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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 19 recordsLinked to original sources

bioRxiv2026

The Alzheimer's disease-associated rs28834970 variant in PTK2B impairs electrical activity and regulates Tau phosphorylation and APP processing in human neuronal cultures

Background: Genome-wide association studies have identified the PTK2B gene, which encodes Proline-rich tyrosine kinase 2 (PYK2), as a genetic risk factor for Alzheimer's disease (AD). However, its role in AD aetiology remains to be understood, as a complex contribution to amyloid {beta} (A{beta}) toxicity, tauopathy and neuronal dysfunction is suggested by contradictory evidence. Determining how the causal variant among AD-associated PTK2B variants impairs PYK2 function to trigger AD hallmarks could bring clarification. Methods: We combined in silico prediction tools with luciferase reporter assays in neuroblastoma cells to prioritize potential AD-associated PTK2B functional variants. We generated isogenic KOLF2.1J induced pluripotent stem cells (iPSCs) carrying the most relevant functional variant using CRISPR-Cas9 and differentiated them into human neuronal cultures (hNCs). We assessed PYK2 expression via immunoblotting, performed transcriptomic profiling using RNA-sequencing, analyzed neuronal network activity via multielectrode array (MEA) recordings, quantified synaptic density through immunocytochemistry in microfluidic devices, and assessed Tau phosphorylation and amyloid-precursor protein (APP) metabolism. Results: The rs28834970 regulatory variant was identified as the most functionally relevant in our model, with the C risk allele promoting transcription factor C/EBP{beta} binding within a cis-regulatory element. In hNCs, the homozygous rs28834970 CC genotype reduced total PYK2 levels by more than 80%, while increasing the proportion of phosphorylated (activated) PYK2. Transcriptomic analysis revealed 724 downregulated and 113 upregulated gene sets, with altered expression of genes involved in extracellular matrix organization, cytoplasmic translation and neurotransmitter secretion. MEA recordings showed reduced network recruitment and altered burst organization. Immunocytochemistry in microfluidic devices consistently revealed that rs28834970 impacts dendritic development and postsynaptic maturation. The risk genotype significantly elevated Tau phosphorylation at pathological sites (Thr181, Thr217, Thr231, Ser202-Thr205, Ser396-Ser404), and enhanced APP processing, resulting in decreased levels of APP and CTF but increased levels of sAPP, sAPP{beta} and A{beta}. Conclusion: The rs28834970 C risk allele mechanistically links AD susceptibility to downregulation of PTK2B/PYK2 expression and to the increase in Tau pathology and A{beta} levels while compromising synaptic structure and function.

genetics↗

bioRxiv2026

Brain representations of visual short-term memories during healthy human aging: occipital decline and frontoparietal compensation

Visual short-term memory declines steeply with age, but the link to neural representations of memory content remains unknown. We used fMRI decoding to relate remembered motion-direction representations in visual and frontoparietal cortex to age and performance, in 115 adults, aged 25-87, from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort. Decoding was strongest in visual cortex, but also significant in frontoparietal regions, with different profiles. Visual representations weakened with memory load and age, and statistically mediated age-related performance decline, especially during recall. This coupling, however, weakened with age: some older adults retained stronger visual representations than performance implied, suggesting impaired access to a partially preserved memory trace. Frontoparietal representations, instead, were largely insensitive to load and strengthened with age during maintenance, partially offsetting performance decline. Therefore, interventions to boost VSTM in older adults might target compensatory frontoparietal representations during memory maintenance, and readout of untapped visual representations at recall.

