Biology subjects

Yu, Y.

Publications and source records attributed to Yu, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

An oxytocin-gated circuit from the hypothalamus silences olfactory tubercle neurons to drive prosocial grooming

Spontaneous helping behaviors such as allogrooming are vital for survival in social species, yet their underlying neural mechanisms remain largely unknown. Although oxytocin (OXT) is known to modulate allogrooming, the precise neural circuits, molecular pathways, and sensory drivers remain unclear. Here, using a social emergency paradigm in mice, we show that observer mice selectively allogroom distressed, anesthetized conspecifics, a behavior that is guided by main olfactory system cues and mitigates the demonstrators anxiety. We identify an oxytocinergic circuit from the paraventricular hypothalamus to the medial olfactory tubercle (PVNOXT[->]mOT) that is necessary and sufficient for this helping behavior. In vivo fiber photometry reveals that PVNOXT[->]mOT activity and OXT release are temporally locked to allogrooming initiation. This behavioral effect requires oxytocin receptor (OXTR) signaling specifically on mOT dopamine D1 receptor-expressing neurons, where OXTRs suppress neuronal excitability via G protein-gated inwardly rectifying K+ (GIRK) channels. Disruption of this inhibitory mechanism induces neuronal hyperexcitability and impairs allogrooming, a deficit rescued by restoring GIRK function. These findings define a PVNOXT-mOT circuit for prosocial helping, revealing an oxytocinergic pathway with potential therapeutic relevance for neuropsychiatric disorders characterized by social deficits.

neuroscience↗

bioRxiv2026

Transient focal inactivation of the primary visual cortex abolishes saccadic inhibition

Most organisms are perpetually engaged in an active-perception cycle: at any moment, planning, executing, or recovering from a given own movement. In the oculomotor system, such a cycle is under a powerful, reflexive, and short-latency interruptive influence by exogenous sensory stimulation, but the multitude of possible pathways eventually converging on the final oculomotor control gateway make it unknown how reflexive oculomotor inhibition takes place. Here we show that transient focal inactivation of the primary visual cortex abolishes visually-driven saccadic inhibition, suggesting an unequivocal dominance of the geniculostriate visual pathway over this robust behavioral reflex. Using chronic lesions, computational modeling, and fine-grained eye-movement analyses, we then show that latent visual signals bypassing the geniculostriate pathway are still present, but may not be as central as previously anticipated. These results recast classic views on visual-motor reflexes, and motivate functional and theoretical investigations of the multiplicity of parallel input-output loops in the brain.

neuroscience↗

bioRxiv2026

Antibody recycling via FcRn drives atherosclerotic plaque vulnerability

Atherosclerotic plaques accumulate low-density lipoprotein (LDL) together with antibodies targeting LDL and its apolipoprotein B (apoB) component. Given the association between IgG and plaque vulnerability, we hypothesized that apoB-specific immune complexes actively promote plaque destabilization. Using immunohistochemistry in carotid endarterectomy specimens, we quantified antibody deposition across morphologically defined plaque regions, and measured apoB reactivity and immune complex levels in matched plaque and plasma samples. IgG deposition was strongly associated with thin fibrous caps, reduced collagen content, and higher overall plaque vulnerability. Symptomatic patients exhibited increased apoB-specific IgG and reduced apoB-IgG immune complexes within plaques, indicating enhanced IgG recycling and heightened inflammatory activity. The neonatal Fc receptor (FcRn) was predominantly expressed by CD163+ macrophages, and mediated antibody recycling, LDL uptake, and production of tumor necrosis factor (TNF) and matrix metalloproteinase-9 (MMP-9) in vitro. Plaque FcRn expression increased with age and correlated with mediators of vulnerability, including collagen-degrading enzymes and pro-inflammatory cytokines. Ex vivo treatment of human plaques with a clinically used FcRn-blocking monoclonal antibody reduced IgG recycling and suppressed TNF and MMP-9 production. These findings identify FcRn-dependent antibody recycling as a contributor to inflammatory plaque vulnerability and highlight FcRn as a potential therapeutic target in atherosclerosis.

