Biology subjects

Park, S.

Publications and source records attributed to Park, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

GDTR: Layer-wise Settling Depth Reveals Biological Grammar in Genomic Foundation Models

Genomic foundation models capture sequence regularities, yet existing interpretability tools rarely ask where in the layer stack a biological grammar becomes stable. We introduce GDTR (Genomic Deep-Thinking Ratio), a training-free residual-stream lens that assigns each nucleotide token a settling depth c(t): the first layer at which its representation stabilises against the post-final-norm reference. On Evo 2 7B, splice donor and acceptor sites settle approximately two layers earlier than intronic contexts, enhancer-like cCREs show a smaller but measurable shift, and a chr22 calibration transfers to held-out chr17. Perturbing canonical splice donors shows that the signal is bidirectional: disrupting the central GT motif deepens settling, whereas shuffling the flanking grammar makes the preserved motif settle earlier. Differential GDTR further reveals consequence-associated peak-disruption depths across ClinVar variants, with synonymous substitutions peaking deepest but with broad class overlap. GDTR therefore provides a layer-wise interpretability axis for genomic foundation models, complementary to existing prediction and variant-scoring tools.

bioinformatics↗

bioRxiv2026

A targeted mass-spectrometry plasma proteome for simultaneous multi-disease screening

Population health screening is fragmented across dozens of single-condition assays. We asked whether one targeted mass-spectrometry measurement of the plasma proteome could screen simultaneously for many common diseases. Using multiple-reaction-monitoring LC-MS/MS, we quantified 126 proteins (509 peptides) directly in crude plasma from 490 individuals spanning 16 diseases (eight cancers, three inflammatory or renal conditions, and five metabolic and lifestyle disorders) plus age- and sex-matched controls, each protein referenced to a stable-isotope-labelled internal standard. Proteome variation was organised primarily by disease rather than demographics. Cross-validated classifiers detected each disease against matched controls with a mean AUROC of 0.979, a 17-way model identified the specific disease at roughly ten times chance, and a 20-protein subset reproduced full-panel performance. We show that these within-cohort estimates are optimistic upper bounds because each disease was acquired as a separate case-control batch without independent validation. We quantify this, establishing analytical feasibility and defining the validation required for translation.

molecular biology↗

bioRxiv2026

Age-dependent Structural Reorganization of the Human Plasma Proteome

Aging is characterized by progressive physiological decline, yet the molecular mechanisms underlying these changes remain incompletely understood. Although extensive work has examined age-related alterations in protein abundance, the age-dependent structural reorganization of proteins and their interaction networks remains largely unexplored. Here, we quantitatively characterize the structural dynamics of plasma proteins across healthy adult aging and identify age-dependent accessibility patterns that may serve as candidate structural biomarkers. We employed Covalent Protein Painting (CPP) coupled with multiple reaction monitoring (MRM)-based LC-MS/MS to analyze plasma from 24 healthy individuals spanning four age groups (20s to 50s, n = 6 per group). Lysine surface accessibility changes were analyzed using cosine similarity trajectory matching and limma-based linear modeling. The intersection of the two approaches defined five reproducible age-dependent trajectories encompassing 27 proteins and 57 peptides. Integrating STRING/Cytoscape network analysis with AlphaFold3 multimer complex prediction localized several CPP-detected peptides to within [~]5 [A] of predicted protein-protein interaction interfaces (KNG1, C3; REN, ALB; and ALB, FGB), suggesting that age-associated accessibility changes are organized at interaction interfaces rather than occurring as isolated local events. Our findings indicate that the human plasma proteome undergoes coordinated, network-level changes in structural accessibility during adult aging, providing a framework for structure-based biomarker discovery. Because CPP signal reflects both conformational accessibility and protein abundance, and because the cohort is modest and cross-sectional, the trajectories reported here are framed as hypothesis-generating and are interpreted with these constraints made explicit throughout.

molecular biology↗

bioRxiv2026

A multi-agent workflow converts CAR-T patient evidence into experimentally testable hypotheses

