Biology subjects

Li, J.

Publications and source records attributed to Li, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

ctDNA Release Heterogeneity in Luminal Breast Cancer Revealed by Single-Cell Multi-Omics Spatial Analysis

Backgroud Breast cancer is a leading cause of cancer-related mortality, and HR+/HER2-; is the predominant subtype. Molecular pathology, including PIK3CA and ESR1 mutation, informs prognosis and treatment selection. Circulating tumor DNA (ctDNA) offers a non-invasive approach for cancer monitoring, but its clinical utility is limited by tissue plasma discordance, reflecting heterogeneous ctDNA release. The cellular and spatial determinants of this release remain poorly understood, particularly in HR+/HER2-; subtype, where heterogeneity across subclones complicates liquid biopsy interpretation. Results To identify the cellular and spatial determinants of ctDNA release, we developed scMASTER, integrating single-cell transcriptomes and mutations, spatial transcriptomics and matched tumor and plasma DNA sequencing. In ten patients with non-metastatic HR+/HER2- breast cancer, eight recurrent malignant epithelial states showed distinct ctDNA release potential. Antigen-presentation, stress, mitosis and mesenchymal-like states showed high release. PIK3CA and ESR1 mutations were linked to distinct functional states and altered ctDNA detectability. Three spatial architectures, EMT-enriched regions, intraductal luminal progenitors and avascular hypoxic zones, showed high release. Tumor-microenvironment interactions were bidirectional: anti-tumoral immunity correlated with reduced release, whereas immunomodulatory components correlated with increased release. A stratification model based on these features identified high-risk, immunosuppressed patients with poor prognosis, validated across external cohorts. Conclusions Our study establishes a single-cell spatial framework for decoding ctDNA release heterogeneity, linking tumor states, somatic mutations, spatial architecture, and immune interactions to ctDNA release. These findings provide mechanistic insights into tissue-plasma discordance, offer a biological rationale for interpreting ctDNA dynamics, refine patient risk stratification and liquid biopsy-based monitoring in HR+/HER2-; breast cancer.

cancer biology↗

bioRxiv2026

GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma

Metastatic melanoma remains highly lethal despite advances in immunotherapy and MAPK-targeted therapy. The Rac1P29S mutation, present in 4-9% of cutaneous melanomas, confers intrinsic resistance to BRAF and MEK inhibitors. Like other small GTPases, Rac1 lacks suitable pockets for small molecule inhibitor binding, motivating indirect approaches to suppressing its activity. We have previously shown that wild-type Rac1 is sensitive to inhibition of de novo GTP biosynthesis in cancer cells, particularly suppression of the rate-limiting inosine monophosphate dehydrogenase (IMPDH) enzymes. Therefore, we asked whether IMPDH inhibition could suppress Rac1P29S and its associated phenotypes in melanoma. We found that IMPDH inhibition reduced Rac1 activity, impaired Rac1-dependent phenotypes, and induced S-phase arrest in Rac1P29S-harboring cells. Moreover, IMPDH inhibition synergized with the BRAF inhibitor vemurafenib and the MEK inhibitor trametinib in Rac1P29S melanoma cells. Dual BRAF and IMPDH inhibition also resulted in enhanced suppression of MEK and ERK phosphorylation in vitro. In syngeneic mouse models, the FDA-approved IMPDH inhibitor mycophenolate mofetil sensitized Rac1P29S-expressing melanoma tumors to trametinib, including tumors made refractory by prior trametinib exposure. We further identified a feed-forward circuit in which Rac1 sustains IMPDH2 expression levels through JNK and c-Jun/AP1 signaling, potentially coupling the GTPase to its own nucleotide supply. These findings establish GTP biosynthesis as a targetable vulnerability in Rac1P29S melanoma and support IMPDH inhibition as a rational partner for MAPK-targeted therapy.

cancer biology↗

bioRxiv2026

NSD2 deficiency disrupts the epigenetic landscape of cochlear hair cells to enhance ECM expression and to perturb cochlear hair cell function