immunology↗

bioRxiv2026

Sampling protein structural token space enables accurate prediction of multiple conformations

Protein function is fundamentally mediated by ensembles of distinct metastable states. However, existing methods, such as AlphaFold 3, typically exhibit a bias toward predicting a single dominant state, failing to capture alternative conformations or provide robust metrics for identifying high-quality multi-state conformations. Here, we present MultiStateFold (MSFold), a framework that integrates Parallel Tempering into the discrete structure token space of the ESM3 protein language model. By conceptualizing the model's latent space as an implicit energy landscape, MSFold enables global exploration and barrier crossing, thereby overcoming the local sampling limitations inherent in base generative models. Across a benchmark of 313 multi-conformation pairs, MSFold sets a new performance standard: it achieves the highest success rate in modeling native states and substantially outperforms leading methods, including AlphaFold 3, on challenging alternative conformations, while maintaining competitive accuracy for primary structures. Furthermore, we propose Sequence Log-Likelihood (SLL), a novel confidence metric derived from sequence-structure consistency. Our results demonstrate that SLL offers a modest improvement over standard metrics such as pTM and pLDDT. This work establishes a new paradigm for conformational sampling, bridging classical statistical physics with protein language models.

bioinformatics↗

bioRxiv2026

Faf2/Ubx2 potentiates p97/Cdc48 segregase activity via functional priming and reinforcement of the UT3 domain in Ufd1

The AAA+ segregase p97/Cdc48 extracts poly-ubiquitinated proteins from entrenched cellular environments to maintain proteostasis. However, its functional capacity is not uniform; extracting substrates from dense assemblies like stress granules or membrane necessitates a fully potentiated state. Here, using precisely synthesized ubiquitinated substrates, we show that the Faf2/Ubx2 cofactor hyperactivates p97/Cdc48, lowering its minimal ubiquitin chain requirement and broadening linkage specificity. Cryo-EM analysis of the activated complex demonstrates that Faf2/Ubx2 potentiates p97/Cdc48 segregase activity by structurally remodeling the substrate recognition module (K48-diUbProx) and priming its engagement with the AAA+ motor (p97/Cdc48-Npl4). These coordinated actions establish a pump-unit architecture that drives efficient substrate processing. Our findings illuminate a conserved mechanism that unlocks the maximal capacity of p97/Cdc48 and provide a blueprint for therapeutically targeting its hyper-activated state in disease.

biochemistry↗

bioRxiv2026

Histone H2BK120 ubiquitination modulates PRC1 activity and H2AK119ub deposition on nucleosomes

Polycomb group and Trithorax group complexes antagonistically regulate developmental gene expression, yet the mechanisms coordinating their interplay remain poorly understood. Here, we uncover a synergistic histone crosstalk in which H2BK120ub (histone H2B ubiquitination at lysine 120), a Trithorax-associated active mark, enhances Polycomb repressive complex 1 (PRC1) activity by directly binding specific PCGF subunits of PRC1 on the nucleosome surface, as shown in cryo-electron microscopy (cryo-EM) analysis. Beyond regulating enzymatic activity, H2BK120ub also modulates the competitive binding between the catalytic RNF2-BMI1 module and the RYBP subunit of noncanonical PRC1.4 complexes to nucleosomes, potentially restricting H2AK119ub (histone H2A ubiquitination at lysine 119) spreading to neighboring nucleosomes. In mouse embryonic stem cells, H2BK120ub directs the deposition of H2AK119ub within the gene bodies of a subset of developmental genes, which exhibit more rapid activation compared to canonical H3K4me3/H3K27me3 bivalent genes. These findings reveal a previously unrecognized mechanism that links active and repressive histone modifications, providing new insights into the intricate chromatin regulation of gene expression during development.

molecular biology↗

bioRxiv2026

Synergistic activation of TLR2 and Dectin-2 by mannose-capped lipoarabinomannan reprograms macrophage lipid metabolism in tuberculosis

