Biology subjects

Lee, J.

Publications and source records attributed to Lee, J..

At least 163 records · Page 9Linked to original sources

bioRxiv2026

Enabling Skilled Human-Computer Interaction After Paralysis via a Wearable sEMG Interface

Most individuals with tetraplegia retain some myoelectric function in their forearms, which offers the possibility of using surface electromyographic (sEMG) control for human-computer interaction (HCI). We demonstrate the potential of this approach by showing that people with motor-complete (n=5) and motor-incomplete (n=2) tetraplegia can accurately control myoelectric activity in their forearm to perform discrete button-click and continuous positioning tasks. These control inputs were mapped to the firing rate of motor units detected by a wireless wristband sensor designed for everyday use. Participants completed four testing sessions to assess their speed and accuracy. Motor units that displayed a wide dynamic range in their firing rate performed best during tasks requiring continuous, single-axis control. Interestingly, the level of impairment did not affect performance on the clicking and 1D cursor control tasks. However, those with motor-incomplete injuries showed greater independent control over two motor units than participants with motor-complete injuries, who exhibited stronger coupling between units. Participants also confirmed the practical utility of the device, successfully placing and removing the sEMG wristband on their own and consistently rating it as comfortable and easy to manage. These findings are significant because they offer the first demonstration of motor unit-based control in individuals with cervical spinal cord injury (SCI) using a fully wearable wristband interface, highlighting the feasibility of moving these systems out of the lab and into daily life. One-Sentence SummaryPeople with tetraplegia used a wristband sensor to detect forearm motor unit firing and perform human-computer interaction tasks.

bioengineering↗

bioRxiv2026

Interorganelle competition for linoleic acid underlies steatotic liver pathology

Lipid droplets (LDs) are traditionally viewed as protective organelles that sequester potentially cytotoxic lipids. However, whether and how LD biogenesis in pathological contexts actively rewires interorganelle lipid homeostasis to drive organelle dysfunction and disease progression remains unexplored. Here, we identify the adipocyte-enriched protein calsyntenin 3{beta} (CLSTN3B) as a critical promoter of metabolic dysfunction-associated steatotic liver disease (MASLD). CLSTN3B, an ER-LD contact protein previously shown to support LD maturation in adipocytes, is robustly induced in mouse hepatocytes by peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) in response to dietary caloric overload. CLSTN3B drives LD biogenesis and neutral lipid storage by stabilizing hemifusion-like ER-LD membrane bridges via its arginine-rich segment. These bridges preferentially recruit cone-shaped linoleoylated phosphatidic acid (PA), diverting linoleic acid (LA) into triacylglycerides (TAGs) rather than mitochondrial cardiolipin (CL), leading to disrupted cristae architecture, deficient ETC supercomplex assembly, elevated electron leak, and oxidative stress. Hepatocyte-specific CLSTN3B deletion impairs LD formation, reduces TAG accumulation, enhances fatty acid oxidation, restores CL maturation, and mitigates oxidative stress, collectively attenuating MASLD progression. Consistently, hepatic CLSTN3B expression correlates with fibrosis severity and progression in human MASLD. These findings position LDs as active regulators of interorganelle lipid partitioning and establish CLSTN3B as a key determinant of mitochondrial vulnerability, providing a general framework for how dysregulated organelle interfaces shape disease.

cell biology↗

bioRxiv2026

Develop a durable, memory-driven, CspZ-targeting Lyme disease vaccine by rationale adjuvant selection

Rational adjuvant selection is a systematic approach based on adjuvant-mediated immunomodulation to identify safe vaccine regimens that enhance protective immunity. Transmitted through ticks and caused by the bacterium Borrelia burgdorferi (Bb), Lyme disease (LD) is the most common vector-borne disease in the Northern hemisphere. There are no effective vaccines, making it suitable for testing the concept of rational adjuvant selection. Here, we formulated our previously developed and effective LD vaccine antigen, CspZ-YAC187S, with different adjuvants suitable for human use; we analyzed the immune response by transcriptomics and tested the vaccine efficacy after Bb infection. We identified Alum-CpG and Alum-Gal to elicit the highest titers of CspZ-YAC187S-dependent protective antibodies and robust levels of protection but through distinct mechanisms of immunomodulation. We demonstrated that immunization with Alum-CpG formulated CspZ-YAC187S provided up to nine months of protective bactericidal antibody titers, as well as recall-memory response to prevent LD after natural infection. Immunity was linked to elevated levels of IgG1 memory cells in the vaccine-triggered immune responses. This work thus identified a durable, memory immunity-driven LD vaccine, ultimately paving the road to understanding the mechanisms of rationale adjuvant selection for vaccine development.

