrane receptor, LolB accepts triacylated lipoproteins from the periplasmic chaperone LolA before inserting them into the outer membrane. Here we present a structure of LolB in complex with LolA, validated by in vivo and in vitro assays, highlighting how positively charged residues on the convex face of the LolB {beta}-barrel underpin complex formation. A protruding loop of LolB, essential for function, inserts into the LolA cavity in position to initiate the displacement of substrate lipoprotein from LolA to enable transfer to LolB. Structural resolution of a lipoprotein-bound LolB complex in combination with biophysical assays shows how a molecular latch releases the lid of the cavity to accommodate the lipoprotein acyl chains. Modelling of these structures onto computationally predicted orientations for LolB on the outer membrane provides a rationale for LolA release and lipoprotein triacyl group membrane insertion. Taken altogether, our data elucidate atomic resolution of two key intermediates and provide a greater understanding of the terminal steps of lipoprotein trafficking events at the bacterial outer membrane.

microbiology↗

bioRxiv2026

Dysregulated splenic glucocorticoid sensitivity in aging and an α-synuclein transgenic mouse model of Parkinson's disease

Introduction: Parkinson's disease (PD) and aging both disrupt hypothalamic-pituitary-adrenal (HPA) axis function and peripheral immune homeostasis. Whether aging or -synuclein (-syn) pathology alters glucocorticoid (GC) sensitivity of peripheral immune cells has not been investigated. Methods: Using an ex vivo GC sensitivity assay, we assessed the responsiveness of isolated and lipopolysaccharide (LPS)-stimulated splenocytes to the anti-inflammatory effects of increasing doses of corticosterone (CORT) in a wild-type (WT) aging cohort and in a PD -syn transgenic mouse model and respective age-matched controls. Results: Compared with splenocytes from 6-month-old WT mice, splenocytes from 20-month-old WT mice were less sensitive to 0.1 and 0.5 M CORT. Isolated splenocytes from PD vs. control mice were less sensitive to 0.05, 0.1, and 0.5 M CORT specifically at 16 months of age, but not at 6 or 20 months of age. As peripheral immune phenotyping revealed neither differences in HPA axis-related parameters nor in splenic GC receptor expression between PD and age-matched control mice at 6, 16, and 20 months, splenic GC resistance in PD mice at 16 months of age seems to be mediated by downstream GR signaling dysfunction. Conclusion: Together, our results support the hypothesis that -syn pathology accelerates an aging-associated decline in the peripheral sensitivity to anti-inflammatory GCs and may thereby sustain systemic and neuroinflammatory processes in PD.

neuroscience↗