Biology subjects

Zhou, C.

Publications and source records attributed to Zhou, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Differential Survival of Retinal Ganglion Cell Types Following Branch Retinal Vein Occlusion

Background. Branch retinal vein occlusion (BRVO) is a common cause of retinal ischemia, rapidly inducing neuronal death and often producing irreversible vison loss. Interventions such as thrombolysis restore perfusion but cannot recover neurons already lost, and most patients retain permanent visual deficits. Identifying which neuronal populations die, and how rapidly, may therefore reveal timing windows and targets for neuroprotective treatment. Aims. To determine the timing of pathology, we evaluated vascular changes and neuronal degeneration in a photocoagulation-induced mouse model of BRVO. To determine differences in retinal ganglion cells (RGC) type susceptibility, we tracked the survival of RGC subpopulations using immunofluorescence markers. Methods. BRVO was induced by retro-orbital injection of Rose Bengal and FITC dextran followed by targeted photocoagulation of a branch vein. Obstruction was confirmed by fluorescein angiography and vascular damage was viewed by optical coherence tomography angiography. Cell survival was quantified by immunostaining at 3, 7, and 14 days using RNA Binding Protein with Multiple Splicing (RBPMS, pan RGC). RGC subtype markers for intrinsically photosensitive RGCs (TBR2), RGCs (SPP1), ON OFF direction-selective RGCs (CART), and F RGCs (FOXP2) were used to examine differences in survival across RGC types. Results. Occlusion selectively disrupted the superficial and intermediate capillary plexus, sparing the deep plexuses. All examined neuronal populations were significantly depleted, but with markedly different magnitude and timing. RGCs and F RGCs were the most vulnerable subtypes, both approaching complete loss by one week, whereas intrinsically photosensitive RGCs were the most resistant. Conclusion. RGCs, typically resilient in glaucoma, trauma, and excitotoxicity, were markedly vulnerable in BRVO, indicating that RGC subtype susceptibility is insult-specific.

neuroscience↗

bioRxiv2026

A defined multi-kingdom microbial consortium naturalizes the immune system of laboratory mice

Dirty mice experiments suggest that laboratory mice fail to model certain human immune responses due to their limited microbial exposure. The identity, nature, and number of microbes required to normalize the immune system are unknown. Through systematic screening, we uncovered unexpected cross-kingdom microbial interactions and identified four enteric microbes spanning viruses, fungi, and protists sufficient to reproduce key immunological features of pet store mice and adult humans. This consortium also altered cancer outcomes, shifting tumorigenesis toward the anatomical pattern of human familial adenomatous polyposis in ApcMin/+ mice and recapitulating the imperfect response of many patients to chimeric antigen receptor (CAR) T cell therapy. Thus, surprisingly few microbes can profoundly reshape immune states and disease responses, providing a tractable approach to naturalize laboratory mouse immunity.

immunology↗

bioRxiv2026

Protein Deimmunization with a Generative Diffusion Model

Protein immunogenicity is a major cause of biologic drug failure, leading to the production of anti-drug antibodies (ADA) that accelerate drug clearance, rejection of repeated doses, abolished efficacy, and sometimes life threatening anaphylaxis in patients. These responses constrain the clinical use of synthetic protein therapeutics from non-human origin. To efficiently deimmunize protein therapeutics, we developed a generative discrete diffusion model (MESSI), which takes protein structures as input and outputs sequences that preserve structure without containing peptides predicted to bind major histocompatibility complex class II molecules. MESSI designs sequences with high structural recovery and down to 0 predicted epitopes for specified MHC molecules at higher efficiency than post-hoc filtering approaches. Experimentally, we first applied MESSI to deimmunize a luciferase and a de novo designed mini-binder against PD-1, resulting in variants with no predicted epitopes and higher activity than their parents. Lastly, we coupled MESSI with evolution guidance to deimmunize uricase, a clinically approved enzyme with severe immunogenicity, and found deimmunized variants with higher catalytic activity than their natural orthologs. MESSI enables generative design of functional proteins with minimized immunogenicity, potentially making protein therapeutics safer and more effective.

