Biology subjects

Singh, V.

Publications and source records attributed to Singh, V..

At least 19 recordsLinked to original sources

bioRxiv2026

FXR2 Promotes Autophagic Clearance of Sindbis Virus Capsid and Protects Against Viral Encephalitis

Autophagy protects neurons from viral infection by removing toxic viral components, but the host factors that recognize viral proteins and direct their clearance remain incompletely defined. Here, we identify fragile X mental retardation syndrome-related protein 2 (FXR2) as a mediator of protective autophagy during Sindbis virus (SINV) infection. Quantitative proteomic analysis of host proteins associated with SINV capsid identified FXR2, an RNA-binding protein linked to stress granules and protein homeostasis. Co-immunoprecipitation and immunofluorescence confirmed that FXR2 associates and colocalizes with viral capsid in infected cells. Loss of FXR2 increased capsid accumulation, reduced LC3 lipidation and autophagosome formation, and impaired p62 degradation following infection. Reconstitution of FXR2-deficient cells restored autophagy and promoted capsid clearance. Although FXR2 deficiency did not significantly increase viral replication, it enhanced virus-induced cell death, suggesting that FXR2 protects infected cells by limiting viral protein toxicity rather than by directly restricting virus production. Consistent with this model, both Fxr2-null and heterozygous mice exhibited increased mortality following neurotropic SINV challenge, and Fxr2-null mice developed greater neuronal degeneration, inflammation, and cell death despite viral titers comparable to those in wild-type animals. Together, these findings identify FXR2 as a previously unrecognized component of the antiviral autophagy pathway that promotes viral capsid clearance and protects neural tissue from infection-associated damage.

microbiology↗

bioRxiv2026

Modeling of human MLH1 and MLH3 variants in mice reveals novel functions of MutLγ in meiotic DNA repair and the ovarian reserve

The mismatch repair proteins MLH1 and MLH3 form the MutL{gamma} complex that is essential for >90% of meiotic crossovers (CO) in mice. Although deletion of either gene causes infertility, we previously found that mouse models of certain human MLH1/3 missense variants caused elevated aneuploidy and progressive loss of female fecundity despite having a normal ovarian reserve. Here, we report that additional missense and null alleles caused significant pre-pubertal follicle loss independent of alterations to meiotic CO levels. Deletion of the DNA damage checkpoint kinase Chek2 (Chk2) partially rescued the oocyte pool of Mlh1- and Mlh3-deficient mice, indicating that defects in meiotic prophase I triggered oocyte elimination. In spermatocytes, both missense and null alleles caused abnormal {gamma}H2AX flares on autosomes during late pachynema and diplonema, extending into chromatin loops from the synaptonemal complex. These flares frequently contained unusually large foci of the ssDNA binding protein RPA as well as DNA end processing factors including CtIP, RAD50 and BLM, consistent with abnormal and extensive DNA resection. The results reveal a previously unrecognized meiotic function of MutL{gamma} in preventing DNA hyper-resection of spontaneous DNA breaks or of persistent recombination intermediates in late prophase I. Together with our previous studies, the results show that MLH1/3 variants can impair fertility through at least three mechanistically distinct routes: severe crossover loss sufficient to activate the metaphase I spindle assembly checkpoint; subthreshold crossover defects that increase aneuploidy and embryo loss; and abnormal late-prophase DNA processing that activates a CHEK2-dependent oocyte quality-control pathway and depletes the ovarian reserve, causing primary ovarian insufficiency (POI). Thus, MutL{gamma} has broader roles in maintaining meiotic genome integrity than can be explained by crossover formation alone.