Mammalian cochlear hair cells (HC) are crucial for hearing, and histone modifications may play an important role in HC maturation and functions. However, whether and how NSD2, a histone H3 lysine 36 (H3K36) dimethyltransferase, affects cochlear HC maturation remains unclear. Here, we established an HC-specific Nsd2 knockout mouse model and discovered that the loss of NSD2 results in severe structural defects in stereociliary bundles and profound hearing impairment. Integrated multi-omics profiling revealed that NSD2 deficiency leads to a decreased expression of H3K36me2, which in turn alters genome-wide chromatin accessibility and gene expression. Mechanistically, NSD2 deficiency triggers the aberrant upregulation of extracellular matrix (ECM) genes at the transcriptional level, causing excessive collagen accumulation and compromising tissue structure. Crucially, ECM intervention can mitigate NSD2-deficiency mediated hearing damage. Our study reveals an epigenetic mechanism by which NSD2 regulates cochlear HC maturation through inhibition of chromatin remodeling-induced ECM accumulation, and provides a potential new therapeutic direction for hearing impairment.

cell biology↗

bioRxiv2026

Constructing Virtual Viruses in A Spatial Minimal Cell

Viral development links gene expression and genome replication to particle formation within a cell. Here we construct virtual viruses in a JCVI-syn3A-based spatial minimal cell. For mycoplasma virus P1, molecular events connect expression and replication to coarse-grained packaging, followed by a spatial reconstruction of membrane opening and particle release. Individual finite-size particles coexist, move across the boundary and undergo partial crossings and returns before complete exit. In contrast, Acholeplasma phage MV-L1 (L1) expresses its genes and accumulates genomes as the host continues to grow and develops a constricted shape. The coexistence of viral activity and continued host growth is qualitatively consistent with the non-lytic biology of group 1 acholeplasmaviruses. These reconstructions extend the virtual cell to the viruses that develop within it, linking molecular activity, particle behavior and host growth.

synthetic biology↗

bioRxiv2026

Transcription factors read a second regulatory code in chromatin

Transcription factors (TFs) decode gene regulatory information written in DNA, yet how this vocabulary is interpreted within chromatin remains largely unexplored. Here, using an upgraded NCAP-SELEX platform, we systematically map the nucleosomal DNA recognition landscapes of 269 human TFs. We uncover a widespread, chromatin-dependent mode of sequence recognition: many TFs recognize motifs on nucleosomal DNA that are distinct from their canonical naked-DNA binding sites, revealing that nucleosome architecture encodes a second gene regulatory code in chromatin. Cryo-electron microscopy structures of TF-nucleosome complexes demonstrate that this second code is read through a combination of nucleosome-induced DNA deformation and direct protein-histone contacts. Functional analyses show that these chromatin-encoded motifs actively promote chromatin accessibility and drive cell-type-specific cis-regulatory activity in vivo. Strikingly, a single TF can deploy its canonical and nucleosome-derived motif repertoires to partition and govern entirely distinct physiological programs. Together, our findings establish that TFs interpret two complementary layers of genomic information: the primary DNA sequence and a second code written into the nucleosome architecture. This chromatin-encoded layer of regulatory information fundamentally expands our understanding of how TF specificity is achieved and how gene regulatory networks are wired in multicellular organisms.

systems biology↗

bioRxiv2026

Transcriptome analysis reveals CCND2 promotes myogenic differentiation of pig skeletal muscle

ABSTRACT Objective: Skeletal muscle growth rate differs substantially among diverse pig breeds. In the present study, RNA-seq was performed to identify differentially expressed genes (DEGs) across pig breeds with distinct growth rates. CCND2 showed obvious differential expression among pig breeds. Although CCND2 is essential for cell cycle control, its biological function in skeletal muscle differentiation has rarely been reported. This work aims to identify DEGs in pig breeds with different growth rates and explore CCND2 role in porcine skeletal muscle development. Methods: RNA-seq was performed to identify differentially expressed genes (DEGs) across pig breeds with distinct growth rates. Weighted gene co-expression network analysis (WGCNA) was used to identify gene modules potentially associated with skeletal muscle growth and development. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was performed to validate the role of CCND2 in skeletal muscle differentiation. Results We identified 5,416, 4,846, and 2,777 DEGs in the Duroc pig (DU) vs. Jiangquan black pig (JQ), DU vs. Laiwu pigs (LW), and JQ vs. LW comparison groups, respectively. WGCNA identified two gene modules (lightgreen and darkmagenta) potentially associated with skeletal muscle growth and development. CCND2 exhibited differential expression in comparisons between DU vs JQ and DU vs LW, with higher expression observed in Duroc pigs. qRT-PCR analysis revealed that overexpression of CCND2 at day 6 (D6) of cell differentiation significantly increased the expression levels of CCND2 gene and markers of myogenic differentiation (p < 0.05). Conversely, knockdown of CCND2 significantly decreased the expression levels of CCND2 gene and myogenic differentiation markers (p < 0.05). Conclusions This study identified breed-specific DEGs and key gene modules in porcine skeletal muscle and verified that CCND2 promotes myogenic differentiation. These findings provide a genetic theoretical basis for further investigations into skeletal muscle growth and development. Keywords pig, skeletal muscle, transcriptome, WGCNA, CCND2

