Biology subjects

Jung, Y.

Publications and source records attributed to Jung, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury

Although acute kidney injury (AKI) has been implicated as a potential adverse effect of statin therapy, experimental evidence supporting this association remains limited. Here, we investigated whether elevated levels of 25-hydroxycholesterol (25-HC), an oxysterol produced by activated macrophages and monocytes, increase susceptibility to statin-induced AKI. We found that atorvastatin and fluvastatin induced cell death in proximal tubular cells when combined with 25-HC. Consistently, administration of low-dose lipopolysaccharide triggered AKI in statin-treated mice. Mechanistically, impaired protein prenylation disrupted the autophagosome-lysosome pathway in proximal tubular cells. AKI was attenuated by mevalonate supplementation, which restored protein prenylation, and by macrophage/monocyte depletion, which reduced the cellular sources of 25-HC. Furthermore, combined exposure to fluvastatin and 25-HC increased kidney injury molecule-1 (KIM-1) expression in human induced pluripotent stem cell-derived kidney organoids. Together, these findings suggest that elevated macrophage-derived 25-HC under conditions of infection, inflammation, or major surgery may increase susceptibility to statin-induced AKI. Our study identifies a previously unrecognized interaction between statins and 25-HC and suggests potential strategies to mitigate kidney injury while preserving the therapeutic benefits of statins.

pharmacology and toxicology↗

bioRxiv2026

Perceived social value is more strongly linked to gossip decisions with age in adolescence

Gossip is central to social exchange, yet how adolescents select what to share and with whom remains unclear. Across two independent samples aged 10-18 years (behavioural, n = 98; fMRI, n = 101 scanned), adolescents read information about absent third parties, chose whether and with whom to share it, and reported their appraisals. Sharing frequency showed no detectable age association. Valuation-to-decision coupling strengthened with age for interest in both samples, with a smaller age interaction for usefulness. Adolescents selected close friends more often with age when sharing. During scenario reading, before participants reported their choices, BOLD responses in a left inferior frontal cluster tracked subsequent interest ratings more strongly with age (n = 92), also within regions engaged by a separate mental-state judgment task. Together, these findings link age in adolescence to stronger valuation-to-decision coupling for interest and a greater proportion of sharing directed to close friends.

neuroscience↗

bioRxiv2026

Population geometries in frontal cortex coordinate value-based decisions

Decisions often involve trade-offs between benefits and costs, such as a small payment now vs. a larger payment after a delay. Although decision variables are distributed across frontal cortex, how these regions transform competing attributes into a choice remains unclear. Combining large-scale electrophysiology with causal perturbations as mice chose between different reward amounts and delays, we found that population geometry of decision variables differed across regions, reflecting distinct computations. Dorsal frontal areas, including motor cortex, collapsed competing attributes onto a decision axis shared across reward-delay contexts, with projection amplitude predicting choice probability; silencing these areas impaired action selection regardless of delay. In contrast, ventral prefrontal cortex (vPFC) represented choice in higher-dimensional subspaces organized by reward delay, whose geometry predicted how strongly delay influenced choice. Notably, inhibiting vPFC preserved the dorsal decision representation but selectively removed its modulation by reward delay, causing animals to behave as if delay no longer influenced choice. vPFC inhibition had no effect when mice chose between reward amounts. Frontal cortex therefore solves multi-attribute decisions through a generator-modulator architecture: dorsal frontal circuits maintain a shared choice axis guiding decisions across contexts, whereas vPFC maintains competing attributes in distinct subspaces that modulate decisions when options conflict.

neuroscience↗

bioRxiv2026

Longitudinal transcriptomic analysis reveals adaptive transcript usage remodeling associated with PARP inhibitor resistance