genetics↗

bioRxiv2026

Reply to: Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy

In the paper by Nguyen et al, published in Nature Communications in 2024, we describe structural polymorphism in fibrils extracted from patients with ATTR amyloidosis. ATTR amyloidosis is characterized by deposition of transthyretin amyloid fibrils across multiple organs, resulting in marked phenotypic variability. Previous studies on ATTR suggest its phenotypic variability may be linked to differences in fibril structure, as demonstrated in amyloid diseases such as AA amyloidosis, tauopathies, or synucleinopathies. Thus far, most ATTR fibrils adopt a strikingly similar fold across patients and affected organs. The most notable exception is described in the study by Nguyen et al., where we report the identification of two co-existing polymorphs in cardiac fibrils from three patients with the ATTRv-I84S variant. These cardiac polymorphs differ in conformation of the segment Gly57 to Gly67, termed the gate, which regulates access to a central polar channel within the fibril core. In one polymorph, the gate adopts an open conformation, exposing the channel, whereas in the other it is closed, shielding it. Whether these polymorphs extend beyond cardiac tissue remains unknown. Here, we address this question by extending our analysis to additional organs from a fourth patient with ATTRv-I84S amyloidosis.

biophysics↗

bioRxiv2026

Dietary fiber-type-specific gut microbiome preconditioning drives differential susceptibility to sporadic colon cancer development

Background: Dietary fiber intake is broadly associated with reduced colorectal cancer (CRC) risk, yet processed fiber supplements exert inconsistent and occasionally opposing effects on colon tumorigenesis. How structurally distinct dietary fibers differentially shape the gut microbiome-metabolome axis to influence carcinogenic susceptibility remains poorly understood. Objective: To determine whether structurally distinct dietary fibers differentially modulate colon tumor development and characterize the underlying gut microbiome and metabolic mechanisms. Design: Four-week-old male mice were maintained on low-fiber control or fiber-supplemented diets (7.5%w/w: cellulose, agar, pectin, or inulin) for 28 weeks and received eight intraperitoneal azoxymethane injections (AOM; 7.5 mg/kg). Temporal fecal microbiomes were profiled by 16S-rRNA sequencing, cecal metabolites quantified by H-NMR spectroscopy, and microbiome-metabolome interactions assessed by co-occurrence networks. Results: Refined inulin supplementation markedly elevated colon tumor incidence (~70%) compared with all other groups (~10-20%), and cecal extracts from inulin-fed mice promoted HT29 cancer-cell proliferation. Longitudinal microbiome profiling identified 36 inulin-specific microbial signatures converging on two axes: depletion of SCFAs and fermentation cross-feeding taxa and reprogramming of amino acid and nitrogen metabolism. Metabolomics confirmed succinate, fumarate, and lactate accumulation alongside propionate and amino acid depletion exclusively under AOM conditions, with no differences in carcinogen-naive animals. Two stable co-occurrence hubs were identified exclusively in AOM-treated animals, structurally integrating both functional axes. Conclusion: Inulin supplementation preconditions the gut microbiome toward functional vulnerability, characterized by disrupted fermentation throughput and reprogrammed amino acid metabolism, that is amplified by carcinogen exposure into a tumor-promoting ecosystem, providing a mechanistic basis for the disproportionately higher tumor prevalence in inulin-fed animals.

microbiology↗

bioRxiv2026

Resolving Heterogeneous Mechanical Domains via Physics-Aware Deep Clustering of Single-Molecule Force Spectroscopy Data

Many biological processes rely on mechanical forces, with protein molecules acting as key mediators. Understanding how proteins respond to mechanical stress is essential for conditions including cardiomyopathy and muscular dystrophy. Natural proteins such as dystrophin and utrophin are composed of heterogeneous folding domains with distinct mechanical properties; deciphering domain-level behavior provides insights into disease mechanisms and informs therapeutic strategies. Single-molecule force spectroscopy (SMFS) enables probing the mechanical properties of entire proteins, yet current approaches struggle to identify heterogeneous folding domains, particularly without prior knowledge. Here, we present the first automated framework to identify heterogeneous folding domains in SMFS data, applying both existing clustering methods and a novel physics-aware deep clustering architecture, LatentUnfold. LatentUnfold learns complementary latent representations from force magnitude and the force-extension physical relationship through dual autoencoders, jointly optimized for clustering assignments. We apply our framework to experimental SMFS data collected from a synthetic two-domain protein (ddFLN4-Titin I27) as well as natural protein constructs of dystrophin and utrophin, with Monte Carlo simulated datasets serving as controlled validation. For the synthetic protein, we recover mechanical properties consistent with previously reported values for each domain. For the natural proteins, we uncover two mechanically distinct domain populations - corresponding to the N-terminal domain and spectrin-like repeats - with differences in both unfolding force and contour length increase, and reveal different unfolding order between them for the first time. This work enables domain-level biological inference, overcoming prior limitations that relied on averaging and overlooked heterogeneity, thus advancing the understanding of mechanical behavior in protein unfolding.