Clinical studies of chimeric antigen receptor (CAR)-T therapy generate diverse molecular and clinical evidence that remains fragmented across publications, public repositories and patient-derived datasets, limiting systematic therapeutic discovery. Here we present BioPathfinder, an evidence-guided multi-agent workflow for closed-loop biomedical discovery. BioPathfinder constructs a provenance-aware knowledge resource linking publications with patient single-cell RNA sequencing (scRNA-seq) datasets and clinical metadata, and uses role-specialized large language model agents to generate, review and prioritize diverse, falsifiable and dataset-aware mechanistic hypotheses for computational and experimental validation. Applied to a curated corpus of CAR-T-treated patient studies and matched scRNA-seq datasets, BioPathfinder identified candidate mechanisms underlying CAR-T persistence, dysfunction and therapeutic resistance. The workflow prioritized the hypothesis that genes associated with an NK-like transition programme could be targeted to reduce CAR-T exhaustion and improve persistence. Analysis of patient scRNA-seq datasets showed enrichment of this programme in exhausted post-infusion CAR-T cells. Virtual perturbation prioritized transition-associated receptor genes, including KLRC1, KLRD1 and KLRG1, and expert review selected KLRC1, encoding NKG2A, for experimental validation. In vitro and in vivo chronic-stimulation models showed that NKG2A marked activated, exhaustion-associated CD8 CAR-T cells, whereas NKG2A blockade enhanced antitumour activity and persistence-associated functional readouts in vivo. BioPathfinder establishes a generalizable framework that transforms fragmented clinical single-cell evidence into experimentally validated therapeutic hypotheses, providing a scalable strategy for AI-guided biomedical discovery. HIGHLIGHTSO_LIBioPathfinder integrates fragmented CAR-T clinical studies, patient scRNA-seq datasets and metadata into a provenance-aware evidence resource for AI-guided hypothesis discovery. C_LIO_LIA multi-agent workflow generates, critiques and prioritizes diverse, falsifiable, dataset-aware mechanisms underlying CAR-T persistence, dysfunction and therapeutic resistance. C_LIO_LIBioPathfinder prioritizes KLRC1/NKG2A as a therapeutic target, and experimental validation demonstrates that NKG2A blockade enhances CAR-T persistence and antitumour function. C_LI

bioengineering↗

bioRxiv2026

Glutamine Metabolism Supports α cell Mass and Glucagon Secretion

The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical cell regulator. Glutaminase is highly enriched in cells across species. cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in cell growth and hormone secretion and suggest it may play a role in cell adaptation to hyperaminoacidemia.

physiology↗

bioRxiv2026

Lower-limb mechanical power accounts for running energy expenditure and enables single-IMU estimation

Energy expenditure (EE) during running depends on the interplay between active muscle work and elastic energy storage and return, yet the relative contribution of mechanical power to EE remains debated. Quantifying the relative contributions of segment-level mechanical power can provide a way to address this debate. In this study, we aimed to quantify how segment-level mechanical power contributes to EE during running and to demonstrate that these mechanistic insights support wearable-based EE estimation. Joint dynamics and respiratory gas-based EE were collected from healthy young adults running at multiple speeds. Scale factors were derived to quantitatively link efficiency-weighted segment power to measured EE. The stance leg consistently showed the strongest correlation with EE, and this dominance was preserved across speeds. Including swing-leg hip power further improved accuracy. Scale factors were approximately 0.45, suggesting that active muscle work and elastic energy return contribute comparably to the mechanical power associated with EE. Using a lightweight machine learning model, stance-leg and swing-leg hip joint power were reconstructed from a single sacral IMU, enabling accurate EE prediction. These findings demonstrate that lower-limb mechanical power is a robust predictor of running EE, supporting both the extensibility of biomechanically-informed frameworks and wearable-based EE monitoring.

bioengineering↗

bioRxiv2026

Interplay between ferroptosis and guttae in an early-onset murine model of Fuchs endothelial corneal dystrophy (FECD)