bioengineering↗

bioRxiv2026

ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways

TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72-ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.

neuroscience↗

bioRxiv2026

An atlas of eukaryotic centromere architecture reveals recurrent evolutionary dynamics

Centromeres evolved at the root of eukaryotes to segregate chromosomes during cell division. Despite their ancient origin, centromeric DNA sequences evolve rapidly and adopt diverse architectures, including point centromeres, satellite arrays, transposon clusters, and holocentrics. To analyse centromere evolution at a broad scale, we characterised architectures across 325 diverse Darwin Tree of Life genome assemblies. Centromere architecture is evolutionarily labile, and similar configurations arise independently across divergent lineages. In plants and animals, we modelled centromere evolution as a recurrent cycle, in which satellite- and transposon-based architectures interconvert, with independent origins of holocentricity. We curated >23 million satellite repeats comprising 263 families from 165 species. Despite sequence divergence between satellite families, higher order repeats are prevalent, indicating constraint on repeat architecture rather than primary sequence. Satellite arrays are heavily invaded by diverse transposon families, consistent with convergent adaptation to the centromeric niche. In 89 species, transposons themselves constitute the primary centromere structure. We observed centrophilic transposons forming tandem arrays, suggesting mechanisms for satellite regeneration. Our sample includes five independent origins of holocentricity in plants and animals, which vary in association with periodic satellite arrays. We propose that genetic instability, centrophilic transposition, and transmission distortion promote recurrent centromere architectural interconversions during evolution.

genomics↗

bioRxiv2026

Hierarchical chromatin polyvalency governs robust gene regulation and organogenesis

Precise temporal control of gene expression is fundamental for embryonic development, yet the epigenetic and chromatin basis governing transcriptional timing remain poorly understood. The bivalency model, characterized by coexistence of H3K4me3 and H3K27me3, has been proposed to mark a poised state ready for activation. However, this model has been challenged by lacking of rapid gene activation in response to H3K27me3 depletion, suggesting that the H3K27me3 mark is not responsible for the silencing. Here, through temporal epigenomic profiling of post-implantation mouse embryos and use of the protein degradation tag (dTAG) system, we demonstrate that H2Aub, but not H3K27me3, functions as the major repressor. We further reveal a hierarchical repression architecture in which H2Aub is responsible for transcriptional silencing, while H3K27me3 and H3K9me3 serve to reinforce the silencing state in post-implantation embryos. Functionally, disruption of this H2Aub-centered hierarchy perturbs temporal control of polyvalent gene activation, leading to severe organogenesis defects. Mechanistically, acute loss of H2Aub disrupts retinoic acid-FGF signaling pathway, causing somitogenesis arrest. Together, our findings establish chromatin polyvalency model as a multi-layered, hierarchical repression mechanism that governs temporal control of gene expression during embryogenesis.

genetics↗

bioRxiv2026

Structure-aware deep learning predicts influenza antigenicity and guides vaccine strain recommendation

The continuous accumulation of genetic mutations in influenza A viruses (IAVs) drives antigenic drift, necessitating precise antigenic prediction for optimal vaccine strain selection. While sequence-based methods have advanced antigenic surveillance, they neglect the three-dimensional structural context that fundamentally dictates viral antigenicity. Here, we introduce Vir3D, which leverages ESMFold-derived structural information from amino acid sequences to precisely predict viral antigenicity and guide vaccine strain selection. Across both human H3 and highly pathogenic avian H5 subtypes, Vir3D not only accurately discriminates antigenic variants and infers pairwise antigenic distances, but also mechanistically delineates key structural residues driving viral immune evasion. In a decade-long retrospective analysis, Vir3D-prioritized vaccines consistently achieve broader antigenic coverage of circulating strains than World Health Organization (WHO) recommendations. Crucially, Vir3D successfully predicts that the emerging U.S. dairy cattle H5N1 virus (TX/24) remains antigenically stable relative to clade 2.3.4.4b vaccine strains, and subsequent wet-laboratory validation of hemagglutination inhibition (HI) assays definitively corroborates this finding. Overall, Vir3D establishes a powerful, structure-driven framework for proactive influenza surveillance and pandemic preparedness.