biophysics↗

bioRxiv2026

The Neural Impact Score benchmarks drugs in Multi-Region Brain Organoids

Only about 10 percent of drugs that clear animal testing succeed in humans, and central nervous system programs carry an even steeper translational gap. Human-relevant NAMs are gaining global regulatory and funding support, creating an urgent need for interpretable preclinical systems that can generate comparable, decision-ready evidence across assays, models, and species. Yet the multimodal treatment-response data produced by these systems are still evaluated assay by assay, with no unified metric showing whether a compound moves neural tissue toward a desirable or undesirable state. Here we present the Neural Impact Score (NIS), a framework that translates multimodal CNS drug-response data into a bidirectional score across four predefined biological categories: neurodevelopment, neuroinflammation, neurodegeneration, and longevity. A positive score indicates a desirable shift, whereas a negative score indicates the opposite, placing compounds on a single scale across assays, model systems, and species. To demonstrate NIS, we analyzed a vascularized human day-200 multi-region brain organoid (MRBO) composed of cortical, endothelial, and brainstem lineages and mimicking a mid-gestational cortical window (GW18-GW22). We tested five compounds with distinct mechanisms of action: a glucagon-like peptide-1 receptor agonist (GLP-1RA), a norepinephrine-dopamine reuptake inhibitor (NDRI), a selective serotonin reuptake inhibitor (SSRI), a sphingosine-1-phosphate receptor modulator, and an Akt activator. We profiled responses using single-nucleus RNA sequencing, bulk RNA sequencing, proteomics, and multi-electrode array electrophysiology. NIS integrated these readouts into category-specific and composite scores, separating beneficial from adverse effects for each compound and sorting compounds into interpretation tiers. Applying the same framework to independent human and rodent datasets without retraining, we recovered conserved human antidepressant responses despite near-chance gene-level agreement between human MRBO and rat brain, and identified an endothelial-dependent, human-specific GLP-1 response absent from the murine dorsal vagal complex. NIS therefore provides a human-relevant framework for drug evaluation and cross-species benchmarking, with a design extensible to other neural systems.

bioengineering↗

bioRxiv2026

Structural basis of K+/H+ antiport in YcgO and its inhibition by unphosphorylated PtsN

Cation-proton antiporters (CPAs) are vital for the maintenance of ionic homeostasis and normal physiology among diverse cell types. Despite recent insights into K+/H+ exchange transporters, the diversity in their structural organization and regulatory mechanisms of K+-specific CPAs are minimally understood. Here, we explore the architecture of an E. coli CPA1 K+/H+ antiporter, YcgO and its inhibition by the unphosphorylated form of PtsN, the terminal protein of a regulatory phosphorelay, using cryoEM structures at 3.4 [A] and 3.2 [A] resolution, respectively. Homodimeric YcgO bound to K+ ions in the occluded conformation, harbors additional linked cytosolic domains, RCK and CorC, to regulate the movement of the transport helices within the YcgO dimer. These domains are the sites of interaction and efflux inhibition by unphosphorylated PtsN, which interacts with the CorC domains with high affinity and allosterically augments inhibitory interactions of CorC with transport helices of YcgO. Inhibition is relieved leading to constitutive activation, upon disrupting the CorC-transport conduit interface. This study illuminates the structural basis of K+ efflux mediated through regulation of a K+/H+ antiporter in E. coli and related prokaryotes via a metabolic network involving a regulatory phosphorelay.

biochemistry↗

bioRxiv2026

Microbial odours activate protective immune response in Caenorhabditis elegans via specific olfactory neurons