How innate immune receptors integrate signals from complex microbial ligands remains poorly understood, yet this integration may offer new avenues for host-directed therapies. Here, we show that the architecture of a single pathogen-derived component can organize the coordinated engagement of multiple pattern-recognition receptors to reprogram host cell behavior. We find that the mycobacterial lipoglycan mannose-capped lipoarabinomannan (ManLAM) uses distinct structural features to engage two pattern-recognition receptors, Toll-like receptor 2 (TLR2) and Dectin-2, thereby driving macrophage lipid remodeling and lipid droplet accumulation, a process linked to foam cell formation and necrotizing lesion development in tuberculosis. Dual receptor engagement also potentiates NF-{kappa}B-dependent inflammatory signaling, while lipid droplet accumulation proceeds through an mTORC1-PPAR{gamma}-dependent pathway that is largely independent of NF-{kappa}B activation, indicating that metabolic and inflammatory programs are mechanistically separable. ManLAM-induced lipid remodeling closely mirrors that induced by Mycobacterium tuberculosis infection in both neutral lipid composition and pathway dependence. In contrast, other mycobacterial ligands that are lipogenic in vitro do not measurably contribute to lipid droplet accumulation during infection. These findings identify ManLAM as a major mycobacterial driver of lipid remodeling associated with foam cell formation and establish ligand architecture as a mechanism by which complex microbial ligands organize multi-receptor signaling to direct distinct host cell programs. Significance statementOur findings establish the principle that the architecture of a single microbial ligand can organize the co-engagement of multiple innate immune receptors to shape host cell responses. Using the mycobacterial lipoglycan mannose-capped lipoarabinomannan as a model, we show that distinct structural features within a single microbial component coordinate the co-engagement of TLR2 and Dectin-2 to reprogram macrophage lipid metabolism and promote lipid droplet formation, a process linked to foam cell formation and necrotizing tuberculosis lesions. These results identify a mechanism by which complex microbial ligands can integrate host sensing pathways through their molecular structure. By defining the receptor-signaling axes that control foam cell formation, this work highlights host pathways as candidate targets for host-directed intervention.

microbiology↗

bioRxiv2026

CoPrimeEEG: CRT-Guided Dual-Branch Reconstruction from Co-Prime Sub-Nyquist EEG

We present CoPrimeEEG, a neural reconstruction framework that unifies co-prime sub-Nyquist sampling theory with a CRT-guided learning objective for EEG. Two low-rate streams obtained by co-prime decimations feed a dual-branch convolutional encoder whose fused representation is upsampled to reconstruct high-rate EEG while jointly predicting a temporal usefulness mask and canonical bandpower features. We derive a principled loss with four terms: (i) waveform fidelity, (ii) mask sparsity and smoothness, (iii) bandpower supervision in the log-domain, and (iv) a CRT-consistency term enforcing agreement between the reconstruction and its co-prime downsampled counterparts. On real EEG data, CoPrimeEEG achieves state-of-the-art reconstruction quality across MSE, MAE, correlation, SNR, and PSNR while using fewer parameters. The approach provides a practical path to low-power EEG acquisition with high-fidelity downstream analysis.

bioinformatics↗

bioRxiv2026

Functional characterization and molecular engineering of a O-methyltransferase involved in bis-benzylisoquinoline alkaloids biosynthesis from Nelumbo nucifera

