Biology subjects

Huang, T.

Publications and source records attributed to Huang, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MECP2 gene, currently lacks effective treatments. The motor cortex is a pivotal hub in RTT and autism spectrum disorders, and its impairments contribute to motor, social, and cognitive deficits. Here we examined the effects of repetitive transcranial magnetic stimulation (rTMS) targeting motor area in non-human primate of RTT (MECP2-mutant monkey) and investigated neuromolecular basis underlying therapeutic effects. We identified a new treatment target, ventral premotor cortex (PMv), for RTT and found that following a 20-day rTMS course, several behavioral and functional connectivity measures showed directional changes. Neuroimaging analyses confirmed that rTMS induced reorganization of large-scale functional connectivity with enhanced functional integration between the somatomotor and the salience networks and normalized coupling between the motor cortex and both the thalamus and the anterior cingulate cortex. Notably, single-nucleus RNA sequencing revealed that rTMS triggered cell-type-specific transcriptional reprogramming: it rescued pathological hyperactivity of excitatory neurons by restoring the expression and regulatory networks of immediate early genes (e.g., FOS, EGR1) and corrected dysregulated intercellular signaling (e.g., NRG, WNT). These findings indicate that targeting motor cortical areas with brain stimulation may treat RTT, which warrants further clinical validation.

neuroscience↗

bioRxiv2026

Human brain white matter charts in international populations

Brain charts provide normative references for identifying neurodevelopmental milestones and clinically meaningful deviations. Existing white matter (WM) charts are derived predominantly from European and North American populations, limiting generalizability. Here, we established the first set of population-specific WM charts of 198 morphological and microstructural phenotypes for both Chinese (N=19,215) and Western (N=15,584) populations across the human lifespan. Developmental trajectories and spatial organization of WM maturation and degeneration were broadly conserved across the populations, whereas maturational timing varied across pathways and metrics. The Chinese population showed earlier maturation in several projection and sensorimotor pathways, but more protracted maturation in higher-order association and limbic pathways. Chinese population-matched charts more accurately predicted WM phenotypes and detected more extreme disease-related deviations in brain health in the Chinese population than Western-derived models. Individual deviation patterns further discriminated patients from healthy controls and predicted cognitive performance and plasma biomarkers. Our findings reveal population-specific WM maturation and show that reference-population mismatch can reduce the accuracy and clinical sensitivity of normative brain charts.

neuroscience↗

bioRxiv2026

Online synaptic credit assignment in active dendrites

Credit assignment in neural networks is usually formulated as the computation of an abstract error gradient. Whether such a gradient can take a physical, causal form in biophysically detailed multi-compartment neuron models, and enable online, supervised learning, remains unclear. Here we show that the gradient of a detailed neuron's voltage with respect to a synaptic weight is itself a voltage. Differentiating the discrete backward-Euler update solved by standard simulators yields equations of the same form as the original voltage dynamics, driven by gradient currents. Replaying weight-specific gradient currents forward in time reproduces the exact gradient with high fidelity in an L5 pyramidal neuron across diverse input regimes (R2 > 0.998). Pairing the replayed gradient voltage with a local learning signal yields a causal, online learning rule. A single L5 pyramidal neuron with active dendrites learns to reproduce target voltage trajectories containing calcium plateaus and bursts, and recurrent networks of detailed neurons learn to generate target temporal patterns, far outperforming a readout-only control. These results demonstrate that synaptic credit assignment can be implemented online by the voltage dynamics of detailed neurons, potentially suggesting a physical substrate for gradient-based supervised learning in the brain.

neuroscience↗

bioRxiv2026

Catch-bond engineering surpasses high-affinity maturation for T cell receptor therapies against solid tumors

