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Results for “scientific communication and education”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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498 records · Page 28Linked to original sources

bioRxiv2026

Bravais Lattice Sampling: Geometry-Guided Sparse Probing for Connected-Component Detection in 3D Discretized Spaces

We introduce Bravais Lattice Sampling (BLS), a two-phase method for detecting connected high-density regions in three-dimensional space. BLS places probe sites on a Bravais lattice scaled to the expected nearest-neighbour distance dNN of the target structures, then recovers cluster boundaries by depth-first expansion seeded only from occupied probes, replacing the exhaustive raster scan that conventional connected-component labelling uses to discover seeds. The spacing between probe sites is set from the covering radius of the lattice, which is what allows the method to state in advance the size below which a cluster may escape detection. The second phase, an expansion refinement activated only on probes that return an occupied voxel, verifies every edge, so the components returned are true connected components. BLS versatility allows for selection of different Bravais lattice unit cells to match the target structure; for amorphous, non-crystalline shapes, BLS can default to a simple face-centred cubic unit cell, where the expected minimum cluster size is the only parameter that needs to be set. The current BLS implementation has been developed as a post-processing tool for molecular dynamics trajectories, and was tested for searching water ice clusters of different morphologies. BLS returns component counts and maximum cluster sizes identical to exhaustive-labeller algorithms, with 100% recall; it runs at about 0.94 times the cost of depth-first search, and at 0.84 to 0.90 times the cost of the fastest other labeller in our benchmark set. This algorithm, although implemented by us for molecular dynamics applications, could be of interest in other domain areas where searching for high-density elements in 3D space is relevant.

bioinformatics↗

bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗

bioRxiv2026

Conditional Myeloid-Specific Inhibition of UBE2N Hinders YUMM1.7 Growth

The role of UBE2N in myeloid cell-mediated immune suppression in cancer remains undefined. Here, we examined the function of UBE2N in myeloid cell-mediated tumor progression using a temporally inducible myeloid-specific knockout model (LysMCreERUbe2nfl/fl). Temporally induced deletion of Ube2n in myeloid cells (Ube2nMyeKO) significantly hindered growth of YUMM1.7 melanoma. This was accompanied by reduced myeloid cell burden within the tumor microenvironment. We observed altered abundance of PD-1, PD-L1, and SPP1 in the Ube2nMyeKO tumor microenvironment at the tissue level. In vitro analysis showed that knock-in expression of a catalytically deficient UBE2NC87S mutant in bone marrow-derived macrophages (BMDMs) markedly decreased expression of Spp1. We observed decreased SPP1 secretion in Ube2nMyeKO BMDM-conditioned media (CM). Treatment with Ube2nMyeKO BMDM-CM decreased co-expression of PD-1, TIM-3, and LAG-3 on chronically stimulated T cells. Antibody-mediated neutralization of SPP1 in Ube2nWT BMDM-CM decreased PD-1 expression on CD8+ T cells. Together, these findings suggest a role for myeloid UBE2N in YUMM1.7 progression.

cancer biology↗

bioRxiv2026

TALE-independent transcriptional activation of the rice executor gene Xa23 is regulated via histone acetylation during zygote development

Transcription activator-like effectors (TALEs) from Xanthomonas activate transcription of executor (E) genes in host plants, leading to cell death and thereby restricting proliferation of biotrophic pathogens. Because E gene transcripts had only been detected upon activation by cognate Xanthomonas TALEs, E genes were thought to function exclusively in plant immunity. Here, we detect TALE-independent transcription of the rice E gene Xa23 in zygotes 4-6 hours after gamete fusion. Histone deacetylase inhibition induces Xa23 transcription in unfertilized egg cells, implicating histone acetylation in Xa23 regulation. We identified potential cis-regulatory elements and transcription start sites associated with native Xa23 transcription during zygote development. Together, our findings suggest that Xa23 is a developmentally regulated gene with a native role during early zygote development. This supports a previously proposed model in which E genes have native functions in development, while fortuitous upstream polymorphisms can create TALE-binding sites that convert them into immune executors.

plant biology↗

bioRxiv2026

A structural census links penultimate-residue class to N-terminal burial in human protein assemblies

Initiator-methionine excision is among the earliest protein modifications, yet its relationship to assembly geometry is unknown. Burial of the mature first residue was measured across 7,246 deposited human biological assemblies (22,291 chain-level observations; 1,191 proteins). Among 1,143 analyzable proteins, termini in MetAP-permissive penultimate-residue sequence classes were less often interface-engaged than termini in MetAP-nonpermissive classes (37.4% versus 47.4%; adjusted odds ratio 0.65, p = 7.2e-4). Curated processing annotations did not show a corresponding burial difference, and correlated residue properties preclude attributing the sequence-class association specifically to iMet removal. The analysis identified 264 interface-engaged MetAP-permissive candidates concentrated in cellular machines. In a fully recomputed conformer scan of deeply buried proteasome positions, modeled methionine accommodation was less favorable than at observed-methionine controls (median overlap -0.30 versus -1.12 angstrom, p = 0.0049), although most scoreable sites permitted a nonoverlapping placement. The census therefore reveals a graded structural constraint - not universal steric failure - and prioritizes complexes in which altered packing, assembly kinetics, lipidation or N-terminal methylation can be tested.

