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Liu, S.

Publications and source records attributed to Liu, S..

At least 145 records · Page 8Linked to original sources

Bottom-up and generative computations both uniquely explain social brain responses

Making social evaluations from visual input is a core human ability that engages brain regions involved in social perception, including portions of the superior temporal sulcus (STS), as well as higher-level mentalizing regions, such as the temporoparietal junction (TPJ). One common hypothesis proposes that these regions operate hierarchically: social perception regions like posterior STS (pSTS) implement bottom-up computations to generate fast, stimulus-derived representations of social interactions, while mentalizing regions like TPJ perform inverse-planning computations to infer the underlying goals and motivations driving agents behavior. However, this computational-neural mapping has never been formally tested, in large part due to the lack of successful computational models of social processing. We developed computational models aligned with these two frameworks: a graph-neural-network (GNN) model that recognizes social interactions by relying on relational visual information, and a generative inverse-planning model that does so by inverting a model of agents goals and the physical world. In this preregistered study, we collected fMRI responses while participants watched videos of agentive animated shapes depicting social interactions and compared neural responses to both computational models. Surprisingly, we found that both the GNN and inverse-planning model explained neural responses in pSTS and TPJ, even after controlling for variance explained by the other model. Exploratory analyses, however, revealed a shift from early perceptual processing towards later higher-order reasoning in both regions, suggesting a temporal rather than spatial hierarchy. Overall, this study provides the first evidence that both social perception and mentalizing regions carry out a combination of relational bottom-up and higher-level inferential computations, perhaps on distinct timescales. This work also provides the first comparison of an inverse-planning model to neural activity and demonstrates that theory-driven cognitive models can successfully predict fMRI responses to social scenes. Significance StatementThe ability to recognize social interactions between others is central to humans daily lives and engages brain regions supporting social perception and mental state inference. The neural computations underlying this ability, however, are poorly understood. Here we leveraged new models of bottom-up social perception and generative social inference to test the hypothesis that these complementary computations are carried out in separate brain regions. We compared both models to brain responses from subjects viewing procedurally generated videos of social interactions. Surprisingly, we found that both models explained neural activity in both perceptual and mentalizing regions, even when controlling for effects of the other model. These findings challenge the idea of a strict division of labor in the social brain and refine our understanding of the computations supporting human social inference.

animal behavior and cognition↗

Cell Type Architecture and Positional Gene Gradients in an Adult Animal at Subcellular Resolution

The spatial organization of cell types and gene expression underlies tissue architecture and organismal physiology. However, resolving complete cellular and molecular landscapes within a three-dimensional context remains challenging, particularly in organisms with high cellular heterogeneity and complex geometry. Here, we developed a semi-supervised workflow to reconstruct high-resolution three-dimensional spatial transcriptomic models of the planarian Schmidtea mediterranea at single-cell resolution. Planarians are basal bilaterians capable of regenerating body structures after injury. Our reconstruction maps the distribution of cell types and spatially patterned gene expression across the intact organism and identifies 119 candidate positional control genes (PCGs). These genes are expressed across muscle, neural, and epidermal populations. Functional perturbation of selected candidates, including pitx3, ptpn11, pi4ka, upf3b, and cul1, revealed roles in regeneration following injury. In addition, we identify intestinal cells as prominent components of the microenvironment surrounding adult tgs1 pluripotent stem cells (neoblasts). Together, these results demonstrate the utility of three-dimensional spatial transcriptomic reconstruction for mapping cellular architecture and positional gene regulation in complex adult organisms.

developmental biology↗

Geoclimatic oscillations and ancient reciprocal adaptive introgression shape the evolutionary trajectories of threatened Coilia

Geoclimatic oscillations have repeatedly reshaped biodiversity, yet how ancient lineages persist and diversify through profound environmental upheavals remains a central question in evolutionary genomics. By integrating chromosome-level genome assemblies, population genomics, and transcriptomic data across the Coilia species complex, we reconstruct deep evolutionary histories of Coilia along the dynamic East Asian margins. Our analyses reveal divergences dating to the Miocene, coinciding with major tectonic and climatic transitions, including Tibetan Plateau uplift-linked reorganization of the Yangtze drainage toward the East China Sea, and the Middle Miocene Climatic Optimum. Despite long-term separation, we uncover evidence for ancient, reciprocal introgression among Coilia lineages, with gene flow confined to discrete genomic regions rather than distributed genome-wide. These introgressed regions are enriched for loci associated with immune function, vascular development, and osmoregulatory processes, and exhibit population genetic signatures consistent with positive selection. Temporal modelling indicates that this window of adaptive exchange preceded Pleistocene glacial intensification, after which gene flow became effectively restricted. Together, our results suggest that transiently permeable species boundaries historically acted as reservoirs of adaptive variation, shaping evolutionary trajectories and facilitating niche differentiation under repeated geoclimatic oscillations. This study highlights ancient adaptive introgression as an important evolutionary process contributing to the long-term persistence of threatened coastal fishes.