Col8a2Q455K/Q455K (Q455K) mice exhibit features of early-onset Fuchs endothelial corneal dystrophy (FECD), including decreased endothelial cell density (ECD) and guttae formation. Within the context of these clinical features, this study longitudinally evaluates ferroptosis in Q455K and wild-type (WT) mice using in vivo imaging, PCR and immunohistochemistry. Fifty-six Q455K and 56 WT mice were evaluated from 3 to 24 months of age with in vivo confocal microscopy; ECD and guttae were measured. Ferroptosis marker expression was determined with PCR and immunohistochemistry (IHC). Data were analyzed using two-way ANOVA with Tukeys post hoc test, Chi-square test and a paired t-test. The ECD significantly decreased in both groups from 3 to 24 months of age, but more markedly in Q455K (2285 {+/-} 317 to 1012 {+/-} 58 cells/mm{superscript 2}) versus WT mice (2714 {+/-} 139 to 2057 {+/-} 149 cells/mm{superscript 2}, P<0.0001). Guttae were observed exclusively in Q455K mice beginning at 3 months of age and increased over time (P=0.0003). The Q455K mice demonstrate guttae at the vertices of corneal endothelial cells rather than their centers (74.3% vs. 25.7%P<0.001). Expression of ferroptosis-related genes (Tfrc, Slc40a1, Ftl1, Gpx4) were significantly increased in the Q455K versus WT mice (P<0.05). Furthermore, corresponding protein expression (transferrin receptor 1, ferroportin, ferritin and glutathione peroxidase 4) was significantly elevated adjacent to guttae in Q455K versus WT mice (P<0.05). These findings implicate guttae in the initiation of ferroptosis as it relates to the pathophysiology of FECD and provide an optimal window for testing novel FECD therapies using this murine model, particularly those that target ferroptosis. Significance StatementFuchs endothelial corneal dystrophy (FECD) is a major cause of corneal blindness, yet the mechanisms driving endothelial cell loss remain unclear. Using an early-onset Q455K murine model, we show that disease onset occurs by 3 months of age and progresses with characteristic corneal guttae, endothelial cell loss, and morphological abnormalities replicating human FECD. By identifying ferroptosis adjacent to guttae in the Q455K, we demonstrate this mechanism is not specific to genetic mutations, but rather a conserved driver of corneal endothelial loss within the context of guttae formation. These findings establish an FECD progression timeline and reveal a mechanistic link between ferroptosis and guttae, validating this model as a critical tool for evaluating targeted therapeutic strategies.

developmental biology↗

bioRxiv2026

A cholinergic eligibility trace facilitates amygdala plasticity in flavour avoidance learning

When an animal consumes a new food and consequently feels ill, it rapidly and robustly learns to avoid this food in the future, a form of learning termed conditioned flavour avoidance (CFA). Postingestive malaise often occurs long after novel food consumption, necessitating a neural mechanism that can facilitate plasticity between temporally distant events. Neuromodulators, acting through G-protein-coupled receptors (GPCRs) that can influence neuronal excitability on extended timescales, may facilitate this process. The projection of parabrachial (PB) Calca neurons to the central amygdala (CeA) is critical for formation of CFA. Here, we demonstrate that these neurons overlap with a PB population that releases acetylcholine (ACh) in the CeA. ACh is released in CeA during consumption of a novel solution and subsequent visceral malaise, consistent with a role in CFA acquisition. Two-photon calcium imaging in brain slices reveals that ACh widely activates CeA neurons and enhances glutamatergic responsivity on a timescale consistent with CFA learning. CRISPR-Cas9-mediated genetic knockdown and optogenetics demonstrate that ACh from PB facilitates CFA behavior. Large-scale neuronal recordings in the CeA along with our CRISPR approach reveal that loss of ACh signaling to CeA blocks key signatures of CFA-associated plasticity. Together, these data point to the cholinergic input from PB to central amygdala as a critical neuromodulatory signal that links activity over long timespans to facilitate associative learning in CFA.

neuroscience↗

bioRxiv2026

TOX enforces the immunosuppressive program of tumor-infiltrating regulatory T cells

Regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) to suppress anti-tumor immunity, but the transcriptional regulators stabilizing their immunosuppressive state remain poorly defined. Here we show that transcriptional factor TOX is selectively upregulated in tumor-infiltrating (TI) Treg cells across human cancers and mouse tumor models, while remaining low in peripheral and naive Treg populations. Treg-specific deletion of TOX reduced tumor burden, impaired TI Treg-mediated immune suppression, and enhanced effector functions of CD8 and CD4 T cells. In mosaic mice, TOX-deficient Tregs were selectively depleted from tumors, accompanied by increased apoptosis. Single-cell RNA sequencing and TCR clonotype analysis linked TOX expression to an effector-like TI Treg state with clonal expansion, whereas TOX loss shifted cells toward a TCF7-associated progenitor-like phenotype. ATAC-seq revealed enrichment of AP-1 motifs in TOX-sufficient TI Tregs. In contrast, TCF7, LEF1, and FOXO1 motifs in TOX-deficient counterparts, uncovering the opposing transcriptional networks downstream of TOX. Furthermore, TOX deficiency augmented CD8 T cell responses to PD-1 blockade. Together, these findings establish TOX as a key regulator of TI Treg fitness and stability, and identify it as a potential therapeutic target to enhance the efficacy of PD-1-based immunotherapy.

immunology↗

bioRxiv2026

Incomplete killing by antimicrobial metals generates transient antibiotic tolerance via delayed recovery in Escherichia coli

Incomplete killing is common after application of disinfectants or use of antimicrobial surfaces, leaving behind bacterial survivors with poorly characterized physiology. Here, we investigated the effects of short biocidal exposure to the common antimicrobial metals copper and silver as metal ions in suspension or under semi-dry conditions on solid metallic surfaces used against Escherichia coli. Survivors exhibited delayed regrowth and increased tolerance to bactericidal antibiotics without changes in MIC, consistent with a transient, non-genetic tolerance phenotype. When the magnitude of killing by silver or copper was matched between exposure formats, antibiotic tolerance patterns converged across metals and exposure conditions, indicating that the survivor state is governed more strongly by the severity of the primary lethal stress than by metal identity or exposure format alone. Incremental copper exposure revealed a dose- dependent increase in delayed regrowth and antibiotic tolerance but reduced tolerance to subsequent copper exposure. Post-exposure antibiotic tolerance as well as copper hypersensitivity phenotypes reverted after regrowth. Together, this supports a model of injury-linked delayed recovery rather than generalized stress priming. These findings demonstrate that incomplete disinfection can reshape survivor physiology, transiently increasing antibiotic tolerance through combined effects of selective survival acting on pre-existing phenotypic heterogeneity and acute injury-linked delayed recovery.

microbiology↗

bioRxiv2026

Lyophilization Maintains the Storage Stability and Bioactivity of Mesenchymal Stem Cell–Derived Extracellular Vesicles

BackgroundExtracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are emerging therapeutic candidates for bone regeneration, but their long-term stability remains a barrier to clinical translation. This study evaluated whether lyophilization supports the stable storage of extracellular vesicles derived from human epidural fat MSCs (hEF-MSCs) cell line. Research Design and MethodsEVs were isolated, lyophilized with 8.5 % sucrose and HEPES(4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)), and stored for 3 months at -80, -20, 4, and room temperature (20). After reconstitution in phosphate-buffered saline (PBS), structural characteristics were assessed using transmission electron microscopy, nanoparticle tracking analysis, and flow cytometry. Functional activity was evaluated using MC3T3-E1 osteogenic differentiation assays. The main outcome measures included morphology, particle counts, marker expression, cytotoxicity, and sequencing profiles. ResultsLyophilization maintained EV morphology, structural integrity, and particle distribution across all storage temperatures. Marker expression remained comparable among the conditions. Reconstituted EVs promoted osteogenic differentiation of MC3T3-E1 cells without evidence of cytotoxicity. Sequencing profiles revealed no significant differences among storage conditions. ConclusionsLyophilized EVs from hEF-MSCs cell lines exhibited stable structural and functional properties across a range of storage temperatures, supporting their suitability for further development in bone regeneration applications.

