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bioRxiv2026

Feature-based valuation and its impairment in people with compulsive and addictive symptoms

Effective decision-making requires evaluating options based on relevant features while reducing attention to those that are not. However, how attention prioritizes one source of information over another during value-based decisions remains unknown. Across 7 experiments, we show that irrelevant features both constructively and destructively interfered with how values are assigned to choice options. When relevant and irrelevant features agreed, choice accuracy and speed were facilitated; when they conflicted, accuracy decreased and choices slowed in proportion to the value of the irrelevant feature. We modeled this interference as a weighted sum of relevant and irrelevant feature values. This model explained individual differences in choice behavior and, critically, tracked psychiatric symptom severity related to substance abuse and obsessive-compulsive disorder. This suggests that these symptoms may, in part, reflect an impaired ability to weigh relevant against irrelevant information when assigning value to choice options - a process we term feature-based valuation.

neuroscience↗

bioRxiv2026

The pursuit of motivational goals reduces pain through an opioidergic mechanism

Pain promotes protective behavior but can interfere with other biologically important goals. Survival may require overcoming pain to obtain rewards, secure resources or escape danger, yet evidence for pain modulation by competing demands and endogenous modulatory systems during goal pursuit is lacking. We developed a paradigm in which participants chose whether to pursue monetary rewards despite painful heat stimulation during fMRI, under placebo or opioid receptor blockade with naloxone. Actively pursuing motivational goals during painful stimulation reduced perceived pain and increased fMRI signal in pain-modulatory cortical regions, including multiple subregions of the rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex, alongside enhanced rACC-periaqueductal gray coupling, consistent with recruitment of the descending pain modulatory system. Behavioral and neural effects were attenuated by naloxone, supporting a mediating role for endogenous opioids. These findings provide convergent evidence that active goal pursuit engages opioidergic pain modulatory mechanisms to reduce pain in humans.

neuroscience↗

bioRxiv2026

CREST: A Cortical Resting-State EEG Spatial Transformer for Chronic Pain Inference

Chronic pain mechanisms are complex, spanning multiple brain regions and networks. We ask whether resting brain activity carries a readout of that state. From a few minutes of resting-state electroencephalography (EEG), we generate a spectrogram to represent how each region of the cortex oscillates across frequency and time and pass it through CREST (Cortical Resting-state EEG Spatial Transformer): a frozen image-recognition network that reads each region as an image--here, a spectrogram--paired with a graph model that weighs the 56 cortical regions together to classify chronic-pain status. Across 125 people (74 with chronic pain, 51 healthy controls), evaluated through a leave-one-subject-out cross-validation, CREST separates the two groups with an area under the receiver operating characteristic curve (AUROC) = 0.782 (permutation p < 0.005). Control experiments implicate each persons individual alpha rhythm. Clinical relevanceA resting-state EEG readout of chronic MSK pain could clarify pathophysiology and inform treatment.

neuroscience↗

bioRxiv2026

Scaffold Affinity Tunes Biomolecular Condensate Function

Biomolecular condensates (BMCs) organize cellular biochemistry by concentrating selected molecules into dynamic membrane-free compartments. Yet the molecular parameters that determine not only whether condensates form, but also how they behave and what they do, remain poorly defined. Here we show that scaffold binding affinity (Kd) is a quantitative determinant of condensate phase behavior, internal dynamics and biochemical output. Using a modular SUMO-SIM system in which scaffold valency was held constant while binding affinity was systematically varied, we found that affinity governs the phase boundary, resistance to chemical perturbation, and molecular mobility of condensates in vitro and in human cells. In multicomponent mixtures, the highest-affinity scaffold dominated dense-phase composition and dynamics, revealing a hierarchical rule for condensate organization. Finally, affinity-dependent changes in condensate dynamics translated into tunable enzyme activity, establishing binding energetics as an engineerable parameter for programming condensate biochemistry.

biochemistry↗

bioRxiv2026

3D ultrasound fascicle tractography for objective muscle architecture analysis.