evolutionary biology↗

4D Single-Cell Spatial Transcriptomics Reveals Dynamic Morphogenetic Gradients and Regenerative Domains in Planarians

Regeneration relies on precise spatiotemporal gene expression and cellular responses to establish tissue identity and body patterning. Using high-resolution Stereo-seq (715 nm) on 353 sections from 16 whole animals at 8 regeneration timepoints, we constructed a 4D spatiotemporal transcriptomic map of planarian regeneration. Our analysis captured 36 refined cell types from 3,508,004 segmented cells, enabling genome-wide transcriptional imputation of gene expression dynamics across body axes at cellular, tissue, and organismal scales. We identified dynamic positional gradients and distinct spatially distributed cell types during regeneration, including an injury-induced Anterior Regenerative Zone (ARZ). The ARZ exhibited enriched positional signals in epidermal, muscle, and neural cells and was regulated by Mediator 8, which is crucial for polarity remodeling and blastema formation. This study provides a comprehensive spatial molecular and cellular map of regenerative processes, highlighting injury-induced spatial domains and key regulatory factors in planarian regeneration. We also provide an interactive web portal, offering a valuable resource for exploring and analyzing regeneration mechanisms in a spatiotemporal context.

developmental biology↗

Pharmacological Inhibition of SLC33A1 Promotes Endoplasmic Reticulum Hyperoxidation and Induces Adaptive IRE1/XBP1s Signaling

The endoplasmic reticulum (ER) transporter solute carrier family 33 member 1 (SLC33A1) has emerged as an attractive therapeutic target in etiologically diverse diseases, ranging from lung cancer to neurodegenerative disorders. Yet, no pharmacologic SLC33A1 modulators have been described. Here, we show that the small molecule IXA4, a highly selective activator of the adaptive IRE1/XBP1s signaling arm of the unfolded protein response (UPR), binds to SLC33A1 and inhibits its activity. Genetic depletion of SLC33A1 phenocopies the selective induction of IRE1/XBP1s signaling brought about by IXA4 treatment. Chemoproteomic analyses and cryo-electron microscopy show that IXA4 binds SLC33A1 within the central channel to inhibit transport of its substrate metabolite(s). Binding of IXA4 to SLC33A1 leads to the accumulation of oxidized glutathione within the ER, hyperoxidizing the ER lumen and inducing activation of adaptive IRE1/XBP1s signaling. Consistent with this function, we find that pharmacologic inhibition of SLC33A1 with IXA4 selectively reduces viability of KEAP1-deficient lung adenocarcinoma cells that have elevated levels of glutathione, mimicking the sensitivity of these cells to genetic deletion of SLC33A1. Our work demonstrates a new physiologic role of SLC33A1 in regulation of ER redox homeostasis and designates IXA4 as a pharmacologic inhibitor of SLC33A1 that can be used to evaluate the biological impact and therapeutic utility of SLC33A1 inhibition in homeostasis and in disease.

cell biology↗

T2T Genome and Population Resequencing Reveal OfCCD4 Alleles Orchestrate Petal Color and Scent in Osmanthus fragrans

Osmanthus fragrans is prized for its floral color and fragrance, both key targets for genetic improvement. However, the lack of a complete genome assembly and comprehensive population structure hinders gene dissection and marker development for breeding. To investigate the genetic basis of color-scent interaction, a telomere-to-telomere (T2T) genome assembly is generated, and whole-genome resequencing of 100 cultivars is performed. Integrative population and metabolomic analyses reveal a trade-off: orange-red ( Aurantiacus) cultivars accumulate high /{beta}-carotene but low aromatic apocarotenoids (/{beta}-ionone), while yellow-white cultivars show the opposite pattern. Divergence mapping identifies OfCCD4 as the major underlying locus. Three alleles are characterized--functional (A), partially functional (aDel), and a frameshift null (aStop)--with aStop strictly co-segregating with the Aurantiacus phenotype. Transient and stable transformations confirm that A and aDel cleave /{beta}-carotene into /{beta}-ionone, while aStop abolishes this activity. A co-dominant PCR marker is developed based on allele-specific polymorphisms. OfCCD4 is thus established as the key regulator of the color-scent trade-off in osmanthus. The identified alleles and molecular marker enable rapid, low-cost genotyping at the seedling stage--offering particular value for marker-assisted selection in ornamental breeding, where extended juvenility makes phenotypic selection highly time- and resource-intensive.

