Biology subjects

Lee, J.

Publications and source records attributed to Lee, J..

At least 127 records · Page 7Linked to original sources

bioRxiv2026

Early Visual Cortex Represents Sensory and Mnemonic Orientations in Separate Subspaces with Preserved Geometry

How early visual cortex (EVC) represents working memory (WM) content while continuing to process incoming sensory input remains unclear. Using fMRI with prolonged delays to isolate mnemonic activity, together with analyses of cross-decoding, low-dimensional subspace structure, and representational geometry, we examined the relationship between sensory and mnemonic orientation representations in human EVC. Cross-decoding generalized poorly between sensory and mnemonic epochs, but this did not imply unrelated codes. Rather, the two occupied separable low-dimensional subspaces while preserving representational geometry across epochs. During discrimination and estimation, sensory- and mnemonic-trained decoders yielded dissociable readouts of concurrent sensory and mnemonic information from the same EVC measurements. Mnemonic coding showed little dependence on the retinotopic radial bias that characterized sensory coding, and trial-by-trial variability in mnemonic representation predicted both discrimination choices and estimation reports. Our findings support a population-level account in which mnemonic information in EVC is re-expressed in a separable but geometrically preserved format.

neuroscience↗

bioRxiv2026

Coordinated Tuning of Ionizable Lipids and Formulation Redirects mRNA Vaccines Toward Lymphoid-Specific CD4+ T Cell Immunity

The global success of mRNA vaccines has underscored the pivotal role of lipid nanoparticles (LNPs), yet how subtle chemical variations in ionizable lipids and their formulation parameters orchestrate complex immune landscapes remains largely elusive. Here, we report a novel ionizable lipid, N4Z, and demonstrate that its distinct chemical signature selectively intensifies early innate immune programs compared to its structural analogue, N4Y. Single-cell transcriptomic profiling at the injection site reveals that N4Z-based LNPs uniquely prime inflammatory and type I interferon-related transcriptional programs, accompanied by a rapid influx of B and CD4+ T cells. Beyond lipid chemistry, we show that formulation-level tuning, that is independent of the ionizable lipid structure, can reshape the systemic biodistribution from hepatic dominance toward lymphoid tissues. This optimization substantially enhances macrophage-associated antigen expression, which in turn amplifies polyfunctional CD4+ T cell responses, T follicular helper cell differentiation, and germinal center reactions. Our findings establish that the coordinated interplay between lipid engineering and formulation design provides a programmable platform for precision mRNA vaccination, achieving superior protective efficacy and neutralizing activity over clinically validated benchmarks.

bioengineering↗

bioRxiv2026

Biological nitrification inhibition compromises the soil methane sink

Biological nitrification inhibition (BNI) is a plant-mediated process that suppresses nitrification and is widely considered beneficial for reducing nitrous oxide emissions. Here, we show that BNI compounds also inhibit methane oxidation by methanotrophic bacteria, revealing a previously unrecognized trade-off in greenhouse gas regulation. Across soil bioreactor systems and pure cultures of both Type I and Type II methanotrophs, BNI compounds consistently suppressed methane oxidation activity. Kinetic analyses indicated an uncompetitive-like inhibition pattern, characterized by concurrent decreases in Vmax and Km, while reversibility assays showed that inhibition was not associated with loss of cellular viability. Experiments under copper-replete and copper-depleted conditions further showed that inhibition is predominantly associated with particulate methane monooxygenase (pMMO). Transcriptomic analyses demonstrated compound-specific responses, including suppression of methane oxidation pathways and differential regulation of stress-associated genes. These findings suggest that BNI-mediated inhibition of methane oxidation may offset reductions in nitrous oxide emissions, with implications for predicting net greenhouse gas fluxes in agricultural and wetland ecosystems. Incorporating BNI effects into biogeochemical models will be critical for accurately evaluating their role in the global methane budget.

