Biology subjects

Chen, L.

Publications and source records attributed to Chen, L..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

Inhibition mechanism of pancreatic KATP channels by centipede toxins

The pancreatic ATP-sensitive potassium (KATP) channel acts as a crucial metabolic sensor by regulating insulin secretion to maintain whole-body energy homeostasis. Gain-of-functional mutations in this channel lead to neonatal diabetes mellitus, a rare disorder in which certain mutants demonstrate resistance to standard sulfonylurea therapy. Recent studies have identified a centipede toxin, SpTx1, as a potent inhibitor of both human pancreatic KATP channels and their gain-of-functional mutants. This toxin stimulates insulin secretion, offering a promising therapeutic strategy for neonatal diabetes. Nevertheless, the molecular mechanism by which SpTx1 inhibits the KATP channel has remained elusive. Here, we report the crystal structure of SpTx1 and the cryo-electron microscopy (cryo-EM) structure of the KATP channel in complex with SpTx1. Our results demonstrate that SpTx1 binds to the extracellular surface of the Kir6.2 pore-forming subunit of the KATP channel. Multiple interactions at the SpTx1-Kir6.2 interface underpin the high affinity and specificity of SpTx1 for human Kir6.2. We show that SpTx1 inhibits potassium currents by physically blocking the ion conduction pore. Furthermore, a structure-guided search identified another centipede toxin, Sm3a, as a novel KATP channel blocker. Together, these findings provide key insights into the inhibitory mechanism of centipede toxins against the human Kir6.2-containing KATP channel and establish a foundation for developing these toxins into potential therapeutics targeting KATP channel-related diseases.

biophysics↗

bioRxiv2025

β-Catenin Stabilization Protects Against Pulmonary Hemorrhage Through Amphiregulin and BATF- Mediated Regulatory T Cells

Pulmonary hemorrhaging (PH) is a life-threatening condition with a high mortality rate, yet the role of immune cells in its pathogenesis remains poorly defined. Here, we investigated the protective function of {beta}-catenin stabilization in T cells and its impact on PH. Using a novel transgenic mouse model (CAT-Tg) with stabilized {beta}-catenin, we demonstrate that {beta}-catenin stabilization induces a distinct T-cell phenotype characterized by an expansion of central effector memory cells (CD44, CD122, Eomes, T-bet). Mechanistically, this effect was associated with suppression of key proinflammatory pathways, including reduced phosphorylation of STAT1, STAT3, and JAK1. PH was induced using pristane, and CAT-Tg mice were significantly protected from lung damage, showing reduced proteinuria and decreased pulmonary proinflammatory cytokine production compared with wild-type (WT) and T cell-specific {beta}-catenin knockout (cKO) mice. This protection correlated with a marked increase in FOXP3 regulatory T cells (Tregs) in CAT-Tg mice. We further identified a novel mechanism in which {beta}-catenin stabilization enhances lung expression of Amphiregulin and BATF, two molecules essential for Treg function and tissue repair. Adoptive transfer of CAT-Tg Tregs into WT mice with pristane-induced PH conferred superior protection, as evidenced by reduced lung inflammation and proteinuria. The systemic administration of a {beta}-catenin agonist to mice with PH significantly attenuated disease severity. Our bioinformatic analysis confirmed that {beta}-catenin stabilization upregulates pathways associated with tissue repair and immune homeostasis, including PI3K-Akt, angiogenesis, and STAT5 signaling. Collectively, these findings reveal that {beta}-catenin stabilization protects against pulmonary hemorrhage by inducing a specialized T-cell phenotype and establishing a protective Amphiregulin-BATF-Treg axis. This study identifies a novel immunomodulatory pathway with therapeutic potential for PH and other inflammatory lung diseases.

immunology↗

bioRxiv2025

Hierarchical regulation of cerebellar neurogenesis by Sin3A-mediated gene repression

Cerebellar granule cells (GCs) are critical for motor and cognitive functions. Lineage tracing studies have identified a hierarchical developmental progression of GC neurogenesis, transitioning from Sox2+ stem-like cells to Atoh1+ rapidly proliferating granule cell precursors (GCPs), and ultimately to NeuN+ mature GCs. However, the molecular mechanisms governing these transitions remain poorly understood. In this study, we identified a transient, slow-cycling progenitor population defined by co-expression of Sox2 and Atoh1. We show that GC maturation depends critically on the repressive function of the Sin3A/Hdac1 complex, which sequentially silences Sox2 and then Atoh1 to ensure orderly progression through developmental stages. Loss of these repressions prolongs progenitor states, compromises survival, and markedly reduces GC output. We also identify NeuroD1 as a co-repressor that collaborates with Sin3A/Hdac1 to inhibit Atoh1 transcription. Our findings highlight the central role of the Sin3A complex in orchestrating distinct stages of cerebellar GC lineage development and may provide insights into Sin3A-related cerebellar disorders and medulloblastoma in human. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/683101v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1f7ebdaorg.highwire.dtl.DTLVardef@19d4cc9org.highwire.dtl.DTLVardef@1c595eorg.highwire.dtl.DTLVardef@12f4b34_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISin3A is sequentially required for GC lineage progression C_LIO_LISin3A promotes the transition of slow-cycling progenitors to GCPs by repressing Sox2 expression C_LIO_LISin3A facilitates GCP differentiation by repressing Atoh1 expression C_LIO_LINeuroD1 recruits the Sin3A/Hdac1 complex to suppress Atoh1 expression C_LI