plant biology↗

A Single-Cell Temporal Atlas of Mouse Nasal Embryonic Development

The mammals breathe and perceive odors through anatomically and functionally distinct respiratory and olfactory regions of the nose; however, how the early embryo endows this system remains largely unknown. Here, we present a temporal high-resolution single-cell RNA sequencing (scRNA-seq) atlas of mouse nasal development, comprising 183,247 cells collected from 20 embryos spanning embryonic day 10.5 (E10.5) to E18.5. We identified 7 major cell clusters and 52 molecularly defined subtypes, including previously unrecognized rare populations and niche-derived signaling components involved in progenitor cell maintenance. Lineage reconstruction of epithelial and mesenchymal compartments revealed dynamic cell fate transitions and highlighted candidate regulators of lineage specification, including Foxa1 as a regulator of nasal respiratory ciliated epithelium differentiation. Integration with adult nasal epithelium datasets further delineated transcriptional dynamics of olfactory stem cells. This study provides a molecular roadmap of nasal development and offers a valuable resource for future research into nasal biology and regenerative strategies.

developmental biology↗

Correlations of 276 missense variants of PSEN1, PSEN2, and APP on the production of Aβ peptides against variant effect predictors and biophysical structures

INTRODUCTIONEarly-onset Alzheimers disease (EOAD) is mostly caused by mutations in Presenilin-1,2 (PSEN1, PSEN2), and amyloid precursor protein (APP) genes. Both genetic and experimental evidence has supported the PSEN-APP amyloid hypothesis as the leading pathogenesis of AD. Thus far, 276 missense variants from PSEN1,2, and APP have been identified. Herein, we report the development of algorithm platforms for predicting the degrees of pathogenic potentials of these various missense mutations in AD. METHODSWe performed extensive pairwise correlations between 276 in vitro functional assays of missense variants from PSEN1, PSEN2, and APP and clinical data among EOAD patients against 37 variant effect predictors (VEPs). Furthermore, we used the structural models of all three proteins to refine understanding of the molecular basis of missense variants in dominant negative (DN) or loss-of-function (LoF) effects. RESULTSWe found that VEPs were consistently correlated with age of onset (AAO) among EOAD patients and the A{beta}42/A{beta}40 ratio biomarker. This study also identified discrepancies in the predictor variable leading to an increase in the A{beta}42/A{beta}40 ratio; The increased A{beta}42/A{beta}40 ratio was due to decreased A{beta}40 levels by Sun et al., (2016), while Petit et al., (2022) argued that increased A{beta}42 level was the culprit. We also identified that with increased predicted pathogenicity, there were decreased A{beta}38 levels. Conversely, this study found no direct correlations with A{beta}37 and A{beta}43. Lastly, structural studies show characteristics of either DN and LoF mechanisms, as there were numerous variants located in buried hydrophobic domains and those on charged surfaces of the proteins. DISCUSSIONCurrently, a major limitation in the field is the lack of reliable approaches for predicting the pathogenicity of variants in EOAD. We show that VEPs are promising in deciphering the effects of variants in PSEN1, PSEN2, and APP genes, especially between multiple pathogenic mutations. Our study also illuminates the need for experimental studies to identify the predictor variable causing the increased A{beta}42/A{beta}40 biomarker. Our biophysical studies also identify the need to characterize whether the mechanism of pathogenesis caused by DN or LoF effects is in scope of the presenilin hypothesis. Research in ContextO_LISystematic review: The authors reviewed experimental evidence of pathogenic PSEN1, PSEN2, and APP variants in scope of the presenilin hypothesis. To our knowledge, the pathogenesis of EOAD remains incompletely understood. There are also no predictive tools/models available for informing clinical translation. C_LIO_LIInterpretation: VEPs demonstrate strong correlations with AAO and A{beta} levels from pairwise correlations with 276 missense variants. Structurally, it appears that mutations demonstrate characteristics of dominant negative and loss-of-function effects. C_LIO_LIFuture Direction: Larger studies are necessary of VEPs for realistic clinical usage. C_LI HighlightsO_LIWe performed correlations of 37 VEPs against in vitro data of EOAD variants. C_LIO_LIVEPs demonstrate potential as diagnostic tools for early onset Alzheimers disease. C_LIO_LIPathogenic missense variants show characteristics of DN and LoF effects. C_LI

neuroscience↗

ATLAS: Population-Level Disease Locus Discovery via Differential Attention in Genomic Language Models