The sensitivity of T cell receptors (TCRs) has traditionally been attributed to their affinity, a principle that has long underpinned both T cell biology and TCR engineering. Currently, high-affinity maturation remains the predominant strategy employed to enhance TCR sensitivity; however, this approach has been associated with severe off-target toxicities in clinical settings. In this study, using the only FDA-approved TCR-T therapy as a clinical reference, we demonstrate that force-induced catch bonds, rather than static affinity, primarily determine TCR sensitivity and facilitate the development of more effective TCR engineering strategies. Among polar and charged amino acids, histidine was determined to be the most effective residue for pinpointing engineering hotspots. TCRs engineered to form catch bonds exhibited superior performance compared to the FDA-approved TCR subjected to high-affinity maturation, improving the efficacy of TCR-T cell therapies against solid tumors without eliciting off-target toxicity or alloreactivity. Mechanistically, a correlation was observed between TCR sensitivity and the strength of catch bonds, whereas no such relationship was found with affinity. The duration of T cell-tumor cell interactions, immunological synapse formation, and the intensity of subsequent signaling are governed by catch bonds rather than by affinity. Structural and computational investigations have demonstrated that force-induced reconfiguration of the ligand-receptor interface, along with the formation of a novel hydrogen bond network, augments the specificity of interactions between the TCR and antigenic peptides. Furthermore, bispecific T cell engagers utilizing the TCR scaffold also formed catch bonds with tumor antigens, indicating intrinsic mechanosensory properties of the extracellular domains of TCRs and suggesting a novel therapeutic modality based on catch-bond-engineered TCRs.

immunology↗

bioRxiv2026

First community challenge for automated virus taxonomy

The rapid rate of virus discovery renders manual curation by taxonomy experts increasingly impractical, creating a need for reliable software that can reproducibly assign viral contigs to taxa at all fifteen ranks of the virus taxonomy. We led an open community challenge for the computational taxonomic classification of viruses and assembled a dataset of virus sequences combining expert-curated and metagenomic sequences. Seventeen teams contributed a total of thirty-four automated, fully reproducible classification pipelines. Most tools correctly assigned viruses belonging to established species, genera, or families, but viruses that are unclassified at those lower ranks remain challenging. This study provides datasets, open-source software, novel approaches, and recommendations to benchmark computational taxonomic classification of viruses, and support organizing the many viruses discovered in big omics data.

microbiology↗

bioRxiv2026

CWF19L2 couples pre-mRNA alternative splicing with the maternal-to-zygotic transition to safeguard female fertility

The maternal-to-zygotic transition (MZT) requires precise spatiotemporal execution of pre-mRNA alternative splicing (AS), yet the core splicing machinery driving this developmental reprogramming remains incompletely understood. Here, we identify the CWF19-like protein 2 (CWF19L2) as an indispensable pre-mRNA AS regulator that safeguards against oocyte and early embryo competence defects (OECD). While murine germline-specific depletion of Cwf19l2 spares morphological folliculogenesis, oocyte maturation, or fertilization, it induces complete female sterility characterized by profound developmental arrest at the 2-cell stage. Mechanistically, maternal deficiency of CWF19L2 localized to nuclear speckles disrupts transcription-splicing-translation coupling, collapsing AS homeostasis during maternal reserves and zygotic genome activation. We further demonstrate that CWF19L2 orchestrates the pre-mRNA splicing network through directly binding to target transcripts and indirectly modulating via interacting with the core spliceosomal factor PRPF8. Importantly, exogenous Cwf19l2 mRNA partially rescues the embryonic arrest. Together, our findings establish CWF19L2 as an indispensable AS engine during the MZT, providing a mechanistic foundation for OECD and a novel molecular etiology for female infertility.

Cell Biology↗

bioRxiv2026

Multisensory integration of a host metabolite coordinates bacterial predation of macrophages

The crisis of antimicrobial resistance demands new strategies that circumvent conventional killing. Here, we show that Yersinia pseudotuberculosis intercepts host mesifurane, a mimic of quorum-sensing signal AI-2. Rather than acting through a single receptor, mesifurane is directly and independently sensed by three receptor classes, YcrA, NarX, and CusR, that converge on a "Sense, Arm, Recruit" program. YcrA drives chemotaxis toward host cells; NarX-NarP licenses T6SS-mediated killing; and CusR amplifies AI-2 production to recruit more bacteria. YcrA is conserved across Gram-negative pathogens, creating a therapeutic vulnerability. Suramin sodium, a repurposed drug blocking YcrA, disarms this circuit without inhibiting growth. In murine sepsis, suramin sodium conferred 80-90% survival against WHO critical-priority pathogens, including carbapenem-resistant A. baumannii, E. coli, and P. aeruginosa, even when delayed 8 hours post-infection, without selecting for resistance. These findings establish that disrupting sensory perception, rather than viability, provides an anti-infective strategy bypassing resistance while imposing minimal selective pressure.