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of ovarian and breast cancers with homologous recombination deficiency (HRD). Despite substantial initial efficacy, the frequent development of acquired resistance poses a critical clinical challenge, necessitating a deeper understanding of the underlying molecular mechanisms. While genomic profiling provides information on baseline HRD status, it is insufficient to capture the dynamic and functional adaptations accompanying resistance during treatment. In this study, we investigated the role of alternative splicing in PARPi resistance using longitudinal pre- and post-treatment RNA-sequencing data from an ovarian cancer patient cohort (n=40). We demonstrated that profiling alternative splicing dynamics and differentially used transcripts (DUTs) provides transcriptomic insights distinct from conventional differential gene expression analysis. Notably, we observed significant differences between acquired resistance (AR) and innate resistance (IR) groups. Specifically, longitudinal analysis revealed that AR tumors exhibit a distinct transcript usage pattern, characterized by an increase in canonical protein-coding transcripts involved in cell-cycle processes and a decrease in non-canonical non-coding transcripts within the homologous recombination pathway following treatment. Extending this comparison across AR and IR tumors at both pre- and post-treatment stages, these transcriptomic features were most pronounced in the AR post-treatment group. Further analysis of subsequent treatment outcomes showed that, among AR patients, greater resistance-associated transcriptomic remodeling was associated with poorer response and shorter progression-free survival. The resistance-associated transcriptomic signatures identified through longitudinal profiling were further recapitulated in an independent pre-treatment cohort (n=71; 43 AR and 28 IR), with more pronounced differences among BRCA wild-type patients. Taken together, our findings identify differential transcript usage as dynamic transcriptomic features associated with acquired PARPi resistance and establish a framework for utilizing longitudinal transcriptome dynamics to investigate the molecular basis of clinical drug resistance.

cancer biology↗

bioRxiv2026

Expanded Group-Constrained Parcels Enhance Coverage and Reproducibility of the Scene-Selective Cortex

A common approach for investigating high-level visual cortex with functional magnetic resonance imaging (fMRI) is to define regions of interest (ROIs) in individual participants using functional activation clusters and anatomical landmarks. Although highly productive, this approach requires manual decisions about which clusters correspond to specific canonical regions, limiting reproducibility and posing challenges in populations with lower signal-to-noise ratios, such as children. The Group-Constrained Subject-Specific (GSS) approach reduces this subjectivity by using group-level parcels to constrain subject-specific functional ROI definition. However, the original GSS parcel set provides limited coverage of the occipital place area (OPA) and does not include more recently characterized scene-selective regions. Here, we introduce an updated and expanded set of GSS parcels for scene-selective cortex. Using a larger adult sample and dynamic scene stimuli, we generated updated parcels for OPA, parahippocampal place area (PPA), and retrosplenial complex (RSC), and for the first time, delineated a parcel for a newly discovered scene-selective region in the superior parietal lobule (superior place area; SPA). We evaluated these parcels in independent adult and pediatric datasets by testing whether they improve cross-subject coverage while preserving functional selectivity. The updated OPA parcel increased cross-subject coverage relative to the original parcel by Julian and colleagues. Moreover, ROIs defined using the updated parcels showed equal or greater scene selectivity across OPA, PPA, and RSC, indicating improved functional ROI definition without sacrificing specificity. Across scene-selective regions, the updated parcels reliably identified scene-selective cortex and reproduced canonical response profiles and in pediatric data. These parcels provide more complete and reliable coverage of the scene-processing network, supporting objective and reproducible ROI definition across adult and pediatric fMRI datasets. HighlightsO_LIExpanded group-constrained parcels improve coverage of scene-selective cortex C_LIO_LIDynamic stimuli yield improved cross-subject overlap for OPA C_LIO_LINew parcel introduced for the scene-selective region in the superior parietal lobule, now called superior place area (SPA) C_LIO_LIUpdated parcels reproduce canonical response profiles in adult data C_LIO_LIParcels reliably identify scene-selective voxels in pediatric datasets C_LI

neuroscience↗

bioRxiv2026

Microenvironmental Determinants of Reaction Kinetics in Biomolecular Condensates Probed with Protein Ligation

