Biology subjects

Kim, K.

Publications and source records attributed to Kim, K..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Chemogenetic Inhibition of the Ventrolateral Orbitofrontal Cortex Disrupts Prediction Error and Salience-Guided Memory-Updating at the Hippocampal Engram Level

RationaleAdaptive behavior requires revising memories when outcomes deviate from expectations. The orbitofrontal cortex (OFC) is implicated in representing outcome expectancies, but its role in memory-updating, beyond value-based learning, remains unclear. ObjectivesWe tested whether the ventrolateral OFC (VLO) contributes to hippocampal-dependent memory-updating in the Objects in Updated Locations (OUL) task, where novelty-driven exploration provides a behavioral readout consistent with successful updating of spatial information MethodsUsing inhibitory DREADDs, in male and female (Swiss Webster and C57BL/6) mice, we suppressed VLO activity during the Updating session, when new object-location information was introduced. ResultsControl mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test. ConclusionsThese results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations. Significance StatementUsing a spatial paradigm that distinguishes detection of changed information from incorporation of that information into an updated hippocampal representation, we found that ventrolateral orbitofrontal cortex (VLO) activity is required for memory-updating when new information is present. We found behavioral deficits accompanied by impairments in hippocampal ensemble representations, indicating VLO activity is necessary for memory-updating at the hippocampal engram level. Through this mechanism, the OFC supports the flexible updating of expected outcomes when environmental conditions shift, allowing for the re-evaluation of previously learned associations. These findings extend models of orbitofrontal cortex function beyond reward-guided behavior and identify a cortical contribution to predictive spatial memory processes. Disruption of this computation may contribute to the cognitive rigidity observed in neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Machine learning guided cell-free expression maps the biochemical landscape of carbonic anhydrase

Carbonic anhydrases are among the fastest known biocatalysts, reversibly facilitating the hydration of CO2 to HCO3- at rates up to 107 s-1, which warrants their investigation for industrial carbon capture technologies. However, engineering carbonic anhydrases to maintain stability under harsh industrial process conditions remains a key challenge, and sequence-to-function datasets compatible with machine learning to inform forward engineering are lacking. Here, we developed a high-throughput platform that couples cell-free gene expression with a gaseous CO2 colorimetric assay to map the fitness landscapes of carbonic anhydrases. From 96 diverse natural homologs, we identified a robust variant from the Aquificota phylum and conducted an exhaustive mutational scan and functional assessment of this enzyme at 70{degrees}C and 90{degrees}C, covering >99% of all single-amino acid substitutions (totaling 4,365 mutations assayed in 39,285 reactions). This biochemical landscape was used to benchmark 22 zero-shot protein fitness models and identify critical mutations that improved enzyme stability at 90{degrees}C by more than three-fold. We then used both zero-shot protein language models and supervised learning to filter 419 model-generated variants from a ProteinMPNN library of 100,000 sequences, leading to a best-in-class enzyme that retained activity after incubation at 95{degrees}C. This work demonstrates that integrating cell-free enzyme engineering with machine learning enables opportunities for high-throughput experimental measurements to benchmark and improve protein language models, accelerate design loops, and expand functional exploration within protein families where experimental information is limited.

synthetic biology↗

bioRxiv2026

A Snakemake-based bacterial whole genome comparison pipeline for multi-group clinical isolates

Organisms have continuously evolved in response to environmental conditions. Pathogenic bacteria evolve under host and environmental pressures, reshaping their genomes through insertions, inversions, deletions, and duplications during infection. In clinical settings, phenotypic traits of pathogenic bacteria such as virulence or antimicrobial resistance directly affect disease severity, transmission, and treatment. Conventional genotyping provides insights into genomic relatedness but does not always align with these clinically relevant traits, limiting its utility for phenotype-driven interventions. Here, we develop ABComp (Assembly polishing and Bacterial whole-genome Comparison for multi-group clinical isolates), a modular and Snakemake-based workflow for phenotype-driven comparative genomics. ABComp automates assembly polishing, group-wise pangenome analysis, and enables flexible pathogenic marker discovery through user-defined comparisons. We validated ABComp using a Klebsiella pneumoniae ground truth dataset stratified by yersiniabactin presence and successfully recovered the entire locus as a group-specific core marker. By applying ABComp to another dataset of clinical isolates with experimentally measured virulence, we discovered the ferric citrate (Fec) uptake system as a potential marker specific to a hypervirulent group. These results demonstrate ABComps utility in uncovering phenotype-linked genomic markers with clinical significance, supporting targeted treatments and rapid diagnosis.