microbiology↗

bioRxiv2026

ANCHOR: haplotype-aware allelic and isoform inference from single-cell long-read RNA sequencing with de novo variant calling

Long-read RNA sequencing enables haplotype- and isoform-resolved allelic analysis of transcriptomes, yet extending this capability to single cells and distinct cell types remains computationally challenging due to sparse coverage, sequencing errors, incomplete variant information, and reference-biased transcript assignment. Here we present ANCHOR, a haplotype-aware framework for single-cell long-read RNA sequencing that performs de novo expressed-variant discovery, molecule-level haplotype assignment and isoform-resolved allelic quantification. ANCHOR combines a signed-graph variant caller, pair hidden Markov modelling and beta-binomial UMI aggregation to infer parental allele counts for genes and splice-resolved isoforms, without requiring a pre-existing phased genotype or deep learning. In human single-cell long-read RNA benchmarks, ANCHOR improved variant-calling performance over tested long-read RNA callers at single-cell and low-to-moderate coverage, and its beta-binomial model reduced depth-driven false positives in allele-specific expression testing. Applied to newly generated single-cell long-read RNA-seq data from reciprocal mouse crosses during gastrulation, ANCHOR resolved cell-type- and isoform-specific parent-of-origin imprinting and identified an antagonistic maternally biased Sgce isoform. ANCHOR provides a general framework for allele-and isoform-resolved analysis of diploid single-cell long-read transcriptomes.

bioinformatics↗

bioRxiv2026

Mechano-Initiated PIEZO1-VEGFR2 Interaction Governs CD34+ Cell Differentiation and Repair in Arteriovenous Fistula