microbiology↗

bioRxiv2026

A Rapidly Excretable, ROS-Scavenging Ionizable Lipid Decouples mRNA Delivery Potency from Toxicity

The broader clinical application of mRNA therapeutics remains constrained by dose-limiting toxicities, vector-associated immunogenicity, and prolonged tissue retention of lipid nanoparticles (LNPs) in vivo. Here, we report a class of ionizable lipids incorporating a sulfur-bearing hexyl 2-hydroxyethyl sulfide (HHES) motif that decouples mRNA delivery potency from these safety liabilities through dual functionality: the sulfur moiety acts as an intrinsic reactive oxygen species scavenger to suppress oxidative stress, while undergoing oxidative conversion into hydrophilic metabolites to promote rapid systemic clearance. HHES-based LNPs demonstrated a 3.3-fold shorter hepatic half-life and 29-fold lower total hepatic exposure than MC3, while maintaining robust protein expression including functional monoclonal antibody production in vivo. Repeated dosing in non-human primates confirmed negligible systemic, hepatic, or hematological toxicity. Leveraging this safety profile, subretinal HHES LNP delivery achieved up to 57% genome editing efficiency in retinal pigment epithelium, suppressing choroidal neovascularization by [~]65% in a wet age-related macular degeneration model without structural damage or microglial activation. This dual-function design provides a generalizable framework for safe, transient, non-accumulative mRNA nanomedicines.

bioengineering↗

bioRxiv2026

Multiparametric Classification of Pure-tone Responses Distinguishes Neurons in Inferior Colliculus Subdivisions

The inferior colliculus (IC) integrates ascending auditory and descending multimodal inputs within distinct subdivisions, the central nucleus (CNIC) and cortex (CtxIC). Despite differences in connectivity, auditory responses in these subdivisions are similar, complicating localization during in-vivo recordings. Here, we tested whether recordings can be assigned to CNIC or CtxIC using only response properties in awake and anesthetized mice. We constructed frequency response areas (FRAs) from pure tone responses and extracted tuning and firing metrics. Individual FRA features could not reliably localize recordings. In contrast, a random forest classifier combining FRA-derived features accurately localized recordings to CNIC or CtxIC across states. These findings demonstrate that while IC subdivisions differ only subtly along individual response parameters, appropriate multiparametric approaches can enable robust classification. More broadly, our results illustrate how biologically meaningful distinctions may be revealed by combining weakly informative features, an approach that can be applied across diverse brain regions and modalities.

neuroscience↗

bioRxiv2026

Nextstrain automates real-time phylodynamic analysis of open data for endemic and emerging pathogens

MotivationGenome sequencing provides an exceptional window into the evolutionary and epidemiological dynamics of endemic and emerging pathogens, and thus allows for better, more targeted, public health interventions. Online genomic surveillance platforms can provide near real-time insight into these dynamics. ResultsNextstrain provides continually updated real-time genomic surveillance for 21 viruses and the bacterial pathogen Mycobacterium tuberculosis, with most analyses relying solely on open sequence data. Each pathogen includes steps to fetch and curate open data, classify sequences using established nomenclature systems, perform phylogenetic analyses, and share the results publicly. These analyses are automated, with most running daily to provide continually updated snapshots of pathogen evolution. Availability and ImplementationAll source code is available at https://github.com/nextstrain. Phylogenetic results can be visualized and downloaded at https://nextstrain.org/pathogens, and open sequence data and curated metadata are available at https://nextstrain.org/pathogens/files.

bioinformatics↗

bioRxiv2026

Tabula Sapiens reveals the non-coding RNA landscape across 22 human organs and tissues