neuroscience↗

bioRxiv2026

Lexical surprisal drives pupil dilation during continuous story listening

The pupil famously adjusts its dilation in response to light, but its role extends far beyond this basic sensory function. Its fluctuations index arousal and mental effort, beyond luminance-related dynamics, making it a sensitive marker of internal cognitive states. A growing body of work shows that these pupil-linked signals extend beyond the visual domain. However, which processes drive pupil responses in more naturalistic settings remains unclear as most evidence comes from tightly controlled paradigms that strip away the richness of real-world experience. Language offers a uniquely powerful window into this question, as it can allow us to create rich paradigms without having any visual, i.e. luminance, confounds. Moreover, language comprehension hinges on continuous prediction: listeners constantly generate expectations about upcoming input, and the discrepancy between expectation and actual input - contextual prediction error, or surprisal - carries measurable cognitive costs. Here, we tested the hypothesis that pupil-linked arousal indexes these linguistic surprisal signals during naturalistic listening. We recorded pupil responses while volunteers listened to naturalistic spoken stories in darkness, which were either intact or reversed. Reversed speech preserves the acoustics of the signal while destroying its intelligibility. Pupil dilation selectively tracked lexical surprisal within a late window of 1,700 to 2,350 milliseconds following word onset, in forward, but not control, backward speech. These findings indicate that pupil-linked arousal is tuned to global, context-dependent processing, tracking the cognitive cost of updating a predictive model during naturalistic listening.

neuroscience↗

bioRxiv2026

Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease

MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. We test the hypothesis that an endosomal recycling pathway regulated by the interaction of SORL1 with retromer, which is pathogenically disrupted in AD, might drive the neurodegenerative process via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling AD's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, taken together with other findings, the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.

neuroscience↗

bioRxiv2026

Generation of human iPSC-derived motor neurons with defined regional identities across the rostrocaudal axis

This study establishes a unified pipeline for generating human induced pluripotent stem cell (iPSC)-derived motor neurons (iMNs) with defined hindbrain, cervical, and lumbar identities to support anatomically resolved studies of motor neuron development and degeneration. Conventional differentiation methods can efficiently produce iMNs but provide limited control over rostrocaudal identity and frequently generate populations with heterogeneous HOX profiles. We addressed this limitation by optimizing developmental morphogen combinations and treatment windows, establishing three complementary protocols that reproducibly generated hindbrain/rhombomere-associated motor neurons (RiMNs), cervical motor neurons (CiMNs), and lumbar motor neurons (LiMNs) across iPSC lines from six non-diseased donors balanced by sex. Transcriptomic and protein analyses demonstrated graded rostrocaudal specification from RiMNs through CiMNs to LiMNs, together with region-appropriate motor neuron subtype features. These identities showed the expected relationships to human week 9 fetal rostrocaudal HOX programs. High-density multielectrode array analysis further revealed synchronized network firing, electrically active neurite networks, and enhanced axonal signal propagation in the regional iMN populations compared with conventionally differentiated iMNs. Spike-sorted recordings additionally revealed protocol-associated differences in single-neuron electrophysiological profiles. Together, this three-protocol pipeline enables the reproducible generation and comparative analysis of anatomically defined human motor neuron populations and provides region-matched cellular models for investigating motor neuron development, selective degeneration, and therapeutic responses.

neuroscience↗

bioRxiv2026

C19 trityl and silyl andrographolide analogs exhibit in vitro anticancer activity in murine cancer models

Andrographolide, a labdane diterpenoid isolated from A. paniculata has been investigated for activity in a broad panel of biological contexts, including its anti-inflammatory, antiviral, and anticancer properties. Previously, A-ring analogs of andrographolide bearing silyl and trityl ethers at C19 have demonstrated improved in vitro anticancer activity in human cancer cell lines, with putative activity through the Wnt1/{beta}-catenin signaling axis. In order to investigate the activity of this series of C19 andrographolide analogs, alongside a cyclic A-ring acetonide analog, as anticancer agents in murine cancer cell models, we evaluated antiproliferative activity of these compounds in B16F10 melanoma, CT26 colorectal adenocarcinoma, Neuro2a neuroblastoma, and 4T1 mammary ductal carcinoma cell lines, and found that most compounds exhibited potent micromolar level anticancer activity. Among these, all trityl ethers exhibited nearly indistinguishable IC50 values of 4-20 M, and generally exhibited greater potency compared to C19 silyl ether analogs. This anticancer activity was further validated through apoptosis flow cytometry, wherein we concluded that our compounds induced apoptosis to a greater extent than the parent compound, andrographolide. Further, we examine the role of modulation of canonical Wnt1/{beta}-catenin signaling in a series of co-delivery assays with CHIR-99021, a selective GSK-3{beta} kinase inhibitor, and MSAB, a selective {beta}-catenin degrader. Finally, we demonstrate that a selection of silyl ether analogs of andrographolide elicit cell cycle arrest by flow cytometry in a manner that is decoupled to in vitro potency trends. Altogether, we report the first in vitro evaluation of trityl and silyl ether analogs of andrographolide within murine adherent cancer cells.