Molecular Biology↗

bioRxiv2026

Lyophilized Extracellular Vesicles Retain Regenerative Activity and Accelerate Wound Healing

Extracellular vesicles (EVs) are promising therapeutic agents for tissue regeneration because they regulate intercellular communication and modulate inflammatory responses. However, preserving EV bioactivity during long-term storage remains a major barrier to clinical application. We examined whether lyophilized EVs stored at -80 {degrees}C maintain their structural integrity and therapeutic efficacy in an in vivo wound-healing model. Mesenchymal stem cell-derived EVs were isolated and freeze-dried before storage at -80 {degrees}C. We evaluated EV physicochemical characteristics before and after lyophilization using nanoparticle tracking analysis, transmission electron microscopy, and EV marker-expression analysis. To assess regenerative efficacy, lyophilized EVs were applied topically to full-thickness ear wounds in CCR2-GFP mice. Wound-healing progression and CCR2-positive cell infiltration were monitored during tissue recovery using intravital microscopy. Lyophilized EVs preserved their characteristic morphology, particle-size distribution, and EV surface marker expression after storage. In vivo analysis showed that EV-treated wounds closed significantly faster than phosphate-buffered saline-treated controls. Additionally, lyophilized EV treatment reduced CCR2-positive inflammatory cell recruitment during healing, suggesting an immunomodulatory role in tissue regeneration. These findings show that EVs lyophilized and stored at -80 {degrees}C retain biological function and therapeutic potential in vivo. Lyophilized EVs may, therefore, provide a practical strategy for long-term storage and delivery of EV-based regenerative therapeutics.

Cell Biology↗

bioRxiv2026

Dual lineages of Langerhans cells cooperate to restore the immune barrier after skin injury

Langerhans cells (LCs) are key immune sentinels of the epidermis. How this network reorganizes to safeguard epidermal immunity after injury has remained unclear. Here, we uncover a previously unrecognized two-lineage program of LC repopulation during wound repair. Classically, tissue-resident embryonically derived LCs (eLCs) migrate to lymph nodes in response to antigens. In contrast, we find that injury triggers nearby eLCs to migrate into wounds, providing immediate coverage. In parallel, circulating monocytes infiltrate the skin and differentiate into long-lived monocyte-derived LCs (mLCs) that integrate stably into the network. We identify the chemokine receptor CXCR2 as a novel regulator of eLC migration into wounds, distinct from the CXCR4/CCR7 pathways mediating LC egress to lymph nodes. Pharmacological inhibition of CXCR2 impairs directional eLC migration and is accompanied by increased mLC infiltration, preserving immune barrier density. These findings reveal a coordinated and flexible two-lineage repair program that ensures robust restoration of epidermal immunity.

cell biology↗

bioRxiv2026

Substrate and target selectivity of 4'-fluoroadenosine against viral and host polymerases

Developing safe and effective treatments against emerging RNA viruses is an important goal in pandemic preparedness efforts. 4'-fluorouridine (4'-FlU) is a broad-spectrum antiviral that was shown to inhibit viral RNA-dependent RNA polymerases (RdRps). Given its notable range of antiviral activity, this class of nucleoside analogs warrants further investigation. Here, we studied the antiviral activity and underlying mechanism of inhibition of 4'-fluoroadenosine (4'-FlA). Like 4'-FlU, 4'-FlA demonstrates a broad-spectrum of antiviral activity against eight prototypic viruses representing diverse families. Enzyme kinetics show that the triphosphate (4'-FlA-TP) is efficiently incorporated by viral RdRps. A cryo-EM structure of RdRp of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in complex with double-stranded RNA and the incorporated monophosphate (4'-FlA-MP) characterizes interactions at the active site. The incorporated analog elicits heterogeneous inhibition patterns in primer extension reactions. In contrast, templates with embedded 4'-FlA-MP inhibit incorporation of complementary UTP across the viral RdRps. However, incorporation of 4'-FIA-TP is not limited to viral polymerases and likewise includes human mitochondrial RNA polymerase. These results demonstrate the general potential for 4'-fluorinated nucleotides as antiviral drugs and guide the development of more selective derivatives for medical use in appropriate settings.

