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bioRxiv2026

A century of soybean breeding increased photosynthetic capacity but not NPQ relaxation

Accelerating photoprotective regulation to improve carbon assimilation is a promising strategy to increase crop productivity. Although rapid non-photochemical quenching (NPQ) relaxation has been validated as a target through metabolic engineering, it remains unclear whether conventional breeding has improved this trait. Here, we investigated whether more than a century of soybean breeding enhanced NPQ relaxation alongside light-saturated carbon assimilation and seed traits. We evaluated a historical panel of 24 soybean genotypes across vegetative and reproductive developmental stages by integrating NPQ relaxation, gas exchange parameters, xanthophyll-cycle pigment profiles, expression of key photoprotective genes (VDE, PsbS, and ZEP), seed number and seed weight. NPQ relaxation parameters were not consistently associated with genotype release year, seed number, or seed weight at either developmental stage. The only exception was the amplitude of the rapidly relaxing NPQ component (AqE), which was negatively correlated with all three variables during the reproductive stage. In contrast, genotype release year was positively associated with maximum net CO2 assimilation rate (Amax), maximum carboxylation rate of Rubisco (Vcmax), maximum electron transport rate (Jmax), seed number, and seed weight, while Amax and Vcmax were positively correlated with seed number and seed weight. These findings indicate that the greater photosynthetic capacity of modern genotypes was not accompanied by faster photoprotective response. Thus, photoprotective regulation has not kept pace with gains in photosynthetic capacity under field conditions. We conclude that rapid NPQ relaxation remains an important target for synchronizing photoprotection with the high photosynthetic capacity of modern soybean lines.

plant biology↗

bioRxiv2026

Widespread SARS-CoV-2 infection in free-ranging Neotropical bats suggests repeated human-to-bat spillback

Bats harbor exceptional coronavirus diversity and are considered ancestral sources of several human pathogens. As SARS-CoV-2 transitioned from pandemic emergence to global endemicity in humans, concern has shifted from wildlife-to-human spillover toward reverse zoonosis. However, infection of free-ranging bat populations under natural conditions has not previously been demonstrated. Here, we report widespread detection of SARS-CoV-2 RNA in wild Neotropical bats sampled across Andean and Amazonian ecosystems of Southern Ecuador. RT-qPCR screening of 126 individuals, representing nine taxa, detected SARS-CoV-2 RNA in 34.12% of bats across multiple sites. Partial to near-complete viral genomes recovered from five individuals showed >99% nucleotide identity to contemporary human SARS-CoV-2 lineages and clustered within multiple global phylogenetic clades. Mixed-effects modeling revealed pronounced species-level heterogeneity, a positive association between elevation and infection probability, and higher infection probability in females compared with males. The close phylogenetic affinity of bat-derived genomes to circulating human variants and their distribution across multiple lineages suggest repeated anthropogenic spillback rather than sustained bat-specific circulation. These results expand current understanding of the ecological footprint of the COVID-19 pandemic and highlight the importance of integrating wildlife surveillance into long-term One Health strategies for emerging infectious diseases.

microbiology↗

bioRxiv2026

Background proteome correction promotes confident identification of dynamic protein-protein interactions between different biological contexts

Affinity purification-mass spectrometry (AP-MS) enables the characterization of protein-protein interactions (PPIs), and the ease and sensitivity of such experiments has progressively increased. Beyond steady-state interactions of target proteins, a strong interest has emerged in monitoring how PPIs change upon significant biological perturbations, such as in disease contexts or small molecule modulation of the target protein. These perturbations likely not only induce PPI changes but can also lead to altered expression of proteins not of direct interest. Changes in protein abundance may alter which proteins adsorb to the affinity purification matrix, and due to the sensitivity of modern mass spectrometers, these differential ''background binders'' can masquerade as differential interactors. Contemporary approaches often do not account for differences in the background proteome, potentially inflating the number of false positives and negatives reported. Here, we provide technical considerations for the reliable annotation of dynamic PPIs, using the O-GlcNAc transferase (OGT) as a case study. We describe the installation of affinity epitope tags on endogenous OGT in mouse embryonic stem cells (mESCs), which we then apply for OGT interactor identification via AP-MS. We show that accurate representation of the bead background, which depends on the affinity matrix in use, is critical for elimination of false positive and false negative PPIs. This became even more pertinent as OGT PPI dynamics were measured under OGT catalytic inhibition via OSMI-4, which is known to perturb gene expression. The proteomes of OSMI-4-treated and control-treated mESCs differed, leading to distinct bead backgrounds in which the differential background proteins appeared as interaction gains or losses. These false positives were resolved by incorporating straightforward experimental controls through a practical statistical framework, allowing for a direct and confident comparison between treatment conditions. Incorporating these considerations into workflows investigating PPI dynamics will improve data fidelity and reproducibility.