immunology↗

bioRxiv2026

Engineering Functionality-Optimized Fully Human B7-H3 CAR T Cells for Enhanced Solid Tumor Therapy

B7-H3 is a cell surface protein overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR) T cell therapy. The most clinically advanced B7-H3 CARs are derived from murine monoclonal antibodies (mAbs) 376.96 and MGA271, which are now in phase 1/11 trials. However, non-human mAb sequences can provoke immune responses, leading to CAR T-cell rejection and therapeutic failure. Although scFv humanization reduces this risk, residual foreign residues within the variable domains remain. To overcome this limitation, we used in vitro phage display to generate fully human B7-H3-specific scFvs for CAR design. In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 were well tolerated and demonstrated superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induced complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors.

immunology↗

bioRxiv2025

BNIP3-mTOR Signaling Mediates Resistance to MET Inhibition in Glioblastoma

Glioblastoma (GBM) is an aggressive primary brain malignancy with poor prognosis due to rapid progression, extensive invasiveness, and intrinsic resistance to standard therapies. Aberrant activation of receptor tyrosine kinases (RTKs), particularly MET, drives tumor proliferation, invasion, and therapy resistance. Here, we show that MET inhibition with crizotinib induces senescence and mitochondrial dysfunction in glioma-initiating cells (GICs), in part via downregulation of the mitochondrial protein BNIP3. However, BNIP3 downregulation activates mTOR signaling, enabling adaptive resistance. Targeting mTOR with everolimus in combination with crizotinib synergistically enhances anti-tumor effects, inducing apoptosis, senescence, and necroptosis, and significantly reducing cell viability and sphere-forming capacity. In orthotopic GBM xenograft models, this combination, particularly in a sequential regimen, markedly prolongs survival without overt toxicity. Our findings identify a BNIP3-mTOR signaling axis as a critical mediator of resistance to MET inhibition and provide a mechanistic rationale for combined MET and mTOR targeting as a promising therapeutic strategy in GBM. Statement of Translational RelevanceGlioblastoma (GBM) remains a highly aggressive and treatment-resistant brain tumor with limited therapeutic options. Our study identifies a BNIP3-mTOR signaling axis as a key mediator of resistance to MET inhibition. We show for the first time that combined MET and mTOR inhibition exhibits synergistic effects against GBM in vitro and in vivo. This combination prolongs survival without overt toxicity, providing a strong preclinical rationale for clinical evaluation in GBM patients with high MET expression and offering a promising strategy to overcome adaptive resistance.

cancer biology↗

bioRxiv2025

Microbiome-host interactions drive a trade-off between sleep quality and lifespan in Drosophila

Understanding the interactions between various aging processes and the resulting heterogeneity in aging is crucial for promoting healthy aging. Here, we provide evidence that heterogeneity in microbiome and host interactions contributes to diversifying aging phenotypes in sleep, gut integrity, and longevity in Drosophila. Aged flies exhibiting sleep fragmentation preserve gut integrity, accompanied by a shift in microbiota composition, particularly an increase in Acinetobacter junii. A. junii induces sleep fragmentation via its metabolite, urocanic acid, through serotonin receptor-dependent dopamine upregulation. In parallel, A. junii exploits the host response to promote its growth, leading to lifespan extension, which is recapitulated by genetically modified Escherichia coli, suggesting a trade-off between sleep quality and lifespan. Our study demonstrates a systematic mechanism underlying aging heterogeneity, suggesting interventions through bacterial supplements.

animal behavior and cognition↗

bioRxiv2025

Automated, modular assembly of reconstituted cell-free systems from in vitro-produced components