Nelumbo nucifera (lotus), a traditional aquatic plant in Asia, is valued for its nutritional and therapeutic properties. Benzylisoquinoline alkaloids (BIAs) are its major bioactive components, with significant bioactivities and pharmacological values. O-methyltransferases (OMTs) play a crucial role in shaping the structural and functional diversity of BIAs. Herein, we characterized a specific OMT, designated Nn7OMT, which exhibits a novel catalytic function: methylating the C7 position of the bisbenzylisoquinoline (bisBIA) skeleton. Nn7OMT also displayed substrate promiscuity, catalyzing O-methylation at the C7 position of bisBIAs, C6/C7 positions of 1-benzylisoquinolines, C7 position of aporphines, and C9 position of protoberberines, with isoliensinine as its preferred substrate. The expression profile of Nn7OMT correlates with bisBIA accumulation in planta, supporting its involvement in bisBIA biosynthesis in N. nucifera. Protein engineering guided by molecular docking and molecular dynamics simulations identified key residues critical for Nn7OMT activity. Mutants M158A and V306A retained catalytic activity toward isoliensinine while showing nearly undetectable activity against 1-benzylisoquinoline alkaloids, thereby significantly improving Nn7OMTs substrate specificity. These findings advance our understanding of BIAs biosynthesis in lotus and provide valuable biocatalysts with enhanced specificity. SIGNIFICANCEIn this study, we report the innovative discovery and characterization of Nn7OMT, the first O-methyltransferase isolated from Nelumbo nucifera that harbors a novel catalytic activity toward the bisbenzylisoquinoline alkaloid (bisBIA) backbone. Nn7OMT displayed substrate promiscuity, catalyzing methylation at the C7 position of the bisbenzylisoquinoline skeleton (isoliensinine), C6/C7 positions of the 1-benzylisoquinoline skeleton (norcoclaurine, coclaurine, N-methylcoclaurine), C7 position of the aporphine skeleton (lirinidine), and C9 position of the protoberberine skeleton (scoulerine)--with isoliensinine as its most preferred substrate. Innovatively, the catalysis of isoliensinine by Nn7OMT was a novel function and the first O-methyltransferase identified to catalyze the bisbenzylisoquinoline backbone, which may be involved in the biosynthesis of neferine. Nn7OMTs expression profile correlated with bisBIA accumulation in planta, further supporting its role in bisBIA biosynthesis in N. nucifera. We further engineered Nn7OMT using molecular docking and MD simulation-guided strategies. Mutants M158A and V306A retained catalytic activity for isoliensinine while showing nearly undetectable activity against 1-benzylisoquinoline alkaloid substrates. This targeted engineering significantly improved the specificity of Nn7OMT, rendering it highly suitable for methylated isoliensinine biosynthesis by reducing by-product accumulation and simplifying purification processes. Our work deepens understanding of the unique BIA metabolic pathway in N. nucifera through the identification of the first bisBIA-catalyzing O-methyltransferase, and provides valuable biocatalysts with enhanced substrate specificity.

molecular biology↗

bioRxiv2026

Prophylactic Lipoxin A4 Attenuates Clostridioides difficile Infection by Augmenting Epithelial Barrier and Resolving Inflammation

Clostridioides difficile infection (CDI) is a leading healthcare-associated diarrhea with high recurrence rates, partially due to antibiotic-induced dysbiosis and dysregulated host inflammation. Specialized pro-resolving mediators (SPMs), such as Lipoxin A4 (LXA4), offer promise in controlling excessive inflammation and promoting tissue repair, yet their role in CDI remains unexplored. Here, we developed a compact, gas-tight gut-on-a-chip (GOC) system that reconciles the anaerobic requirements of C. difficile with the oxic needs of human intestinal epithelium, enabling physiologically relevant co-culture within a standard incubator. A CDI in vitro model was established based on this GOC system. Using the model, we demonstrated that prophylactic administration of LXA4 significantly preserved epithelial barrier integrity, attenuated pro-inflammatory cytokine secretion (IL-8 and IFN-{gamma}), and reduced bacterial colonization. Transcriptomic analysis revealed that LXA4 pretreatment upregulated genes involved in cell junction organization while downregulated immune activation pathways. These protective effects were validated in a murine CDI model, where LXA4 pretreatment reduced weight loss, pathological damage, and fecal bacterial burden. Furthermore, prophylactic administration of LXA4 synergized with vancomycin treatment further enhanced antibiotic efficacy while allowing a 50% dose reduction without compromising therapeutic outcomes. Our study establishes a robust approach for CDI research and highlights the prophylactic and adjuvant potential of inflammation-resolving strategies, offering a novel approach to mitigate CDI incidence and improve treatment outcomes.