Caenorhabditis elegans, like other animals, relies on attractive odours for foraging and on aversive odours for avoidance of pathogens. An odour produced by pathogenic bacterium Pseudomonoas aeruginosa induces immune response as well as avoidance in C. elegans via AWB olfactory neurons. We asked whether AWB neurons provide broader immunity to a wide range of pathogens. We activated AWB neurons using three chemically distinct bacterial odours and found that activation indeed induces protective immunity. Conversely, silencing of AWB neurons early during infection enhances susceptibility to infections. Mechanistic investigation revealed that the activation of AWB using odours upregulates detoxification pathways and other protective pathways in non-neuronal tissues. Specifically, odour exposure activates UDP-glucuronosyltransferase UGT-18 in the intestine that protects worms from the phenazine toxin of Pseudomonas aeruginosa and promotes broader immunity to Gram-negative bacteria (P. aeruginosa and Salmonella enterica), Gram-positive bacteria, (Enterococcus faecalis and Staphylococcus aureus), and yeast (Cryptococcus neoformans). Altogether, our findings highlights microbial odours as non-canonical molecular patterns for activating immune responses.

neuroscience↗

bioRxiv2026

Genic Position and Methylation Context Shape DNA Methylation-Expression Relationships in Rice Internode Development

Elongating rice internodes present a developmental gradient from dividing meristem to mature cells, providing an elegant pseudo-time course for study of plant vegetative development. We tested the hypothesis that DNA methylation regulates gene expression during rice internode development by integrating RNA-seq and bisulfite DNA sequencing across eight internode segments. Previously described topologically associated chromatin domain borders aligned with transcription start sites of constitutive expressed genes. CpG and CHG differential methylation was enriched in young segments, consistent with maintenance methylation; whereas CHH methylation showed similar differential abundance in young and old segments. CHH and CHG methylation in upstream regions, CpG methylation within gene bodies, and any methylation in 5' and 3' untranslated regions were permissive of moderate to high gene expression. Very low expression was associated with CpG methylation upstream, CHG and CHH methylation within gene bodies, and CpG and CHG methylation downstream. A nonrandom subset of genes, including cell wall-related glycoside hydrolases, lignin and tricin biosynthesis enzymes, and WD40 proteins, showed methylation-expression correlations, with expression changes enriched in triple-marked elements. These results suggest that internode phenotypes of DNA methylation machinery mutants relate to alteration of specific target genes, opening approaches for grass culm improvement for lodging resistance and biomass production. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/737558v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@b726eaorg.highwire.dtl.DTLVardef@5bd017org.highwire.dtl.DTLVardef@1bac873org.highwire.dtl.DTLVardef@1be3474_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance statementStems of cereals and other grasses have an important function in supporting grain production and serving as a source of carbon for the bioeconomy. This study supports methylation of the cytosine bases of DNA as a regulator of chromatin structure and gene expression in the stems of rice. Different methylation contexts are implicated in specific roles in both positive and negative gene expression regulation that might be leveraged to improve stem properties.

plant biology↗

bioRxiv2026

SupeRJump: Determining normal and leukemic differentiation fate through semi-supervised jump diffusion modeling

Single cell RNA-seq (scRNA) has provided unprecedented resolution into cellular and clonal heterogeneity. Computational approaches have enabled recovery of differentiation dynamics, yet current approaches do not evaluate discontinuous differentiation processes present in malignant leukemia. To address these gaps, we developed SupeRJump: a jump-drift-diffusion based supervised cell-fate model (https://github.com/namwob44/SupeRJump/). We deploy this approach in human bone marrow, murine aging hematopoiesis, and lentivirally barcoded mouse models of acute myeloid leukemia. Our framework introduces a semi-supervised pseudotime strategy to fit a jump-drift-diffusion model and batch correction for lineage fate predictions from absorbing Markov chains. We introduce metrics to quantify a cells skewness toward particular lineages, transitions through intermediate progenitor states toward terminally differentiated states, and discontinuous transition dynamics. We use these metrics to identify cells preferentially biased for differentiation, their underlying transcriptional networks, and gene programs responsible for differentiation discontinuity.

bioinformatics↗

bioRxiv2026

Pleiotropic antimalarial activities and immunomodulation exhibited by Himalayan Buransh (Rhododendron arboreum) in human and rodent malaria models