Muscle architecture shapes muscle function and changes with age, growth, training and disease, yet quantifying three-dimensional (3D) muscle architecture in vivo remains challenging. We introduce a hybrid fascicle tractography approach for freehand 3D ultrasound data that accurately reconstructs 3D muscle fascicles with respect to an objective, anatomically relevant coordinate system defined by the muscle's central aponeurosis. The hybrid approach combines Hessian-based fascicle detection with wavelet-based refinement to generate volumetric fascicle orientations. In a synthetic dataset with known ground truth, fascicle orientations and lengths were estimated with errors of [≤]2{degrees} and ~1.5%, respectively. In vivo, the approach detected physiologically plausible fascicle lengthening in the human tibialis anterior following a passive plantar flexion rotation, whereas diffusion tensor imaging of the same muscle did not. The proposed method enables anatomically relevant, objective and non-invasive quantification of 3D muscle architecture in vivo, providing a practical framework for applications in clinical and applied muscle physiology.

bioengineering↗

bioRxiv2026

PRISM: A Plasmid-based Reporter for Intracellular Spectral Microscopy

Organelles form an interconnected network whose morphology, positioning and interactions reflect cellular state. However, reproducibly quantifying these organelle phenotypes across large cell populations and diverse cell types remains a significant challenge. Here we present PRISM (Plasmid-based Reporter for Intracellular Spectral Microscopy), a PiggyBac-integrable construct encoding five unique fluorescent organelle reporters for spectral microscopy, with an accompanying modular analysis pipeline. PRISM stably labels the Golgi, peroxisomes, endoplasmic reticulum, mitochondria and lysosomes in multiple cell types while remaining compatible with additional molecular or functional probes. The workflow extracts over 500 metrics per cell, describing organelle morphology and distribution alongside pairwise and higher-order contacts. We use PRISM to characterise organelle responses to cytoskeletal perturbation, map PI(4)P redistribution during lysosomal damage, and reveal how Zika virus remodels the organelle landscape during infection. PRISM provides a reproducible approach for investigating organelle network remodelling across biological contexts

cell biology↗

bioRxiv2026

Autism-risk gene mutations convergently disrupt sexually dimorphic oxytocin circuits to lower social engagement

Autism arises from diverse genetic risk factors, yet how they converge to produce core symptoms and contribute to its sex bias remains unestablished. Oxytocin increases sociability in multiple murine autism models, presenting an opportunity to identify a potentially shared mechanistic basis across etiologies. Here we show that spontaneous social investigation triggers overlapping patterns of aberrant functional connectivity across social and sensory brain regions in two knockout (KO) mouse models, which are rescued by oxytocin. We also report that, during social investigation, wildtype mice exhibit sexually dimorphic oxytocin release and neuronal activity dynamics in the nucleus accumbens and the amygdala. These patterns are disrupted in both KO models, but can be restored by sex- and circuit-specific stimulation of endogenous oxytocin release, accompanied by enhanced social engagement. These findings identify impaired oxytocin recruitment of sexually dimorphic social circuits as a convergent consequence of autism-risk gene mutations that may underlie low sociability.

animal behavior and cognition↗

bioRxiv2026

MHC class II in dopaminergic neurons prunes GABAergic synapses in neurodevelopmental disorders

Although the brain was traditionally considered immune-privileged, recent studies show immune factors play key roles in brain function. Dysfunction of these factors is linked to neurodevelopmental disorders, but mechanisms remain unclear. Using a maternal immune activation (MIA) mouse model, we investigated immune-related genes in neurodevelopmental disorder pathogenesis. MIA mice showed increased locomotor activity and disrupted prepulse inhibition. RNA-seq and qPCR analyses revealed persistent increases in major histocompatibility complex class II (MHCII) expression and persistent decreases in GABAergic synapse-related gene expression, particularly glutamate decarboxylase (Gad) expression, in dopaminergic regions. These expressions were negatively correlated, and immunohistochemistry showed MHCII at postsynaptic GABAergic synapses on dopaminergic neurons. Patch-clamp recordings confirmed reduced mIPSC frequency in MIA mice. MHCII knockout mice showed opposite phenotypes, while MHCII overexpression in dopaminergic neurons decreased Gad expression. These results suggest MIA-induced MHCII upregulation enhances pruning of GABAergic synapses on dopaminergic neurons, leading to behavioral deficits.

neuroscience↗

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

Hidden molecular states of bacterial replicons beyond the chromosome-plasmid dichotomy