Identifying disease-associated genetic variants remains a key challenge in genomics, especially in small cohorts or for rare and complex mutation types where genome-wide association studies (GWAS) often fall short. We introduce ATLAS, a population-level framework that leverages attention signals from pretrained genomic language models (gLMs) to detect disease-associated genes and loci directly from raw sequences--without requiring explicit variant calls or supervised training. ATLAS first performs gene-level differential attention analysis to prioritize candidate genes, followed by base-level analysis to localize disease-associated regions at single-haplotype resolution. We validate ATLAS on synthetic and {beta}-thalassemia datasets, demonstrating robust performance across diverse allele frequencies (down to 10%), cohort sizes (below 200 individuals per group), and genomic scales. Compared to GWAS, ATLAS achieves higher recall of known loci and captures haplotype-specific signals missed by traditional methods. Cross-model benchmarking further shows that precise localization depends on both model size and pretraining on diverse human genomes. In summary, ATLAS offers a scalable, sequence-native alternative to traditional statistical genetics.

genetics↗

The genetic repertoire of the deep sea: from sequence to structure and function

The deep sea as the largest and maybe most hostile environment on Earth is still underexplored especially regarding its genetic repertoire. Yet, previous work has revealed significant habitat-specific deep-sea biodiversity. Here, we present an integrated deep-sea genetic dataset comprising 502 million nonredundant genes from 2,138 samples and 2.4 million predicted structures, and used it to link specific protein structures with genetic variants associated with life in the deep sea and to assess their biotechnology potential. Combining global sequence analysis with biophysical and biochemical measurements revealed unprecedented sequence diversity, yet substantial structural conservation of proteins. Especially proteins involved in replication, recombination, and repair were identified to be under rapid evolution and with specialized properties. Among these, a structurally divergent helicase exhibited advantages in controlling nanopore sequencing speed. Thus, our work positions the deep sea as a unique evolutionary engine that generates and hosts genetic diversity and bridges genetic knowledge with biotechnology.

bioinformatics↗

The CD8 immgenT framework as a universal reference of mouse CD8 Tαβ cell differentiation states

Mouse CD8+ T cell differentiation has been studied extensively in models of infections and tumors, yet no unified framework spans the full spectrum of immunological contexts. Within the immgenT project, we profiled RNA, surface markers, and TCR clonotypes in conventional CD8+ T cells across >600 samples, spanning multiple perturbations, tissues, and timepoints. Twenty-one clusters across naive, effector, circulating memory, tissue-resident memory, progenitor-exhausted, and terminally-exhausted CD8+ T cell compartments emerged, with striking molecular convergence across acute and chronic infections, tumors, autoimmunity, aging, and homeostasis, illustrating that shared transcriptional states support protective or dysfunctional outcomes depending on developmental history and microenvironment. We validate immgenT as a comprehensive reference by integrating external datasets from conditions not represented in immgenT and by defining a flow cytometry panel spanning the CD8+ T cell landscape. Thus, immgenT-CD8 provides a molecular framework for harmonizing CD8+ T cell literature and clarifies relationships across diverse immune challenges.

immunology↗

Mechanical coordination of counter-gradient growth maintains organ curvature in apical hooks

How growing tissues convert mechanical tension into signals that stabilize form remains a central question in morphogenesis. Curved organ shapes in plants arise from differential growth, yet how such curvature is actively maintained while organs continuously grow remains poorly understood. In etiolated seedlings, the apical hook provides a tractable model to dissect this process, as its curvature is stably maintained over extended periods despite ongoing cell expansion. Using quantitative imaging and computational modeling, we show that antagonistic growth gradients at apical and basal regions are both necessary and sufficient to maintain hook curvature, with cuticle integrity being critical for establishing these counter-gradients. Mechanical cues linked to cuticle structure, coupled with apoplastic reactive oxygen species (ROS), coordinate cellular growth anisotropy, and disruptions in cuticle biosynthesis trigger defective hook development. These findings reveal that the apical hook curve maintenance is not a simple switch between growth promotion and repression, but a highly dynamic, tightly regulated process where mechanical and biochemical signals coordinate organ-scale morphogenesis, fundamentally reshaping how we understand developmental growth.