BackgroundEndothelial cell (EC) injury induced by disturbed flow drives neointimal hyperplasia in arteriovenous fistulas (AVFs), where CD34+ cell-mediated repair may be involved. PIEZO1 and VEGFR2 are important mechanosensors with critical role in maintaining endothelial function. However, whether PIEZO1 interacts with VEGFR2 during CD34+ cell differentiation to orchestrate the vascular repair remains unknown. MethodsAVF model was established in several mouse strains. Single cell RNA sequencing was performed for human and mouse samples. Cd34-CreERT2; R26-tdTomato; Piezo1flox/flox mice were used to investigate the effect of Piezo1 deletion on endothelial repair in AVFs. CD34-high human umbilical vein ECs (CD34high HUVECs) was sorted and exposed to different flow patterns to determine the role of shear stress in CD34high cell differentiation. Co-immunoprecipitation, proximal ligation assay and complementary approaches were performed to delineate mechanotransduction initiated by PIEZO1-VEGFR2 interaction. ResultsSingle cell RNA sequencing and immunostaining showed abundant CD34high cells in the vessel wall of AVFs in humans and animal models. Exposure of CD34high HUVECs to different flow patterns showed that laminar shear stress downregulated CD34 while upregulating VE-cadherin and claudin-5 expression. In contrast, oscillatory flow produced the opposite effects, indicating impaired endothelial maturation. PIEZO1 knockdown in CD34high HUVECs attenuated shear stress-induced endothelial marker expression. In Cd34 conditional Piezo1 knockout mouse model of AVF, we observed decreased number of CD34-derived cells, more compact cellular arrangement, and attenuated neointimal hyperplasia. Mechanistically, we found PIEZO1 interacts with VEGFR2, thereby mediating the distinct effects of laminar and oscillatory shear stress on AKT-FoxO1 axis, which critically regulates endothelial marker expression. Furthermore, pharmacological activation of AKT signaling in AVF mouse model enhanced CD34+ cell-mediated endothelial repair and attenuated neointimal hyperplasia. ConclusionPIEZO1-VEGFR2 complex-mediated mechanotransduction plays a key role in regulating CD34+ cell-derived endothelial repair in AVFs via AKT-FoxO1 axis. AKT activation enhances endothelial maturation, thereby attenuating neointimal hyperplasia in AVFs. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIIn arteriovenous fistulas (AVFs), abnormal shear stress induces endothelial cell injury, and the resulting neointimal hyperplasia is a major cause of anastomotic stenosis. C_LIO_LICD34 cells actively participate in vascular endothelial repair. C_LIO_LIPIEZO1 is a mechanoreceptor mediating endothelial sensing of hemodynamic shear stress, contributing to the maintenance of atheroprotective endothelial phenotype under laminar shear stress, whereas its activation induces pro-inflammatory effects under disturbed shear stress. C_LI What New Information Does This Article Contribute?O_LICD34 cells participate in repairing endothelial injury induced by abnormal shear stress in AVFs. PIEZO1 knockout in CD34+ cells improve endothelial repair and attenuates neointimal hyperplasia in AVF. C_LIO_LILaminar shear stress induces CD34 downregulation and upregulates VE-cadherin and claudin-5 expression in CD34-high human umbilical vein endothelial cells, whereas oscillatory shear stress upregulates CD34 expression and suppresses VE-cadherin and claudin-5 expression. C_LIO_LIMechano-stimuli lead to PIEZO1-VEGFR2 complex formation regulating CD34 cell-mediated endothelial repair through the downstream AKT-FoxO1 axis. C_LI Abnormal hemodynamic shear stress-induced endothelial injury initiates neointimal hyperplasia in AVFs. The present study identifies PIEZO1 as a key mechanosensor that regulates CD34+ cell-derived endothelial repair in response to distinct blood flow patterns. PIEZO1 promotes CD34+ cell differentiation into mature ECs for endothelial repair under laminar shear stress, whereas it disrupts the differentiation of CD34+ cells into mature endothelium under oscillatory shear stress. Mechanistically, a novel shear stress-sensing complex comprising PIEZO1 and VEGFR2 was identified in regulating flow-induced differentiation of CD34+ cells into mature ECs via the AKT-FoxO1 signaling axis, thereby controlling the expression of endothelial maturation markers VE-Cadherin and Claudin-5. These findings define a novel PIEZO1-VEGFR2 mechanotransduction axis in CD34+ cell-mediated endothelial repair and support AKT pathway activation as a potential therapeutic strategy against neointimal hyperplasia in AVFs.

cell biology↗

bioRxiv2026

Pathology-Targeted EP4 Agonism Reverses Fibrosis in a Rat Model of DMD

Duchenne muscular dystrophy (DMD) presents a critical therapeutic gap in adolescent patients, where extensive fibro-fatty muscle replacement and depletion of the regenerative niche render existing interventions insufficient. Prostaglandin E2 signaling through the EP4 receptor stimulates bone and muscle regeneration and repair, but systemic off-target effects have limited the clinical translation of EP4 agonism in diseases such as DMD. We therefore evaluated irodanoprost (IROD), a bone-targeted prodrug of an EP4-selective agonist, in a DMD rat model, comparing early- and late-intervention cohorts. In adolescent rats, 8 weeks of treatment reduced body weight deficit by 41.4% and restored hindlimb muscle mass and maximum tetanic force to wild-type levels. IROD dose-dependently inhibited fibro-adipogenic progenitor differentiation into -SMA myofibroblasts, facilitating active resolution of established fibrosis below pre-treatment baseline. This was accompanied by re-activation of a synchronized regenerative program marked by clustered eMHC fibers, restoring the total myofiber pool to wild-type levels. A strong linear correlation between intramuscular fat reduction and fibrosis resolution suggests that MRI-based fat imaging may serve as a non-invasive surrogate for monitoring anti-fibrotic efficacy. The efficacy of IROD is likely aided by the fact that while it selectively distributes to bone in healthy animals, we observed markedly enhanced accumulation of the drug in dystrophic muscle. These findings establish IROD as a pathology-targeted approach capable of resolving the fibro-fatty niche and restoring regenerative capacity in advanced DMD. SummaryPathology-targeted EP4 agonism resolves established fibrosis and restores myofiber regeneration in a rat model of adolescent Duchenne dystrophy. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/728674v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@20447dorg.highwire.dtl.DTLVardef@70929dorg.highwire.dtl.DTLVardef@a99628org.highwire.dtl.DTLVardef@1c158f4_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Dual histone methylation reader ZCWPW2 links histone methylation to initiation of meiotic recombination