Bacterial genomes are organized into autonomous replicons, traditionally classified as either chromosomes or plasmids-a binary framework that underpins genome annotation and evolution models. Yet whether this binary framework captures the full diversity of replicon organization remains unclear. Here we show that bacterial replicons occupy three recurrent organizational states rather than two canonical categories. By integrating quantitative measures of chromosome-plasmid sequence affinity (plasmidness) across more than 72,000 replicons from 21 bacterial genera, we identify a distinct class-intermediate replicons-that occupies a positional and functional middle ground. These replicons are plasmid-sized, harbor substantial chromosomal sequence ancestry, and lack canonical replication signatures typically associated with either class. Multiple complementary molecular properties converge on this same state. Comparative genomic analyses reveal their enrichment near recurrent chromosome remodeling regions and reveal close evolutionary ties to conjugative and antimicrobial resistance plasmids. Metagenomic data further corroborate their presence across natural ecosystems. Together, these findings reveal a previously unrecognized replicon state and redefine bacterial genome organization beyond the chromosome-plasmid dichotomy.

microbiology↗

bioRxiv2026

Chemosensory ERP Suggest Peripherally Driven Olfactory-Trigeminal Interactions in Healthy Older Adults

The olfactory and intranasal trigeminal systems interact closely, influencing chemosensory perception, yet the mechanisms underlying their interaction remain poorly understood and have been studied mainly in young adults. We aimed to characterize olfactory-trigeminal interactions in aging by comparing electrophysiological and behavioral responses under ipsilateral and contralateral olfactory-trigeminal co-stimulation, to determine the relative contributions of peripheral and central mechanisms. Using chemosensory event-related potentials and a localization task, 44 healthy older adults (66.3 {+/-} 4.6 years; 29 women) were tested under four conditions: pure trigeminal (carbon dioxide; CO2), pure olfactory (2-phenylethanol; PEA), ipsilateral co-stimulation (PEA+CO2 in the same nostril), and contralateral co-stimulation (PEA+CO2 in opposite nostrils). Ipsilateral, but not contralateral olfactory-trigeminal co-stimulation, improved trigeminal localization performance and induced larger late positive component amplitudes. Together, these findings suggest that olfactory-trigeminal interactions are driven primarily by peripheral rather than central mechanisms. This study also provides normative CSERP data for healthy older adults.

neuroscience↗

bioRxiv2026

Calibration-free compression brings Evo 2 to its full million-token context on a single GPU

Evo 2 is the largest openly available genomic foundation model, but its forty billion parameter configuration cannot be loaded onto a single 80 GB accelerator, placing genome-scale analysis beyond most laboratories. We present TurboQuant-Bio, an open toolkit that compresses Evo 2s weights and attention cache to four bits without calibration data, and serves both through fused kernels. Compression is near-lossless across perplexity spanning the tree of life, genomic classification, splice-site prediction, gene completion and clinically relevant variant-effect prediction. It brings Evo 2 40B onto one 80 GB GPU and Evo 2 7B to its full million-token context within a 40 GB memory budget, an eightfold gain in reachable context. We further show that the released chunked-prefill path is silently incorrect, returning plausible but uncorrelated likelihoods, and derive the block-wise continuation that repairs it: a complete 580-kilobase bacterial genome is now scored in one context in 22 minutes rather than 13.7 hours.

bioinformatics↗

bioRxiv2026

Scaling recipes for single-cell RNA sequencing foundation models: when do scaling laws hold?

Deep learning models exhibit empirical scaling laws whereby performance changes predictably with model size, dataset size, and training compute. Although these relationships are well established in domains such as language and image modelling, their applicability to biological data remains unclear. Here, we investigate scaling behaviour in foundation models trained on large collec tions of single-cell transcriptomes. We show that pre-training loss decreases systematically with model capacity and training compute, exhibiting a power law dependence on model size. The strength and regularity of these trends differ between model formulations. We identify and quantify empirical relationships linking the optimal learning rate and depth-to-width ratio to model size and depth or compute. These results demonstrate that scaling principles extend to transcriptomic modelling. More broadly, they provide a quantitative framework for estimating the expected returns from additional resources and selecting suit able hyperparameters and architectures, thereby supporting the development of increasingly capable foundation models for omics data.

bioinformatics↗

bioRxiv2026

An ancestral pronephric contribution reveals the multilineage origin of the teleost gonad and revises the evolution of vertebrate gonadogenesis

Challenging the paradigm that pronephric field contribution to gonadal formation would be an amniote innovation, we demonstrate this trait is ancestral to bony vertebrates. Using cell lineage tracing, single-cell and spatial transcriptomics, and functional validation, we show that the teleost gonad arises from three distinct embryonic tissues, the pronephros, the coelomic epithelium, and the lateral plate mesoderm, in contrast to amniotes. This multi-tissue origin generates an unexpected lineage-based cellular diversity. Further cross-species comparisons over medaka, mouse, chicken and turtle unravel how lineage-specific deviations shape early gonadal development. Specifically, we map these variations amongst the different gene regulatory networks, outlining their physiological implications for specialized gonadal functions. Our results support a model in which heterochronic shifts are coupled to regulatory rewiring of conserved gene networks, driving lineage-specific developmental trajectories through a canalized developmental system drift.