Cells utilize liquid-liquid phase separation to organize biochemical reactions within biomolecular condensates, which function as membraneless organelles. Although these assemblies are known to enhance reaction rates by concentrating reactants, the mechanisms beyond simple mass-action effects remain poorly understood. Here, we examined how the physicochemical microenvironment within condensates modulates reaction kinetics using spontaneous protein ligation as a model reaction, conducting a systematic analysis across various condensates, ranging from structured scaffolds (PRM-SH3 systems) to intrinsically disordered protein (IDP)-based scaffolds such as LAF, TAF, and FUS. We designed a FRET-based proximity-sensitive client probe to quantify increases in effective local concentration arising from excluded-volume effects. In parallel, we measured internal hydrophilicity and water activity, revealing them as additional key determinants of reaction acceleration. Together, the findings presented here elucidate how phase-separated compartments regulate biochemical reactions through the interplay of physical (effective concentration) and chemical (hydrophilicity and water activity) microenvironments and provide mechanistic insights for engineering condensates with tunable reactivity.

biochemistry↗

bioRxiv2026

Visualizing early Mycobacterium tuberculosis interactions with murine lung macrophages using intravital imaging

Intravital microscopy enables direct visualization of dynamic cellular processes within intact tissues, but its application to Mycobacterium tuberculosis (Mtb) has been limited by Biosafety Level 3 (BSL-3) containment requirements and the technical challenges of stabilizing the lung for high-resolution imaging. Here, we present a protocol that combines the thoracic Window for High-Resolution Imaging of the murine Lung (WHRIL) with a genetically defined, triple-auxotrophic Mtb strain (mc27902) approved for use under BSL-2 conditions. We describe the construction of a tdTomato-expressing derivative (mc28471) preparation of bacteria for intravenous infection and intravital imaging in reporter mice. This system enables visualization of rapid bacterial entry into the pulmonary vasculature, subsequent aggregation, and vascular occlusion, dissemination into the lung parenchyma, and macrophage uptake over three days post-infection. This protocol provides the first practical platform for real-time intravital imaging of mycobacteria in the lung and establishes a foundation for mechanistic studies of bacterial physiology, host recognition, and immune-mediated clearance using safe Mtb surrogates. SummaryThis protocol describes a biosafety level 2 (BSL-2)-compatible intravital imaging platform for visualizing Mycobacterium tuberculosis (Mtb) in the intact murine lung at single cell resolution. By combining the Window for High-Resolution Imaging of the murine Lung (WHRIL) with a fluorescently labeled, genetically defined triple auxotrophic Mtb strain (mc27902), this approach overcomes long-standing biosafety and technical barriers that have prevented real-time imaging of mycobacterial infection in vivo. The method enables direct visualization of early bacterial localization, aggregation, vascular interactions, and macrophage uptake during the initial hours to days following infection, providing a practical foundation for mechanistic studies of host-pathogen interactions under safe experimental conditions.

immunology↗

bioRxiv2026

Metastatic dissemination of breast cancer stem cells requires MenaINV for lung extravasation but not survival

Cancer stemness is a pivotal driver of tumor initiation, treatment resistance, and tumor cell survival. Cancer stem cells (CSCs), though constituting only a small fraction of primary tumor cells, are progressively enriched during metastatic progression: from circulating tumor cells traveling in the bloodstream, to disseminated tumor cells lodged in the lung vasculature, to extravasated tumor cells that have entered tissue parenchyma. However, whether CSCs have an intrinsic advantage for extravasation over cancer non-stem cells (CnSCs), or simply their increased representation in circulation renders them more likely to extravasate, remains unresolved. MenaINV, an invasive isoform of the actin regulatory protein Mena, promotes tumor cell transendothelial migration in primary and secondary sites, yet the direct mechanistic link between stemness and MenaINV in lung metastasis remains unresolved. Here, using a validated fluorescent stemness reporter (SORE6) to identify CSCs, we found that CSCs display elevated MenaINV expression relative to CnSCs. High-resolution intravital imaging showed that CSCs extravasate efficiently into lung parenchyma and survive at higher levels, robustly forming metastatic lesions, while CnSCs show limited extravasation, low survival, and poor colonization. Mechanistically, MenaINV disruption in CSCs specifically impaired extravasation without affecting survival, demonstrating that MenaINV is the key extravasation effector downstream of stemness, whereas stemness-associated factors independently confer survival advantages. Moreover, reintroduction of MenaINV in CnSCs restores their extravasation ability upon which extravasated CnSCs reactivate stem program and form metastases. Overall, we discovered a hierarchical framework where stemness regulates both survival and extravasation capacity, with MenaINV as the key CSC extravasation effector. Significance: This study reveals how breast cancer stem cells achieve metastatic dominance through separable pathways: MenaINV-dependent extravasation and MenaINV-independent survival, providing rationale for targeting stem program to improve patient outcome.