bioinformatics↗

bioRxiv2026

Rescue schizophrenia-related phenotypes caused by Setd1a deficiency by histone demethylase inhibitors

Schizophrenia (SCZ) is a genetically complex neuropsychiatric disorder in which rare loss-of-function mutations in the histone methyltransferase SETD1A confer substantial risk. Although SETD1A haploinsufficiency had been linked to morphological, synaptic and behavioral abnormalities in the prefrontal cortex, whether and how SETD1A coordinates transcriptional and functional programs across different brain regions remains unknown. Here, we delineate the brain region-specific effects of SETD1A-associated dysfunction using conditional Setd1a knockout mice. We find that the dorsal striatum (dStr) and mediodorsal thalamus (MD) exhibit distinct transcriptomic and neuronal alterations to those in the PFC, and show transcriptomic enrichment for other SCZ risk genes. Loss of Setd1a in the dStr or MD drives selective vulnerability in key behavioral assays, suggesting important roles for these brain regions in the etiology of SCZ. By screening 6 existing H3K4 demethylase inhibitors, we identify the LSD1 (KDM1A) inhibitor TAK-418 as a potent modulator capable of restoring H3K4me3 levels and gene expression, as well as rescuing synaptic and SCZ-like behavioral phenotypes in the Setd1a+/- mice. Thus, our work provides a mechanistic link between high-penetrance SETD1A variants and region-specific brain dysfunction, establishing a framework for connecting rare loss-of-function variation in chromatin regulators to multidimensional neuropsychiatric phenotypes.

neuroscience↗

bioRxiv2026

Subcellularly Resolved 3D Translatome in Mouse Oocytes and Early Embryos

Spatial patterning of mRNA translation is a fundamental process in early embryogenesis. Existing RNA translation profiling methods lack subcellular spatial resolution at the single-molecule level, limiting our understanding of spatial RNA biology in embryogenesis. To address this, we profiled the spatial translatome of intact mouse embryos at near-genomic scale by adapting RIBOmap and incorporating multiplexed organelle staining. In oocytes, 2-cell and 4-cell embryos, we systematically analyzed RNA translation across three spatial scales: organelle, subcellular, and intercellular. We found that functionally related genes exhibit spatially and temporally controlled translation patterns near distinct organelles. Using Harmonics, a graph signal processing framework, we demonstrate that embryo asymmetry emerges at the first cell division and is amplified at later stages. This work paves the way for comprehensively investigating the fundamental spatial post-transcriptional regulation at the earliest moments of mammalian life.

developmental biology↗

bioRxiv2026

Hologenomics of xylotrophic bivalves reveals a minimalist, remote-acting evolutionary strategy of wood digestion

Wood constitutes the largest reservoir of biogenic carbon on Earth, yet remarkably few animals can exploit it. While terrestrial wood-feeders like termites rely on highly diverse gut microbiomes, xylotrophic marine bivalves have evolved a fundamentally different approach: a spatially segregated system where intracellular gill symbionts produce enzymes that act remotely within a nearly sterile cecum. However, the genetic and evolutionary basis of this unique symbiosis remains largely elusive. Here, we integrate hologenomics, transcriptomics, and biochemistry of a shallow-water shipworm (Teredo navalis) and a deep-sea borer (Xyloredo sp.). We find that despite diverging approximately 147 million years ago and occupying drastically different habitats, these bivalves maintain a strictly conserved ancestral karyotype and a shared genomic architecture for wood digestion. Our models reveal a clear host-symbiont division of labor. The host genome is specialized for lignin modification and targeted enzyme transport, whereas a highly streamlined symbiont community is responsible for core polysaccharide degradation. Central to this minimalist strategy is a lineage-specific GH5-GH6 dual-catalytic enzyme. By sharing amino acids across proximal binding pockets, this fusion protein unites endo- and exo-cellulase activities, enabling highly synergistic cellulose cleavage without the need for complex microbial communities. Ultimately, our comparative analysis with terrestrial models demonstrates that these marine invertebrates achieve efficient biomass degradation not through microbial expansion, but through extreme functional streamlining and molecular innovation, offering a distinct evolutionary paradigm for marine carbon cycling.