microbiology↗

bioRxiv2026

Adrenomedullin Restores Mitochondrial Bioenergetics and Rescues Interneuron Phenotypes in Human Models of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, is the strongest genetic risk factor for schizophrenia, yet the cellular mechanisms underlying this vulnerability remain incompletely understood. Using iPSC-derived human subpallial organoids (hSOs) and forebrain assembloids (hFAs), we identified key 22q11.2DS cellular and molecular phenotypes in migrating cortical interneurons and rescued them with Adrenomedullin (ADM), a 52-amino-acid peptide hormone that acts through the CLR/RAMP2 receptor complex. Specifically, we discover that 22q11.2DS interneurons exhibit impaired migration patterns, and that this is associated with excessive mitochondrial fragmentation, reduced oxidative phosphorylation, and dysregulated calcium signaling. Transcriptomic analysis reveals a glycolytic shift and widespread downregulation of oxidative phosphorylation genes. Next, we identify ADM as a potent rescue agent that restores mitochondrial morphology, membrane potential, respiration, calcium homeostasis, actin retrograde flow, and interneuron migration. Mechanistically, we find that ADM signals through two parallel pathways: PKA-mediated DRP1 Ser637 phosphorylation, which promotes mitochondrial fusion, and PLC-mediated calcium signaling, which normalizes actin dynamics. These phenotypes and their rescue are recapitulated in primary developing human cortical tissue carrying the 22q11.2 deletion. Overall, our study establishes a mitochondrial-cytoskeletal axis as a novel biological mechanism underlying the alterations observed in neuronal development in human preclinical models of 22q11.2DS and identifies possible therapeutic molecular targets for 22q11.2DS-associated neuropsychiatric pathology. HIGHLIGHTSO_LIInhibitory neurons in 22q11.2DS organoids and assembloids show mitochondrial fragmentation and impaired migration C_LIO_LIADM rescues mitochondrial morphology, respiration, and interneuron migration C_LIO_LIPKA and PLC pathways mediate separate arms of ADMs rescue mechanism C_LIO_LIPhenotypes and ADM rescue are validated in human cortical tissue C_LI

neuroscience↗

bioRxiv2026

Telomere-to-telomere, accurate, and gapless genome assembly (TTAGGA) of the Korean Jindo dog with a single-contig Y chromosome

Complete canine reference genomes are essential for studies of structural variation, sex-chromosome evolution, and breed-specific architecture, yet existing references remain incomplete on the Y chromosome and retain internal gaps across multiple chromosomes. Here, we introduce TTAGGA (Telomere-to-Telomere, Accurate, Gapless Genome Assembly), a stricter completeness standard requiring chromosomes assembled end-to-end with zero internal gaps and Merqury consensus QV [≥] 50, and present Jindo1-G-TTAGGA, the first canine assembly to meet this standard, achieved under a stringent QV [≥] 60 threshold. From 813 Gb ([~]340x coverage) of multi-platform data (PacBio HiFi [~]150x, ONT ultra-long [~]103x, parental Illumina [~]40x per parent) generated from a male Korean Jindo dog, trio binning with hifiasm produced two haplotype-resolved assemblies of 2,441.6 Mb (Hap1, maternal, chrX-carrying) and 2,340.5 Mb (Hap2, paternal, chrY-carrying). Both haplotypes are gap-free at every internal position, with canonical telomeric repeats verified at both ends of all 39 chromosomes (tidk), Merqury consensus QV of 78.0 (Hap1) and 76.8 (Hap2), trio switch-error rates below 0.13%, BUSCO completeness of 99.3% (Hap1) and 96.4% (Hap2; the lower value reflects absent X-linked orthologues in the Y-bearing haplotype), and Genome Continuity Index values of 98.2 (Hap1) and 94.7 (Hap2). Hap2 carries a single 21,255,890 bp gap-free Y chromosome with TTAGGG telomeric repeats at the q-arm terminus and an acrocentric satellite-rich p-arm, representing a 5.4-fold increase over the 3.94 Mb chrY of ROS_Cfam_1.0 and adding approximately 14 Mb of newly resolved Y-linked sequence; this corresponds to roughly 79% of the cytogenetically estimated 27 Mb full-length canine chrY. Jindo1-G-TTAGGA provides a chromosome-scale, haplotype-resolved, gap-free canine reference for studies of canine structural variation, sex-chromosome evolution, and canid phylogenomics.