Meiotic homologous recombination initiates with the formation of programmed DNA double-strand breaks (DSBs) by complexes comprising SPO11 and accessory proteins at discrete sites called recombination hotspots. In mammals, PRDM9-dependent H3K4me3 and H3K36me3 define recombination hotspots, but how these epigenetic characteristics determine the physiological DSB formation remains unknown. Here we show that dual histone methylation reader ZCWPW2 can recognize H3K4me3 and H3K36me3 marks in testis. The binding activity of ZCWPW2 to histone methylation is dependent on PRDM9 function. Moreover, we find the epigenetic writer-reader axis PRDM9-ZCWPW2 is essential for DSB formation at meiotic recombination hotspots, which may be partly explained by the finding that ZCWPW2 can physically interact with HORMAD1, IHO1, MEI4, and REC114. Finally, the absence of ZCWPW2 leads to disrupted chromosomal synapsis and recombination, thereby obstructing meiotic progression. Taken together, our findings provide new insights into how histone modifications and their associated regulatory proteins collectively regulate meiotic homologous recombination initiation.

cell biology↗

bioRxiv2026

A unified law for inhibitory control in active dendrites

Neuronal computation depends on the balance between excitation and inhibition, yet how this balance is implemented across the dendritic tree remains unclear. Classical views predict that inhibition should be most effective near the soma or along the path from excitation to output, but many interneuron subtypes preferentially target remote dendritic compartments. This apparent paradox is sharpened by active dendrites, where local NMDA spikes, calcium plateaus and backpropagating action potentials can make distal branches powerful contributors to somatic firing. Here we develop an analytical framework that extracts general principles of inhibition from biophysically detailed multi-compartment simulations. By reformulating the implicit voltage update of detailed neuron models as a matrix recursion, we derive exact voltage sensitivities to inhibitory synaptic perturbations. This leads to a unified {Phi}-a law: the somatic impact of inhibition factorizes into a global dendritic susceptibility term and a local synaptic perturbation term. Using this law to map inhibitory leverage and identify optimal inhibitory interventions, we show that active dendritic excitation can shift inhibitory hot zones from perisomatic regions toward distal or intermediate compartments. Across neocortical, hippocampal and striatal neuron models, the same response law explains convergent inhibitory strategies despite distinct cellular mechanisms. Our framework turns detailed numerical simulation into analytical theory, providing a general principle for how diverse dendritic inhibition controls active neurons.

neuroscience↗

bioRxiv2026

PTM-dCN: Latent Space Control for Post-translational Modification-aware Protein Design

AO_SCPLOWBSTRACTC_SCPLOWPost-translational modifications (PTMs) are critical for protein function, yet their precise design by harnessing site specific information derived from native proteins remains challenging. Here, we present a deep learning-based PTM design framework that integrates latent diffusion models with ControlNet for sequence generation with site-specific PTM-control. The framework incorporates a PTM-aware protein language model featuring extractor, trained on a curated SwissProt PTM dataset with specialized modification tokens. Through de novo generation of protein sequences with designated PTM sites, our framework facilitates the exploration of PTM-driven functional landscapes and advances position-aware protein engineering.

bioinformatics↗

bioRxiv2026

PA-SfM: Tracker-free differentiable acoustic radiation for freehand 3D photoacoustic imaging