genomics↗

bioRxiv2026

A bipolar disorder-associated ultra-rare AKAP11 protein-truncating variant attenuates stimulus-dependent PKA activation and induces anxiety- and depression-related behaviors in mice

Rare genetic variants associated with psychiatric disorders are thought to have larger individual effect sizes and direct biological roles, offering a unique opportunity for understanding causal relationships between genetic architecture and disease phenotypes. A recent whole-exome sequencing meta-analysis identified an increased burden of ultra-rare protein-truncating variants (PTVs) in AKAP11 in patients with bipolar disorder and schizophrenia. AKAP11 encodes an A-kinase anchoring protein that mediates the association of protein kinase A (PKA) and its substrates. How ultra-rare AKAP11 variants contribute to psychiatric disorder pathogenesis remains unknown. Here, using CRISPR-Cas9 genome editing, we introduced into the mouse Akap11 locus an ultra-rare PTV identified in a human patient with bipolar disorder. This ultra-rare PTV reduced Akap11 mRNA and protein levels without producing stable novel mRNA isoforms, leading to Akap11 haploinsufficiency. Male heterozygous mice exhibited behavioral abnormalities consistent with anxiety- and depression-like phenotypes. Transcriptomic and proteomic profiling of the neocortex revealed molecular changes involving synaptic organization, synaptic signaling, and neurite morphogenesis. Notably, the heterozygous mutant showed selective elevation in type I, but not type II, PKA regulatory subunits, as well as PKA catalytic subunits, in the neocortex. Functionally, these changes were accompanied by reduced phosphorylation of PKA substrates, attenuated stimulus-dependent PKA activity in cortical excitatory neurons, and impaired nascent dendritic development in cortical neurons. Together, our study presents a clinically relevant and genetically precise mouse model that provides mechanistic insight into how ultra-rare PTVs may contribute to psychiatric disorder pathogenesis, and a platform for testing rational therapeutics.

neuroscience↗

bioRxiv2026

Connectivity allometry is a robust organizing principle of the human functional connectome

A defining feature of the human brain is its multiscale organization, in which regional processes are integrated into coherent whole-brain network architecture. How local functional organization adapts to variation in this global architecture, however, remains largely unknown. Here, we addressed this question by applying an allometric scaling framework to resting-state functional magnetic resonance imaging data from four large-scale datasets spanning different cultures, cognitive states, developmental stages, and clinical conditions. We found that human functional networks were organized according to a robust and spatially heterogeneous connectivity allometry, whereby regional functional connectivity scales nonlinearly with whole-brain connectivity strength. This scaling architecture closely followed the cortical sensorimotor-association hierarchy, with lower-order systems exhibiting supralinear scaling and higher-order systems exhibiting sublinear scaling. Connectivity allometry was further associated with multiscale neurobiological organization, including regional metabolic properties, neurotransmitter receptor distributions, and transcriptomic landscapes, indicating that local-global functional scaling is embedded within fundamental biological gradients of cortical organization. Moreover, the scaling pattern and its biological associations were highly reproducible across independent cross-cultural cohorts. Importantly, connectivity allometry remained remarkably stable across working memory conditions regardless of cognitive load, emerged by late childhood, and was broadly preserved in children and adolescents with autism spectrum disorder despite region-specific alterations. Together, these findings establish connectivity allometry as a previously unrecognized organizational principle of the human functional connectome and provide a quantitative framework linking regional functional organization to whole-brain network architecture in health and disease.

neuroscience↗

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

OpenLipid: a large language model workflow for targeted analysis of DIA mass spectrometry data in lipidomics

