Biology subjects

Kim, S.

Publications and source records attributed to Kim, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Developmental Dynamics of Naturalistic Social Behavior Revealed by Longitudinal Multi-Animal Tracking

Early-life social experiences with parents and littermates are critical for the development of social behavior and cognition in social species. Yet, how naturalistic social interactions evolve across development remains poorly understood, because reliable tracking of multiple freely interacting animals is challenged by frequent occlusion and body overlap. To address this challenge, we developed Move-Altogether (MovAl), a multi-animal pose estimation pipeline integrating video object segmentation and contour-guided preprocessing that improved identity stability and pose accuracy compared with widely used methods. Using MovAl-derived pose sequences, we established a denoising autoencoder (DAE)-based framework to map longitudinal home-cage behavior within a common three-dimensional space defined by inter-animal spacing, social orientation, and interaction dynamics. Within this space, control mice showed progressive reorganization of group behavior from 3 to 8 weeks of age, establishing a developmental reference for naturalistic social organization. Against this reference, prenatal valproic acid (VPA) exposure produced prominent alterations in social behavior organization at 3-5 weeks of age, demonstrating that the consequences of neurodevelopmental perturbation can be detected through changes in naturalistic group behavior among littermates. Extending the analysis to preweaning mother-pup interactions revealed increased maternal movement and reduced mother-pup proximity in the VPA condition, indicating alterations in the early social environment that preceded postweaning behavioral differences. These findings suggest that quantitative characterization of early social interactions may provide a means to identify early behavioral alterations associated with atypical neurodevelopment. Together, the MovAl-DAE framework enables longitudinal quantification of naturalistic social behavior, defining its developmental organization and revealing alterations associated with neurodevelopmental perturbation.

neuroscience↗

bioRxiv2026

Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia

In this study, we present the largest rare coding variant association study of schizophrenia to date, with 87,959 schizophrenia cases and 150,587 controls. We identify 16 genes at exome-wide significance: SETD1A, ZMYM2, HERC1, RB1CC1, SCAF1, XPO7, SP4, FYN, PPP3CA, CUL1, HDAC9, JARID2, ATP9A, PTK2, STAG1, and SCN2A, and an additional 24 at a 5% false discovery rate. Cases carrying ultra-rare, damaging variants, primarily protein-truncating and deleterious missense mutations, show strong enrichment in constrained genes with consistent effects across ancestries. Half of the 40 identified genes overlap with those implicated in developmental delay, autism, or bipolar disorder, underscoring shared neurodevelopmental risk. All 40 genes identified are highly expressed in excitatory and inhibitory neurons, and their expression patterns span diverse developmental stages. Functionally, the identified genes implicate chromatin regulation, protein degradation, and synaptic function. Overall, our results advance understanding of the genetic architecture of schizophrenia, provide a foundation for modeling risk genes in cellular and animal systems, and offer a framework for future work toward biologically informed patient stratification.

genetics↗

bioRxiv2026

Rac1 and CHK1 Converge on Abi-1 to Regulate DNA Repair Dependency and Treatment Response in Human Cancers

Radiation therapy (RT) resistance remains a major clinical challenge, yet biomarkers guiding precision radiosensitization are lacking. We previously demonstrated that Rac1 promotes RT resistance in glioblastoma (GBM) by inducing Abi-1-S323 dephosphorylation and enhancing non-homologous end joining (NHEJ). Here, we identify Abi-1-S323 as a key regulator of DNA repair states and a determinant of therapeutic efficacy in human cancers. Clinically, loss of Abi-1-S323 phosphorylation was associated with poor outcomes in patients with RT-treated GBM. Bioinformatic analyses revealed that non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) are among the cancers with frequent RAC1 amplification, suggesting that these tumor types may have increased Rac1-Abi-1 signaling activity. Loss of Abi-1-S323 phosphorylation also predicted poor outcomes in patients with RT-treated HNC. Consistent with these clinical observations, high Rac1 activity and low Abi-1-S323 phosphorylation were associated with enhanced DNA double-strand break repair and radioresistance in NSCLC and HNC models, whereas genetic or pharmacological inhibition of this signaling impaired DNA repair and radiosensitized tumors in vitro and in vivo. Mechanistically, we identified CHK1 as a kinase that phosphorylates Abi-1 at S323 and defines an alternative homologous recombination (HR)-dependent repair state. Tumors with high Rac1-Abi-1 signaling exhibited elevated NHEJ capacity and were selectively radiosensitized by Rac1 inhibition, whereas tumors with low Rac1-Abi-1 signaling displayed high CHK1 activity, preferentially relied on HR, and were selectively radiosensitized by CHK1 inhibition. These findings establish Abi-1-S323 as a biomarker defining therapeutically distinct DNA repair states and provide a framework for precision radiosensitization.