The biological significance of non-coding RNAs has been increasingly appreciated as their roles in various cellular processes are uncovered. However, single-cell transcriptomic profiling of human samples has focused primarily on protein-coding genes by targeting polyadenylated RNA transcripts, leaving the expression patterns of non-coding RNA underexplored. Here, we expand Tabula Sapiens to the non-coding transcriptome with single-cell and single-nucleus total RNA sequencing across 22 human organs and tissues. By simultaneously profiling both polyadenylated and non-polyadenylated transcripts, the resulting dataset enables joint analysis of the protein-coding and non-coding transcriptomes at single-cell and subcellular resolution. Using these data, we assessed the cell type specificity of non-coding genes and found that a greater proportion of non-coding genes are differentially expressed by single cell types compared to protein-coding genes. We then compared single-cell and single-nucleus data from the same samples to infer subcellular localization patterns, revealing cell type-dependent nuclear and cytoplasmic enrichment of specific non-coding RNAs. Next, we showed that tRNA repertoires are cell type-specific and that this specificity is not simply explained by differences in codon usage across cell types. Finally, we characterized dynamic expression patterns of non-coding RNAs across the cell cycle and senescence-associated cell states, identifying non-coding genes with putative roles in cell division and growth arrest. Our work establishes a resource for investigating the landscape of non-coding RNAs across a diverse set of human tissues and cell types.

cell biology↗

bioRxiv2026

A novel fracture lattice in spiny mouse skin facilitates tissue autotomy and regeneration

Autotomy is a unique phenotype whereby an animal sheds a body part to escape predation1-3. The timing and location of autotomy are tightly regulated by preformed planes of weakness (aka fracture planes) which facilitate tissue loss. While autotomy is often followed by regeneration, these phenotypes are rarely reported in mammals4-9. A notable exception are spiny mice (Acomys) which exhibit skin autotomy and more remarkably, complete tissue regeneration10-14. Presently, mechanisms underlying autotomy and complete regeneration in Acomys skin remain elusive. Here, we report the discovery of a honeycomb-like fracture lattice in Acomys skin whose design directs tissue destruction but also facilitates regenerative healing. Unlike the single continuous surface of a fracture plane, this fracture lattice consists of a three-dimensional array of hexagonal units whose boundaries guide tissue breakage. Moreover, we identify collagen VI as the main constituent of the fracture lattice and find that it is distinctly arranged to initiate fracturing and propagation of skin tearing. By preconditioning the tissue for autotomy, the fracture lattice dampens the damage-induced inflammatory response but also upregulates a pro-regenerative gene signature, accelerating skin appendage regeneration. Lastly, we discovered the key role of spiny hairs in fracture lattice formation, as inhibiting their development leads to abnormal pattern formation and changes in skin fracture mechanics. Our results present a novel example of a uniquely evolved structural adaptation in mammalian skin that links tissue patterning, autotomy and regeneration. We expect that the application of a modular compartment structure to artificial skin and other organ engineering may enhance resilience to injury and facilitate efficient regeneration.

developmental biology↗

bioRxiv2026

Persistent vulnerability to heroin relapse across the adult lifespan in rats

Relapse to opioid use during abstinence is often triggered by drug-associated cues but the persistence of this effect across the lifespan is unknown. Using a rat model, we found that relapse provoked by heroin-predictive discriminative stimuli persisted for over one year of abstinence, suggesting enduring, potentially lifelong opioid relapse vulnerability.

animal behavior and cognition↗

bioRxiv2026

A network-based deep learning model integrating subclonal architecture for therapy response prediction in cancer