Mass spectrometry has become a central technology for lipidomics, with data-independent acquisition (DIA) enabling broad and reproducible sampling of lipid signals. However, the multiplexed fragment-ion spectra in DIA data complicate lipid identification. Here, we introduce OpenLipid, a large language model (LLM)-based workflow for targeted DIA lipidomics. Using assay libraries built from data-dependent acquisition (DDA) results, OpenLipid directly evaluates extracted ion chromatograms (XICs) from DIA data in a zero-shot setting to identify target lipid peaks and generate human-readable rationales for individual lipid identification decisions. We benchmarked OpenLipid against manual annotations across four datasets comprising human plasma and mouse feces analyzed in positive and negative ionization modes. The plasma assay libraries contained 199 target lipids in positive mode and 147 in negative mode. The fecal assay libraries contained 181 target lipids in positive mode and 264 in negative mode. At a 5% false discovery rate (FDR) threshold, OpenLipid identified 110 (55.3%) and 28 (19.0%) library targets in plasma and 130 (71.8%) and 84 (31.8%) in feces, in positive and negative ionization modes, respectively. OpenLipid achieved an overall identification rate comparable to that of DIAMetAlyzer (57.8%, 19.7%, 89.0%, and 17.8% across the corresponding datasets) and substantially higher than that of untargeted MS-DIAL DIA analysis (12.6%, 0.0%, 47.5%, and 0.0%) on the same assay-library targets. LLM-derived chromatographic features also enabled supervised discrimination between correct and incorrect candidate peak groups for target lipids, with median cross-validation average precision values of 0.838-0.912. Together, these results demonstrate that OpenLipid is an effective LLM-based workflow for FDR-controlled targeted analysis of DIA lipidomics data.

bioinformatics↗

bioRxiv2026

Striatal cholinergic interneuron pathology and muscarinic signaling independently shape motor dysfunction in a DYT-TOR1A dystonia model

Antimuscarinic drugs are among the most effective pharmacological treatments for dystonia, yet the neural substrates underlying their therapeutic effects remain poorly understood. Striatal cholinergic interneurons (ChI) are strongly implicated in dystonia pathophysiology. In a symptomatic mouse model of DYT-TOR1A dystonia, torsinA loss from all striatal neurons causes selective ChI degeneration during juvenile maturation; surviving ChI exhibit persistent morphological, physiological, and connectivity abnormalities. Whether motor dysfunction arises from ChI degeneration, dysfunction of surviving ChI, or altered cholinergic signaling elsewhere in the striatal circuit remains unknown. Here, we distinguish these mechanisms using complementary genetic, pharmacological, and cell-ablation approaches. Surviving ChI became hyperactive coincident with the emergence of neurodegeneration and abnormal movements. Selective prenatal restoration of torsinA in ChI prevented their degeneration and reduced abnormal movements, identifying ChI as an important cellular locus of torsinA-dependent motor dysfunction. Systemic antimuscarinic treatment during juvenile striatal maturation produced persistent behavioral improvement outlasting treatment without preventing ChI degeneration. Direct intrastriatal antimuscarinic administration nearly abolished abnormal movements, identifying the striatum as a critical site of therapeutic action. Surprisingly, extensive ablation of the remaining dorsal striatal ChI neither prevented nor ameliorated abnormal movements and did not diminish the efficacy of systemic or intrastriatal antimuscarinic treatment. Thus, torsinA-dependent ChI pathology contributes causally to motor dysfunction, yet the continued presence of dorsal striatal ChI is not required for either expression of the motor phenotype or its suppression by muscarinic antagonists. These findings dissociate a developmental contribution of ChI pathology from the striatal mechanisms through which antimuscarinic drugs suppress dystonia-related movements.

neuroscience↗

bioRxiv2026

A One-Step Chemoselective Strategy for Hydroxymethylcytosine Sequencing in DNA and RNA

5-Hydroxymethylcytosine (5hmC) is a relatively stable chemical mark formed by oxidation of 5-methylcytosine in DNA, while its RNA counterparts, 5-hydroxymethylcytidine (hm5C) and 2'-O-methyl-5-hydroxymethylcytidine (hm5Cm), have recently emerged as potential regulators of post-transcriptional processes. Existing 5hmC enrichment methods rely on anti-bodies or enzymatic {beta}-glucosyltransferase labeling, are largely DNA-specific, and are not readily applicable to RNA. Here we report bisulfite-assisted labeling by thiol sequencing (BALT-seq), a one-step chemoselective strategy that installs a biotin-thioether handle directly onto hydroxymethylcytosine in DNA or RNA under mild acidic bisulfite conditions, without using enzymes. Mechanistic studies show that thiol capture of the bisulfite-activated 5hmC intermediate competes with canonical cytosine-5-methylenesulfonate formation, yielding a stable adduct that DNA polymerases bypass efficiently and that resists APOBEC-mediated deamination. In mouse embryonic stem cells, BALT-seq produces genome-wide 5hmC profiles highly concordant with 5hmC-Seal, TAB-seq, and oxBS-seq, recovers expected gene-body and chromatin-state enrichment, and extends to low-input cell-free DNA. On RNA, BALT-seq enriches hm5C/hm5Cm-containing transcripts more effectively than antibody-based hMeRIP and reveals structured modification landscapes across tRNA species and LINE/LTR repeat families. BALT-seq thus establishes a unified, enzyme-free chemical platform for hydroxymethylcytosine profiling across DNA, cell-free DNA, and RNA.