High-performance cell-free protein synthesis has transformative potential for synthetic biology, yet the prohibitive costs of PURE kits and the labor intensity of in-house preparation have restricted accessibility and scalability. We developed i-POPFLEX (Purified components OPtimized for FLEXible protein expression), a modular cell-free protein synthesis system in which 34 translation factors, individually synthesized in vitro, are assembled using automated liquid handling. This workflow minimizes manual input and supports parallelized production, generating complete, ready-to-use systems within two days. i-POPFLEX achieves up to 5-fold higher protein yields and a 95 % cost reduction (20-fold lower cost) compared with commercial kits. Its flexible architecture also enables selective component inclusion for genetic code reprogramming and site-specific incorporation of non-canonical amino acids. By coupling modular design with automation, i-POPFLEX provides an accessible, customizable, and economically viable platform for next-generation biomanufacturing workflows. Technology readinessi-POPFLEX is a reconstituted cell-free system (CFS) composed of 34 translational components that are individually synthesized in vitro and assembled by automation. This system achieves up to 5-fold higher protein yields with a 95 % cost reduction (20-fold lower; <USD 0.06 {micro}L-1) compared with commercial PURE kits (USD 1.36 {micro}L-1) and reduces preparation time from four days to two. The workflow has been validated across diverse protein and peptide synthesis applications, including genetic code reprogramming and site-specific incorporation of non-canonical amino acids, and integrates seamlessly with benchtop automated liquid-handling platforms. These capabilities place i-POPFLEX at Technology Readiness Level (TRL) 4-5: integrated components validated in a laboratory setting and advancing toward pilot-scale readiness. For full-scale deployment, several key challenges remain. Matching crude lysate costs (USD 0.03 {micro}L-1) will require bulk reagent production, optimized procurement strategies, and specialized equipment for high-throughput component synthesis. Enabling milliliter- and liter-scale production will demand improvements in upstream synthesis, downstream purification, and quality control to ensure consistent performance at industrial throughput. Overcoming these barriers would enable production of thousands to millions of fully assembled i-POPFLEX systems for biofoundry-scale enzyme engineering, metabolic pathway prototyping, and large-scale variant screening, democratizing reconstituted CFS technology, and accelerating adoption in next-generation biomanufacturing pipelines.

synthetic biology↗

bioRxiv2025

CRYPTID-exon: streamlined detection of cryptic exons from RNA-seq data

Cryptic splicing has emerged as a pervasive feature of mammalian gene expression, with recent studies uncovering thousands of previously unannotated splice sites. Despite its prevalence, the functional consequences of this hidden layer of splicing remain largely unknown due to challenges in identifying the exact exonic regions introduced into mRNA transcripts. Here, we introduce a novel computational approach, CRYPTID-exon, that accurately predicts exon boundaries by modeling RNA-seq read coverage around empirically derived splice sites. We use CRYPTID-exon to identify and characterize thousands of cryptic exons in nascent and mature RNA from human cells. Additionally, we demonstrate that CRYPTID-exon is well powered to identify exons that are sensitive to translation-mediated degradation processes. Finally, given the growing interest in leveraging cryptic exons to modulate gene expression levels, we use our approach to identify cryptic exons in disease-relevant genes. We see that targeting these cryptic exons with splice-switching antisense oligonucleotides (ASOs) can alter gene expression and splicing patterns of the parent genes. Our study provides a framework to systematically identify and characterize cryptic exons, which will enable downstream insights into their impact on mRNA stability and translation.

genomics↗

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2025

Endogenous Osteocyte-Osteoclast Signaling Enables Growth Factor-Free Bone Remodeling, Drug Response, and Cancer Invasion in a Nanoscale Calcified Bone-on-a-Chip Model