biochemistry↗

bioRxiv2026

Proteolytic Remodeling of Cargo Receptor Networks by RHBDL4 Tunes Secretory Pathway Flux

Cargo receptors are central organizers of the secretory pathway, yet the mechanisms controlling their abundance remain poorly understood. The endoplasmic reticulum (ER)-resident intramembrane protease RHBDL4 promotes substrate turnover via a non-canonical branch of ER-associated degradation and has recently been implicated in regulating secretory pathway components. We previously identified the p24 cargo receptor TMED7 as an RHBDL4 substrate, suggesting that cargo receptor turnover contributes to secretory pathway regulation. Here, quantitative proteomics identify members of the ER-Golgi intermediate compartment (ERGIC) cargo receptor family as endogenous RHBDL4 substrates, demonstrating that RHBDL4 targets multiple cargo receptor families within the early secretory pathway. Accordingly, RHBDL4 modulates multiple ERGIC-dependent transport pathways. In addition, unbiased secretome analysis reveals increased secretion of lysosomal precursor proteins upon RHBDL4 ablation. Mechanistically, we show that this phenotype is mediated, at least in part, by RHBDL4-dependent cleavage of the lysosomal cargo receptor sortilin/SORT1. Together, these findings identify cargo receptors as a major class of RHBDL4 substrates and establish proteolytic remodeling of cargo receptor networks as a mechanism for regulating secretory pathway flux.

cell biology↗

bioRxiv2026

TigerAI: An AI-powered genetic evidence platform to support clinical development

Genetic evidence is a major determinant of clinical success in drug development, yet its aggregation has long relied on laborious human curation. Large language models (LLMs) have the potential to rapidly synthesize knowledge across biomedical resources, providing a route to scalable AI-driven genetic evidence generation. Here we develop a novel domain-grounded instruction framework to systematically evaluate GPT-5 for producing genetic evidence relevant to clinical trial success. Using 13,022 target-indication pairs from a comprehensive drug development database, we benchmark LLM-derived evidence against a recent exhaustive human expert-curated study. We find that GPT-5 yields genetic evidence that is at least as informative as expert curation for inferring clinical success, while substantially expanding coverage relative to traditional curation resources. Building on these results, we introduce TigerAI (https://tigerai.bio/), a dual-purpose platform for AI-powered genetic evidence that (i) benchmarks emerging state-of-the-art LLMs and (ii) provides an accessible service for querying reliable AI-generated genetic evidence. These contributions outline a practical, domain-grounded pathway for integrating AI-powered genetic evidence into drug development pipelines and for realizing the potential of LLMs to inform clinical success.

genetics↗

bioRxiv2026

Clonal memory in human embryonic stem cells biases fate potential during endoderm differentiation

Cell fate decisions during development are shaped not only by extrinsic signals but also by heritable intrinsic states passed on across cell division. The extent to which this phenomenon, termed clonal memory, can explain the persistent heterogeneity observed from directed differentiation of human embryonic stem cells is unclear. Here, we combine lineage tracing with single-cell transcriptomics and chromatin accessibility profiling to track clonal behaviour across human embryonic stem cell differentiation towards definitive endoderm. Using a lentiviral barcoding system coupled with a split-well sampling strategy, we find that clonally related cells exhibit reproducible, probabilistic fate outcomes that cannot be explained by signalling environment alone. Fate-biased clones are transcriptionally indistinguishable at the pluripotent stage yet display distinct chromatin accessibility landscapes at lineage-specific cis-regulatory elements. Pre-existing accessibility at these lineage-specific regulatory regions distinguish clones that undergo successful endoderm differentiation from those that generate off-target mesoderm derivatives. Together, these findings provide an explanation for how off-target populations arise during directed differentiation, identifying heritable chromatin states within pluripotent cultures as a source of variability relevant to stem cell-derived in vitro models and cell therapies.

developmental biology↗

bioRxiv2026

Adolescent blockade of complement signaling in the lateral septum increases social novelty seeking behavior in male mice