genomics↗

bioRxiv2026

Diffusion-based stimulus optimization reveals functional organization across higher visual cortex

Characterizing the fine-grained functional organization of human higher visual cortex remains a central challenge, as traditional neuroimaging experiments constrain the diversity of stimuli that can be sampled. In prior work we addressed this challenge by developing a novel data-driven tool, termed "BrainDiVE" (Luo et al. 2023), which synthesizes naturalistic images predicted to strongly activate specific brain regions. BrainDiVE leverages pretrained image diffusion models guided by gradients from an image-computable fMRI encoding model. Here, we experimentally validated BrainDiVE by generating images predicted to maximally activate different functional regions of interest and then presenting them to new participants (n=12) in an fMRI study. The model-generated images elicited robust, spatially specific responses in the targeted brain regions, producing significantly greater category selectivity than natural images, validating the methods ability to capture generalizable neural tuning properties in human ventral visual cortex. We further showed that region-targeted images exaggerate specific sets of low-level and mid-level image statistics, suggesting that category-selective regions are tuned to continuous directions in feature space. Moreover, we demonstrated fine-grained experimental control by differentially activating two face-selective regions, the occipital face area (OFA) and fusiform face area (FFA), providing additional evidence that these regions encode distinct aspects of faces. Finally, we identify a posterior-to-anterior functional gradient within the occipital place area (OPA), suggesting topographic organization based on scene properties such as distance and indoor-outdoor location. These findings enhance our understanding of the representational structure of category-selective regions and introduce a new paradigm for probing neural selectivity in human visual cortex.

neuroscience↗

bioRxiv2026

Environmental Regulation and Gene-by-Environment Interaction Influence RAP1 Activity and its Impact on Gene Expression

Gene-by-environment (GxE) interactions play a major role in shaping both phenotypic and molecular variation, with important implications for human health and disease. In this study, we used the Doxycycline (Dox) regulated, tetracycline-responsive (Tet-Off) promoter system to sequentially reduce or titrate gene expression levels of the essential yeast transcription factor Repressor Activator Protein 1 (RAP1) similar to a hypomorph allele series, across three distinct environments: Yeast Peptone Dextrose (YPD) media, YPD media with Heat Shock (HS), and Yeast Peptone Acetate (YPAC) media. We then performed RNA sequencing (RNA Seq) to assess global transcriptional responses to RAP1 reduction in these different growth environments. Our analysis first focused on the independent effects of varying RAP1 expression levels within and across environments. We then explored GxE interactions, revealing a subset of genes with significant consequences of reduced levels of RAP1 and environment-specific expression patterns. Notably, many genes exhibited opposite effects of RAP1 titration on gene expression when yeast were grown in YPAC media compared to YPD media and/or HS, suggesting environment-dependent regulatory architecture. This design reveals how cells integrate internal transcriptional and regulatory changes with external environmental cues, providing a deeper view of GxE architecture. Using Weighted Gene Co-expression Network Analysis (WGCNA), we identified co-regulated gene modules, and by combining this with transcription factor motif enrichment tests, our study identified candidate regulators driving their dynamics. Our findings demonstrate that gene regulatory networks can vary dramatically depending on the environmental context an organism experiences, which can then influence the specific phenotypes produced by a particular genetic perturbation. This illustrates the complexity of genotype-environment interactions and the importance of studying gene function in multiple environments to gain a truly comprehensive understanding of a genes sometimes numerous and diverse functions.

genomics↗