developmental biology↗

bioRxiv2026

Assessing specificity testing in Lesion Network Mapping

Lesion Network Mapping (LNM) is a framework used for identifying symptom-related brain circuits by projecting lesion locations onto a normative connectome. Recent methodological investigations have raised concerns about the biological interpretation and specificity of the circuits derived using this method, with published LNM maps often showing high similarity across clinically unrelated conditions. Specificity testing has subsequently been put forward as the decisive step to ensure specificity to the symptom in question, accompanied by the argument that this step was not evaluated in the original methodological investigation. Yet, sensitivity testing, specificity testing, case-control LNM, permutation of group labels, and symptom-based LNM involve related operations on connectivity matrix C. We expand on specificity testing in LNM, clarify its relationship to other LNM steps and variants, and examine the persistent repetition among LNM specificity networks across studies. These considerations advance our understanding of the disease-specificity limitation of LNM and encourage the development of new methodological approaches for identifying brain circuits underlying psychiatric and neurological disorders.

neuroscience↗

bioRxiv2026

Both environmental filtering and intraspecific variation shape small mammals' elementomes

The biogeochemical niche hypothesis (BNH) proposes the multi-elemental composition of organisms - their elementome - as a new ecological dimension. However, which ecological factors shape elementome assembly remains little known, especially in animals. Here, we studied the mandibular elementome of two sympatric small mammals - Apodemus flavicollis and Clethrionomys glareolus - to assess how intraspecific variability (ontogenetic changes in body mass and sex under the vertebrate bone hypothesis; VBH) and environmental filtering (season and habitat) shape essential and non-essential elementome assembly. Species showed moderate elementome segregation and seasonal niche partitioning, with implications for coexistence. Ontogenetic body mass predicted elemental variation and calcium substitution, with several hypermetric scalings in autumn indicating strong departures from mass-invariant homeostasis. Finally, our results suggest a dichotomy: essential elementomes were mainly driven by intraspecific variation, whereas non-essential elementomes were rather shaped by environmental filtering. Our results position animal elementomes as an integrative ecological dimension linking organismal biology, species interactions, and environmental filtering across individuals, populations, and species.

ecology↗

bioRxiv2026

A human-derived two-antibody cocktail confers prophylactic and therapeutic protection against authentic Mpox virus.

With sustained human-to-human transmission worldwide, Mpox virus remains a significant global health burden. However, there are no licensed therapeutics against Mpox, with clinical management limited to supportive care and pain management. Given the virus complex life cycles, effective treatments require the inhibition of both mature intracellular virions (MV) and extracellular virions (EV). Here, we describe the isolation of human monoclonal antibodies (mAbs) from antigen specific memory B cell using flow cytometry-based cell sorting. We also characterize the therapeutic potential of 2-mAb cocktails targeting both MV and EV using an in vitro neutralization assay and a mouse challenge model. Several developed human 2-mAb cocktails neutralized authentic Mpox in vitro. When administered 24 hours before or after Mpox challenge, the lead 2-mAb cocktail inhibited viral loads in mouse tissues, with the exception of the testes. Overall, our study identifies several human 2-mAb cocktails with therapeutic potential for controlling Mpox disease.

microbiology↗

bioRxiv2026

OMICON: a community resource for studying gene coexpression networks in normal and neoplastic human brain samples

Genome-wide coexpression analysis of intact tissue samples is a powerful approach for identifying reproducible signatures of cell types and states, since it can survey vast numbers of individuals, cells, and transcripts. However, it can be difficult to optimize gene coexpression network construction and compare results from independent analyses. To address these challenges, we developed OMICON (theomicon.ucsf.edu) for research on human brain gene coexpression networks. OMICON contains gene expression data from >17K normal and neoplastic human brain samples with standardized metadata. Systematic analysis of independent datasets identified >250K gene coexpression modules, which were characterized and compared via enrichment analysis with >40K gene sets. All modules are discoverable via an advanced search engine that can filter by genes, metadata, and enrichment results. Analyses can also be browsed with an interactive workflow visualization tool, and users can communicate within OMICON using @mention functionality to support communal research on human brain gene coexpression networks.

neuroscience↗