cancer biology↗

bioRxiv2026

FAK Inhibition Remodels the Metastatic ECM and Restores CD8+ T Cell Trafficking and Immunosurveillance

Metastatic breast cancer remains largely incurable, driven in part by immunosuppressive microenvironments that limit CD8+ T cell-mediated clearance. Using a murine pulmonary metastatic breast cancer model, we show that the focal adhesion kinase (FAK) inhibitor VS-4718 promotes a CD8+ T cell-dependent regression of metastatic lesions by reprograming the metastatic microenvironment. VS-4718 reduced immunosuppressive myeloid and regulatory T cells while increasing CD8+ T cell infiltration. Cellular and secreted proteome profiling revealed that VS-4718 downregulates ECM components such as laminin 5 and collagen VIII1, which we show impair CD8+ T cell migration and activity. In human breast cancer cohorts, elevated LAMA5/COL8A1 expression and a FAK-dependent ECM signature associate with poor outcome and prognostic for residual disease. Intravital imaging demonstrated that VS-4718 enhances CD8 T cell extravasation and induces T cell-tumor cell contacts necessary for cytotoxicity. Ex vivo lung slice cultures recapitulated these findings, showing enhanced T cell swarming, metastatic cluster shrinkage, and apoptosis. These findings reveal how FAK inhibition remodels the metastatic ECM to potentiate coordinated CD8+ T cell responses. VS-4718 might aid in clearing metastases in breast cancer patients through modulating both stromal and immune components. STATEMENT OF SIGNIFICANCEFocal adhesion kinase (FAK) inhibition remodels collagen- and laminin-rich extracellular matrix barriers and alleviates physical constraints that limit CD8 T cell access and activity in metastases. This enhances infiltration, migration, and tumor cell engagement, and synergizes with PD-1 blockade, supporting combined therapeutic strategies in metastatic breast cancer.

cancer biology↗

bioRxiv2025

A machine learning framework for predicting and modulating condition-dependent protein phase separation

Protein phase separation is a fundamental process in organizing membraneless organelles and is implicated in a wide range of pathological conditions. Importantly, rather than being a static feature of specific proteins, phase separation is a condition-dependent phenomenon governed by environmental parameters, including protein concentration, temperature, and solvent composition. However, most existing machine learning models infer phase-separation propensity solely from amino-acid sequences, failing to capture these context-dependent behaviors. Here, we present LLPSense, a machine learning framework that integrates pre-trained protein language model embeddings with environmental parameters to achieve accurate, condition-aware predictions of protein phase separation. We demonstrate LLPSenses predictive power and utility through three key experimental demonstrations. First, the model revealed that SGTA, previously unrecognized as a phase-separating protein, exhibits complex, temperature-dependent reentrant phase behavior. Second, LLPSense accurately predicted mutations in -synuclein that either enhance or suppress phase separation, enabling systematic mapping of residues potentially relevant to Parkinsons disease. Third, using model-guided mutagenesis, we inverted the phase behavior of UBQLN4, shifting it from high-temperature to low-temperature separation. Collectively, LLPSense provides a robust computational tool for interrogating the condition-dependent landscape of protein phase separation, enabling mechanistic studies of disease-associated phase separation and the rational design of programmable condensates.