Emerging drug resistance against the malaria parasite is worrisome and necessitates the development of novel antimalarials. Himalayan Buransh (Rhododendron arboreum) is a well-known medicinal plant found in the northern states of India. In this study, we observed the pleiotropic antimalarial activities and immunomodulation exhibited by the aqueous extract of Buransh flower (AEBF). AEBF demonstrated significant IC50 values (16-29 {micro}g/ml) against the asexual stages of various P. falciparum strains (3D7, Dd2-chloroquine-resistant and C580Y-artemisinin resistant). The oral administration of AEBF (200 mg/kg) in mice, suppressed [~]80% P. berghei parasitemia, improved mean survival time (MST-23.5 days) and prevented splenomegaly. Notably, the combination of AEBF and artesunate not only cleared primary infection, but also conferred sustained immunity. This immunomodulatory effect, driven by protective IFN-{gamma} resulted in reduced parasitemia during a homologous challenge without the need for further treatment. It is important to highlight the malaria transmission blocking activity of AEBF, resulting in reduced sexual stage male gametocyte exflagellation. Furthermore, the virtual drug screening of selected bioactive constituents from Buransh flower demonstrated potent binding against multiple P. falciparum proteins, suggested a pleiotropic mode of action. Altogether, our results corroborated the first ever evidence of the multistage antimalarial potential of Buransh flower, supported by in vitro cell studies, in vivo rodent malaria model and in silico docking analyses. Based on our studys findings and the traditional use of Buransh juice as a medicinal beverage in Uttarakhand, India, we propose exploring it as an adjunct therapy for drug-resistant malaria, subject to further clinical validation.

pathology↗

bioRxiv2026

SLD5/GINS4 controls dynein-dependent centrosome maturation and exposes a candidate mitotic vulnerability in cancer.

Faithful proliferation requires coordinated DNA replication with centrosome maturation and spindle-pole integrity. SLD5, encoded by GINS4, is a core component of the GINS replication complex and is frequently elevated in tumors, but whether it links replication-associated cancer states to centrosome control has remained unclear. Here, we show that GINS4/SLD5 is recurrently upregulated across human cancers at transcript and protein levels and marks tumor programs enriched for DNA replication, chromosome segregation, and mitotic control. In cancer cells, Sld5 depletion dispersed PCM1, AZI1, and CEP290-positive centriolar satellites without eliminating these satellite proteins, reduced dynein heavy chain expression, and destabilized dynein-dynactin localization at spindle poles. Direct depletion of dynein heavy chain, co-depletion analyses, and pharmacological inhibition of dynein motor activity with ciliobrevin D phenocopied Sld5 loss, causing satellite dispersion, defective recruitment of PLK1, Aurora A, CEP192, and CEP215 to centrosomes, and multipolar spindle formation. These defects occurred without detectable DNA damage or checkpoint activation, indicating a non-canonical Sld5 function beyond its role in the replisome. Cancer dependency and kinase network analyses further nominate SLD5-associated mitotic and checkpoint pathways as therapeutic targets. Our findings identify SLD5/GINS4 as a regulator of dynein-dependent centrosome maturation and a candidate vulnerability in replication-driven cancers, with potential value for biomarker-guided therapeutic stratification. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/723511v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@525d9org.highwire.dtl.DTLVardef@1f7d7eeorg.highwire.dtl.DTLVardef@815586org.highwire.dtl.DTLVardef@115f286_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

CRTAC1-A reprograms extracellular matrix viscoelasticity to constrain glioma progression

Mechanical remodeling of the extracellular matrix (ECM) influences glioma progression, yet the molecular regulators that control tumor matrix mechanics remain poorly understood. By comparing low-grade gliomas (LGGs), associated with improved patient survival, with glioblastomas (GBMs), which carry a poor prognosis, we identified the cartilage-derived ECM protein CRTAC1-A as enriched in LGGs and significantly reduced in GBMs, with elevated expression correlating with improved patient survival. Restoration of CRTAC1-A suppressed glioma cell proliferation and invasion and enhanced temozolomide efficacy in three-dimensional tumor spheroid models. Mechanistically, CRTAC1-A directly interacts with collagen I and reorganizes collagen networks across multiple length scales, generating a mechanically compliant yet structurally resilient ECM with reduced stiffness, enhanced elastic recovery, and resistance to persistent remodeling. This viscoelastic normalization limits invasive remodeling while preserving matrix permeability and drug penetration. Together, these findings identify CRTAC1-A as a reversible regulator of tumor ECM mechanics that suppresses glioma malignancy.