cancer biology↗

bioRxiv2026

SEME enables programmable transcript reconstruction through synthetic microexon incorporation

Precise correction of pathogenic mutations remains challenging for therapeutic applications because genome editing within protein-coding exons can generate unintended insertion-deletion byproducts that disrupt coding integrity and protein function. To address this limitation, we developed the Spliceable Editable Microexon Element (SEME), an intron-targeting platform that enables programmable microexon incorporation through endogenous splicing. In induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), SEME corrected aberrant splicing caused by the dilated cardiomyopathy-associated FLNC c.2003A>G variant by restoring the five nucleotides missing from exon 12, thereby recovering filamin C expression. Together, these findings establish programmable microexon incorporation as a proof-of-concept strategy for correcting diverse disease-causing transcript defects.

bioengineering↗

bioRxiv2026

Curcumin Enhances Alcoholic Fermentation in Yeast by Promoting Osmotic Stress Adaptation

Spices contain diverse plant secondary metabolites with antimicrobial and antioxidant activities that can influence plant-microbe interactions. Among these metabolites, curcumin and piperine are major bioactive constituents of turmeric and black pepper, respectively. In this study, we demonstrate that curcumin and piperine enhance alcoholic fermentation in the budding yeast Saccharomyces cerevisiae. Curcumin significantly promoted alcoholic fermentation under high-glucose conditions (20-40% glucose), which impose substantial osmotic stress on yeast cells. Under these conditions, curcumin enhanced yeast growth, improved osmotic stress tolerance, and increased resistance to cell wall digestion, suggesting enhanced stress adaptation during fermentation. Furthermore, deletion of HOG1, which encodes the central MAP kinase of the High-Osmolarity Glycerol (HOG) pathway responsible for the osmotic stress response, abolished the fermentation-enhancing effect of curcumin, indicating that Hog1 function is required for this effect. Consistent with this result, transcriptomic and RT-qPCR analyses revealed increased expression of stress adaptation-related genes, including known HOG pathway-responsive genes. In contrast, the expression of genes involved in amino acid catabolism was decreased at 12 h after the initiation of fermentation, while metabolomic analysis revealed increased intracellular levels of amino acids, including glutamate and asparagine, at 24 h. These coordinated transcriptional and metabolic changes are consistent with reduced amino acid catabolism and a shift toward a metabolic state favorable for sustained fermentation. Together, these findings suggest that curcumin enhances alcoholic fermentation under osmotic stress by promoting stress adaptation that supports yeast growth and sustained fermentation.

microbiology↗

bioRxiv2026

RNA-guided transcriptional repression by TIGR-Tas systems

Tandem interspaced guide RNA (TIGR)-TIGR-associated protein (Tas) systems are a widespread family of RNA-guided DNA-targeting proteins whose diversity has remained uncharacterized because their arrays, unlike CRISPR arrays, lack the sequence conservation required by existing annotation tools. We developed TIGRFinder, a motif-based pipeline that identified 6,685 TIGR arrays from genomic and metagenomic data. Phylogenetic and structural analysis of Tas proteins revealed clade-specific insertions in stem-loop binding Tas proteins that co-vary with features of their cognate tigRNAs. Cryo-electron microscopy structures of two stem-loop binding TasR ribonucleoprotein complexes demonstrate how these protein insertions directly accommodate extended tigRNA stems while maintaining DNA binding through catalytically inactive RuvC domains. We also show that these catalytically dead TasR proteins, along with the nuclease-lacking TasA, function as RNA-guided transcriptional repressors. These findings establish TIGR-Tas as a functionally diverse family of RNA-guided effectors, with comprehensive annotations available through TIGRSafari (https://tigr.bio) to support further exploration and engineering.