Three-dimensional photoacoustic imaging (3D PAI) has shown great potential in preclinical studies and clinical implementations, while it commonly has sparse sensor arrays, limiting both spatial sampling and the field of view (FOV). Freehand scanning could overcome these limitations through anatomy-adaptive scanning that extends spatial coverage and provides complementary views beyond the fixed array aperture, but its flexibility is conventionally constrained by the need for motor feedback or external pose tracking. Here we introduce PA-SfM, a tracker-free structure-from-motion (SfM) framework that recovers multiple poses directly from PA measurements with superior precision, enabling freehand 3D PAI without external pose measurements. PA-SfM integrates a differentiable acoustic radiation model with hierarchical optimization and rigid array constraints, it jointly estimates inter-view transformations and reconstructs 3D volumes. The performance of PA-SfM was demonstrated in numerical simulations, animal studies and human imaging experiments. Compared with motor encoder-based fusion of the mechanically scanned system, PA-SfM produced sharper and more continuous vascular reconstructions with an expanded FOV. In controlled quantitative validations, PA-SfM achieved high reconstruction fidelity, with PSNR values over 40 dB and SSIM values above 0.98 relative to ground truth or known pose reference reconstructions. These results demonstrate that PA-SfM enables robust freehand 3D PAI, with particular potential for clinical implementation of large-scale freehand imaging. The source code is publicly available at https://github.com/JaegerCQ/PA-SfM.

bioengineering↗

bioRxiv2026

Perceiving latent dynamics: Innate and coachable visual estimation of limb damping

Humans are remarkably adept at extracting latent dynamic information from purely visual cues. Prior work shows that people can innately estimate differences in limb stiffness using solely their visual observation of movement, which suggests that components of mechanical impedance may be embedded within humans internal predictive models of movement. We tested whether humans can similarly perceive damping, a force-velocity relationship, and whether targeted coaching can enhance this visual ability. Specifically, 30 participants observed abstract two-link arm simulations with systematically varied elbow damping and rated their perceived level of damping for several trials. Participants completed two sessions separated by one of three brief coaching interventions: (1) no coaching, (2) coaching to attend to hand velocity, or (3) coaching to attend to elbow-angle velocity. Results reveal that (1) humans can innately perceive changes in arm damping using solely their visual observation of motion and (2) coaching further improved performance, with the elbow-angle coaching group showing a significantly greater increase in rating accuracy compared to the other two groups. This work extends our understanding of how action-perception coupling supports inference of mechanical impedance. Moreover, we demonstrated that perceptual strategies for estimating damping are malleable and can be systematically improved through coaching. We not only identified the visual cues observers relied on but also guided them toward more classifiable features, effectively strengthening their perceptual models of limb dynamics. Author summaryHumans are remarkably adept at understanding an objects latent dynamic properties simply by watching it move, even when the underlying forces are unseen. In this paper, we demonstrated that people can notice differences in how "damped" a moving limb is using vision alone. Moreover, we found that brief coaching helped participants focus on the most informative features, significantly improving their ability to differentiate the damping levels. These results demonstrate how people can visually infer aspects of movement that are normally thought to require physical interaction, offering insight into how the motor system links action and perception. They also show that strategies can be shaped and improved, supporting real-world healthcare applications. In stroke rehabilitation, physical therapists physically assess the resistance of a patients limb, so better guidance on the most relevant visual cues can help clinicians learn faster and even provide care remotely. In robot-assisted surgery, surgeons operate a console to perform procedures with limited or no force feedback, so they must estimate tissue dynamics properties largely from visual observation. Understanding how people visually estimate these dynamics can inform training for more precise surgical decisions. Overall, our findings clarify how humans interpret movement dynamics and how coaching can support more consistent and accurate perceptual decisions.

neuroscience↗

bioRxiv2026

Reln haploinsufficiency alters fentanyl-induced striatal activity and adaptive responding without affecting opioid reinforcement