cancer biology↗

bioRxiv2026

Targeting the APRIL-BAFF axis in IgA nephropathy: preclinical insights from influenza challenge and single-cell spatial profiling

BackgroundAPRIL and BAFF are TNF superfamily cytokines that regulate B-cell development, survival, and antibody production, and are emerging therapeutic targets for IgA nephropathy (IgAN). Selective APRIL and dual APRIL/BAFF inhibitors both reduce IgA and proteinuria in IgAN clinical trials, but whether their broader immunological consequences differ has not been systematically characterized. MethodsWe compared selective APRIL and dual APRIL/BAFF inhibition using influenza vaccination and lethal challenge, KLH immunization, serological profiling, and flow cytometry in mice, alongside human B-cell survival assays in vitro. Single-cell CITE-seq and in situ spatial transcriptomics were applied to characterize molecular and tissue-level changes in the spleen. ResultsBoth modes of inhibition reduced serum IgA by [≥]60% in mice. However, dual APRIL/BAFF inhibition nearly abolished vaccine-mediated protection against lethal influenza challenge (10% versus 70% survival in controls; p < 0.01), whereas selective APRIL inhibition had limited impact on protective immunity. This functional divergence was underpinned by broad cellular disruption under dual blockade, including >80% depletion of splenic B cells, loss of T follicular helper cells, and impaired antigen-specific IgM and IgG responses. Selective APRIL inhibition left these populations and responses largely intact. Consistent with these findings, human B-cell survival in vitro was dependent on BAFF, not APRIL. Single-cell and spatial transcriptomics revealed that dual blockade collapsed follicular architecture, eliminated germinal centers, and disrupted chemokine organization, whereas these structures remained intact under selective APRIL inhibition. At the molecular level, dual blockade, but not selective APRIL inhibition, downregulated NF-{kappa}B survival signaling and antigen presentation programs and shifted surviving germinal center B cells toward a pro-apoptotic state. ConclusionsSelective APRIL and dual APRIL/BAFF inhibition both reduce IgA, the pathologically relevant isotype in IgAN, but only dual blockade disrupts B-cell maturation, germinal center function, tissue architecture, and protective immunity. These findings inform the benefit-risk assessment of chronic B cell-targeting therapies in IgAN.

immunology↗

bioRxiv2026

Metacontam: A Negative Control-Free Decontamination Method for Metagenomic Analysis

Shotgun metagenomic sequencing enables high-resolution profiling of host-associated microbial communities. However, contaminant DNA can substantially distort biological interpretations, especially in low-biomass samples. Here, we introduce Metacontam, a control-free method for species-level decontamination of shotgun metagenomic data. Metacontam integrates blacklist-guided community detection within a species correlation network with average nucleotide identity (ANI) to identify contaminants arising from shared sources. Across diverse low-biomass and mixed-biomass datasets, Metacontam outperformed existing approaches, improving the detection of low-abundance and low-prevalence contaminants while retaining biologically plausible taxa. It also reduces kit-specific biases in skin metagenomes and improves downstream analyses of tissue microbiome data. Together, these results demonstrate that Metacontam enables accurate identification of contaminant taxa across diverse metagenomic datasets, even in the absence of negative controls.

bioinformatics↗

bioRxiv2026

XRRA1 acts as a molecular brake on radiation-induced DNA damage signaling and immunogenic cell death in tumor cells.