Predicting treatment response remains challenging in oncology, particularly given the growing diversity of therapeutic options. Despite efforts using gene expression signatures, or integrative multi-omics frameworks, robust and interpretable biomarkers remain limited. We present SubNetDL, a deep learning framework that integrates subclonal mutation profiles and protein-protein interaction networks via network propagation. Unlike condition-specific approaches, SubNetDL leverages somatic mutations alone and is applicable across diverse cancer types and treatment modalities. Applied to ten TCGA cancer-drug combinations, SubNetDL achieved consistently strong performance (median AUROC = 0.74) and successfully generalized to two independent immunotherapy datasets (median AUROC = 0.77). Importantly, it identified candidate biomarker genes with treatment-specific relevance. SubNetDL prioritized genes that were not central in the network, highlighting its ability to capture context-specific patterns beyond traditional metrics. In conclusion, our approach offers a robust and interpretable framework for identifying predictive biomarkers and stratifying patients based on mutation profiles and network context. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/711567v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@d31c74org.highwire.dtl.DTLVardef@1f12b13org.highwire.dtl.DTLVardef@430916org.highwire.dtl.DTLVardef@109a13c_HPS_FORMAT_FIGEXP M_FIG C_FIG MotivationIntratumoral heterogeneity is a fundamental driver of therapeutic resistance, yet most predictive models rely on aggregate mutational burdens or static gene expression signatures, overlooking the subclonal dynamics that shape treatment outcomes. While network biology offers a functional lens to interpret genomic alterations, a framework that explicitly bridges subclonal architecture with system-level molecular interactions has been lacking. To address this, we developed SubNetDL, a deep learning framework that integrates patient-specific subclonal profiles with protein-protein interaction networks. By leveraging only somatic mutation data, SubNetDL captures the functional convergence of subclonal evolution, providing a robust and interpretable platform for patient stratification and biomarker discovery across diverse oncological contexts.

cancer biology↗

bioRxiv2026

Reinforcement Learning for Antibiotic Stewardship: Optimizing Prescribing Policies Under Antimicrobial Resistance Dynamics

Antimicrobial resistance (AMR) threatens antibiotic effectiveness, but quantitatively evaluating stewardship strategies under partial observability and delayed feedback remains difficult in real-world data. We developed abx_amr_simulator, a Gymnasium-compatible simulation framework, and used it to benchmark reinforcement learning (RL) prescribing policies against value-iteration (VI) benchmarks and fixed prescribing rules across four experiment sets of increasing complexity, with varying levels of information degradation. Across scenarios, temporal abstraction was consistently important: flat PPO was competitive only in simpler settings, whereas hierarchical PPO was generally needed when prescribing decisions had delayed, coupled effects on future resistance. We found that adding recurrent memory did not uniformly improve performance; its value was context-dependent. In some degraded-information settings, memoryless policies performed better by adopting conservative update-responsive behavior, while in more complex, multi-signal partially observable settings, recurrent memory provided modest advantages. Patient heterogeneity and risk-stratification signals were major determinants of policy quality. When agents could differentiate higher-from lower-risk patients, they more reliably learned selective treatment behavior, stabilized AMR, and improved clinical outcomes. Exaggerated risk stratification modestly outperformed accurate stratification, while compressed stratification produced moderate degradation. In more realistic settings combining noisy patient observations, delayed AMR surveillance, and multi-patient decisions, hierarchical agents outperformed fixed prescribing rules across both stewardship and clinical metrics, converging to conservative low-AMR equilibria with reduced cross-seed variance. Across experiments, results support the utility of hierarchical RL as a best-case policy-analysis tool for stewardship under uncertainty, while also highlighting that performance estimates are sensitive to observation structure and training horizon design. The framework provides a controlled environment for hypothesis generation and for stress-testing prescribing strategies before translation to policy-relevant settings.

bioinformatics↗

bioRxiv2026

Blautia wexlerae Transforms Dietary Fatty Acids to Activate Enteroendocrine Signaling and Improve Metabolic Health in Mice and Humans

Metabolites produced by the gut microbiome influence host metabolic health, but how this occurs remains incompletely defined. Here, we report that a common human gut commensal, Blautia wexlerae, converts dietary fats into bioactive metabolites that induce gut hormone production to affect glucose metabolism and suppress appetite. We found that colonization with Blautia wexlerae correlated with healthier eating behaviors in humans. Blautia wexlerae encodes a unique acyl transferase and is capable of producing acyl amines from nutrient substrates. These Blautia acyl amines stimulated human enteroendocrine cells to secrete GLP-1 and other gut peptide hormones more potently than endogenously produced acyl amines. When fed to mice, acyl amines improved glycemic control and decreased appetite. In humans, higher stool levels of Blautia DNA encoding acyl amine synthesis genes correlated with leanness and decreased dietary fat intake. These results define a mechanism of action for how Blautia wexlerae affects host metabolic control.