evolutionary biology↗

bioRxiv2026

Health-associated gut bacteriocins target TLR4 to suppress intestinal inflammation

The human microbiome maintains host immune homeostasis by secreting bioactive metabolites. However, extending beyond well-characterized metabolites, the functions of most microbiome-encoded peptides remain poorly defined. In this study, we developed a multi-cohort metagenomic framework to profile protective class II bacteriocins--unmodified, ribosomally synthesized peptides--that are enriched in healthy individuals but depleted in patients with inflammatory bowel disease (IBD). We have designated these health-associated bacteriocins as gutcins. Two gutcins, which lack canonical antimicrobial activity, potently attenuate intestinal inflammation in murine models. Cryo-electron microscopy (cryo-EM) reveals that one gutcin, named gutcin 03, directly engages the C-terminus of TLR4, blocking its dimerization and downstream inflammatory signaling. Guided by this structural interface, we generated truncated variants with enhanced potency, demonstrating the amenability of these simple peptides to rational optimization. Collectively, our findings reposition class II bacteriocins from antimicrobial agents to endogenous immunomodulatory effectors and establish a structural and mechanistic foundation for their development as next-generation therapeutics for inflammatory intestinal disorders.

microbiology↗

bioRxiv2026

Prenatal Dibutyl Phthalate Exposure Dysregulates Fetal-Placental Vascular Function and Placental Vasculature-Specific Lipid Metabolism

IntroductionIn humans, prenatal dibutyl phthalate (DBP) exposure is associated with increased risks of adverse fetal outcomes as well as metabolic and cardiovascular diseases in the offspring in a fetal sex-specific manner. However, mechanisms underlying these prenatal DBP exposure-associated adverse fetal/offspring outcomes are unclear. We hypothesize that environmentally relevant low-dose prenatal DBP exposure dysregulates fetal-placental vascular function and lipid metabolism in a fetal sex-specific manner, thereby impairing placental efficiency and programming adverse offspring metabolic outcomes. MethodsFemale CD-1 adult mice (8-10 weeks) were orally dosed with vehicle or an environmentally relevant low-dose DBP (0.1g/kg/day) daily from 30 days pre-pregnancy through gestational day (GD) 18.5. Fetal-placental vascular hemodynamics of these dams were examined using high-frequency ultrasound at multiple timepoints. The effect of prenatal environmentally relevant low-dose DBP exposure on placental efficiency, spatial transcriptomic profiles, lipid homeostasis, and placental vascular endothelial cells function in male and female fetuses were evaluated at gestational day (GD) 18.5. ResultsThe prenatal low-dose DBP exposure dysregulated the fetal-placental vascular hemodynamic indices from mid-to late gestation. DBP exposure impairs placental efficiency in male, but not female placenta at GD18.5. Further, female placentas exhibited fetal labyrinth vasculature-specific transcriptomic adaptations that preserves placental efficiency and endothelial function. In contrast, male placentas exhibited minimum transcriptomic adaptation, together with compromised placental efficiency and endothelial function associated with lipotoxic lipid profile. ConclusionsIn conclusion, prenatal low-dose DBP exposure dysregulates placental vascular function and lipid homeostasis in a fetal sex-specific manner, with male fetuses being more susceptible to DBP exposure.

physiology↗

bioRxiv2026

Near-complete genomes for nine haplochromine cichlid fishes reveal a novel centromeric satellite structure organised around a pair of inverted elements