cancer biology↗

bioRxiv2026

Algorithmic Geometry Shapes the Biological Meaning of Thalamocortical Structural Covariance

Neuroimaging studies often derive and discuss structural covariance (SC) as a representation of underlying brain circuitry that reflects coordinated maturation, anatomical connectivity, transcriptional similarity, and shared genetic influences. These associations motivate its use to study brain organization across development, aging, and disease. However, the algorithms used to derive SC networks impose constraints that may shape their biological interpretation. To understand the impact of algorithm choice, we used the thalamocortical system as an example and compared five common representations of voxelwise SC, namely, principal component analysis (PCA), independent component analysis (ICA), non-negative matrix factorization (NMF), orthogonal projective NMF (OPNMF), and \textit{k}-means clustering, in 755 participants aged 8--22 years from the Philadelphia Neurodevelopmental Cohort (PNC). SC networks derived from deformation-based morphometry (DBM) were evaluated against three complementary biological benchmarks: age-related individual differences, fractional-anisotropy (FA)-based microstructural connectivity of regionally-specific thalamocortical connections, and Allen Human Brain Atlas gene expression. Each algorithm demonstrated underlying sensitivity to differing aspects of neurobiology: PCA and OPNMF showed the strongest associations between participant-level component weights and age. NMF, OPNMF, and \textit{k}-means showed greater spatial overlap between positive cortical SC and tractography-derived projections. ICA and PCA showed stronger correspondence between thalamic and cortical gene-expression profiles across the transcriptome, whereas NMF, OPNMF, and \textit{k}-means more often identified thalamic components with relatively high core-matrix gene expression. This study emphasizes that algorithmic constraints effectively act as biological priors and decomposition methods do not provide neutral compression of the data. We conclude that it is critical to consider whether the algorithmic objective matches the representational geometry of the neurobiology being studied. Overall, our findings suggest that SC studies should select and justify algorithms according to the biological question, explicitly considering whether their constraints favour distributed gradients, overlapping regional parts, or discrete clusters. Meanwhile, interpretations of SC findings could also be informed by the specific algorithmic constraints used to derive them.

neuroscience↗

bioRxiv2026

The Structural Basis of Genome Silencing: The Inactive X Chromosome Resolved by Electron Spectroscopic Imaging