microbiology↗

bioRxiv2026

Fixative eXchange (FX)-seq: Scalable Single-nucleus RNA Sequencing Analysis of PFA-fixed or FFPE Tissue

Single-nucleus RNA sequencing (snRNA-seq) of clinical formalin-fixed, paraffin-embedded (FFPE) samples has long been a challenge due to low reverse transcription (RT) yields. Here, we present Fixative-eXchange (FX)-seq, a highly scalable snRNA-seq method for heavily paraformaldehyde (PFA)-fixed and/or FFPE samples. We employ an organocatalyst to facilitate the removal of PFA crosslinks to increase RT yield and additional regiospecific Pt(II)-based crosslinking of RNA molecules to prevent leakage. FX-seq reveals cellular heterogeneity across multiple fixed samples by analyzing 321,710 nuclei, including PFA-fixed tissue, FFPE blocks, thin FFPE and hematoxylin and eosin (H&E)-stained sections from mouse brain and human cancer specimens such as gastrointestinal stromal tumor and colorectal cancer. FX-seq enables integrated analysis with pathologist annotation to label tumor and non-tumor regions of H&E-stained sections. FX-seq can also be applied to PFA-perfusion-based animal studies, large human cohort studies, and personalized drug treatment through precision medicine.

genomics↗

bioRxiv2026

EvoStructCLIP: A Mutation-Centered Multimodal Embedding Model for CAGI7 Variant Effect Prediction

AO_SCPLOWBSTRACTC_SCPLOWWe present EvoStructCLIP, a mutation-centered multimodal embedding model that integrates local 3D structural windows and evolutionary constraints to predict missense variant effects. EvoStructCLIP combines two encoders: a structure voxel encoder derived from AlphaFold residue neighborhoods and an MSA-based evolutionary encoder. It aligns the modalities through CLIP-style contrastive learning, with FuseMix regularization and an auxiliary pathogenicity loss trained on 153,787 ClinVar variants. Evaluations using lightweight regressors demonstrate that EvoStructCLIP embeddings capture highly transferable predictive signals across diverse phenotypes, including gene-specific functional readouts of BRCA1, KCNQ4, and PTEN/TPMT. This transferability is further supported in the CAGI7 blind competition setting, where models generalized to predicting different gene-specific readouts for BARD1, FGFR, and TSC2 without target-specific retraining and achieved competitive performance across heterogeneous biological tasks.

bioinformatics↗

bioRxiv2026

Lung-Selective Immune Reprogramming via In Situ Red Blood Cell Hitchhiking Nanoparticles

Premature clearance and limited organ targeting remain major barriers for nanoparticle (NP) drug delivery. Hitchhiking NPs on red blood cells (RBCs) can enhance circulation and organ-selective accumulation, but most approaches require ex vivo RBC extraction and reinfusion, limiting clinical translation. Here, we report an in situ RBC-hitchhiking strategy, named i-Bind, which employs polyphenol surface functionalization to enable spontaneous NP attachment to RBCs directly in the bloodstream. Driven by strong interactions of phenolic motifs with RBC membranes, i-Bind NPs exhibited markedly enhanced and more stable hitchhiking onto RBCs under flowing whole blood conditions. In both healthy and diseased mice, i-Bind NPs preferentially target the lungs, resulting in an over 20-fold increase in lung-to-liver deposition ratio compared to unmodified NPs. Additionally, i-Bind NPs show preferential targeting to distinct lung immune cell subsets in a pathology-dependent manner, including cDC2s in healthy lungs, neutrophils in acute lung injury, and cDC1s in lung metastases. In a melanoma lung metastasis model, delivery of the STING agonist diABZI via i-Bind NPs significantly inhibited lung metastasis progression by reprogramming the lung immune microenvironment. Collectively, i-Bind provides a simple and versatile platform for organ-targeted drug delivery and immune reprogramming. TeaserSurface functionalization of nanoparticles enables in situ red blood cell hitchhiking, unlocking new paths for organ-selective immune reprogramming

bioengineering↗

bioRxiv2026

Structural variants in human congenital heart disease disrupt distal genomic regulatory contacts of developmental genes