The haplochromine cichlid fishes of Lake Malawi form one of the most dramatic examples of recent rapid radiation in vertebrates. Here we describe nine new diploid telomere-to-telomere (T2T) genome sequences generated using ultra-long ONT reads, which include 78 ungapped chromosomes. We provide accurate annotations of transposable elements and tandem repeats, identify rDNA cluster regions and putative centromeres, and confirm previously reported large chromosomal inversions. The putative centromeres are primarily composed of satellite tandem arrays of previously reported 237 bp repeats, but notably on most chromosomes these are organised in a novel structure in which four blocks of satellites in alternating orientation are separated by an inverted pair of [~]15 kb sequences we term "centroids", which have similarity to a non-autonomous DNA transposable element and containing potential CENP-B binding boxes. The methylation dip region indicating the likely active centromere always lies between the centroids, whose separation is almost always around 200 kb (interquartile range 151-221kb). A structurally equivalent but non-homologous organisation is seen in the distantly related Etroplus cichlid genera from South Asia. By comparing these structures across chromosomes and species, we suggest how they may have evolved, and potentially how they could contribute to the rampant sympatric speciation seen in these species, based on meiotic drive and chromosome missegregation.

genomics↗

bioRxiv2026

A glycoRNA switch for malignancy: SNORA73B activates TIAR-dependent oncogenic signaling in lung adenocarcinoma

Although glycosylated small non-coding RNAs are emerging players in cancer, their functions in lung adenocarcinoma (LUAD) are largely unknown. We identify SNORA73B as a glycosylated small nucleolar RNA (glycol-snoRNA) that carries sialic acid-capped O-glycans in both normal lung epithelial and LUAD cells. SNORA73B is markedly elevated in LUAD, and its plasma levels distinguish early-stage LUAD from healthy controls with an area under the curve (AUC) of 0.7903. Subcellular fractionation reveals predominant nuclear localization. Functional assays demonstrate that SNORA73B depletion curbs LUAD cell proliferation, migration, and invasion, whereas its overexpression fosters these malignant phenotypes and accelerates tumor growth. Mechanistically, SNORA73B directly binds the T-cell-restricted intracellular antigen-related protein (TIAR), thereby enhancing TIAR protein abundance without affecting its mRNA levels. TIAR then recognizes the 3-untranslated region (3-UTR) of MYC mRNA to upregulate c-Myc, which subsequently augments AKT phosphorylation. Importantly, c-Myc knockdown largely rescues the oncogenic phenotypes and tumorigenesis induced by SNORA73B overexpression. Collectively, our data unveil a glycoRNA-dependent oncogenic axis SNORA73B-TIAR-c-Myc-AKT that drives LUAD progression. These findings position SNORA73B as a promising early diagnostic biomarker and a candidate therapeutic target in LUAD.

Cancer Biology↗

bioRxiv2026

Hybridisation and herbivory fuel Amazonian tree radiations

Tropical rainforests, and Amazonia in particular, contain more tree species than anywhere else, most of which arose through rapid evolutionary radiations 1-3. Rapid radiations are often catalysed by ecological opportunity 4-6, which in rainforest trees is presented by intense insect herbivore pressure, spurring the evolution of novel plant defence chemistry to escape it 7. However, we do not understand how long-lived trees can adapt quickly enough to keep pace with rapidly-evolving insect herbivores. Here we show that hybridisation in rainforest trees, which was considered rare, allows exchange of gene clusters used in chemical defence against herbivore attack, facilitating rapid adaptation and diversification. Using genome sequencing for 461 individuals from the genus Inga, a characteristic Amazonian tree radiation, we find that regional tree communities form syngameons - networks of closely related, co-occurring species connected by gene flow. Integrating these genomes with herbivore abundance data from the same communities across the tropical Americas, we show that herbivore compositional turnover coincides with local, recurrent interspecific transfer of defence gene clusters that are retained by balancing selection, consistent with fluctuating selective pressure imposed by shifting herbivore communities. Together, our results demonstrate that hybridisation allows long-lived tropical trees to rapidly evolve chemical defences, fuelling adaptation to the relentless insect herbivory that structures the worlds most species-rich forests.