bioinformatics↗

bioRxiv2026

TOX enforces the immunosuppressive program of tumor-infiltrating regulatory T cells

Regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) to suppress anti-tumor immunity, but the transcriptional regulators stabilizing their immunosuppressive state remain poorly defined. Here we show that transcriptional factor TOX is selectively upregulated in tumor-infiltrating (TI) Treg cells across human cancers and mouse tumor models, while remaining low in peripheral and naive Treg populations. Treg-specific deletion of TOX reduced tumor burden, impaired TI Treg-mediated immune suppression, and enhanced effector functions of CD8 and CD4 T cells. In mosaic mice, TOX-deficient Tregs were selectively depleted from tumors, accompanied by increased apoptosis. Single-cell RNA sequencing and TCR clonotype analysis linked TOX expression to an effector-like TI Treg state with clonal expansion, whereas TOX loss shifted cells toward a TCF7-associated progenitor-like phenotype. ATAC-seq revealed enrichment of AP-1 motifs in TOX-sufficient TI Tregs. In contrast, TCF7, LEF1, and FOXO1 motifs in TOX-deficient counterparts, uncovering the opposing transcriptional networks downstream of TOX. Furthermore, TOX deficiency augmented CD8 T cell responses to PD-1 blockade. Together, these findings establish TOX as a key regulator of TI Treg fitness and stability, and identify it as a potential therapeutic target to enhance the efficacy of PD-1-based immunotherapy.

immunology↗

bioRxiv2026

Human meningiomas arise from developmental meningeal mosaicism

Meningioma is the most common primary intracranial tumour, yet its genetic origin and the temporal sequence of mutational events remain poorly defined. Here, we analysed 80 triple-matched tumour, histologically normal meninges, and blood samples from 22 patients. NF2 or TRAF7 driver mutations are detectable in phenotypically normal meninges in 81.8% of cases (95% CI: 59.7-94.8%; VAF [~]0.02%), corroborated by high-depth sequencing, single-cell cloning, and phylogenetic analysis. By distinguishing developmental mosaic mutations from postnatal tumour-private mutations, we revealed distinct mutational signatures and resolved the temporal sequence of meningioma evolution. The developmental origin was further underscored in patients with multiple meningiomas, where identical driver mutations were shared across genomically distinct tumours and meninges, and in intraventricular meningiomas (IVM), where driver mutations were detected in distant cranial dura. Reconstruction of mutational timing revealed lineage-specific trajectories, linking mosaicism to diverse disease presentations including solitary meningioma, IVM, meningiomatosis, and NF2-related schwannomatosis. Together, these findings reveal an early origin of human meningioma, in which developmental mosaicism establishes a pre-neoplastic field within the meninges, providing a developmental framework for adult tumourigenesis.

Cancer Biology↗

bioRxiv2026

Mtf2 Safeguards Naïve Pluripotency by Restricting Trophectoderm Competence

The first fate decision in mammalian embryos segregates embryonic and extraembryonic lineages, establishing a largely irreversible transition from totipotency to pluripotency. The mechanisms that enforce this unidirectionality remain incompletely understood. Here, we identify the PRC2.1 subunit Mtf2 as a key epigenetic barrier that safeguards lineage fidelity in naive embryonic stem cells (ESCs). Despite globally elevated H3K27me3 levels in naive ESCs, loss of Mtf2 derepresses trophectoderm (TE) regulators, enhances cellular plasticity, generating both ICM- and TE-like populations. Mtf2-deficient cells readily acquire expanded potential with extraembryonic competence and form blastoids without trophoblast stem cell supplementation, whereas loss of the PRC2.2 subunit Jarid2 has minimal effects. Integrated CUT&Tag and transcriptomic analyses reveal that Mtf2 directly represses TE-associated genes in naive ESCs. Thus, reduced Mtf2 occupancy permits their activation in expanded potential states. Collectively, our findings establish Mtf2 as a central epigenetic barrier that stabilizes naive pluripotency and restricts inappropriate acquisition of extraembryonic fate.