Predicting the functional significance of structural variants (SVs) associated with genetic diseases remains challenging. To test the hypothesis that SVs from people with congenital heart disease (CHD) disrupt developmental chromatin interactions, we developed CardioAkita, a machine-learning model that predicts how variants alter 3D chromatin structure. Analyzing previously genotyped de novo SVs (dnSVs), we observed a positive association between CHD severity and CardioAkita scores across dozens of families. From whole-genome sequencing of three individuals with CHD we predicted disruptive dnSVs. Induced pluripotent stem cells engineered to harbor these variants confirmed CardioAkitas predictions of 3D chromatin changes, and further revealed aberrant expression of local genes including cardiac developmental genes, suggesting that chromatin reorganization plays a significant mechanistic role in the genetic etiology of CHD. Our findings highlight the potential for models of 3D chromatin organization to predict the pathogenicity and underlying mechanisms of SVs in human disease.

genomics↗

bioRxiv2026

THERM-D Uncovers Distinct Neural Mechanisms Separating Morning and Evening Body Temperature Rhythms in Drosophila

Animal body temperature rises throughout the day and peaks in the evening, a pattern conserved across diurnal endotherms and ectotherms. However, the mechanisms driving the robust body temperature rhythms (BTR) remain largely unclear. Here, we developed a machine learning-based platform, temperature homeostasis evaluation of rhythmicity in model Drosophila (THERM-D), enabling continuous, high-throughput analyses of BTR. Using THERM-D, we identified robust BTR patterns reflecting flies morning and evening behaviors and revealed the function of CRYPTOCHROME (CRY)-negative clock neurons. About half of all clock neurons lack CRY, yet their function was unclear. Newly developed Gal4 drivers targeting CRY-negative neurons demonstrated that these neurons control the morning temperature rise without affecting evening BTR. The data suggests that separate clock circuits regulate morning and evening BTR. Thus, THERM-D elucidated the role of CRY-negative clock neurons, which are specialized for BTR regulation and distinct from the circuits controlling sleep-wake cycles.

neuroscience↗

bioRxiv2026

Chemical activation of mitophagy via the N-degron pathway alleviates mitochondrial neuropathies

Pharmacological activation of mitophagy offers a promising strategy to eliminate dysfunctional mitochondria. We previously identified the autophagy receptor p62/SQSTM1 as an N-recognin whose activity is enhanced by Arg/N-degrons. Here, we show that Arg/N-degrons generated by ATE1-encoded R-transferase regulate p62-mediated mitophagy by promoting its recruitment to damaged mitochondria. Structural modification of Arg/N-degrons yielded ATB1071, a 443.5-Da orally bioavailable compound that activates p62 and induces stress-selective mitophagy through both Parkin-independent pathways involving NIPSNAP1 and NIPSNAP2, and a Parkin-dependent pathway involving the substrate EBP1/PA2G4. In Ndufs4-/- mice, a Leigh syndrome (LS) model, ATB1071 induced mitophagy in the brain and exerted therapeutic benefits by reducing neuroinflammation, improving muscle strength and neuromuscular coordination, and extending lifespan. In cerebral ischemia-reperfusion (IR) model mice, ATB1071 reduced infarct volume and neuronal death, and ameliorated multiple behavioral deficits through EBP1-dependent mitophagy. Pharmacokinetic (PK) and toxicological analyses support ATB1071 as a preclinical candidate for mitochondria-associated neurological injury.

cell biology↗