evolutionary biology↗

bioRxiv2026

Cardiomyocytes Undergo a Mesenchymal-Like Fate Transition in Myocardial Fibrosis

BACKGROUNDMyocardial fibrosis, a pathological hallmark of adverse cardiac remodeling and heart failure, has been conventionally attributed to the activation of resident fibroblasts. Although recent studies suggest contributions from non-fibroblast lineages, direct in vivo genetic evidence that cardiomyocytes can undergo a mesenchymal-like fate transition during myocardial fibrosis remains absent. This study aims to investigate whether such a transition occurs and to elucidate the underlying regulatory mechanisms. METHODSHuman myocardial infarction (MI) tissues were analyzed by immunohistochemistry and integrated with public single-nucleus RNA sequencing (snRNA-seq) data to detect mesenchymal-like signatures in cardiomyocytes. Genetic lineage-tracing was performed in MI mice, and in cardiomyocyte-specific Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate) gene knockout mice, to map the fate of cardiomyocyte-derived cells. Mechanistic insights were obtained through proteomic and snRNA-seq analysis of Hgs knockout hearts and validated through gain- and loss-of-function experiments targeting Aldh1a2 (aldehyde dehydrogenase 1 family member A2). RESULTSIn human MI samples, a subset of cardiomyocytes showed reduced expression of cardiomyocyte markers concurrent with acquisition of mesenchymal-associated markers. Genetic lineage tracing demonstrated that adult cardiomyocytes can adopt a mesenchymal-like cell fate during post-MI remodeling. We identify HGS as a factor constraining this transition. Hgs knockout in adult cardiomyocytes upregulated Aldh1a2, triggered the mesenchymal-like fate transition, and gave rise to cells expressing markers of activated fibroblasts or osteoblasts, accompanied by pronounced myocardial fibrosis and calcification. Forced Aldh1a2 overexpression in cardiomyocytes drove the mesenchymal-like fate transition in vitro and in vivo, whereas Aldh1a2 deletion in cardiomyocytes mitigated MI-induced myocardial fibrosis. CONCLUSIONSThis study provides in vivo genetic evidence that adult cardiomyocytes possess the capacity to undergo a mesenchymal-like fate transition under pathological conditions. Our data suggest that HGS and ALDH1A2 serve as regulators of the transition, offering a new basis for understanding cellular and molecular mechanisms of myocardial fibrosis. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIMyocardial fibrosis is primarily driven by resident fibroblast activation, with additional contributions from cardiac CD34+ cells, pericytes, and macrophages. C_LIO_LIAdult cardiomyocytes exhibit phenotypic plasticity and transdifferentiate into epicardial-like or pacemaker cells under specific conditions. C_LI What New Information Does This Article Contribute?O_LIA subset of cardiomyocytes adopts a mesenchymal-like cell fate during myocardial fibrosis, marked by downregulation of cardiomyocyte identity markers and loss of aligned cell-cell contacts. C_LIO_LIThese cells acquire mesenchymal morphology and markers, ECM components, migratory gene signatures, and proliferative capacity. C_LIO_LIHGS and ALDH1A2 act as regulators of this mesenchymal-like fate transition. C_LI Myocardial fibrosis drives heart failure progression, yet the cellular sources of pathological fibroblasts remain incompletely defined. Here, we demonstrate that a subset of cardiomyocytes adopts a mesenchymal-like cell fate during myocardial fibrosis by using an integrated approach combining human MI samples, murine genetic lineage tracing, and snRNA-seq. Mechanistically, we identify HGS and ALDH1A2 as regulators of this transition. Cardiomyocyte-specific Hgs deletion upregulates Aldh1a2, triggering the mesenchymal-like fate transition. Furthermore, Aldh1a2 overexpression drives this transition, while its deletion attenuates MI-induced fibrosis. These findings reveal a previously unrecognized plasticity of adult cardiomyocytes and identify potential therapeutic targets for fibrotic heart disease.

genetics↗

bioRxiv2026

Cross-Modal Benchmarking of Acoustic Prosody and Ventral Striatal BOLD for Depression-Related Anhedonia Classification: A Pre-Registered Study with the ClinicalWhisper Pipeline