Social behaviors are critical for survival and change dramatically over the lifespan. Adolescence is a critical period of development during which social novelty seeking peaks before declining into adulthood. Adolescence is also a time of pronounced neural circuit refinement as excess synapses are eliminated. One critical mechanism supporting this maturation of neural circuits is microglial pruning of synapses through the classical complement signaling cascade. However, it remains unclear how microglial pruning of the neural circuitry supporting social novelty preference shapes the trajectory of this behavior during adolescence. To address this, we blocked microglial complement-dependent pruning during adolescence by injecting neutrophil inhibitory factor (NIF; blocks the adhesion of ligands to CD11b/C3 receptor) in the lateral septum (LS), a key node in the social circuitry supporting social novelty preference, in male mice. We found that NIF administration into the LS during adolescence increased preference for the novel social chamber over the familiar as compared to control PBS administration. LS-NIF treatment had no impact on anxiety-like behavior in the light-dark box test and no effect on sociability. LS-NIF treatment also decreased the expression of immune-related genes in the LS as compared to PBS treatment. These data support the hypothesis that complement-dependent microglial synaptic elimination in the LS is critical for the developmental progression of social novelty preference.

neuroscience↗

bioRxiv2026

Trans-Allosteric Activation Releases Distinct Conformational Traps in Kinase Heterodimers

Protein kinases function as dynamic, mechanically coupled nodes, yet the conformational drivers of multimeric activation remain unclear. Here, we present AlloQuant, a computational suite that translates AlphaFold3 structural ensembles into quantitative metrics of kinase regulation, including internal network rigidity, metastable-state populations, and sub-angstrom conformational drivers. Applying AlloQuant to CDK1, we demonstrate that binding of the Cyclin B1 (CCNB1) cofactor mechanically decouples a hyper-rigid inactive kinase core, allowing activating phosphorylation (pT161) to subsequently re-impose localized tension on the catalytic machinery. Conversely, the C-terminal Src kinase (CSK) faces a distinct conformational trap. While nucleotide-free monomeric CSK spontaneously samples a pre-active geometry, ATP binding excludes the active C-In conformation in all but 1 of 225 models. We show that docking partner engagement overcomes this blockade. Autophosphorylation of SRC at the activation loop (Y419) redistributes SRC conformational states without altering bulk rigidity. This redistribution is structurally coupled to the conformational state of CSK via the regulatory spine, not the catalytic machinery. Rather than mechanically deforming CSK, SRC engagement acts by conformational selection, committing roughly a quarter of CSK molecules to a fully active state. Thus, trans-allosteric kinase activation operates by defining the accessible conformational landscape of the receiver kinase. That control is exerted through mechanical remodeling in cofactor-dependent complexes and through conformational selection in transient kinase-kinase heterodimers. These findings establish AlloQuant as a general framework for quantifying how a binding partner reshapes a kinase's conformational landscape, applicable across the kinome because it assigns landmarks by profile-HMM alignment.

biophysics↗

bioRxiv2026

Geometry of antigenic evolution improves influenza vaccine selection

Anticipating antigenic evolution is essential for selecting effective seasonal influenza A/H3N2 vaccine strains. To this end, we integrated hemagglutination-inhibition and neutralization titers spanning 2002 to 2025 into a unified Bayesian antigenic map. The map resolves twelve antigenic clusters advancing in discrete steps, with several clusters co-circulating in most seasons. In 15 of 21 seasons, the WHO-recommended vaccine belonged to an earlier cluster than the dominant circulating cluster. The direction of each vaccine update relative to recent viral drift predicted vaccine effectiveness one season ahead in out-of-sample forecasts. Antigenic distance, the conventional measure of vaccine-virus match, was weakly associated with effectiveness until update direction was accounted for. Retrospectively ranking candidate strains by predicted effectiveness would have selected a strain predicted to outperform the WHO recommendation in every season, raising mean predicted effectiveness by 10 percentage points.

evolutionary biology↗

bioRxiv2026

GNMCADS: Sampling For Protein Conformation Diversity With Gaussian Network Model Guided Condition Annealed Diffusion Sampler

Proteins are dynamic molecules existing in diverse conformational states underlying their biological functions. Although recent approaches have enabled diverse conformational sampling by emulating molecular dynamics simulations, perturbing evolutionary information, or steering internal mechanisms of structure prediction models, predicting conformations resulting from major domain motions or motions that occur over long timescales still remains a challenge. To this end, we introduce GNMCADS, a conformational sampling strategy that enhances the diversity of protein diffusion models by selectively annealing the conditioning signal guided by the intrinsic dynamical organization of the sampled protein. Further, we implement GNMCADS in the diffusion module of AlphaFold3, enabling the generation of diverse protein conformations. When benchmarked across 92 proteins that include 54 class A GPCRs, 15 transporters, and 23 proteins with major domain movements, GNMCADS exhibits improved sampling diversity compared to other current conformational sampling methods.

bioinformatics↗