Developmental Biology↗

bioRxiv2026

Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.

BackgroundCardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits -ketoglutarate dehydrogenase (-KGDH) and is associated with reduced cardiac contractile function. MethodsWe combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress. ResultsWe uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of -KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation. ConclusionOur results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.

systems biology↗

bioRxiv2026

Population-scale Y chromosome assemblies reveal recurrent remodeling within constrained architectures

The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.

genomics↗

bioRxiv2026

Supplemental deinoxanthin ameliorates bone marrow microenvironmental impairments and recovers functional damage of bone marrow-retained cells in total body irradiation-exposed mice

Total body irradiation (TBI) can impair the bone marrow (BM) microenvironment and dysregulate the fates of BM-residing cells by overproducing reactive oxygen species (ROS) and inflammatory mediators. This study aims to investigate the potency and mechanism of Deinococcus radiodurans-derived deinoxanthin (DEIX) in mitigating TBI-mediated injuries in the BM microenvironment and BM-resident cells. C57BL/6 mice were divided into control, TBI, TBI+DEIX, and/or DEIX groups, in which the mice were exposed to sub-lethal TBI (5 Gy) or in combination with oral DEIX supplementation (25 mg/kg body weight). While the DEIXs effect on BM and BM-resident cells was determined after five weeks of TBI, RNA sequence profiling on the mouse group-derived BM cells was performed after two weeks of TBI. Supplementation with DEIX protected mice against TBI-mediated decrease in bone mineral density of trabecular bones. Supplemental DEIX suppressed BM microenvironmental impairment and the induction of oxidative stress and senescence in BM cells of TBI-exposed mice. That suppression was orchestrated by the DEIX-induced restoration of TBI-stimulated disorders in osteogenic, osteoclastogenic, and adipogenic activation in the BM. Ex vivo assays using BM cells supported the notion that DEIX restores TBI-mediated defects in BM cell function, including colony formation, migration, and differentiation. RNA sequence profiling demonstrated DEIXs potency to modulate the expression of genes that regulate cellular and systemic immune responses, cell proliferation and differentiation, and bone metabolism. Collectively, our results highlight the roles and associated mechanisms of DEIX in mitigating TBI-mediated microenvironmental impairment and in regulating BM-resident cells.

cell biology↗

bioRxiv2026

Long-Lasting Electrohydrodynamically Printed Transparent Soft Microelectrode for Implantable Biointerfaces

Reliable and scalable soft implantable neural interface fabrication remains a key challenge for chronic bioelectronic applications. Here, we present a transparent soft microelectrode fabricated with electrohydrodynamic (EHD) printing, utilizing the fluorinated polymer poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly (3, 4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT: PSS) to form seamless, selectively patterned multilayer structures with low impedance and long-term stability. Controlled in situ curing during printing yields dense, void-free substrate and encapsulation layers, suppressing interfacial defects and ionic pathways, while maintaining high optical transparency (>60%) with PEDOT:PSS. The printed microelectrodes exhibit low impedance, high charge storage and injection capacities, and stable electrochemical behavior under biomimetic conditions. In addition, the devices demonstrate robust mechanical and electromechanical stability under cyclic deformation in both dry and wet environments, as well as under prolonged electrical stimulation. Accelerated aging studies project multi-year operational lifetimes, and in vitro/in vivo biocompatibility assessments confirm excellent tissue integration. These results establish EHD-printed fluorinated polymer-based microelectrodes as a scalable and durable platform for chronic implantable biointerfaces. ToC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/726391v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@f4f717org.highwire.dtl.DTLVardef@8a34a1org.highwire.dtl.DTLVardef@185540dorg.highwire.dtl.DTLVardef@51462a_HPS_FORMAT_FIGEXP M_FIG C_FIG This report presents an electrohydrodynamically printed transparent soft microelectrode for chronic purposes. Electrohydrodynamic printing promotes seamless multilayer structures with selective deposition and long-term mechanical stability. The devices show low impedance, high charge capacity, and robust electrochemical/electromechanical properties. Accelerated aging projects [~]7.2 year lifetimes, and XPS/SEM-EDS confirm strong ion barrier properties and biocompatibility for chronic implantation.