Can computational analysis of a brief voice recording classify depression-related anhedonia as effectively as task-based fMRI? We address this question through a pre-registered cross-modal benchmarking study (osf.io/bsvrj) that evaluates two independent classification pipelines against depression-related anhedonia operationalized via self-report. Anhedonia-- the diminished capacity to experience pleasure or motivation to pursue rewards--is a transdiagnostic marker of reward-system dysfunction that predicts treatment resistance in major depressive disorder, yet current assessment requires either expensive functional neuroimaging or subjective self-report scales, neither of which scales to routine screening. We benchmarked two independent classification pipelines: Stream A extracted 88 acoustic prosody features from DAIC-WOZ clinical interviews (n = 142) using the ClinicalWhisper pipeline (Whisper Large-v3, pyannote diarization, OpenSMILE eGeMAPS v02); Stream B extracted nucleus accumbens BOLD activation during a reward task from the UCLA ds000030 dataset (n = 272). Three classifiers (logistic regression, random forest, gradient-boosted trees) were evaluated under stratified 5-fold cross-validation with fixed, pre-registered hyperparameters. Stream A achieved a best AUC-ROC of 0.63 (random forest; permutation p = .049), confirming H1 that acoustic prosody classifies PHQ-8-defined anhedonia above chance at = .05 (uncorrected), though this result does not survive Bonferroni correction for three classifiers (/3 = .017). Bootstrap analysis of {Delta}AUC confirmed non-inferiority relative to Stream B (H2: 95% CI lower bound > -0.10). However, Stream B itself did not achieve above-chance classification (p = .057), so this non-inferiority finding reflects comparable, modest performance across both modalities rather than equivalence to a validated neural biomarker. Pitch variability features (F0) ranked among the top 5 predictors by SHAP value in the gradient-boosted trees model (H3: partially supported). An exploratory combined model (eGeMAPS + recurrence quantification analysis) reached AUC = 0.65 (GBT; p = .032), though this lift was not statistically significant by DeLong test (z = -0.44, p = .66). These results provide initial evidence that vocal prosody, acquired through a standardized, open-source pipeline, carries depression-related information comparable to fMRI-derived ventral striatal activation for binary classification. However, neither streams operationalization isolates anhedonia from general depressive symptomatology, and the cross-modal design compares different constructs across different cohorts. We refer to the classification target throughout as the "anhedonia composite" to acknowledge that PHQ-8 Items 1+2 conflate anhedonia with dysphoria. We discuss these constraints and their implications for the causal framework motivating this work.

neuroscience↗

bioRxiv2026

Uracil/guanine mismatches trigger MutS HOMOLOG1-dependent mitochondrial DNA double-strand breaks in Arabidopsis

Angiosperm mitochondrial genomes exhibit exceptionally low nucleotide substitution rates, likely supported by active homologous recombination-mediated repair, while maintaining genome integrity by suppressing illegitimate recombination between imperfectly matched sequences that could otherwise cause deleterious structural rearrangements. The nuclear-encoded MutS HOMOLOG1 (MSH1) protein has been proposed to help resolve this paradox by recognizing mismatches and promoting DNA double-strand break-associated repair responses that suppress both point mutations and illegitimate recombination. However, direct experimental evidence for this proposed activity of MSH1 has been lacking. Here, we demonstrate that targeted base editing using a mitochondrial TALE-cytidine deaminase fusion (mitoTALECD) in Arabidopsis mitochondria induces deletions at the redundant gene atp6-2. These deletions phenocopy those generated by mitochondria-targeted TALEN (mitoTALEN) cleavage at the same locus. Notably, deletion events that encompass the base-editing target site were markedly reduced in msh1 mutant backgrounds, indicating that functional MSH1 promotes their formation. In vitro assays further demonstrated that recombinantly expressed MSH1 efficiently recognizes U:G mismatches derived from deoxycytidine-to-deoxyuridine deamination events and performs coordinated double incisions, thereby generating staggered dsDNA breaks with short 3' overhangs. Together, these findings provide direct experimental support for the long-postulated role of MSH1: the induction of mismatch-triggered DNA double-strand breaks. This MSH1 activity likely promotes the repair of mismatched bases and prevents illegitimate recombination by rejecting annealing between imperfect repeat sequences, thereby helping maintain the characteristic mutational stasis and recombinational dynamics of angiosperm mitochondrial genomes.

Plant Biology↗