biochemistry↗

bioRxiv2026

How to pour a cup of coffee

Pouring a drink feels deceptively trivial, yet it requires guiding a boundary-free fluid into a vessel without spilling, overflowing, or toppling it -- a task at which robots remain notoriously brittle. How humans achieve this so effortlessly is unknown, as motor control has predominantly been studied in brief, highly constrained laboratory tasks, leaving the control principles underlying ecological tasks largely unknown. Here we measured continuous sensorimotor control during liquid pouring across various containers, vessels, and speed demands. Despite substantial variation in movement trajectories and durations, individuals maintained a strikingly invariant preferred fill level. Counterintuitively, fill level variability decreased at higher fill levels, and precision was maintained even under time pressure. A stochastic optimal control model combining a data-driven nonlinear approximation of flow dynamics with a cost that balanced individualised fill level, energy expenditure and flow-rate reproduced the behaviour. Humans thus pour optimally, given their sensorimotor limits and idiosyncratic notion of "full".

neuroscience↗

bioRxiv2026

Parallel evolution under constraint shapes echinocandin resistance in Candida auris

Drug resistance emerges repeatedly in outbreaks of Candida fungal pathogens, but little is known about its origins or persistence. Here, we investigated the evolutionary processes shaping echinocandin resistance in Candida auris, a globally emerging and predominantly clonal fungal pathogen. Genome-wide association across over 600 isolates identified mutations in the {beta}-1,3-glucan synthase gene FKS1 as the most significant driver of resistance to an echinocandin drug. Ancestral reconstruction of this population traced shared resistance mutations among small groups typically consisting of 2-3 closely related isolates, but clusters could include up to 16 isolates. Nearly all resistant clusters consisted of isolates collected in the same year and region, consistent with local transmission. To further examine population-level selection, we measured adaptive signatures in FKS1 and the highly diverged paralog FKS2 across 22,000 genomes. This revealed excess nonsynonymous polymorphisms in FKS1, primarily due to independent, recurrent mutations at resistance hotspots, consistent with parallel evolution and incomplete fixation of adaptive alleles. In FKS2, there is no evidence of hotspots and little support for diversifying selection. Together, these results indicate that resistance mutations emerge under strong genetic constraint, with adaptation restricted to only one FKS homolog and predominantly at mutational hotspots.

genetics↗

bioRxiv2026

INFORME: coupling information-theoretic experimental design with nonlinear mixed-effects modeling for efficient observation scheduling

Mathematical models of treatment response can inform individualized therapy, but their calibration often requires longitudinal measurements that are costly, burdensome, and collected on fixed schedules. Such schedules may be inefficient, over-sampling patients whose response is already well characterized while delaying informative measurements for those whose model parameters remain uncertain. We present INFORME (INFORmation-theoretic design with Mixed Effects), a framework that combines Bayesian information-theoretic experimental design with nonlinear mixed-effects modeling to adaptively select each patients next measurement time. Population and response-subgroup parameter distributions learned from an existing cohort provide informative priors, allowing candidate measurement times to be ranked by their expected reduction in patient-specific parameter uncertainty. As observations accumulate, priors can be updated to reflect the response subgroup most consistent with the patients data. We evaluate INFORME in two radiotherapy datasets: 150 synthetic tumor volume trajectories from a hybrid cellular automaton model of prostate cancer spheroids (HD1) and longitudinal tumor volumes from 39 patients with head-and-neck cancer (HD2). In HD1, population priors allowed omission of both pretreatment scans, while adaptive scheduling reduced the protocol from nine scans to three or four, with the response group identified from a single post-treatment scan on day 27. In HD2, the adaptive schedule used three scans instead of six and improved prediction by delaying the first on-treatment scan from week 1 to week 2, avoiding transient dynamics that produced false-positive and false-negative response projections. Across both datasets, the adaptive schedules used a mean of 2.7 scans in stead of seven and advanced completion of the patient-specific prediction by a mean of 15.5 days (95% CI, 6.7-24.3) relative to the equidistant protocol, while treatment duration remained unchanged. INFORME therefore reduces measurement burden and accelerates patient-specific prediction by concentrating observations at times that are most informative for model calibration.