molecular biology↗

bioRxiv2026

Characterization of tri-culture alveolar-like organoids to study fibrotic lung diseases

Rationale: Fibrotic interstitial lung diseases are progressive disorders characterized by lung scarring and declining respiratory function. Repeated injury and dysregulated epithelial-mesenchymal crosstalk are implicated in disease pathogenesis but remain incompletely understood. Three-dimensional (3D) organoids incorporating epithelial-mesenchymal crosstalk provide a physiologically relevant platform for investigating these mechanisms. Here, we present a 3D tri-co-culture alveolar organoid model and evaluate its responses to two profibrotic stimuli, TGF-{beta} and bleomycin. Methods: CI-huArlo, NCI-H441, and MRC-5 cells were co-cultured for 14 days to generate alveolar-like organoids. Cell marker expression was assessed by immunofluorescence (IF). To test injury response, organoids were exposed to TGF-{beta} (50 ng/mL) or bleomycin (20 g/mL) for 48 hours and characterized. Supernatants were collected to assess interleukin 8 (IL-8) and procollagen I by ELISA. qPCR assessed expression of CDKN1A and COL1A1 following treatments. Bulk RNA sequencing (RNA-seq) evaluated the transcriptomic responses to fibrotic stimulus. Results: Cellular marker expression was confirmed using IF for aquaporin-5 (alveolar type I cell marker) and TE-7 (fibroblast marker). Bleomycin exposure reduced viability and significantly increased IL-8 (126.3 {+/-} 16.86 vs. 48.88 {+/-} 4.470 pg/mL; p = 0.0002; N=6), with no change in secreted procollagen I compared to control. TGF-{beta} stimulation significantly increased secreted procollagen I (149.6 {+/-} 27.07 vs. 53.38 {+/-} 5.672 pg/mL; p <0.0001; N=6) without affecting viability or IL-8 release. qPCR resulted in no change in CDKN1A expression, while COL1A1 expression was increased with TGF-{beta} treatment compared with control and bleomycin. RNA sequencing demonstrated distinct and reproducible transcriptional responses to TGF-{beta} and bleomycin. TGF-{beta} induced 750 significantly upregulated and 641 downregulated genes, including increased COL1A1, COL4A1, FN1, and TGFB1, with enrichment of epithelial-mesenchymal transition and TGF-{beta} signalling programs. In contrast, bleomycin induced 953 significantly upregulated and 552 downregulated genes relative to untreated controls and was characterized by p53 signalling, DNA-damage responses, and reduced cell-cycle progression. Reference-state analysis further indicated reduced normal alveolar epithelial signatures following both treatments, with TGF-{beta} producing the strongest aberrant basaloid and myofibroblast-associated signatures. Conclusions: Tri-culture alveolar-like organoids exhibited stimulus-specific responses in a 3D multicellular system, supporting their use for mechanistic studies of epithelial-mesenchymal crosstalk, environmental exposures, and therapeutic responses.

cell biology↗

bioRxiv2026

How do Co-Folding Models Organize Structural Information?

Co-folding models accurately predict biomolecular complexes, but how their internal representations support joint structure prediction remains unclear. We analyze the Boltz-1 trunk by decomposing its pair representation into intra-chain and inter-chain blocks and applying ablation, layer-wise representation geometry, and activation patching. Our results show that structural information is distributed across three streams: the single representation carries token-internal atomic detail, the intra-chain pair representation encodes chain-level geometry, and the inter-chain pair representation controls relative molecular arrangement. Across the trunk depth, representations follow a Mix-Compress-Refine trajectory, while linear probes reveal that intra-chain distance content is largely supplied by MSA preconditioning and inter-chain distance content is constructed progressively across Pairformer layers at each recycle. Apo-holo patching further shows that ligand-induced backbone changes are not fully resolved before diffusion; instead, the diffusion module reconciles partially inconsistent intra- and inter-chain constraints. These findings provide a mechanistic view of how co-folding trunks organize structural information and suggest more partition-aware designs for future biomolecular structure prediction models.

bioinformatics↗

bioRxiv2026

Skin-Related Effects of Corynebacterium amycolatum SB-1 Ferment Filtrate and Functional Characterization of Ellagic Acid