The eukaryotic nucleus has a hierarchical organization that permits genomic regulation. The genome is packaged as chromatin, which is silenced conditionally as facultative heterochromatin, or more stably silenced as constitutive heterochromatin. The smaller fractions of the genome that contain gene-rich sequences are organized into open chromatin conformations known as euchromatin. The inactive X (Xi) chromosome territory presents a uniquely powerful model system to investigate chromosome-scale gene silencing, as the entire chromosome undergoes coordinated epigenetic repression. The unique chromosome-wide silencing event provides a tractable system for investigating how molecular mechanisms of gene repression are translated into mesoscale structural features. This work builds on previous structural studies of the Xi that have leveraged conventional electron microscopy (EM) and cryo-EM, which have led to remarkable insights into the structural underpinnings of genome silencing. These approaches, however, are unable to directly distinguish chromatin from RNA and protein features. To resolve the molecular composition of the Xi chromosome territory and to provide a model of the structural organization of the chromatin, RNA and protein we analyzed the Xi using Electron Spectroscopic Imaging (ESI). We are able to resolve structural features without the use of contrast enhancing stains, using the distinct elemental signatures of chromatin, RNA and protein and combining them into composite images. By coupling ESI and electron tomography, we can circumvent the projection limitation of EM and provide an unprecedented view of the spatial organization of chromatin fibres in relation to structural features including RNA and proteins in 3D. Additionally, we employed correlative light-microscopy with ESI in physical serial sections and computationally assembled a structural model of the entire Xi chromosome territory revealing an intricate spatial network with distinct chromatin domains, distributed RNA-protein clusters, and identified a large, and previously uncharacterized mesoscale non-chromatin structure. Together, these observations provide new insights into the architecture of the Xi chromosome territory and shed electrons on the structural basis of chromosome-scale genome organization.

cell biology↗

bioRxiv2026

Climate change and extreme weather events to intensify West Nile virus activity

Vector-borne zoonotic diseases pose a substantive risk to public health worldwide, yet predicting outbreaks at scales useful for public health response remains a critical challenge. Transmitted by Culex mosquitoes, West Nile virus is the leading cause of arboviral disease in the United States, progressing to neuroinvasive disease in approximately 1% of infections. Arizona's record-breaking 2021 outbreak, with 1,715 reported human cases and 127 deaths exemplifies this growing burden. Using a decade of mosquito surveillance data coupled with time-lagged weather patterns in a random forest framework, we developed spatial models predicting Culex abundance and West Nile virus occurrence across Arizona at weekly temporal and fine spatial resolution. Our weighted models classified viral occurrence with 98.9% accuracy and explained 65.3% of weekly variation in county-level human cases, with human cases lagging modeled activity by one week. Neither mosquito abundance nor viral occurrence declined at the extreme temperatures characteristic of Arizona summers, suggesting that thermal refugia sustain transmission. Drought-monsoon cycling, rather than temperature alone, emerged as the primary driver of West Nile activity, and projections through 2100 indicate intensifying activity under all climate change scenarios.

ecology↗

bioRxiv2026

Differing patterns in community composition and diversity of biofilm-forming bacteria and fungi along a large salinity gradient

Aim: Biofilms are complex ecosystems formed by phototrophic and heterotrophic organisms, such as bacteria and fungi. Biofilms are hotspots for microbial activity and crucial for the functioning of all aquatic ecosystems, but they are overlooked and poorly studied, especially along large environmental gradients. We aimed at resolving the responses of bacterial and fungal communities to environmental variation along a gradient with strong variation in environmental factors, especially salinity. We also investigated whether the diversity of biofilm-forming bacteria and fungi follows the pattern predicted by the Remane curve, which posits that species diversity is lowest at intermediate salinity. Location: 2300-km-long spatial gradient in the Baltic Sea, Northern Europe Time period: August 2018 Major taxa studied: Biofilm-forming bacteria and fungi Methods: We investigated the composition and diversity of bacteria and fungi by collecting biofilm samples from 42 shallow benthic ecosystems. We also characterized key environmental variables, such as salinity, nutrient concentrations, wind exposure, and climatic conditions. Bacterial and fungal communities in biofilm samples were identified using Illumina MiSeq sequencing. Results: We found that bacteria and fungi responded differently to environmental variation. Bacterial communities were mainly controlled by salinity, and their diversity was lowest in the intermediate salinity. Bacterial communities were also dominated by different bacterial orders in high, intermediate, and low salinity. Fungal communities, instead, were jointly controlled by several environmental variables, i.e., salinity, water temperature, wind exposure, and nutrients, and their diversity or composition did not show a clear pattern along the salinity gradient. Main conclusions: To our knowledge, this is one of the first studies to investigate the biofilm-forming communities, especially fungal communities, along large environmental gradients. Our results highlight the role of biofilms as complex ecosystems where organisms ecological requirements are unique and variable.