systems biology↗

bioRxiv2026

Extracellular Vacuole-derived bodies (EVacs) mediate RNA secretion in plants

Extracellular RNAs are found in the plant extracellular space, but how they are exported from cells remains unclear. We found that the plant vacuole is a major source of extracellular RNA and identified a class of large extracellular vacuole-derived bodies, which we termed EVacs, that are key mediators of this transport. EVacs are marked by the vacuolar membrane (tonoplast) proteins {gamma}-TIP and V-ATPase and originate as intravacuolar structures formed by inward folding of the tonoplast, encapsulating intact cytoplasmic material, including both RNAs and proteins. These intravacuolar bodies then escape the vacuole and are subsequently released from the plasma membrane of mesophyll cells into the apoplast. These findings provide a novel mechanism for the unconventional secretion of macromolecules in plants.

plant biology↗

bioRxiv2026

Neogenin-1 marks myeloid-primed fetal hematopoietic stem cells that undergo progressive lineage-restriction with age

During aging, hematopoietic stem cells (HSCs) increasingly shift from balanced to myeloid-biased differentiation, resulting in reduced lymphoid output and impaired adaptive immunity. The question of whether this lineage bias is established in a subset of HSCs during early development or primarily emerges with aging warrants further investigation. Here, we investigate whether myeloid-biased HSCs (my-HSCs) are established at the fetal liver stage by specifically examining Neogenin-1 (NEO1), a previously defined marker of my-HSCs. We identify two distinct populations of Hoxb5+ HSCs in the fetal liver: NEO1+ and NEO1-, with NEO1+ HSCs exhibiting transcriptional and functional characteristics consistent with my-HSCs. With age, my-HSC-associated transcriptional programs become increasingly reinforced across the Hoxb5+ pHSC compartment, with NEO1+ cells showing early enrichment of this program and both NEO1+ and NEO1- cells acquiring broader myeloid-biased features in aging. These findings suggest that lineage programming can begin early in development and is further shaped by age-related changes, potentially contributing to the functional decline observed in the aging hematopoietic system.

developmental biology↗

bioRxiv2026

De novo design of CR2 binder as vaccine scaffold

Efficient B cell activation during vaccine-induced humoral immunity relies on both B cell receptor (BCR) antigen recognition and synergistic signaling from co-receptors. Complement receptor 2 (CR2), the primary BCR co-receptor on B cells, lowers the activation threshold and amplifies downstream kinase signaling by orders of magnitude when engaged by complement fragment C3d decorated antigens. Targeting CR2 therefore represents a rational vaccine enhancement strategy, yet native C3d suffers from low affinity, poor stability, and manufacturing challenges. Here, we report the de novo design of a highly stable, high-affinity CR2 binder using deep learning driving protein design methods. Biophysical characterization, high-resolution cryoEM structural determination, and functional assays in vitro and in vivo confirm that the designed binder matches computational design models and specifically engages CR2 to boost B cell activation. When fused to antigen as a vaccine scaffold, the trimeric CR2 binder elicits robust humoral immune responses comparable to nanoparticle vaccines, while retaining the simplicity of single-chain protein production. Our work establishes a modular CR2 targeting vaccine scaffold platform with broad translational potential for next-generation protein vaccines.

immunology↗

bioRxiv2026

CyChat: a conversational Cytoscape app for no-code, reproducible network analysis