bioinformatics↗

bioRxiv2025

TMEM Doorway Mediated Metastasis in Pancreatic Ductal Adenocarcinoma by Tie2 Signaling

Pancreatic ductal adenocarcinoma (PDAC) is almost invariably fatal due to early hematogenous dissemination that occurs before the primary tumor is clinically detectable, yet the cellular mechanism of tumor cell intravasation has remained unknown. Using multiphoton intravital imaging in autochthonous and orthotopic PDAC models, we demonstrate that intravasation occurs at Tumor Microenvironment of Metastasis (TMEM) doorways--tri-cellular structures comprising a MENA-expressing tumor cell, a Tie2 macrophage, and an endothelial cell in direct contact. These structures are abundant in human PDAC, enriched for Tie2 macrophages, and markedly reduced after neoadjuvant chemotherapy. Selective pharmacologic inhibition of Tie2 with rebastinib decreases TMEM-associated transient vascular openings, suppresses circulating and hepatic disseminated tumor cells, and--when combined with perioperative FOLFIRINOX after curative-intent resection--improves median survival in murine PDAC. These findings establish TMEM doorways as a common, druggable mechanism of intravasation across epithelial cancers and identify Tie2 macrophages as a therapeutic target to prevent metastatic seeding in PDAC, a disease with no anti-metastatic therapies. TMEM doorway-mediated intravasation in PDAC supports its role as a common gateway for hematogenous metastasis in carcinoma.

cancer biology↗

bioRxiv2025

Effects of human stress on horse behavior and interaction quality

Human-horse interaction can be influenced by the emotional and physiological state of humans, as horses are highly sensitive to human stress. Understanding these effects is essential for improving outcomes in equine-assisted activities. This study examined how human stress impacts horse behavior and interaction quality. Seven humans and seven horses participated in a crossover design experiment in which participants viewed either stressful or relaxed video stimuli prior to interacting with horses. Electroencephalography (EEG), heart rate variability (HRV), and salivary cortisol was collected to assess human physiological responses, while the Human-Animal Interaction Scale (HAIS) and an ethogram evaluated interaction quality and horse behaviors. Stressful stimuli significantly increased beta and high-beta activity and altered HRV indices, indicated by increased low-frequency power and decreased high-frequency power. HAIS scores were lower under stress conditions, reflecting reduced interaction quality. Horses exhibited more pushing behavior and less lip-licking when handlers were stressed, although task completion time did not differ between conditions. These results demonstrated that human stress negatively influences both physiological states and behavioral outcomes within human-horse interactions. Therefore, managing emotional states and stress levels may enhance interaction quality and effectiveness in equine-assisted programs.

animal behavior and cognition↗

bioRxiv2025

Associations between canine temperament and salivary levels of cortisol and serotonin

Temperament influences canine behavior and helps determine a dogs suitability as a companion or working animal. Although several temperament assessment tools exist, many rely on subjective evaluations, highlighting the need for scientifically validated methods. This study evaluated the validity of the Wesen temperament test by examining its association with physiological biomarkers--salivary cortisol and serotonin. Twenty-four dogs (11 females and 13 males) completed a modified Wesen test comprising seven subtests: Unconscious Confidence, Sociality, Noise Stability, Movement Stability, Desire for Play and Predation, Behavior in Stressful Situations, and Separation. Saliva samples were collected pre- and post-assessment, and cortisol and serotonin levels were measured using ELISA. Hormonal levels and temperament scores were analyzed using correlation, regression, and Kruskal-Wallis tests. Pre-assessment cortisol levels were negatively correlated with total average temperament score and several subtest scores. Post-assessment cortisol levels showed significant negative correlations with total average scores and all subtests. Changes in cortisol levels from pre- to post-assessment were negatively associated with temperament scores. Dogs with higher temperament scores exhibited significantly higher serotonin levels than those with lower scores. These findings support the utility of temperament assessments validated through physiological markers and provide novel evidence linking canine temperament with endocrine function.