ecology↗

bioRxiv2026

A droplet-to-data workflow for antimicrobial screening of complex matrices

Screening plant extracts and other complex natural matrices for antibacterial activity is complicated by optical interference and population averaging in conventional bulk assays. Droplet-based assays mitigate interference while enabling high-throughput assessment of bacterial subpopulations. However, analyzing the resulting image data involves difficult image processing, classification, and interpretation. Here, we present a democratized workflow for antimicrobial screening in complex matrices that combines a polydisperse droplet-based assay with EasyFlow 2.0 (EF2), our updated droplet image analysis platform. EF2 offers stable containerized deployment, expanded polydisperse droplet support, automated thresholding and MIC estimation, LLM-assisted data exploration, and import of other software outputs such as CellProfiler (CP) measurements and CellProfiler Analyst (CPA) classification models. As proof of concept, we applied this workflow to assess the antibacterial and aggregation-modulating effects of chemically distinct extracts of Taraxacum officinale, Rhodiola rosea, and Lonicera caerulea against Escherichia coli. Extracts were chemically characterized by HPLC-MS and evaluated using both standard 96-well plate microdilution and droplet-based assays. In total, 27,059 droplets were segmented in CP, classified into four growth phenotypes using a CPA random forest model, and analyzed in EF2. The droplet-based assay reached minimal inhibitory concentration (MIC) at lower extract concentrations than 96-well plate microdilution and revealed extract-specific aggregation effects: L. caerulea reduced E. coli aggregation, whereas T. officinale did not. R. rosea reduced growth in the 96-well plate microdilution assay, but high concentrations caused droplet gelation that prevented droplet-based analysis, showing that sample components must be checked for compatibility with droplet formation. These results illustrate that the EF2-centered workflow supports rapid, automated MIC estimation through unsupervised thresholding when labels are unavailable, and four-class aggregation phenotyping when a CPA model is supplied. This workflow offers flexible, scalable screening, potentially extendable beyond plant extracts to other complex sample matrices.

microbiology↗

bioRxiv2026

Experimental evolution unveils a role for structural variants and sex-specificity in the genetic architecture of lifespan

Insights into the genetic basis of lifespan evolution can link evolutionary theory with an understanding of health, disease and adaptation. We leverage the power of >200 generations of experimental evolution in a seed beetle to unveil the genomic architecture of lifespan evolution. Replicated populations evolved under regimes favoring either a short or long life, resulting in a near doubling of lifespan. Whole genome re-sequencing revealed that short- and long-lived lines were strongly differentiated (global FST = 0.41) and more than 700 genes showed consistent signs of divergent selection. Remarkably, short- and long-lived lines were consistently divergent in a large number of regions harboring copy-number variants (CNVs), involving >600 genes. The evolution of a long life involved many distinct biological processes, such as DNA fidelity, mitotic integrity, reproduction, metabolism, immunity and stress response. A pedigree-based genome scan for quantitative trait loci (QTLs) uncovered several QTLs with large effects on lifespan, but the genetic basis of a long life was dominated by a very large number of regions with medium and small effects. The genome-wide spatial association with QTL effects was, if anything, stronger for CNVs than for sequence variants. The genetic effects of QTLs on lifespan were positively correlated overall between the sexes, but four regions showed pronounced sex-differences. Our results show that structural variants play a significant role in the evolution of an extended lifespan and the highly polygenic genomic architecture is to some extent sex-specific, consistent with differences in physiology and life history tradeoffs between the sexes.

evolutionary biology↗

bioRxiv2026

Reinforcement Learning Reveals Spatial Strategies for Slowing Biological Invasions