genomics↗

bioRxiv2026

Oncogenic fusions induce an extensive cancer-restricted cryptic proteome in Ewing sarcoma

How tumors generate a cryptic "dark" proteome absent from healthy tissues, and whether it can be reversibly activated, remains unclear. In Ewing sarcoma, all tumors are driven by EWSR1::ETS fusions, making it a tractable model to study dark proteome activation. Integrating matched transcriptomes, translatomes and proteomes from 48 patient tumors with long-read RNA sequencing, single-cell Ribo-seq, proteomics and immunopeptidomics in cell line models, we show that EWSR1::FLI1 acts as a reversible switch recurrently inducing hundreds of cancer-specific neoproteins. Many arise from canonical coding regions via intragenic transcription start sites, generating truncated or out-of-frame neoproteins. We uncover a fusion-dependent increase in ribosomal readthrough into poly(A) tails, generating a stable 80-amino-acid TRPM4 neoprotein that, despite lacking a stop codon, is the most abundant tumor-specific microprotein across patients. Proteomic, immunopeptidomic, and immunofluorescence analyses validate neoproteins as tumor-restricted antigens, revealing a therapeutically actionable cancer dark proteome controlled by one oncogenic fusion.

cancer biology↗

bioRxiv2026

A J-protein-licensed CHD3 chromatin remodeling complex promotes H3K27me3 spreading to maintain cell identity in plants

Stable inheritance of epigenetic states is essential for cellular identity and developmental robustness and requires ATP-dependent chromatin remodeling, yet the molecular composition and regulatory mechanisms of plant CHD3 chromatin remodelers have remained unknown. Here we show that the Arabidopsis CHD3 remodeler PICKLE (PKL) assembles with a defined set of J-domain proteins (JDPs) to form stable CHD3 chromatin remodeling complexes in plants that are compositionally distinct from their animal counterparts. Loss of JDPs phenocopies pkl mutants, and JDPs are required for nucleosome densification and H3K27me3 spreading at thousands of Polycomb target genes. Mechanistically, JDPs perform dual functions by promoting PKL protein stability while directly stimulating PKL chromatin remodeling activity through their plant-specific DUF3444 domain that binds the N-terminal tail of histone H3. Deletion of the DUF3444 domain severely impairs PKL remodeling activity without disrupting complex assembly, leading to defective H3K27me3 spreading, impaired facultative heterochromatin maintenance, and loss of cell identity. Together, our findings define plant CHD3 chromatin remodeling complexes and reveal a mechanism that regulates CHD3-mediated chromatin remodeling to support the propagation of repressive chromatin states in plants.

plant biology↗

bioRxiv2026

Genetic regulation of circulating metabolome in cattle

The circulating metabolome is a vital intermediate layer linking genetics to complex phenotypes, yet existing genome-wide studies-even in humans-rarely capture dynamic physiological contexts or cellular regulatory mechanisms. Here, we present the Cattle Metabolome Atlas (https://cattlema.farmgtex.org/), a comprehensive resource of 3,436 plasma metabolites and 4,851 serum metabolites from 4,651 animals with matched sequence-level genotypes across highly dynamic parity and lactation stages. We mapped 728 plasma and 622 serum metabolite quantitative trait loci (mQTL), revealing widespread context-dependent regulatory architectures. Integrating these mQTL with the multi-tissue expression quantitative trait loci (eQTL) and single-cell atlas of 59 tissues demonstrates that 74-79% of mQTL colocalize with eQTL across 29 tissues, prioritizing the liver as the primary systemic hub and resolving metabolic programs at single-cell resolution. Furthermore, we charted 538 causal gene-tissue-metabolite-trait cascades across 11 complex traits in cattle. Finally, cross-species analyses demonstrate partial evolutionary conservation of genetic metabolism between cattle and humans, establishing this atlas as a powerful asset for cattle genetics and genomics, selective breeding, and comparative biology.