Previous research has established a link between the genus Corynebacterium in the skin microbiota and skin health; however, studies investigating the specific effects of Corynebacterium-derived substances on skin cells remain limited. In this study, we isolated eight strains of Corynebacterium from the facial skin of female participant. To investigate the potential skin improvement effects of these isolates, three cultured skin cell lines (Hs68, HaCaT, and B16-F10) were treated with the supernatants of each strain. We then evaluated and compared the gene expression levels (ELN, COL1A1, IL-1{beta}, and HAS3) alongside their inhibitory effects on melanin biosynthesis. Corynebacterium amycolatum SB-1 was selected as the final candidate for subsequent analysis, primarily based on its rapid growth rate and high cell yield. Using LC-TOF/MS, we screened the postbiotic candidates from the SB-1 strain and identified ellagic acid as a known polyphenolic antioxidant with potent anti-melanogenic effects beneficial for skin improvement. To validate the effects of ellagic acid on skin cells, we assessed FLG gene expression and its inhibition of melanin biosynthesis. Additionally, RNA sequencing was performed to elucidate the underlying molecular mechanisms, revealing that ellagic acid is significantly involved in inhibiting melanogenesis and promoting collagen synthesis. Taken together, our results highlight ellagic acid derived from strain SB-1 as a highly effective bioactive compound for improving skin health, specifically targeting hyperpigmentation and skin aging.

genomics↗

bioRxiv2026

Cryo-EM structures reveal the mechanism of phosphatidylserine remodeling by membrane-bound glycerophospholipid O-acyltransferase 1

Lands cycle remodeling of glycerophospholipid acyl chains is crucial for cells to maintain appropriate membrane composition. Glycerophospholipids are cleaved at the glycerol sn2-position by phospholipase A. The lysophospholipids are reacylated by enzymes of the membrane-bound O-acyltransferase (MBOAT) family to incorporate specific fatty-acyl chains to adjust membrane properties. How MBOAT enzymes recognize specific acyl-CoA donors, select lysophospholipid acceptors, and release products is unclear. Phosphatidylserine (PS), a critical anionic phospholipid, controls membrane surface charge, signaling-protein recruitment, and cell-death-associated membrane recognition, and PS acyl-chain remodeling is linked to ferroptosis resistance. Here, we showed that MBOAT1 preferentially generates monounsaturated fatty acid-containing PS from lyso-PS. High-resolution cryo-electron microscopy structures of human MBOAT1 captured distinct binding poses of the fatty acyl donor, lyso-PS acceptor, and PS product. With lipidomics, enzymology and molecular dynamics simulations, these structures reveal the mechanism and pathway of MBOAT1-dependent PS remodeling.

biochemistry↗

bioRxiv2026

AI-driven framework modeling perturbation in brain organoids reveals candidate genes for autism

Autism gene discovery is constrained by the rarity and heterogeneity of damaging variants, requiring large cohorts to identify susceptibility genes. Neural organoids and single-cell foundation models enable perturbation modeling in neurodevelopmental contexts. Here, we show that perturbation-informed foundation modeling of neural organoids can provide functional context for prioritizing candidate genes with genomic and clinical support. We constructed a 3.6-million-cell organoid atlas and trained models to predict genome-wide perturbation responses. Benchmarking 17 models identified a telencephalic neuron-specific model best preserving autism-relevant perturbation structure. Genome-wide profiling revealed two clusters associated with mid-fetal synaptic neuronal processes and early radial glia ubiquitin signaling. These clusters were supported by damaging-variant enrichment and clinical phenotypes across 89,916 family-based samples. Logistic-regression prioritization identified 343 candidates, including 167 in the key clusters, with convergence across TADA signals and recurrent evidence for NBEA and KLHDC10. This framework integrates predicted perturbation effects with genomic evidence to support autism candidate prioritization.

bioinformatics↗

bioRxiv2026

Nanoscale 3D profiling of the T cell membrane reveals CD2 enrichment at microvilli tips, positioning adhesion near TCR zones in the immunological synapse