plant biology↗

SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis

The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 leads to GSSG accumulation in the ER and a liposome-based assay demonstrates that SLC33A1 directly transports GSSG. Cryo-EM structures and molecular dynamics simulations reveal how SLC33A1 binds GSSG and identify residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induces ER stress and dependency on the ER-associated degradation (ERAD) pathway, driven by a shift in protein disulfide isomerases (PDIs) toward their oxidized forms. Altogether, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.

cell biology↗

Functional Annotation of the Major Histocompatibility Complex Locus

The human major histocompatibility complex (MHC) locus has the greatest density of disease-associations in the human genome, including links to over 100 polygenic disorders. Its complex haplotype structure, rich gene density, and high degree of linkage disequilibrium combine to make deciphering the gene regulatory logic of the MHC locus extremely challenging. Employing complementary high-throughput CRISPR interference (CRISPRi) and activation (CRISPRa) epigenetic screens coupled with single-cell transcriptome profiling across three distinct human cell types, we identified hundreds of new connections between cis-regulatory elements (CREs) and their target genes in this locus. These CRE-gene links are largely cell type-specific and act as enhancers. Additionally, some CREs have complex features, including harboring both active and repressive histone marks, lacking chromatin accessibility, targeting multiple genes, or acting as silencers. Computational methods fail to predict a majority of these CRE-gene connections. These findings emphasize the potential for functional perturbation experiments to dissect complex loci and reveal shared and cell type-specific regulatory mechanisms relevant to genomics of complex diseases. Collectively, this study provides a unique resource for understanding the complex regulatory landscape within the MHC locus and supports the need for creating new models that encompass CRE-gene interactions, cell type-specific gene expression, and disease genetics in the noncoding genome.

genomics↗

IR-B deficiency and fatty acid dysregulation accelerate prostate cancer progression via PI3K/AKT signaling

The insulin receptor (IR) is markedly overexpressed in both human and mouse prostate cancer, with a significant elevation in the IR-A/IR-B ratio across patient tissues, cell lines, and Hi-Myc mouse prostates. To elucidate the role of IR-B in prostate tumorigenesis, we generated a prostate-specific IR-B knockout (KO) mouse model using Pbsn-Cre-driven recombination. Prostate-restricted loss of IR-B was confirmed at the transcript level and did not affect other tissues. Crossing these mice with Hi-Myc transgenics revealed that IR-B deficiency promotes accelerated progression to invasive adenocarcinoma, characterized by enhanced cellular proliferation and atypical histopathology. Transcriptomic and metabolomic profiling of dorsolateral prostate lobes demonstrated activation of PI3K/AKT and mTOR signaling, along with upregulation of IRS1/2/4 and IGF2. Metabolite analyses indicated elevated fatty acid levels and enhanced lipolysis pathways, implicating metabolic reprogramming in tumor progression. Notably, glucose and lipid metabolism genes, including GLUT1, GLUT12, FASN, and GPR120, were upregulated, accompanied by an increased BCL2/BAX ratio, suggesting apoptosis inhibition. Functional studies further revealed opposing roles of dietary fatty acids: {omega}-3 polyunsaturated fatty acids (EPA, DHA) suppressed prostate cancer cell survival, proliferation, and PI3K/AKT signaling while promoting apoptosis, whereas {omega}-6 fatty acid (arachidonic acid) exerted pro-tumorigenic, anti-apoptotic effects. Collectively, these findings identify IR-B loss as a driver of metabolic and signaling reprogramming that accelerates prostate tumorigenesis, while highlighting {omega}-3 fatty acids as potential modulators counteracting IR-B-deficient prostate cancer progression.

cancer biology↗

Co-repression of Yap1 and Sox9 Abrogates Established Cholangiocarcinoma by Eliminating Transcriptional Compensation