Managing biological invasions requires deciding where, when, and how to act while populations continue to grow and spread. Invasive species threaten ecosystems and livelihoods, but limited management resources mean that managers cannot treat every affected area. This study asks how control efforts can be directed across a landscape to slow an invasion while keeping costs low. We develop a reinforcement-learning framework that can use broader spatial context to control biological invasions, using the spongy moth as a case study. The stochastic simulator captures host-dependent growth, short- and long-distance dispersal, density-dependent mating, and the effects of multiple treatments. The reinforcement-learning strategies are compared with benchmarks that are based on local treatment rules. We find that reinforcement learning achieves the lowest mean cost, with its advantage widening as management complexity increases, such as with simultaneous advancing-front control, nascent-colony management, and established-colony containment on heterogeneous-host landscapes. The reinforcement-learning strategies exhibit highly context-dependent treatment behavior, adjusting treatment choices as invasion dynamics evolve and coordinating interventions across long distances, all of which is learned from scratch.

ecology↗

bioRxiv2026

Spatial expression evolution of duplicated genes post-whole genome duplication in cultivated tomato

The mechanisms by which whole genome duplication contributes to expression divergence of duplicate genes, which can impact the evolution of form and function, has been a long-standing question in evolutionary biology. We compared expression patterns of paralogs derived from the most recent Solanaceae-specific genome triplication event across 23 tissues and inferred ancestral expression states to investigate patterns of expression evolution. While the partitioning of ancestral expression states is traditionally considered the second most common (after the gene loss) trajectory of duplicate expression evolution, we found that the ancestral expression states tended to be retained by most (~66%) duplicates, with ~6% of gene lineages experiencing expression gain events and ~20% experiencing expression losses. The genes that gained expression in fruit tissues are significantly enriched with functions associated with fruit quality. Notably, asymmetrical expression divergence is prevalent among duplicates, especially when ancestral genes were either not expressed or were highly expressed. Our study demonstrates the utility of integrating paralog expression comparisons with phylogenetic analyses to document the potential evolutionary history of spatial expression patterns and gain insight into how expression divergence contributes to the evolution of function across tissues.

plant biology↗

bioRxiv2026

Epigenetic Remodeling Increases Plasticity of Bovine Fibroblasts Without Improving Embryo and Stem Cell Development

Epigenetic memory, reinforced by redundant heterochromatic networks, is a major barrier to somatic cell reprogramming. In cattle, single-agent chromatin-modifying treatments show inconsistent efficacy, likely due to compensatory crosstalk among repressive marks. Here, we evaluated a multi-target small-molecule cocktail, GUSTC, combining GSK343 (EZH2 inhibitor), UNC0638 (G9a/GLP inhibitor), Sodium Butyrate (HDAC inhibitor), Trichostatin A (HDAC inhibitor), and Chaetocin (SUV39H1 inhibitor) to simultaneously target facultative and constitutive heterochromatin in bovine fibroblasts. At optimized, non-cytotoxic concentrations, GUSTC treatment reduced H3K9me2, H3K9me3, H3K27me3, and HP1-alpha levels while increasing H3K9 acetylation by immunofluorescence. Using GUSTC-treated fibroblasts as donor cells for somatic cell nuclear transfer did not significantly change cleavage (83.6% vs. 92.2%; p = 0.15), blastocyst rate (28.4% vs. 39.0%; p = 0.20), bovine embryonic stem cell line derivation efficiency (26.3% vs. 33.3% of seeded blastocysts; p = 0.57), or the core pluripotency marker profile (OCT4, NANOG, SOX2) of the resulting lines. In a separate, serum-free, pluripotency-permissive culture system, GUSTC-treated cells adopted a colony-like morphology and showed increased POU5F1 and NANOG expression, along with increased DNMT1, EHMT2, HDAC1, HDAC2, and SUV39H1 transcripts. GUSTC thus reduces repressive heterochromatin marks in donor fibroblasts and is associated with a potentially more reprogramming-permissive state, without detectable improvement in preimplantation developmental competence. It provides a starting point for chemical reprogramming strategies in cattle.