Radiotherapy kills cancer cells by inducing DNA damage, but adaptive responses that buffer injury and limit immunogenic signaling remain incompletely understood. Although ionizing radiation can activate cytosolic DNA sensing and immunogenic cell death, the tumor-intrinsic regulators linking these processes to radioresistance are not well defined. Here, we show that XRRA1 is a stress-adaptive determinant of radioresponse identified by integrating discovery proteomics into chronic myeloid leukemia with clinical tissue validation and functional studies across multiple tumor models. In peripheral-blood proteomes, XRRA1 was quantitatively reduced in chronic myeloid leukemia yet associated with a favorable prognosis and with networks enriched for RNA regulation, apoptosis, and DNA-repair biology. In human biopsy specimens, XRRA1 protein abundance was increased in radiation-exposed tissues, and in cultured cells, ionizing radiation induced XRRA1 more strongly and persistently in normal cells than in cancer cells. Silencing XRRA1 had little effect on basal growth but markedly enhanced radiation-induced loss of viability, apoptosis, spheroid disruption, and clonogenic failure, while increasing {gamma}H2AX- and DNA-PK-associated damage signaling and linking XRRA1 to non-homologous end joining factors. XRRA1 depletion also amplified cGAS-STING-TBK1-IRF3 activation, interferon-stimulated gene expression, extracellular ATP release, and cell-surface calreticulin exposure. These findings identify XRRA1 as a molecular brake that limits the conversion of radiation-induced DNA damage into immunogenic stress responses. XRRA1, therefore, represents a candidate biomarker of radioadaptive stress and a potential target for radiosensitization and radiotherapy-immunotherapy combinations.

cancer biology↗

bioRxiv2026

Neural cell state modulation by PARK2 and dopaminergic neuroprotection by small molecule Parkin agonism

Parkin, an E3 ubiquitin ligase encoded by PARK2, plays a key role in both hereditary and sporadic Parkinsons disease (PD), yet there are no therapies currently available that can target this important pathway. Here, we show that Parkin is critical for successful neuronal differentiation and survival, and we develop small-molecule Parkin agonists that can protect dopaminergic neurons. Upon differentiation of neural progenitor cells, loss of Parkin results in a reduced capacity to maintain neuronal cell state, dopaminergic neuronal phenotypes, and stress resistance. Moreover, Parkin loss disrupted cell morphology and the stability of neurites. Transcriptional and single-cell analyses reveal that Parkin controls critical pathways regulating stem-like cell transitions and is needed for stable neuronal maturation. We also examined the effects of FB231, a small molecule enhancer of Parkin E3 ligase activity, in models of PD. FB231 reduced pathological -synuclein and enhanced cell survival in human iPSC-derived dopaminergic neurons treated with -synuclein preformed fibrils. Furthermore, FB231 attenuated -synuclein pathology and dopaminergic neurodegeneration in a gut -synuclein murine model of PD. Our findings support that Parkin plays a crucial role in maintaining neuronal homeostasis and that pharmacologic activation of Parkin may be a promising strategy to attenuate neurodegeneration in PD.

neuroscience↗

bioRxiv2026

Increased CSF volume, altered brain development and emotional reactivity after postnatal Zika virus infection in infant rhesus macaques

Although congenital Zika virus (ZIKV) syndrome is well-characterized, the neurodevelopmental consequences of postnatal infection are less understood. Here we used a rhesus macaque model to investigate the developmental consequences of ZIKV infection during infancy on the brain and behavior, building on our prior research. Male and female infant rhesus macaques infected with ZIKV at 1 month of age were compared to sex-, age-, and rearing-matched uninfected controls and infants treated with the TLR3 agonist PolyIC as a control for activation of the innate immune system. Longitudinal behavioral assessments revealed alterations in emotional regulation following ZIKV exposure, including poor state control scores obtained from the Infant Neurobehavioral Assessment Scale early after ZIKV infection and longer-term displays of increased hostility during an acute stressor. While attachment bonds to caregivers were preserved, ZIKV-infected infants showed sex-specific alterations in behavioral regulation during caregiver separation compared to controls. At 3 months of age, MRI scans revealed larger total cerebrospinal fluid (CSF) volume and reduced volumes in visual processing regions in ZIKV-infected infants compared to controls. Postnatal ZIKV exposure also resulted in sex-specific brain structural alterations with males exhibiting amygdala hypertrophy, whereas ZIKV-infected females had volumetric reductions in temporal-limbic and temporal-auditory cortices. These findings demonstrate that postnatal ZIKV infection disrupts the development of sensory, social and emotion-regulatory systems and CSF function, highlighting the critical need for long-term monitoring of exposed children. One-Sentence SummaryPostnatal Zika virus infection disrupts emotional regulation and alters brain development in infant rhesus macaques, revealing a critical window of neurodevelopmental vulnerability that extends beyond the fetal period.

neuroscience↗