Bone homeostasis depends on spatially orchestrated interactions among osteoclasts, osteoblasts, and osteocytes that are embedded within a unique extracellular matrix that is mineralized on the nanoscale. Reconstructing these interactions to enable autonomous cell differentiation and tissue remodeling has remained a significant challenge towards mimicking adequate bone physiology and disease in-vitro. Here, we present an engineered model that spatially defines the paracrine communication of heterogeneous cell populations within bone tissue that supports the rapid maturation of primary osteoblasts into osteocytes, the differentiation of immune cells into osteoclasts, and calcified tissue resorption within a mineralized cell-laden bone-like tissue. We demonstrate that nanoscale mineralization of cell-laden collagen hydrogels on-a-chip enhances osteoblast to osteocyte differentiation, whereas osteocytes in the matrix accelerate osteoclastogenesis and remodeling in a spatially defined manner without the need for exogenous growth factors. Osteocyte-dependent osteoclastogenesis on-a-chip outperformed conventional stimulation with RANKL and M-CSF, reproduced the clinical response of anti-resorptive drugs, and mimicked established tumor-bone interactions observed in invasive oral cancer. By replicating essential aspects of bone composition and function, this system provides a robust, self-regulated microphysiologic model to investigate bone remodeling, cancer-bone crosstalk, and therapeutic interventions.

bioengineering↗

bioRxiv2025

Multi-modal, multi-species, and multi-task latent-space model for decoding level of consciousness

Assessing the degree and characteristics of consciousness is central to caring for patients with Disorders of Consciousness (DoC), yet current standard of care is a bedside questionnaire. Using a laminar neural probe we introduce a self-supervised, multi-modal representation learning approach that constructs an interpretable 2-D latent space of brain state from continuous neural recordings. We jointly encode local field potentials (LFPs), single-unit firing rates, and a movement proxy into a time-aware autoregressive VAE (TN-VAE). In rats, pigs and humans undergoing controlled depth anesthesia experiments, the learned latent trajectories nonlinearly, but smoothly, separate four expert-defined states (awake, light, moderate, deep) at 2s resolution, exceeding the temporal granularity of behavioral scoring (15m). The latent space supports linear readout of both coarse state and individual behavioral components, and its axes align with known physiology: delta/alpha power differentiates unconscious sub-states, while gamma and unit firing distinguish wakefulness. To enable cross-species use and incomplete modality sets, we add lightweight, species-specific stitching layers. This model pretrained on tri-modal rat data and fine-tuned with unimodal (LFP) pig data and unimodal human intraoperative data, successfully separates awake versus anesthetized states in new unseen human subjects, demonstrating zero-shot multi-subject transfer without per-patient calibration. The model further generalizes in a multi-task manner to predict the results of additional stimuli. These results highlight a path toward a foundation model for DoC that generalizes across sessions, subjects, species, and stimuli to enable scalable, continuous brain-state monitoring and clinical decision support.

neuroscience↗

bioRxiv2025

Master clock-thalamic-prefrontal circuit controls circadian social priority

Social behaviors arise from complex brain operations that adapt to changing social contexts and internal states. However, how internal states guide the resolution of competing social goals remains unclear. Here, we show that prioritization between competing instincts follows a circadian pattern via a circuit linking the suprachiasmatic nucleus (SCN) to the medial prefrontal cortex (mPFC). Specifically, SCNVIP neurons project to Vipr2-expressing neurons in the nucleus reuniens (RE), which innervate the mPFC to regulate social prioritization. Vipr2 signaling in the RE is essential for circadian modulation of appetitive and consummatory social behaviors, aligning social behaviors with clock-regulated reproductive system. Overall, this SCN-RE-mPFC circuit provides a neural principle through which the master clock coordinates the prefrontal cortex to resolve a conflict of motivated behaviors by referencing an internal state.