developmental biology↗

bioRxiv2026

STRIPAK associates with Rabex5-Rabaptin5 to promote Rab5-dependent early endosome formation and EGFR transport

His Domain Protein Tyrosine Phosphatase (HD-PTP) is required for multivesicular body (MVB) formation and endosome maturation, with Rab5-GTP levels raised upon HD-PTP depletion (Parkinson et al., 2021. doi: 10/1242/jcs.259192). Mass Spectrometry-based interactomics revealed that HD-PTP depletion increased association of Rabaptin5, a component of the early endosome Rabex5-Rabaptin5 Rab5-GEF, with multiple components of STRIPAK (striatin-interacting phosphatase and kinase). Native IPs and co-expression studies confirmed association between STRIPAK and Rabex5-Rabaptin5, including Strip1-Rabex5 and SLMAP-Rabaptin5 interactions. Consistent with functional Rabaptin5-STRIPAK links, co-depletion of Strip1 or Rabaptin5 with HD-PTP restored normal early endosome positioning and Rab5 distribution. Strip1 depletion impaired formation of central, Rab5-positive early endosomes, reduced cellular Rab5-GTP levels, and prevented the accumulation of internalised EGF-EGFR into centrally located endosomes. SLMAP depletion accentuated the central clustering of early endosomes and other endosomal compartments while also retarding the generation of new, EGFR-containing endosomes and EGFR lysosomal transport. We conclude that STRIPAK is a novel co-assembly factor of Rabex5-Rabaptin5, exerting subunit-specific effects on early endosomes.

cell biology↗

bioRxiv2026

Mesoscale Soft Robotics for Mechanically Perturbing and Functionally Monitoring Responses in Human Organoids

Human organoids represent promising models for studies of significance to the biology and medical communities. Of the existing approaches for monitoring organoids, none offers the ability to apply programmable mechanical forces while simultaneously recording multi-modal physiological responses, of relevance to phenomena spanning from traumatic brain injuries to cardiac rhythm disorders. Here, we present a mesoscale soft robotic organoid interface that enables programmable delivery of forces to organoids of diverse shapes, and to map electrophysiological activity and mechanical responses. The platform combines actuation elements with integrated sensors for quantitative measurement and control. Studies using this technology reveal that spheroidal cortical organoids exhibit distinct responses to mechanical trauma, including silencing, recovery, and changes in neuronal firing patterns. Additional experiments on cardiac ring tissues demonstrate that sustained stretching induces beat-to-beat rhythm variability and altered conduction. The results establish a framework for investigating force-triggered transitions between physiological and disease-like states in human tissue models.

bioengineering↗

bioRxiv2026

Somatostatin-excitatory coordination emerges with dexterous motor skill learning

Motor skill-learning increases spatio-temporal consistency in neuronal activity in primary motor cortex (M1), and Somatostatin-expressing (SST) interneurons are causally involved in these learning-related activity changes. Yet, how SST-excitatory interactions shape population level activity changes during motor skill acquisition is still unknown. Here, we imaged large populations of excitatory neurons and identified SST or parvalbumin-expressing (PV) interneurons across successive days as mice learned a dexterous, persistently M1-dependent reach-to-grasp task. Sparse, temporally coordinated, trial-resolved, and rate-controlled functional interactions between SST neurons and skill-modulated excitatory neurons emerged with learning and were stronger than those in excitatory-excitatory or PV-excitatory pairs. Interactions strengthened as neurons were recruited to the skill-modulated ensemble and weakened when skill modulation was lost. SST activity also became temporally reliable earlier than excitatory or PV activity, and SST consistency was significantly associated with behavioral performance even after controlling for training session number. Additionally, SST neurons carried more information about movement kinematics than randomly selected subsets of excitatory neurons. Overall, SST neurons became selectively coordinated with behaviorally relevant excitatory populations, revealing a cell-type-specific functional architecture for dexterous motor learning.

neuroscience↗