neuroscience↗

bioRxiv2025

Identification and characterization of emNagⅡ, a novel β-1,2-N-acetylglucosaminidase from Elizabethkingia meningoseptica

N-Acetylglucosamine exists in various forms and linkage patterns within organisms, playing a crucial role in numerous vital biological processes. However, research focusing on {beta}-1,2-linked N-acetylglucosamine within complex biantennary N-glycans on the cell surface remain largely unexplored. Currently, there is a lack of efficient tools and methods capable of directly modifying terminal N-acetylglucosamine on living cells. In this study, we identified a novel {beta}-N-acetylhexosaminidase from Elizabethkingia meningoseptica, which demonstrated favorable enzymatic stability within a pH range of 5-8 and at temperatures from 4 {degrees}C to 37 {degrees}C. This enzyme specifically cleaves non-reducing terminal {beta}-1,2-N-acetylglucosamine, enabling direct removal of this modification from oligosaccharides and native glycoproteins. More importantly, we demonstrate for the first time that this enzyme successfully removes {beta}-1,2-linked N-acetylglucosamine on living cell surfaces. Given its microbial origin and potential utility in living cell glycan editing, we have named it emNagII or cell-surface glycan-editing N-acetylglucosaminidase (csgeNagII). Through sequence analysis and alanine scanning mutagenesis, we identified a predicted active pocket containing the catalytic residue pair Asp317-Glu318, with Asp317 being essential for enzymatic activity. In summary, our findings provide an effective and reliable method for the targeted removal of {beta}-1,2-N-acetylglucosamine on living cell surfaces, establishing a foundation for further functional studies and practical applications.

biophysics↗

bioRxiv2025

Calcium transient was triggered by Na+ influx in phase 0 and regulated by Ca2+ influx in phase 2 of the action potential in adult rat left ventricular cardiomyocyte

BackgroundCa2+-induced Ca2+ release (CICR) has been the prevailing model in cardiomyocytes for over 50 years. However, whether Na+ influx plays a direct role in triggering Ca2+ release has remained unclear. We previously discovered that action potential (AP) phase 0 triggered Ca2+ release while phase 2 regulated the decay phase during the Ca2+ transient (CT). We hypothesized that CICR might only exist under experimental conditions, not during physiological AP cycles. MethodsSimultaneous recordings of ion currents and CT from the same rat left ventricular cardiomyocyte were employed to investigate the temporal relationship between cation influxes and CT. ResultsThe reactivation time for CT was approximately 250 ms. AP phase 0 triggered the CT, while phase 2 only regulated CT width. Pulses from -40 to +80 mV with 6 ms duration were applied to validate whether the reverse Na+/Ca2+ exchanger (NCX) could trigger CT. Pulses of -40 and -30 mV with 6 ms duration induced giant Na+ influx and tail current, but only Na+ influx triggered CT, not tail current. Pulses from -20 mV to +80 mV with 6 ms duration triggered CT via tail current, not via reduced Na+ influx. In Ca2+ free solution, Na+ influx was still able to trigger CT until sarcoplasmic reticulum (SR) Ca2+ content was remarkably reduced. Moreover, increased reverse NCX current induced by ramp-like depolarizing pulses did not trigger CT but widened its shape. Additionally, when SR function was destroyed by caffeine (20 mM/L), field stimulations caused progressively elevated cytosolic Ca2+ levels, indicating that SR has a buffering function for maintaining cytosolic Ca2 concentration. ConclusionsOnce Na+ influx triggers CT, Ca2+ influx cannot trigger a second CT during an AP cycle due to the limitation imposed by the reactivation time. Na+ influx might enter SR via an unknown channel or transporter at the terminal cisternae during the AP and induce Ca2+ release by acting on the SR luminal-facing site of the ryanodine receptor 2 (RyR2) channel and/or by increasing the positive potential gradient across the SR membrane.