bioengineering↗

bioRxiv2026

RNA Quality Control Enables Antibiotic Tolerance

The mechanisms underlying adaptation to antibiotic pressure within complex host environments remain incompletely understood. By experimentally evolving Streptococcus pneumoniae subjected to various antibiotics and immune states, we demonstrate populations adopting distinct adaptive strategies depending on specific selective context. General antibiotic stress drives convergent mutations in rny, encoding the RNA degradosome scaffold RNase Y, that exhibit broad-spectrum antibiotic tolerance and accelerated recovery. Single-cell transcriptomics revealed antibiotic-induced death is driven by transcriptional collapse, a catastrophic loss of RNA quantity and integrity. In contrast, rny mutants avert this via a bet-hedging strategy: a resilient minority maintains a baseline transcriptional profile, while a quiescent majority undergoes selective RNA degradation to preserve transcript fidelity. Upon stress removal, these populations execute a prioritized transcriptional ribosomal reboot, facilitating accelerated recovery. These findings identify RNA turnover as a tunable master regulator to survive combined pressures of antibiotics and immunity.

microbiology↗

bioRxiv2026

Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined small cell lung cancer

Combined small-cell lung cancer (cSCLC) is a rare and aggressive subtype of small-cell lung cancer (SCLC) characterized by mixed histology comprising SCLC and non-small cell lung cancer (NSCLC) or large cell neuroendocrine carcinoma (LCNEC) components. Despite its histological heterogeneity and even poorer prognosis than de novo SCLC, cSCLC is clinically managed as pure SCLC, largely due to the lack of molecular insights into its biology, lineage plasticity, and tumor microenvironment (TME). Here, we perform multi-omics profiling, including spatially-resolved whole-exome sequencing (WES), spatial transcriptomics (ST) and single-nucleus RNA sequencing (snRNA-seq), across 19 treatment-naive cSCLC tumors spanning all major histological subtypes. Our analysis reveals that SCLC and NSCLC/LCNEC components share a monoclonal origin, with histological divergence characterized by distinct mutation and copy number alteration patterns. ST and snRNA-seq uncover spatially exclusive or interspersed tumor domains, with distinct TME compositions and immune landscapes. Notably, fibroblast-rich regions enriched for an aggressive fibroblast subtype form boundaries between tumor domains, potentially influencing immune TME and treatment responses. We identify extensive lineage plasticity within cSCLC, including active LUAD-to-SCLC transdifferentiation and SCLC subtype coexistence, suggesting transitional cellular states not captured by traditional diagnostics. Leveraging these insights, we developed the cSCLC Detector, a sensitive mutation-based diagnostic assay that improves the detection of cSCLC in tissue and liquid biopsy samples. Our findings offer critical insights into cSCLC lineage plasticity, cellular evolution, and microenvironmental interactions, underscoring the need for tailored treatment strategies and diagnostic frameworks for this aggressive cancer subtype.

cancer biology↗

bioRxiv2026

Dysregulation of xenobiotic metabolism and mitochondrial dysfunction exacerbate acetaminophen-induced hepatotoxicity in human antigen R-deficient male mice

Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide. The RNA-binding protein Human antigen R (HuR) is a multifunctional post-transcriptional regulator that plays a pivotal role in cellular stress responses, including those triggered by APAP toxicity. This study investigated the mechanisms by which HuR protects against APAP-induced hepatotoxicity in male mice. Hepatocyte-specific HuR-deficient (HuRHep-/-) male mice on a C57BL/6N background and wild-type (WT) littermates were treated with 200 mg/kg APAP, and liver tissues were collected at 2, 6, and 24 hours post-treatment. APAP administration increased hepatic HuR mRNA expression and induced HuR cleavage and the formation of a higher-molecular weight HuR-immunoreactive band, with the latter two correlating with injury severity. Compared with WT controls, HuRHep-/- mice exhibited markedly increased susceptibility to hepatotoxicity at both 2 and 6 hours. Metabolite profiling revealed altered APAP metabolism and reduced glutathione S-transferase (Gst) expression in HuRHep-/- livers, consistent with impaired APAP detoxification and increased APAP-protein adduct formation. Fourier-transform infrared (FTIR) spectroscopy further identified early biochemical differences between WT and HuRHep-/- livers as early as 2 hours after APAP exposure. Additionally, HuR deficiency resulted in pronounced mitochondrial structural abnormalities and dysfunction at 2 and 6 hours, accompanied by reduced expression of the mitochondrial fission and fusion proteins Drp1 and Mfn2, increased mitochondrial protein release, and enhanced hepatocyte death. Although pro-inflammatory cytokine levels were elevated in HuRHep-/- mice relative to WT controls at 24 hours, hepatocyte proliferation was similarly blunted in both genotypes, consistent with severe liver injury and delayed recovery. Collectively, these findings identify hepatocyte HuR as a critical regulator of xenobiotic metabolism and mitochondrial integrity and establish its essential role in early protection against APAP-induced hepatotoxicity in male mice.