Network-based analyses of molecular interactions are useful for interpreting high-throughput omics data and identifying therapeutic targets. Cytoscape is the standard platform for these tasks, but users face a trade-off between accessible graphical workflows that are difficult to document and reproducible automation in Python or R that requires programming expertise. General-purpose coding assistants can generate Cytoscape Automation scripts, but remain external to Cytoscape. We present CyChat, a Cytoscape Desktop app that integrates a chat interface and a large language model (LLM) agent into the application. CyChat translates natural language into executable Cytoscape Automation workflows, runs generated Python code, and exports chat sessions with executed code as standalone Jupyter notebooks. To reduce setup barriers, CyChat includes an embedded Python runtime and supports both cloud-based and locally hosted LLMs. CyChat was evaluated across ten Cytoscape workflows using seven LLM providers, each represented by one LLM. The strongest configuration achieves a pass rate above 99%. In a qualitative evaluation based on a published network visualization, CyChat completes the task in 1.5-5 minutes, compared with 15-20 minutes for manual GUI workflows by computational biologists. CyChat is available through the Cytoscape App Store at https://apps.cytoscape.org/apps/cychat.

bioinformatics↗

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

Molecular basis of AMPA receptor labeling by ligand-directed acyl imidazole chemistry in living neurons

Rational design of covalent protein-labeling reagents in complex biological environments requires a molecular-level understanding of how the protein microenvironment governs chemical reactivity; yet, such mechanistic details remain inaccessible to experimental methods alone. In living neurons, Ligand-Directed Acyl Imidazole (LDAI) chemistry has been used to label AMPA receptors as a traceless, affinity-based protein labeling method. Although LDAI labeling reagents have been optimized in the lab, the atomic details of their interactions with the protein and the underlying mechanism remain elusive. In this work, we combined Quantum Mechanical (QM) calculations and molecular dynamics (MD) simulations to propose a detailed reaction mechanism for AMPAR labeling by LDAI reagents and to clarify how the protein microenvironment governs reactivity. Although Lys residues are usually protonated at physiological pH and therefore less nucleophilic in water, our QM results show that Lys labeling is energetically more favorable than competing reactions with Ser or water. MD simulations reveal that PFQX ---the LDAI reagent precursor--- binds dynamically to the GluA2 AMPAR as an antagonist, inducing conformational changes that reshape the local environment of the acyl imidazole (AI) warhead, underscoring that ligand identity strongly affects labeling outcomes. We also identified intra and intermolecular hydrogen bond networks that may contribute to further immobilize and pre-organize the LDAI reagent. Moreover, the probe's chemical nature shapes its interactions with the Ligand Binding Domain (LBD), offering a plausible rationale for the previously experimentally observed ligand-dependent fluorescent response. Taken together, our results establish design principles for exploiting the reagent geometry and binding pocket hydrogen-bonding networks for the rational design of LDAI reagents.

biophysics↗

bioRxiv2026

Function-driven geometry directs human pilosebaceous unit development

Single-cell technologies have generated cell censuses of tissues, however, how tissue geometry reflects functional needs remains poorly characterized. The human pilosebaceous unit offers a tractable model, a prenatally-formed complex mini-organ combining hair and sebum production with a stem cell reservoir. Using histomorphology, spatial transcriptomics, and single-cell multiomics on the same human prenatal scalp skin samples (8-19 post-conception weeks), integrated and analyzed using machine learning approaches, we built a spatiotemporal map of pilosebaceous unit development. We demonstrate that epithelial-mesenchymal interactions coordinate cellular fate and organogenesis, using an in vitro hair-bearing skin organoid model to validate this tissue-patterning. In addition, we show sebaceous gland developmental programmes are overcome during tumor formation. Our large-scale multi-modal analysis provides a unique framework for understanding form and function of tissues with applications in tissue engineering and pathology.

developmental biology↗

bioRxiv2026

A Metabolic Labeling Strategy for Tracking Protein Synthesis in Complex Biological Systems