The T cell membrane features a specialized molecular and topological organization critical for signaling and immune function. During antigen detection, T cells utilize finger-like protrusions called microvilli to dynamically scan the antigen-presenting cell (APC) surface. Enriched with T cell receptors (TCRs) and key signaling molecules, microvilli serve as primary signaling hubs, yet their nanoscale architecture remains poorly defined. Upon antigen engagement, TCR activation drives the formation of the immunological synapse (IS), a highly organized membrane contact with the APC critical for T cell function. However, profiling IS architecture at the nanoscale remains technically challenging. Here, we introduce NanoMAP (Nanoscale Membrane Architecture Profiling), an expansion microscopy-based platform that resolves receptor organization on T cell microvilli and within the IS at 35-60 nm resolution. Using NanoMAP, we show that effector CD8+ T cells possess a 5.1-fold higher microvillar density than naive CD8+ T cells. Mapping the adhesion receptors CD2 and LFA-1 on the T cell surface reveals that CD2 exhibits a stronger preference for localizing to microvilli tips compared to TCR and LFA-1. Within microvilli, CD2 displays a strong spatial association with TCR clusters, contrasting with a markedly weaker TCR-LFA-1 association. At the IS, TCR and CD2 co-occupy close membrane contacts, while LFA-1 is excluded to more distal regions. Upon termination of activation, TCR clusters selectively disengage from microvilli, whereas CD2 and LFA-1 persist. These results suggest a coordinated, activation-dependent organization of adhesion receptors that drives microvillar adhesion during scanning and stabilizes IS membrane contacts. Together, NanoMAP establishes a powerful framework for dissecting nanoscale membrane architecture and spatial signaling in T cells.

immunology↗

bioRxiv2026

MAFB is essential for the maintenance of adult human α-cell identity and glucagon secretion

Dysregulated hormone secretion and erosion of endocrine cell identity are features of type 1 and type 2 diabetes, but the transcriptional programs maintaining adult human islet identity and function remain poorly defined. The large MAF transcription factor MAFB is expressed in human - and {beta}-cells, marks their most functionally mature subpopulations, and is downregulated in diabetes, but its role in adult human islets has not been tested directly. Using shRNA-mediated MAFB knockdown (KD) in whole and CD26+ -cell-enriched human pseudoislets, we found that whole pseudoislet MAFB KD impaired glucagon synthesis and secretion while only modestly reducing insulin content and cAMP-potentiated insulin release. Single-cell profiling detected no {beta}-cell transcriptional response beyond MAFB KD itself, consistent with buffering by the related {beta}-cell-enriched MAFA transcription factor. In contrast, -cell-restricted MAFB KD unmasked a cell-autonomous requirement for MAFB in stimulus-secretion coupling. MAFB deficiency also destabilized -cell identity, downregulating canonical -cell and neuroendocrine secretory genes while ectopically inducing mesenchymal and extracellular matrix remodeling programs. In addition, MAFB-dependent downregulation of electron transport chain genes was confined to a large -cell subcluster, manifesting as impaired islet-wide mitochondrial respiration within the broader -cell population. Together, these findings identify MAFB as an essential adult human -cell maintenance factor that links diabetes-associated downregulation to impaired glucagon secretion, -cell identity erosion, and mitochondrial dysfunction. RESEARCH IN CONTEXTO_LIWhat is already known about this subject? O_LIMAFB is expressed in adult human - and {beta}-cells, marks their most functionally mature subpopulations, and is downregulated in type 1 and type 2 diabetes C_LIO_LIIn human stem cell models, MAFB is essential for generating insulin-producing {beta}-like cells, whereas glucagon-producing -like cells are reduced but still formed C_LIO_LINeither model addresses adult human islets: rodent MafB becomes -cell restricted after birth, and stem cell models capture differentiation, not maintenance C_LI C_LIO_LIWhat is the key question? O_LIIs MAFB required to maintain identity and secretory function in adult human islet cells? C_LI C_LIO_LIWhat are the new findings? O_LIMAFB knockdown in primary human pseudoislets impaired glucagon synthesis and secretion but minimally affected {beta}-cells, consistent with buffering by MAFA C_LIO_LIKnockdown in CD26+ -cell-enriched pseudoislets revealed a cell-autonomous requirement for MAFB in stimulus-secretion coupling, and destabilized -cell identity by inducing mesenchymal and extracellular matrix programs C_LIO_LIMAFB loss downregulated electron transport chain genes in the largest -cell subcluster and reduced mitochondrial respiration C_LI C_LIO_LIHow might this impact on clinical practice in the foreseeable future? O_LIPreserving MAFB activity in adult human -cells may represent a strategy to limit -cell dysfunction in diabetes C_LI C_LI