pharmacology and toxicology↗

bioRxiv2026

Nab-paclitaxel fused with the de novo designed receptor binder exhibits enhanced tumor targeting and therapeutic efficacy

Chemotherapy has been widely used in cancer treatment, but most of the chemotherapeutic drugs rely mainly on passive accumulation due to lack of target specificity, which may lead to systemic toxicity and limited clinical utility. Recent advances in artificial intelligence-based protein design provide new opportunities for developing precision therapeutics. Here we modify the albumin-bound paclitaxel (Nab-PTX), one of the most widely used drugs in chemotherapies, by applying the fusion proteins of albumin with the de novo designed protein binders targeting human EGFR or HER2. The resulting particles, EGFRmb-Nab-PTX and HER2mb-Nab-PTX, retain the similar physicochemical properties of Nab-PTX while acquiring the receptor-specific binding capacities. The in vitro assays show that both binder-modified Nab-PTX particles have increased uptake and inhibitory effects significantly in the cancer cell lines with high receptor expression levels. Furthermore, the data from a xenograft model, including tumor growth, excised tumor analysis, organ histology, and fluorescence imaging, show that the binder-modified Nab-PTX enhances tumor accumulation, improves tumor suppression, and reduces off-target toxicity compared with the conventional Nab-PTX, suggesting that they may have promising clinical potential in cancer treatment. Overall, this strategy provides an adaptable modular platform for generating albumin-based chemotherapeutic drugs with target specificities, which can be readily customized with diverse target binders to enable precise cancer therapies.

cancer biology↗

bioRxiv2026

An enzyme-level benchmark based on environmental bacterial laccases for predicting contaminant fate in water

Bacterial laccases are widespread multicopper oxidases whose roles in the fate of anthropogenic chemicals in aquatic environments remain poorly understood. Here, we integrate metagenomic analysis, a miniaturized high-throughput assay and machine learning to establish an enzyme-level benchmark for predicting biotransformation of wastewater-relevant trace organic contaminants by laccase-mediator systems. Using a laccase from an ammonia-oxidizing bacterium as a model enzyme, we screened 183 compounds and identified 38 that underwent significant removal. Following phylogenetic analysis of environmental homologs, we expressed and purified two additional laccases from the bacterial methanotrophic phylum Methylmirabilota and an archaeal phylum Thermoproteota, demonstrating the activity of this enzyme family across domains. Graph convolutional network models trained on the dataset achieved up to 78% accuracy in classifying degradable versus persistent chemicals, while quantum-chemical descriptors highlighted key electronic properties governing oxidation. This bottom-up approach to enzyme-chemical interactions establishes a trajectory towards predicting contaminant persistence in engineered and natural waters.

biochemistry↗

bioRxiv2026

Biotransformation and biodefluorination of chlorinated polyfluorocarboxylic acids by Acetobacterium species