The Reln gene encodes the extracellular glycoprotein Reelin that regulates synaptic plasticity and activity-dependent gene expression with implications in several neuropsychiatric disorders, including substance use disorder. While reduced Reln expression alters responses to psychostimulants and cannabinoid, its role in opioid-related behaviors remains unknown. Here, we examined whether Reln haploinsufficiency modifies behavioral and molecular responses to the synthetic opioid fentanyl. Heterozygous Reeler (Reln+/-) mice and wild-type littermates were assessed using using complementary contingent and non-contingent models of fentanyl exposure, including multi-phase fentanyl intravenous self-administration paradigm, conditioned place preference paradigm, locomotor assay, and dorsal striatal immediate early gene expression. Reln haploinsufficiency did not alter acquisition, extinction, or cue-induced reinstatement during self-administration, indicating stable opioid reinforcement and relapse-like behavior. Progressive ratio testing revealed a sex-dependent effect in which male Reln+/- mice showed reduced motivation for fentanyl compared to male wild-type mice. In contrast, following passive fentanyl exposure, Reln+/- mice exhibited enhanced fentanyl-induced locomotion and increased Fos immunoreactivity in the dorsal striatum, while CPP remained unchanged. Together, these findings demonstrate that Reln haploinsufficiency does not substantially modify opioid reinforcement or cue-driven drug seeking but enhances acute pharmacological sensitivity to fentanyl. These results identify Reln as a modulatory factor in opioid-responsive neural circuits that preferentially influences acute drug-evoked neuronal activation rather than the associative learning processes underlying opioid reinforcement.

neuroscience↗

bioRxiv2026

A T-cell engager platform induces deep plasma cell depletion in autoimmune dry eye

Bispecific T cell engagers (TCEs) have transformed targeted immunotherapy but remain constrained by ex vivo manufacturing and systemic delivery, limiting their application in autoimmune disorders. Here, we introduce the first in vivo TCE platform, utilizing a T cell-targeted integration-deficient lentiviral vector (T-IDLE) to reprogram endogenous T cells into engineered T cells secreting BCMAxCD3 TCEs (STCEs) directly in vivo. In murine Sjogrens syndrome-associated dry eye model, a single intravenous administration of T-IDLESTCE achieved deep and sustained depletion of plasmablasts and plasma cells, reversing lacrimal gland inflammation and restoring tear production without detectable off-target transduction. Longitudinal studies in cynomolgus monkeys confirmed translational promise, demonstrating potent plasma cell clearance and favorable safety profiles over 12 weeks post-vector dosing. Mechanistic analyses demonstrated attenuation of Th1/Th17-mediated inflammation and controlled cytokine responses, accompanied by negligible vector integration in non-T cell lineages, thereby substantiating the safety profile of the integration-deficient design. This first-in-class in vivo TCE approach represents a manufacturing-free, scalable immunotherapy strategy for autoantibody-mediated diseases.

bioengineering↗

bioRxiv2026

Fibrin barriers limit vancomycin penetration into staphylococcal abscess communities and maintain S. aureus in an unstressed, transcriptionally-responsive state

During Staphylococcus aureus infection, bacteria are frequently organized into staphylococcal abscess communities (SACs), multicellular bacterial aggregates encased within a host-derived fibrin barrier. Fibrin barriers are thought to insulate SAC-resident bacteria from host immune cells, as strains unable to form these barriers exhibit marked attenuation of virulence in animal infection models. However, the clinical consequences of these structures on antibiotic penetration, and whether the structures also impact bacterial physiology and alter antibiotic susceptibility, remains understudied. Here, we built upon prior work to develop a three-dimensional (3D) collagen gel matrix-based model, utilizing human coagulation components, that supports high throughput in vitro staphylococcal community (SC) formation and is compatible with timelapse microscopy and bulk transcriptional profiling. Using this system, we show that the fibrin barrier protects SCs from vancomycin by restricting drug penetration. Furthermore, we show that the fibrin barrier impacts transcriptional responses, leading to both shared and distinct transcriptional profiles between WT and fibrin barrier-deficient SCs. Together, these findings expand our understanding of SC fibrin barriers beyond immune evasion to include modulation of antibiotic interactions and bacterial physiological state.

microbiology↗