biophysics↗

bioRxiv2025

Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection

Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts (median 4 days) between the last-negative and first-positive RNA tests, we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 38% in these as well as placebo recipients from the AMP trials was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. Viral populations exhibited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.

microbiology↗

bioRxiv2025

Causal Modeling Reveals Cell-Cell Communication Dynamics in the Tumor Microenvironment During Anti-PD-1 Therapy in Breast Cancer Patients

BackgroundImmune checkpoint blockade (ICB) targeting PD-1/PD-L1 plays a crucial role in breast cancer treatment. Despite clinical success, how ICB reshapes the tumor microenvironment (TME) to enhance anti-tumor activity remains unclear. Anti-PD-1 therapy alters TME cells beyond PD-1+ T cells, with extensive cell-cell communication (CCC) playing a key role. Understanding the dynamic CCC changes upon anti-PD-1 treatment can illuminate ICB mechanisms of action and TME dynamics. MethodsWe analyzed single-cell RNA-seq data from 31 breast cancer patients before and after anti-PD-1 (pembrolizumab) treatment (Bassez et al., 2021). We identified differentially expressed genes (DEGs) induced by treatment in major cell types. We then applied an instrumental variable approach to uncover causal relationships between T-cell and non-T-cell DEGs. We further mapped ligand-receptor interactions mediating signal transduction between cells and constructed a CCC network from T to non-T cells. ResultsAnti-PD-1 therapy induced widespread transcriptional changes across multiple cell populations. Key pathways modulated in T cells included NF-{kappa}B, interferon-{gamma}, and interleukin signaling. CD4+ and CD8+ exhausted T cells engaged in distinct ligand-receptor interactions with tumor-associated macrophages (TAMs) and other types of cells, reshaping the TME. Our results indicated CD4+ exhausted T cells activated M1-like TAMs via TNF-TNFRSF1A and TNFSF14-LTBR, while CD8+ exhausted T cells engaged M1-like TAMs through ICAM1-ITGAL/ITGB2 and CCL8-CCR2, promoting anti-tumor immunity. Conversely, immunosuppressive interactions were also observed, such as TNF-TNFRSF1B (TNFR2) and TNFSF14-TNFRSF14 (HVEM) from CD4 T cells, as well as CSF1-CSF1R and RPS19-C5AR1 from CD8 T cells, which likely promote M2-like tumor-associated macrophage (TAM) polarization and contribute to pro-tumor immune regulation and resistance to therapy. Notably, key receptors in the causal CCC networks, such as C5AR1, TNFR2, and CSF1R, emerged as potential targets to enhance anti-PD-1 efficacy. ConclusionsThese findings elucidate TME remodeling during anti-PD-1 therapy and underscore the pivotal role of CCC in treatment response. Our study identifies critical communication networks that may be biomarkers for immunotherapy responsiveness and highlights novel therapeutic targets, including C5AR1 and HVEM. Furthermore, our application of causal inference methodologies provides a robust framework for dissecting CCC mechanisms in immunotherapy.

bioinformatics↗

bioRxiv2025

A Population-scale Single-cell Spatial Transcriptomic Atlas of the Human Cortex

The genetic and spatial determinants of cell type diversity in human cerebral cortices remain poorly defined. Here, we present a population-level single-cell spatial transcriptomic atlas of human cortices from 71 donors across the lifespan. We identified 906 layer-specific genes showing conserved and divergent laminar expression patterns between humans and other species. Spatial analysis revealed neuronal vulnerability and glial activation during aging, together with a decline in the proportion of superficial SST neurons and their interactions with other cells. Disease-associated genes exhibited high cell-type and layer-specific expression, implicating the pathogenic role of spatially specific gene expression. Spatial cis-eQTL analysis identified regulatory variants linked to genes related to diseases like Tourette syndrome. Cross-species comparison demonstrated glial expansion in the human cortex, accompanied by enhanced neuron-glia communication via the neuregulin signaling. Together, we provide a comprehensive single-cell atlas of the human cortex that is essential for understanding aging, evolution, and disease pathogenesis.

neuroscience↗

bioRxiv2025

Investigation of anti-SARS CoV-2 multimeric bicyclic peptide inhibitors in a range of pre-clinical therapeutic settings