Chlorinated per- and polyfluoroalkyl substances (Cl-PFAS) represent an important subgroup in replacement chemicals for legacy PFAS, and they have been detected in various environments including water bodies, soil, as well as air particles. However, the biodegradability of these chemicals is largely unknown. A recent study reported dechlorination triggered anaerobic biodefluorination of Cl-PFCAs by activated sludge communities. In this study, we further investigated the biodefluorination of Cl-PFCAs by pure cultures. Six of ten selected Cl-PFCAs displayed significant defluorination by Acetobacterium bakii, and corresponding pathways were proposed according to transformation product analysis. Several additional Acetobacterium species were all capable of defluorinating 3,5,7,8-tetrachloro-2,2,3,4,4,5,6,6,7,8,8- undecafluorooctanoic acid (CTFE4) with >50% removal of organic fluorine. On the contrary, Clostridium homopropionicum cannot defluorinate CTFE4. Crude protein extraction experiment showed that the enzymes responsible for CTFE4 dechlorination and defluorination required anaerobic atmosphere to function. Differential gene expression was analyzed according to RNA sequencing analysis, and the results indicated vitamin B12 related enzymes may involve in CTFE4 dechlorination.

microbiology↗

bioRxiv2026

Viral Capsid-Membrane Interactions Propel Non-Brownian Movements of Non-enveloped Reoviruses during Entry

Understanding how non-enveloped viruses breach host cell membranes is critical for developing strategies to block viral entry, a key step in infection. Despite extensive study, how viral capsids and host lipid membranes dynamically cooperate during membrane penetration remains poorly defined. Here, using reovirus as a model non-enveloped virus and planar model membranes, we identify previously unrecognized non-Brownian membrane motions of infectious subvirion particles (ISVPs) by single-virus tracking. We then integrate experiments with computational modeling to dissect the stepwise, processive capsid-membrane interactions encoded in these distinct dynamics. We show that ISVP motion transitions from an initial phase of directed translocation to progressively confined diffusion. This behavior reflects a multistep entry mechanism in which initial capsid-membrane contact triggers release of the membrane-active 1N peptide. As 1N accumulates within the bilayer, it generates membrane-associated viral retention sites that promote further virus adsorption and increasingly constrain particle mobility. By directly visualizing these motion signatures, we resolve transient and cooperative capsid-membrane interactions that are difficult to capture using conventional biochemical approaches. Together, these findings provide new insight into early membrane penetration events of non-enveloped viruses. SIGNIFICANCE STATEMENTNon-enveloped viruses must penetrate host cell membranes to initiate infection, yet the dynamic mechanisms by which viral capsids engage and remodel lipid membranes remain poorly understood. By directly visualizing the motion of individual reovirus particles on model membranes, we uncover previously unrecognized non-Brownian dynamics that encode stepwise capsid-membrane interactions during viral entry. Integrating single-virus tracking with computational modeling reveals how peptide-mediated membrane remodeling feeds back to regulate viral engagement. This work provides the first direct visualization of processive, stepwise capsid-membrane interactions during non-enveloped virus entry and establishes viral particle dynamics as a quantitative readout for dissecting membrane penetration mechanisms.

biophysics↗

bioRxiv2026

Medication and Developmental Stage Shape the Brain-Age Gap in ADHD

Identifying robust biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) remains challenging. The brain-age gap (BAG), which is the difference between predicted biological brain age and chronological age, has been proposed as a marker of atypical neurodevelopment, yet findings have been inconsistent across studies, limiting its clinical translation. We hypothesized that two major sources of heterogeneity, medication status and developmental stage, contribute to these discrepancies. To test this, we analyzed structural MRI data from a large multi-site cohort (N = 947; ages 7-26 years). Individuals with ADHD were stratified by medication history (medicated vs. unmedicated) and developmental stage (childhood vs. adolescence) and compared with matched typically developing controls. We estimated global- and network-level BAG using publicly available pretrained models. Our results revealed that BAG differences were contingent on medication status, with abnormalities predominantly observed in unmedicated individuals. Developmental stage further moderated the presence of this effect: BAG abnormalities were present significantly in children with ADHD but not in adolescents. Network-level analyses demonstrated spatial specificity, with significant effects in visual, ventral attention, and dorsal attention networks. Together, these findings provide compelling evidence that BAG in ADHD is both medication- and development-dependent, highlighting the need to account for treatment exposure and developmental stage when evaluating BAG as a biomarker and further underscoring the importance of early intervention during childhood.

neuroscience↗