physiology↗

bioRxiv2026

Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism

Krabbe disease is a rare autosomal recessive lysosomal disease caused by deficiency of galactocerebrosidase (GALC), leading to accumulation of galactosylceramide and formation of the toxic metabolite galactosylsphingosine (psychosine). While psychosine accumulation is well-established as a primary pathogenic mechanism, the broader metabolic consequences of GALC deficiency remain incompletely understood. In this study, we used stable isotope tracing to comprehensively characterize metabolic perturbations in a human oligodendrocellular Krabbe disease model. This approach revealed elevated de novo ceramide synthesis in GALC knock-out cells, characterized by increased incorporation of glucose-derived serine into ceramide biosynthetic pathways. This enhanced ceramide production was amenable to pharmacological intervention by tezacaftor, an inhibitor of sphingolipid {Delta}4-desaturate (DEGS); tezacaftor administration also normalized psychosine levels, raising the possibility of its use as substrate reduction therapy. Additionally, we identified significant disruption of UDP-hexose metabolism, manifesting as an overabundance of truncated and hypogalactosylated glycans. These findings suggest impaired protein glycosylation as a previously unrecognized pathogenic mechanism in Krabbe disease. Our findings reveal novel metabolic dysregulation in Krabbe disease extending beyond established psychosine toxicity. The identification of enhanced de novo ceramide synthesis presents a new therapeutic target, while the discovery of galactose-deficient glycosylation defects supports galactose supplementation as a potential therapeutic intervention. These metabolic insights provide new mechanistic understanding and therapeutic opportunities for this devastating neurodegenerative disorder.

systems biology↗

bioRxiv2026

Intrauterine growth restriction is associated with adaptive hematopoietic reprogramming and selective immune rewiring in monozygotic twins

BackgroundPrenatal growth restriction has been associated with adverse neonatal and long- term health outcomes, yet the epigenetic mechanisms by which an adverse intrauterine environment shapes fetal immune development remain incompletely understood. Monozygotic dichorionic-diamniotic twins with selective fetal growth restriction (sFGR) provide a unique human model for investigating environmentally driven developmental programming independent of genetic variation and inter-twin placental vascular anastomoses. MethodsUmbilical cord blood buffy coat samples were collected from three sFGR and two gestational age-matched concordant control twin pairs. Bulk RNA sequencing and genome-wide DNA methylation analysis were performed, followed by differential expression, pathway enrichment, hematopoietic and immune module analyses, differential methylation, and integrative transcriptomic-epigenomic analyses. ResultsCompared with concordant control twin pairs, discordant twins exhibited broad attenuation of immune and inflammatory transcriptional programs alongside enrichment of erythroid- and hypoxia-related pathways, consistent with adaptive hematopoietic responses to intrauterine stress. Within discordant twin pairs, the growth-restricted co-twins displayed marked transcriptional asymmetry characterized by selective enrichment of cytotoxic lymphoid signatures despite global suppression of myeloid and antigen-presenting cell-associated programs. Integrated transcriptomic and epigenomic analyses further revealed coordinated epigenetic remodeling, with hypomethylated regions in growth-restricted twins enriched for immune regulatory pathways, including T cell differentiation and leukocyte activation. At selected loci, concordant hypomethylation and increased gene expression suggested a potential epigenetic basis for the observed immune remodeling. ConclusionsThese findings suggest that intrauterine growth restriction is associated with coordinated hematopoietic and immune reprogramming at birth, consistent with both compositional and cell-intrinsic alterations. In genetically identical twins, relative growth divergence was associated with polarized transcriptional states, highlighting how intrauterine environmental differences may shape early immune development independent of genetic background.

genomics↗

bioRxiv2026

Cryptic disease-prone states in human mesocortical assembloids revealed by multimodal profiling