bioengineering↗

bioRxiv2026

NeuroPupil: A generalization-first framework for scalable and biologically informative cross-species pupillometry

Quantitative pupillometry provides a noninvasive window into brain state and neurological function, but its broader use across experimental and clinical settings is limited by challenges in achieving accurate, scalable, and generalizable measurements. Here, we present NeuroPupil, a deep learning framework for high-throughput, cross-species pupillometry that emphasizes robust generalization across subjects, behavioral contexts, and imaging conditions. Through systematic benchmarking of training strategies and network architectures, we identify pooled multi-subject training combined with an optimized U-Net architecture as a key determinant of reliable and transferable pupil tracking performance. Across diverse mouse and human datasets, NeuroPupil achieves improved accuracy and substantial gains in computational efficiency compared to existing approaches, enabling practical analysis of large-scale datasets. We further demonstrate that improved pupil tracking fidelity enhances downstream biological inference: NeuroPupil-derived pupil features significantly improve prediction of distributed cortical activity in behaving mice and preserve diagnostically relevant temporal structure in human clinical recordings. These findings highlight the importance of precise and scalable measurement for linking pupil dynamics to brain activity and clinical phenotypes. By integrating benchmarking, scalability, and accessible software tools, NeuroPupil provides a reproducible framework for large-scale pupillometry and facilitates its application in systems and translational neuroscience.

neuroscience↗

bioRxiv2026

Riemannian Tensor Analysis Identifies a Bifurcation State in the Single-Cell Transcriptomic Landscape of Parkinson's Disease

The transition from healthy aging to Parkinsons disease (PD) involves highly volatile transcriptomic rewiring that remains invisible to conventional mean-based analyses. To decode this critical tipping point, we integrated single-cell RNA-sequencing with a novel Log-Euclidean Riemannian tensor framework. By conceptualizing distinct transcriptomic states as symmetric positive definite (SPD) covariance tensors, we bypassed Euclidean geometric artifacts to accurately map the macroscopic network architecture of the human prefrontal cortex. Our analysis identified a highly unstable, intermediate bifurcation (BIF) state. Thermodynamic and topological validation demonstrated that this BIF state operates as a definitive geometric saddle point, characterized by maximal von Neumann entropy and positioned perfectly equidistant between the healthy (HC) and pathological (PD) Frechet means on the non-Euclidean manifold. Furthermore, spectral deconstruction of differential covariance networks [Formula] isolated the exact topological drivers of this transition--revealing the catastrophic structural collapse of core synaptic and electrophysiological hubs prior to overt pathological commitment. Ultimately, this ab initio geometric framework fundamentally redefines PD progression, providing a quantitative blueprint to intercept neurodegenerative trajectories during their final reversible window.

systems biology↗

bioRxiv2026

Metabolic signals regulate resuscitation speed of antibiotic persister bacteria during infection

All living organisms adjust their metabolism in response to environmental changes. Under unfavorable conditions, organisms enter a state of dormancy by halting metabolism, enabling survival. Dormant bacteria become highly tolerant to antibiotics-a phenomenon called persistence. Here, we demonstrate that selective metabolic reprogramming controls the resuscitation speed of persister after antibiotic exposure. Using multi-omics and in silico modeling, we found that dormant bacteria reprogram metabolic pathways to modulate persister awakening. Accumulation of L-serine and reduction of arginine drive rapid resuscitation. L-serine promotes cysteine biosynthesis and motility while reducing energy metabolism to facilitate rapid resuscitation. In contrast, arginine slows regrowth from dormancy by enhancing ethanol-aldehyde and energy metabolism. L-serine and arginine can, respectively, promote or inhibit the regrowth of antibiotic persister cells in macrophages and mouse models, and regulate the awakening speed of Salmonella, E. coli, and methicillin-resistant Staphylococcus aureus (MRSA). These findings suggest new strategies to target chronic bacterial infections. TeaserL-serine speeds and arginine slows the awakening of antibiotic persisters, revealing targets for chronic infection.