genetics↗

bioRxiv2026

A T2T Benchmark Reveals How Reference Choice Shapes Human Genome Interpretation

The completion of telomere-to-telomere (T2T) human genomes has expanded the accessible landscape of human genetic variation, yet benchmark resources remain limited to conventional high-confidence regions defined by existing reference frameworks. Here, we generated a near-perfect diploid T2T genome (T2T-LIN) from a Chinese individual and established assembly-based truth sets by comparison with T2T-YAO, an ancestry-matched near-perfect T2T reference genome. The benchmark showed a heterozygous/homozygous SNV ratio of ~2, consistent with expectations under Hardy-Weinberg equilibrium, and enabled genome-wide evaluation of reference-dependent biases. We found that reference choice substantially influences genome interpretation: ancestry-matched linear T2T references provided the most faithful representation of individual genomic variation and enabled more accurate genome reconstruction than unmatched linear, diploid and graph-based references. Benchmarking previously inaccessible repetitive and structurally complex regions revealed substantial limitations of current variant callers that were masked by conventional metrics. The T2T-LIN and YAO-LIN benchmarks establish a T2T-era framework for evaluating reference-dependent genome interpretation and variant discovery across nearly the complete human genome.

genomics↗

bioRxiv2026

Reduction of forebrain interneurons alters cellular organization and cortical neurogenesis in a mouse model of X-linked intellectual disability

Arx is an X-linked transcription factor that is expressed in inhibitory neurons within the ganglionic eminences during embryogenesis. In humans, ARX variants are one of the leading causes of X-linked intellectual disabilities (XLID) and related syndromes. While most often studied in males, recent evidence indicates that >50% of heterozygous female carriers of ARX variants also display mild to severe phenotypes. The mechanisms by which Arx mutations lead to a wide range of disease pathologies remains poorly understood. Here we removed Arx in the medial ganglionic eminence (MGE) to generate conditional knockout male and heterozygous female mice. MGE-derived interneurons were reduced in a gene dosage, subtype and brain region dependent manner in Arx mutant mice. Knockout male mice displayed severe phenotypes with infantile spasms and epilepsy, while Het female mice displayed moderate anxiety and locomotor defect mimicking patient symptoms. Single cell sequencing and spatial transcriptomics revealed striking cell autonomous and non-cell autonomous changes throughout development. Notably, loss of MGE-derived interneurons alters dorsal cortical neurogenesis and cell-cell communication resulting cortical malformations. This study reveals mechanistic insights into genetic and cellular changes that occur when Arx is removed from MGE-derived interneurons that advances our understanding of Arx-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2026

The Candida auris Adhesin Scf1 Mediates Broad Host-Protein Recognition through Shared Adhesive Regions

Candida auris (C. auris) is a rapidly emerging, multidrug-resistant fungal pathogen whose persistence is partly driven by adhesion to host tissues and abiotic surfaces. Surface-colonization factor 1 (Scf1) is a C. auris-specific adhesin implicated in surface adhesion, biofilm formation, virulence, and persistence in health care settings. However, the human proteins recognized by Scf1 and the response of these interactions to hydrodynamic flow and shear stress were previously unknown. Using yeast surface display, spinning-disk adhesion and FACS-based binding assays, we show that the N-terminal adhesive domain of Scf1 binds the cell-surface glycoprotein mucin-1 (MUC1) and the extracellular matrix proteins vitronectin (VIT) and fibronectin (FN), while exhibiting no detectable binding to collagen I, collagen IV, or fibrinogen. Hydrodynamic shear stress was found to tune ligand preference, with VIT being preferred at equilibrium and MUC1 being the more strongly bound target under flow. Epitope mapping by deep mutational scanning (DMS) of Scf1 against MUC1, VIT and FN identified shared binding patches consisting of predominantly cationic and aromatic residues involved in recognizing all three ligands. Mutations within these regions reduced binding without compromising yeast display expression levels, indicating that these residues are involved in ligand recognition and that mutations at these positions do not compromise global protein folding stability. These findings establish the Scf1 N-terminal domain as a semi-promiscuous ligand-recognition domain for a structurally diverse set of human proteins and suggest that a mechanosensitive adhesion mechanism contributes to C. auris colonization.

biochemistry↗