Neurodegenerative diseases are characterized by synaptic failure, aberrant protein accumulation, and neuroglial dysfunction that emerge long before clinical onset. Although brain assembloids, which recapitulate interregional circuit connectivity beyond the scope of single organoids, significantly advance the modeling of circuit pathophysiology, they are predominantly evaluated through single-modality approaches that cannot resolve the functional and molecular heterogeneity underlying differential disease susceptibility. Here we show that morphologically identical human iPSC-derived dorso forebrain-midbrain mesocortical assembloids (MCAs) spontaneously bifurcate into disease-prone and non-prone states under identical culture conditions, revealing that MCA heterogeneity reflects intrinsic neurodegeneration susceptibility rather than stochastic culture variability. Using integrated electrophysiological, molecular, and spatial profiling, we find that disease-prone MCAs exhibit a temporally ordered molecular cascade in which neurofilament light chain elevation precedes tau dysregulation, mirroring the sequential biomarker trajectories observed in pre-symptomatic human neurodegeneration. Disease-prone MCAs further display selective cortical hyperexcitability and aberrant brainwave-like oscillatory dynamics that remain undetectable by any single modality. Spatially, a discrete junction-like neuronal population at the midbrain-forebrain interface shows transcriptional priming for synaptic overactivation alongside impaired astrocytic glutamate clearance, defining a spatially confined neuron-glial uncoupling as a candidate early origin of the disease-prone state. These findings reframe MCA heterogeneity as a biological window into pre-symptomatic neurodegeneration, with broad implications for disease modeling, risk stratification, and therapeutic discovery.

neuroscience↗

bioRxiv2026

A longevity-associated ubiquitin E3 ligase UBE3C governs lamin B1 homeostasis through selective autophagy and delay senescence

Nuclear lamina integrity is fundamental to cellular homeostasis across the lifespan 1, and its progressive deterioration is closely linked to human aging 2. Yet, the regulatory mechanism that govern this decline and how they might be counteracted in long-lived individuals remain poorly defined. Here, by combining whole-exome sequencing of Ashkenazi Jewish centenarians with GTEx transcriptomes, we identify ubiquitin E3 ligase UBE3C strongly associated with exceptional longevity and progressively declines with age across human tissues. UBE3C knockdown triggers premature senescence and destabilizes key nuclear lamina components Lamin B1 (LMNB1) and Lamin B receptor (LBR), while the longevity-associated UBE3C variant delays senescence and preserves LMNB1/LBR expression. Mechanistically, UBE3C interacts directly with LMNB1/LBR and modulates their abundance via selective autophagy. Notably, we uncover the ER- resident autophagy trigger CKAP4 3 bridges UBE3C and LMNB1. UBE3C loss enhances LMNB1-CKAP4 binding, linking nuclear lamina turnover to autophagy. Together, our findings establish UBE3C as a central guardian of nuclear lamina maintenance during senescence and offering novel insights into interventions against age-related nuclear lamina deterioration.

cell biology↗

bioRxiv2026

The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice

BackgroundInflammation is an early event that substantially influences Alzheimers disease (AD) pathogenesis, making it a compelling target for therapeutic intervention. Sob-AM2 is a brain-penetrating thyromimetic drug capable of inducing the expression of microglial cell surface receptor TREM2, which mediates the switch from pro-inflammatory to a more restorative microglial state. ObjectiveEvaluate the effects of Sob-AM2 on cognition, AD pathology and microglial activity in the 5xFAD mouse model of amyloid-beta (A{beta}) accumulation. MethodsSeven-month-old 5xFAD mice and their wild-type littermates were administered Sob-AM2 subcutaneously three times per week for 12 weeks. In the last two weeks of treatment mice underwent behavioral tests to assess cognition and monitor for off-target mobility effects. At the end of treatment, brain tissue was harvested for gene and protein expression analyses. ResultsSob-AM2 treatment increased TREM2 expression in the brains of 5xFAD mice. This was accompanied by an improvement in both spatial and associative memory as well as an increase in the expression of synaptic genes synaptophysin and PSD-95. No significant changes were detected in A{beta} plaque burden or the expression of microglial activation marker Iba1 in Sob-AM2 treated animals, however, the expression of the phagocytic marker CD68 was significantly increased in the hippocampus, but not the cortex, in Sob-AM2 treated 5xFAD mice. ConclusionThese results suggest that the cognitive-enhancing effects of Sob-AM2 are not the result of reduced overall plaque burden. Future work is needed to further investigate the neuroprotective mechanism of Sob-AM2 and how it may be affecting microglial phenotypes.

neuroscience↗