physiology↗

bioRxiv2025

Rapid CAR Screening and circRNA-driven CAR-NK Cells for Persistent Shed-resistant Immunotherapy

Chimeric antigen receptor (CAR)-based immunotherapies against solid tumors face two major hurdles, the "decoy effect" of shedding antigens that sequester CARs, and the limited persistence of immune effectors within the immunosuppressive tumor microenvironment. Here, we present a mechanistic approach to overcome these barriers by integrating a physiologically relevant screening platform with circular RNA (circRNA) engineering. Unlike conventional screens using immortalized cell lines, we performed rapid functional screening directly in human primary natural killer (NK) cells to identify a novel scFv, CLMS10. Structural modeling revealed that CLMS10 targets a membrane-proximal epitope that overlaps the proteolytic cleavage site, thereby evading inhibition by soluble mesothelin (solMSLN). Furthermore, we demonstrated that circRNA-mediated CAR expression, when codelivered with interleukin-21 (IL-21), confers sufficient stability to withstand the continuous antigen shedding induced by cancer-associated fibroblasts (CAFs), resulting in reduced CAR downregulation. In an in vivo metastatic pancreatic cancer model, IL-21-augmented circCAR-MS10-NK cells exhibited potency comparable to that of lentivirally engineered CAR-NK cells while offering superior manufacturability. Overall, this study establishes a paradigm for generating shed-resistant CAR therapeutics through the strategic integration of epitope-specific functional selection and enhanced RNA stability.

bioengineering↗

bioRxiv2025

Cinnamomum cassia Extract and Its Novel Isolated Compound Suppress Inflammation via Autophagy Induction in Sepsis

Uncontrolled inflammation is central to the development of diseases such as sepsis, and autophagy has emerged as a critical regulatory mechanism in this process. The ethanol extract of Cinnamomum cassia (EECC) was identified as a potent autophagy inducer through high-throughput LC3 reporter screening. EECC enhanced autophagic flux, as confirmed by RFP-GFP-LC3 imaging and immunoblotting. It also suppressed Toll-like receptor signaling and reduced pro-inflammatory cytokine production in macrophages. EECC inhibited nuclear factor-{kappa}B signaling in an autophagy-dependent manner, as this effect was reversed by autophagy inhibitors. To identify active constituents, 24 compounds were isolated from EECC, including six novel structures. Among the novel compounds, Cassitamine F exhibited dual activity as an autophagy inducer and inflammation suppressor. In a lipopolysaccharide-induced sepsis model, Cassitamine F significantly reduced serum levels of pro-inflammatory cytokines. These findings suggest that EECC and Cassitamine F may hold therapeutic potential for autophagy-targeted treatment of sepsis and other inflammation-related disorders. Highlights- Ethanol extract of Cinnamomum cassia (EECC) identified as a potent autophagy inducer via high-throughput LC3 HiBiT screening. - EECC suppresses Toll-like receptor signaling and pro-inflammatory cytokines through autophagy-dependent pathways. - Twenty-four compounds were isolated from EECC, including six novel structures (Cassitamine A-F). - Cassitamine F exhibits dual activity: induction of autophagy and inhibition of inflammation. - Cassitamine F significantly reduces serum cytokine levels in an LPS-induced sepsis model, suggesting therapeutic potential.