neuroscience↗

bioRxiv2025

Structure of human lymphoid-specific helicase HELLS in its autoinhibitory state

Helicase, Lymphoid Specific (HELLS), also known as Lymphoid-Specific Helicase (LSH), is a member of the SNF2 chromatin-remodeling family that regulates DNA methylation and heterochromatin organization. Unlike most chromatin remodelers, HELLS is catalytically inactive in its apo form and requires the DNA-binding protein CDCA7 for activation, though the underlying mechanism has remained unclear. Here, we combine biochemical, biophysical and cryo-electron microscopy analyses to define the structural basis of HELLS autoinhibition. HELLS alone assembles into a hexameric (trimer of dimers) architecture stabilized by interactions between its N-terminal coiled-coil (CC) domain and ATPase Lobe-1, while ATPase Lobe-2 remains flexible and disengaged. The CC domain functions both as an oligomerization scaffold and as an autoinhibitory module that restricts catalytic activity. Binding of CDCA7 and DNA promotes formation of an active HELLS-CDCA7-DNA ternary complex. CDCA7 recognizes hemimethylated CpG dinucleotides in both B-form and non-B-form DNA and stimulates HELLS ATPase activity. Together, these findings reveal the mechanism of HELLS autoinhibition and its activation by CDCA7 and DNA, providing new insight into how the HELLS-CDCA7-DNA ternary complex maintains DNA methylation and heterochromatin integrity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/692698v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@106b73borg.highwire.dtl.DTLVardef@1e7b33aorg.highwire.dtl.DTLVardef@a7be6eorg.highwire.dtl.DTLVardef@c75a5b_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIHELLS alone assembles into an inactive hexameric trimer-of-dimers C_LIO_LIThe N-terminal coiled-coil mediates oligomerization C_LIO_LICDCA7 and DNA binding activate the HELLS-CDCA7-DNA complex C_LIO_LIThe complex recognizes hemimethylated CpG in non-B-form DNA C_LI

molecular biology↗

bioRxiv2025

Lemborexant Reduces Infarct Volume and Improves Long-Term Functional Recovery in a Murine Model of Ischemic Stroke

IntroductionRecovery following ischemic stroke is highly variable and often incomplete, underscoring the urgent need to develop novel targeted poststroke treatments. While the mechanisms underlying poststroke recovery remain incompletely understood, sleep fragmentation, a common consequence of stroke, has been linked to worse patient outcomes. Lemborexant is a dual orexin receptor antagonist that promotes sleep by suppressing wakefulness and enhancing sleep continuity. We hypothesized that lemborexant would reduce poststroke sleep disturbances and promote recovery in a rodent model of stroke. MethodsWe examined the effects of lemborexant (10 mg/kg and 30 mg/kg) and zolpidem (30 mg/kg) on sleep macrostructure, fragmentation, and EEG spectra in both healthy mice and in stroke model mice, which underwent photothrombotic ischemia of the forelimb somatosensory cortex. We also evaluated whether 12 days of drug administration altered infarct volume and functional recovery following the experimental induction of stroke in model mice. ResultsLemborexant treatment (30 mg/kg) increased the percentage of NREM sleep, while preserving sleep continuity, in both healthy and stroke model mice. In contrast, zolpidem increased NREM sleep after stroke, but also increased sleep fragmentation in both groups. Lemborexant treatment at 10 mg/kg and 30 mg/kg significantly reduced infarct volume eight weeks after the induction of stroke. In addition, lemborexant-treated mice showed greater use of the impaired limb four weeks after stroke. InterpretationThese preclinical findings suggest that lemborexant stabilizes sleep and promotes structural and functional recovery following the experimental induction of stroke in model mice, supporting its potential as a novel therapeutic intervention following ischemic stroke. Summary for Social Media if PublishedO_LIIf you and/or a co-author has a X handle that you would like to be tagged, please enter it here. (format: @AUTHORSHANDLE). @EricLandsness C_LIO_LIWhat is the current knowledge on the topic? Sleep plays a critical role in structural and functional recovery after stroke, but most pharmacologic sleep aids, such as benzodiazepines and zolpidem, can fragment sleep and impair neuroplasticity. Dual orexin receptor antagonists like lemborexant may offer a newer, mechanistically distinct approach with potential neuroprotective benefits. C_LIO_LIWhat question did this study address? This study investigated whether the dual orexin receptor antagonist lemborexant could improve sleep quality, reduce ischemic injury, and enhance functional recovery following stroke in adult mice, compared with the sleep-promoting agent zolpidem. C_LIO_LIWhat does this study add to our knowledge? Lemborexant increased NREM sleep without causing fragmentation, reduced infarct volume, and improved motor recovery when administered. These findings suggest that modulating sleep architecture through orexin antagonism during the subacute phase after stroke can promote neural repair and functional recovery. C_LIO_LIHow might this potentially impact on the practice of neurology? Since lemborexant is already FDA-approved for insomnia, these results could be rapidly translated into a therapeutic opportunity to improve stroke recovery through targeted sleep modulation. This approach may shift poststroke care toward integrating neurorestorative, sleep-based interventions during the subacute phase. C_LI

neuroscience↗

bioRxiv2025

GABA co-release guides the functional maturation of glycinergicsynapses in an auditory sound localization circuit.