microbiology↗

bioRxiv2026

ORION: An agentic reasoning construct for the analysis of complex human immune profiling

The capacity to generate high-dimensional biological datasets has outpaced the ability to interpret them. Technologies such as phage immunoprecipitation and sequencing (PhIP-seq) enable proteome-scale profiling of antibody repertoires, but interpreting thousands of enriched peptides into mechanistic hypotheses remains a labor-intensive bottleneck requiring expert synthesis of statistics, literature, and domain knowledge. Here we describe ORION (Omics Reasoning & Interpretation Orchestrator), a multi-agent framework that uses reasoning-capable large language models to perform end-to-end analysis of complex immune profiling data. ORION integrates statistical analysis, machine learning, and automated literature review into a single structured workflow, producing results that are reproducible and fully traceable. Applied to a published PhIP-seq dataset from autoimmune polyendocrine syndrome type 1 (APS-1), ORION recovered the canonical autoantibody signature in approximately two hours, closely recapitulating an analysis that originally required one to two months of manual effort. To test hypothesis-generation capacity on previously unseen data, we applied ORION to a novel PhIP-seq dataset from individuals with Down syndrome, for which no proteome-wide autoantibody reference exists. ORION distinguished disease from control samples with high accuracy, prioritized candidate autoantibody targets, and organized them into biologically coherent groups spanning immune, gut, and neuronal programs, generating testable hypotheses for experimental follow-up. These results demonstrate that agentic AI systems can compress the analysis of complex immune profiling data from weeks to hours, allowing scientists to redirect their time toward the fundamental biology.

bioinformatics↗

bioRxiv2026

FXR and BET signaling orchestrate to protect β cells

In both type 1 and type 2 diabetes (T1D and T2D), insulin-producing {beta} cells undergo progressive dysfunction due to inflammation, leading to impaired glucose responsiveness, dedifferentiation, and cell loss. While bile acid (BA) dysregulation under diabetic conditions is known to influence metabolic and inflammatory pathways, its mechanistic role in {beta} cell regulation remains incompletely defined1-3. Here we show that bile acid sensor Farnesoid X receptor (FXR) and Bromodomain and Extra-Terminal motif (BET) signaling cooperatively regulates {beta} cell inflammatory response and {beta} cell identity. We identified the physiological protein-protein interaction between FXR and the bromodomain-containing protein 4 (BRD4) as a regulatory axis that protects against {beta} cell dysfunction. We show that FXR activation by Fexaramine (Fex) together with BRD4 inhibition by JQ1 synergistically suppressed IL-1{beta}-induced inflammation while also improving {beta} cell identity and insulin secretion in both db/db model and high-fat diet (HFD) plus multi low-dose streptozotocin (MLD-STZ) model of diabetes. Importantly, this cooperative effect is abolished in {beta} cell-specific FXR knockout ({beta}FXRKO) mice, establishing that FXR is required for the functional synergy between these pathways in vivo. Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved {beta} cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA-bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR-BET targeting as a promising strategy to counter progressive {beta} cell failure in diabetes.

molecular biology↗

bioRxiv2026

A circuit-to-muscle signaling axis controls locomotor gait transitions in C. elegans