Protein synthesis supports most biological processes. In the brain in particular, protein synthesis plays a critical role in physiological and pathological states. Here, we describe Tellurophene-Alkyne Cycloaddition-mediated Amino acid Tagging (TeACAT), a versatile strategy for fast, facile, and flexible tagging of newly synthesized proteins in mice. TeACAT is based on metabolic incorporation of the non-canonical amino acid TePhe into proteins by the endogenous protein synthesis machinery. Due to their high similarity, TePhe can efficiently replace canonical Phe without dietary or genetic manipulation. The subsequent bio-orthogonal reaction of TePhe with either fluorescent dyes or affinity handles enables both visualization and affinity enrichment of proteins synthesized during TePhe exposure. TeACAT is compatible with immunofluorescence for cell-type specific visualization of protein synthesis with subcellular resolution and can be used in conjunction with routine proteomics to identify and quantify newly synthesized proteins. Robust incorporation into the mouse proteome was observed on the scale of hours to days, allowing the interrogation of various biological processes. In summary, TeACAT enables the visualization and quantification of protein synthesis with minimal perturbation for biological discoveries.

molecular biology↗

bioRxiv2026

Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility

Herpes simplex virus 1 (HSV-1) infects approximately 67% of the population worldwide. It establishes lifelong reservoirs in sensory neurons and has been linked to several diseases including neuronal dysfunction. Disruption of mitochondrial homeostasis is a hallmark of HSV-1 infection, however a molecular understanding of these changes and their significance is not yet well defined. HSV-1 infection causes a UL12.5-dependent inhibition of mitochondrial biogenesis through the loss of mitochondrial DNA and mitochondrial transcription factors, PGC-1 (peroxisome proliferator-activated receptor-gamma co-activator) and TFAM (mitochondrial transcription factor). Conversely, UL12.5-independent mechanisms inhibit mitochondrial fusion by activating the OMA1 metallopeptidase that cleaves the inner mitochondrial membrane fusion protein OPA1 (optic atrophy protein 1) and by down-modulating the outer mitochondrial membrane fusion protein MFN2 (mitofusin 2). This inhibition of fusion results in a smaller mitochondrial network that clusters to perinuclear regions, likely supplying energy for viral replication and envelopment. The inner mitochondrial membrane protein TIM23 is also down-modulated during infection in a UL12.5-independent mechanism. Failure of the virus to promote these changes negatively impacts the infection. Despite these changes, mitochondria are protected from mitophagy due to the viral-induced degradation of several mitophagy adaptor proteins, whereby damaged mitochondrial components, including mitochondrial DNA, are extruded via extracellular vesicles. These mitochondrial changes still support functions necessary for HSV-1 infection. Basal cell respiration is preserved, while spare respiratory capacity and extracellular acidification rates increase, indicating glycolytic activity. Mitochondrial membrane potential is also preserved. Overall, our studies provide mechanistic insight into how HSV-1 impacts mitochondria, which could contribute to viral pathogenesis.

microbiology↗

bioRxiv2026

Arabidopsis thaliana ACTIN DEPOLYMERIZING FACTORs are novel susceptibility factors for Colletotrichum higginsianum

Colletotrichum higginsianum (Ch) is a hemibiotrophic fungal pathogen that infects Brassicaceae plants, including Arabidopsis thaliana. The molecular mechanisms underlying the Ch-A. thaliana interaction are not fully understood. Particularly, the susceptibility factor against Ch infection remains to be determined. Here, we report that A. thaliana ACTIN DEPOLYMERIZING FACTORs (ADFs), ancient proteins that regulate the organization and dynamics of actin filaments (AFs), function as susceptibility factors during Ch infection. Among 11 ADFs encoded in A. thaliana genome, subclass I ADFs that include ADF1, -2, -3, and -4, express throughout the plant. We found that knockout mutant of ADF4 and transgenic plants in which the expression of all of subclass I members is suppressed (ADF1-4Ri) exhibited increased resistance to Ch. Cytological analyses revealed that both Ch penetration and secondary hyphae formation were suppressed in adf4 and ADF1-4Ri. This enhanced resistance was associated with suppression of Ch-induced AF fragmentation. In addition, we found that PENETRATION 2 (PEN2) plays a critical role in the Ch resistance in adf4 and ADF1-4Ri. Our findings suggest that subclass I ADFs promote AF fragmentation during Ch infection, thereby suppressing PEN2-associated mitochondria accumulation at Ch entry sites. Together, these results raise the possibility that Ch exploits host ADF-dependent actin regulation to facilitate successful infection.

plant biology↗

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

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↗