In the mammalian brainstem and spinal cord, glycine is the primary inhibitory neurotransmitter. However, during development, many glycinergic neurons also co-release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Although the acute effects of GABA co-release on immature synaptic transmission have been increasingly characterized, its role in synapse maturation and circuit formation remains poorly understood. Here, we investigated the developmental roles of GABA co-release at glycinergic synapses from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO), an auditory pathway essential for binaural integration and sound localization. During the first two postnatal weeks, MNTB-LSO synapses co-release GABA and undergo pronounced synaptic and circuit refinement. Using conditional knockout mice with severely diminished GABA co-release from MNTB neurons, we found that key aspects of circuit refinement, including synaptic silencing and strengthening, occurred normally. However, a disruption of GABA co-release resulted in significantly larger quantal amplitudes and a reduced readily releasable vesicle pool, impairing the high fidelity and temporal precision of synaptic transmission, which are essential for accurate binaural processing. These results reveal a critical developmental role for GABA co-release in shaping the functional synaptic architecture of glycinergic synapses involved in sound localization. Significance StatementGlycinergic neurons in the brainstem and spinal cord often co-release GABA during development, but the role of this co-release in circuit refinement or synapse maturation remains poorly understood. This study found that disruption of developmental GABA co-release at the MNTB-LSO synapse, a key part of the sound localization circuit, did not affect topographic refinement by synapse elimination or strengthening. However, impaired GABA co-release prevented synapses from developing the characteristic features that enable the high-fidelity, temporally accurate transmission required for sound localization. This highlights a critical role for developmental GABA co-release in shaping the specialized functional architecture of glycinergic synapses critical for binaural processing and sound localization.

neuroscience↗

bioRxiv2025

Transition from plasticity to dynamics-based value update for meta-learning

The ability to estimate the value associated with a specific stimulus or action is essential for adaptive behavior. Value can be updated either incrementally through experience or rapidly by inference based on latent environmental structure. Yet, how the brain implements and transitions between these modes of value computation remains unclear. To address this question, we examined the neuronal mechanisms underlying reversal learning. Mice were trained in an odor-outcome association task either with stable contingencies or with dynamically changing contingencies. Mice trained on stable contingencies formed long-term value representations that depended on synaptic plasticity in the basolateral amygdala (BLA). In contrast, mice exposed to repeated reversals acquired the ability to infer values, independent from plasticity in BLA, enabling faster learning but with more rapid memory decay. Recurrent neural network models (RNNs) trained with continuous weight updates recapitulated this transition, shifting from plasticity-based to dynamics-based value computation. Neural activity in the BLA encoded both value and contextual information necessary for computing value based on latent task structure, similar to those found in the RNNs. Disrupting BLA activity before cue delivery preferentially impaired dynamics-based value updating. Furthermore, mice could learn distinct correlation structures that enabled structure-specific value inference. Together, these findings provide a mechanistic framework for fast value updates via inference, a core feature of intelligent behavior.

neuroscience↗

bioRxiv2025

Constraining inference of across-region interactions using neural activity perturbations

Functional interactions between brain regions are often inferred from multi-region models fit to neural activity recorded in behaving animals. Here, we show that inference of acrossregion interactions is hindered by the wide breadth of model fits consistent with naturally occurring neural activity. In contrast, models fit to activity that includes region-wide activity perturbations provide well-constrained estimates of across-region interactions; simulations suggest these estimates can be accurate.

neuroscience↗

bioRxiv2025

Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle

Copper is an essential trace element for mitochondrial respiration and cellular metabolism, yet its physiological role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice causes local copper deficiency, resulting in exercise intolerance, systemic metabolic dysfunction, and hallmarks of mitochondrial myopathy such as ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Mechanistically, copper starvation disrupted the electron transport chain proteome and drove pathological mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator that coordinates mitochondrial copper distribution and morphology. Restoring copper levels via a copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings uncover the functional coupling of CTR1 and MTCH2 as a critical mechanistic link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.

molecular biology↗