Animals switch between locomotor gaits to adapt to changing environments, yet how defined neural circuits and genes coordinate gait transitions remains poorly understood. Here, we show that the head motor neuron SMB acts as a critical gating node that enables the transition from crawling to swimming in Caenorhabditis elegans. SMB ablation disrupts head-body synchronization, prolongs muscle activation, and impairs curvature switching during swimming, indicating that the SMB neurons function to constrain motor output to stabilize swimming-specific oscillations. Through an unbiased forward genetic screen, we identify the NALCN channel complex component UNC-79 and the muscle nicotinic acetylcholine receptor subunit UNC-29 as key molecular determinants of gait transition. UNC-79 functions across multiple head interneuron modules to stabilize circuit-wide excitability required for sustained swimming, whereas UNC-29 acts cell-autonomously in body wall muscles to refine calcium amplitude and propagation dynamics. Genetic epistasis analyses position the SMB neurons upstream of UNC-29-mediated muscle activation, establishing a circuit-to-muscle signaling axis that links defined head motor neurons to downstream molecular effectors. Together, our findings show that gait transition emerges from coordinated modulation of neuronal excitability and muscle calcium dynamics, providing a mechanistic framework for how neural circuits reconfigure motor states to adapt locomotor behavior. HIGHLIGHTSO_LIThe SMB head motor neurons govern the crawl-to-swim transition C_LIO_LIUNC-79/NALCN stabilizes circuit excitability for sustained swimming C_LIO_LIMuscle nAChR subunit UNC-29 tunes calcium gain during gait transition C_LIO_LIA circuit-to-muscle pathway coordinates locomotor state transition C_LI IN BRIEFGait transitions require coordinated changes in neural circuit activity and muscle output. Moon et al. show that the SMB head motor neurons regulate the switch from crawling to swimming in C. elegans by coupling distributed circuit excitability to muscle calcium gain control, defining a circuit-to-muscle pathway that stabilizes locomotor state transitions.

neuroscience↗

bioRxiv2026

Nanoparticle-delivered resiquimod induces brain tumor regression in medulloblastoma and diffuse midline glioma models by interrupting paracrine growth support and activating myeloid immune signaling and phagocytosis

In pediatric brain tumors medulloblastoma (MB) and diffuse midline glioma (DMG), tumor-associated myeloid cells (TAMs) support malignant progression by secreting paracrine growth factors and suppressing local immune function. We studied the potential for reversing this cancer-supportive phenotype by stimulating TAM pathogen receptors using ResiPOx, a brain-permeant, polyoxazoline nanoparticle formulation of the TLR7/8 agonist resiquimod. ResiPOx showed blood-brain barrier penetration and anti-tumor efficacy, extending progression-free survival (PFS) in mice with MB and DMG. Integrated cellular and molecular analysis including scRNA-seq showed that ResiPOx expanded TAM populations and reprogrammed TAMs toward anti-tumoral states, blocking paracrine IGF1 signaling and inducing local cytokine signaling and phagocytosis of tumor cells. In rhesus macaques, systemic ResiPOx was well tolerated and induced brain transcriptional patterns that resembled ResiPOx responses in DMG and MB mouse models, indicating effects in non-human primates that highlight translational potential. Our data show that ResiPOx reshapes the brain tumor microenvironment to inhibit tumor growth. As a systemically administered, brain penetrant immunomodulator, ResiPOx is able to reach multifocal and unresectable brain tumors, including MB and DMG.

cancer biology↗

bioRxiv2026

A sensor of oxidative stress confers virulence via response memory in Acinetobacter baumannii

All living organisms must adapt to environmental stresses to survive. The two-component system (TCS) is a prevalent signal transduction mechanism to alter gene expression in response to stress in bacteria. We report that the PmrB sensor of the PmrA/PmrB TCS senses sublethal oxidative stress and encodes a response memory that promotes virulence in Acinetobacter baumannii. PmrB detects oxidative stress through histidine residues with a nickel (Ni2+) cofactor. Nickel oxidation (Ni2+) induces an allosteric effect by altering PmrB conformation, enabling PmrA activation. Activated PmrA induces antioxidant defense genes, including iron-sulfur cluster repair, ferritin, catalase, and peroxidase. Notably, PmrB remains activated after sublethal oxidative stress is removed, as pathogens encounter in the bloodstream and airways during infection. This response memory enables bacteria to respond strongly to subsequent lethal oxidative stress and antimicrobial peptides. In a murine model, disrupting oxidative sensing reduces virulence. In addition, PmrB-mediated response memory is essential for high virulence in clinically isolated multidrug-resistant A. baumannii. Our findings demonstrate how subinhibitory stress detection enables pathogens to achieve full virulence potential and resist stresses during infection.

microbiology↗