pharmacology and toxicology↗

bioRxiv2025

BIOCOMPATIBILITY OF LARGE-AREA 2-DIMENSIONAL ELECTRONIC MATERIALS WITH NEURAL STEM CELLS

Two-dimensional (2D) electronic materials hold immense promise for next-generation bio/neuro-electronic interfaces, but their biocompatibility has remained uncertain due to conflicting reports from studies focused on exfoliated flakes and suspensions. In this work, we present a comprehensive in vitro evaluation of electronic-grade large-area, chemical vapor deposition (CVD)-grown 2D materials - including platinum diselenide (PtSe2), platinum ditelluride (PtTe2), molybdenum disulfide (MoS2), and graphene - as substrates for mouse neural stem cell culture. Across all CVD-grown materials, the stem cells exhibited outstanding viability, with no significant differences in metabolic activity or live/apoptotic cell ratios compared to laminin-coated glass controls (p > 0.05). Importantly, these large-area 2D materials robustly supported neuronal differentiation, as evidenced by widespread {beta}III-tubulin expression. Strikingly, we found that flaky MoS2 promoted significantly greater neuronal maturation (>75% NeuN neurons) than any other substrate tested (25-50% NeuN; p < 0.05), revealing the critical influence of material format on bioactivity. While PtSe2 showed a tendency to promote glial lineage differentiation, our findings firmly establish large-area CVD-grown 2D materials as biocompatible, tunable platforms for neural interfacing, paving the way for their integration into advanced bio/neuro-electronic devices.

bioengineering↗

bioRxiv2025

Longitudinal deep phenotyping in a mouse model of West syndrome reveals temporal dynamics of synapse remodeling, gliosis, and proteomic and lipidomic changes during seizure evolution

Neurodevelopmental disorders can have long-lasting effects, causing not only early pediatric symptoms but also a range of neurological issues throughout adulthood. West syndrome is a severe neurodevelopmental disorder marked by infantile spasms, an early symptom that typically subsides with age. However, many patients progress to other seizure forms, known as seizure evolution, which is closely linked to poor long-term outcomes. Despite its clinical significance, the neurobiological mechanisms behind seizure evolution in West syndrome remain poorly understood. Recent genetic studies have consistently identified the CYFIP2 p.Arg87Cys variant in West syndrome patients, and the Cyfip2+/R87C mouse model carrying this mutation has been shown to recapitulate key symptoms of the disorder, including infantile spasms. In this study, we aimed to gain deeper insight into seizure evolution by conducting longitudinal deep phenotyping of the Cyfip2+/R87C mouse model from the neonatal stage to seven months of age. We tracked seizure activity through behavioral and EEG recordings and employed multi-omic analyses, including tissue and single-cell level transcriptomics, ultrastructural analysis, proteomics, and lipidomics, to capture a comprehensive view of molecular and cellular changes. Our results showed that after an initial period of neonatal spasms, Cyfip2+/R87C mice entered a seizure-free phase, followed by spontaneous recurrent seizures in adulthood, ultimately leading to premature death. This progression was associated with synaptic remodeling, sequential activation of different glial cell types, lipid droplet accumulation in astrocytes, and significant proteomic and lipidomic changes in the brain. These findings suggest that seizure evolution in West syndrome involves complex, time-dependent interactions between neurons and glial cells, along with alterations in lipid metabolism. Our study highlights the potential of longitudinal multi-omic approaches to uncover underlying mechanisms of seizure evolution and suggests that targeting these changes could offer novel therapeutic strategies. Additionally, the dataset generated here may provide valuable insights for other epilepsy and neurodevelopmental disorder models.

neuroscience↗

bioRxiv2025

Morphogenesis and morphometry of brain folding patterns across species

Evolutionary adaptations associated with the formation of a folded cortex in many mammalian brains are thought to be a critical specialization associated with higher cognitive function. The dramatic surface expansion and highly convoluted folding of the cortex during early development is a theme with variations that suggest the need for a comparative study of cortical gyrification. Here, we use a combination of physical experiments using gels, computational morphogenesis, and geometric morphometrics to study the folding of brains across different species. Starting with magnetic resonance images of brains of a newborn ferret, a fetal macaque, and a fetal human, we construct two-layer physical gel brain models that swell superficially in a solvent, leading to folding patterns similar to those seen in vivo. We then adopt a three-dimensional continuum model based on differential growth to simulate cortical folding in silico. Finally, we deploy a comparative morphometric analysis of the in vivo, in vitro, and in silico surface buckling patterns across species. Our study shows that a simple mechanical instability driven by differential growth suffices to explain cortical folding and suggests that variations in the tangential growth and different initial geometries are sufficient to explain the differences in cortical folding across species.

neuroscience↗