Background/AimsIntrahepatic cholangiocarcinoma (iCCA) represents an unmet clinical need due to its increasing incidence, aggressive biology, and limited treatment options. The extremely low-response rates to current systemic regimens and the emergence of adaptive resistance to targeted therapies underscore the urgent need for alternative therapeutic strategies. Given that the lineage-defining transcription factors SOX9 and YAP1 are central regulators of cholangiocyte and iCCA identity, we investigated their functional roles as potential therapeutic vulnerabilities across multiple preclinical models. MethodsPatient tissue-microarray (TMA) analysis, Sleeping-Beauty hydrodynamic tail vein injection-based iCCA models, and Cre-mediated inducible gene deletion systems were used to investigate the roles of Sox9 and Yap1. Deep-learning-based prediction, RNA-seq, ChIP-seq and immunohistochemistry analyses were performed to delineate transcriptional networks and downstream effectors associated with SOX9/YAP1 signaling. ResultsDual deletion of Sox9 and Yap1 effectively eradicated advanced iCCA while preserving intrahepatic bile ducts, regardless of oncogenic drivers. Mechanistically, SOX9 and YAP1 transcriptionally compensated for each other when one was absent, and ILF2, MGAT5, and WWTR1 were identified as key downstream effectors mediating this compensatory mechanism. Loss of Ilf2, Mgat5, or Taz suppressed iCCA, whereas overexpression of Ilf2 or Taz following Sox9/Yap1 co-deletion restored tumor development, indicating that ILF2 or TAZ can functionally substitute for YAP1 and SOX9 in sustaining iCCA. ConclusionsCo-targeting SOX9 and YAP1 offers a promising and safe broad-spectrum preventive/therapeutic approach for iCCA, potentially overcoming resistance to YAP1 inhibition. The adaptive resistance mechanism identified may extend to other malignancies, providing insights for addressing the advanced resistant to YAP1-TEAD-directed therapies.

cancer biology↗

An Integrated Single-Cell and Epigenomic Resource for Comparative Analysis of the Basal Ganglia

The basal ganglia regulate motor, cognitive, and affective behaviors, and their dysfunction underlies diverse neurological and psychiatric disorders. Comprehensive, accessible multi-omics resources are needed to understand the regulatory mechanisms governing basal ganglia cell types. Here we present an open, interactive web-based platform for exploring single-cell multi-omics datasets from basal ganglia, generated using 10X Multiome, snm3C-seq, and Paired-Tag technologies from the BICAN (NIH BRAIN Initiative Cell Atlas Network) consortium. The platform is available at https://basalganglia.epigenomes.net/ and enables integrated visualization of gene expression, chromatin accessibility, DNA methylation, histone modifications, and chromatin conformation across cell types and human, macaque, marmoset, and mouse species, with direct genome browser support and comparative epigenomic functionality. Representative analyses demonstrate cell-type-specific regulatory landscapes, conserved and species-specific regulatory elements, and links between epigenomic regulation and transcription. This resource provides a scalable, community-oriented foundation for advancing basal ganglia biology and interpreting regulatory mechanisms relevant to brain function and disease. HighlightsO_LIIntegrated single-cell epigenomic resource for basal ganglia C_LIO_LIInteractive genome browser enables multi-omics and cross-species exploration C_LIO_LIReveals cell-type-specific and species-specific regulatory landscapes C_LIO_LISupports community access to complex brain epigenomic datasets C_LI

genomics↗

An Advanced Humanized Systemic Lupus Erythematosus Model Enables Parallel Profiling of B Cell-Targeted Therapies

B cell-targeted therapies represent a transformative frontier for systemic lupus erythematosus (SLE) intervention, yet clinical recommendation of specific treatment is hampered by the challenge to perform head-to-head comparisons of efficacy-toxicity trade-offs and tissue-specific impacts in patients. To address this gap, an advanced Toll-like receptor 7 (TLR7) agonist-induced SLE model is developed in a NCG-M (NOD-Prkdcem26Cd52Il2rgem26Cd22Rosa26em1Cin(hCSF2&IL3&KITLG)/Gpt) human immune system (HIS) mice. This model enables parallel evaluation of multiple B cell-directed therapies within a controlled cohort study. It recapitulates core SLE pathologies--including immune effector cell augmentation, autoantibody production and glomerulonephritis--within 2 months, demonstrating greater severity and clinical fidelity than conventional pristane-induced systems. Validated through replication of clinical responses to rituximab and belimumab, the platform directly compares two emerging modalities: universal chimeric antigen receptor-T cells (UCAR-T) elicits delayed but profound B-cell reset correlating with superior reduction in renal pathology and autoantibodies, while T cell engagers (TCEs) mediate rapid yet partial B-cell depletion and transient efficacy. UCAR-T concurrently induces greater acute inflammatory responses, aligning with its distinct toxicity profile. By resolving therapy-specific effects on human immune dynamics and symptom control, this study empowers context-specific therapeutic selection for SLE, advancing tailored management strategies.

immunology↗