The spread of respiratory viruses, such as Influenza and SARS-CoV-2 has presented significant challenges over the last 30 years with few effective therapeutic options available to this day. Bi-cyclic peptides represent a unique, modular, modality in the antiviral armamentarium against future pandemics. This study provides a deeper evaluation of multivalent bi-cyclic (Bicycle(R)) molecule efficacy in several preclinical SARS-CoV-2 challenge settings. We explore both pre-exposure prophylaxis and post-exposure therapeutic settings via subcutaneous and intranasal routes of administration. We contextualize this further in bespoke scenarios of immune compromisation, and viral transmission. Promisingly, in all studies we observe efficacy, significantly reducing infectious viral burden at each study endpoint. These data further support candidacy of Bicycle molecules as a differentiated antiviral therapeutic class in the context of pandemic preparedness. ImportanceThe COVID-19 pandemic, triggered a rapid wave of innovation, accelerating the delivery of new vaccine technology and anti-viral treatments. In our first paper, we described the discovery and molecular optimization of Bicycle molecules as a novel drug class for the potential treatment of SARS CoV-2. Here, we have performed deeper characterization of these molecules in established animal models that simulate SARS-CoV-2 transmission, testing more convenient delivery routes, such as intra-nasal. The Bicycle molecules demonstrated positive outcomes in each of these studies and suggest that Bicycle molecules, as convenient and effective anti-viral treatments, could be an important addition to help future preparedness against new viral pandemics.

pharmacology and toxicology↗

bioRxiv2025

SpacGPA: annotating spatial transcriptomes through de novo interpretable gene programs

Spatial transcriptomes, especially those from high-density platforms (e.g., Visium HD, Stereo-seq, Xenium Prime 5K), enable detailed tissue mapping but remain challenging to annotate for spatial domains and spatially variable genes (SVGs). Most existing methods depend on companion single-cell datasets and are sensitive to cell segmentation. We present SpacGPA, a segmentation-free, single-cell-independent framework that identifies de novo interpretable gene programs--co-expressed gene modules capturing key biological processes--from spatial transcriptomes. Leveraging GPU-acceleration and block-matrix operations, SpacGPA efficiently detects gene programs based on a graphical Gaussian model in ultra-large datasets. These programs exhibit domain-specific spatial expression patterns and cell type-specific expression in independent single-cell datasets, serving as robust markers for spatial domains. Applied to four mouse and human spatial datasets, SpacGPA identified 58-109 gene programs per dataset, revealing refined tissue structures. Hub genes within these programs correlate with canonical cell type markers and SVGs, enabling systematic SVG identification. The programs are also functionally enriched and transferable across datasets and platforms. Built on AnnData, SpacGPA provides a scalable, low-hardware solution for high-resolution annotation of tissue organization and gene regulation.

bioinformatics↗

bioRxiv2025

Impaired IL-10 Receptor Signaling Leads to Inflammation Induced Exhaustion in Hematopoietic Stem Cells

Hematopoietic stem cells require tight regulation to rapidly initiate emergency hematopoiesis in response to pathogens, but chronic activation leads to proliferation induced exhaustion. Timely reentry into quiescence after inflammatory stimuli is essential for long term sustained HSC maintenance. We identify IL-10R signaling, an established negative feedback regulator in mature myeloid cells, as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Jak2V617F mutant HSCs resist the aging acceleration induced by blockade. Consistent with this resistance, IL-10R blocking antibody promotes Jak2V617F clonal expansion and augments the myeloproliferative neoplasm phenotype. Together, these findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis. SummaryWadley et al. show that IL-10 receptor signaling restrains inflammation-induced hematopoietic stem cell cycling and exhaustion; its blockade prolongs cycling, accelerates aging-related decline, and selectively favors Jak2V617F mutant HSCs, establishing IL-10 signaling as a critical regulator of inflammatory HSC exhaustion and malignant clonal evolution.

cell biology↗

bioRxiv2025

Megaplasmids associate with Escherichia coli and other Enterobacteriaceae

Humans and animals are ubiquitously colonized by Enterobacteriaceae, a bacterial family that contains both commensals and clinically significant pathogens. Here, we report Enterobacteriaceae megaplasmids of up to 1.58 Mbp in length in infant and adult guts, and other microbiomes. Of 19 complete plasmid genomes, one was reconstructed from an E. coli isolate; others were linked to species of Citrobacter and Enterobacter via analysis of genome modification patterns. The detection of related plasmids in different Enterobacteriaceae, conjugation machinery, and more diverse modified motifs in certain plasmids compared to hosts suggests that these elements are self-transmissible, with a broad host range. The plasmids encode multi-drug efflux systems and potential secreted effectors. Up to 208 tRNAs are encoded and include sequence variants that may counter tRNA-centric defense mechanisms. Overall, the vast megaplasmid coding capacity may broaden host range, increase competitiveness, control invasion by other elements, and counter programmed cell death.

microbiology↗

bioRxiv2025

Network pharmacology, bioinformatics, molecular docking and experimental verification of the mechanism of HXZTS treatment on osteoarthritis synovium

BackgroundOsteoarthritis (OA) is a prevalent joint disease characterized by synovial inflammation and synovial fibroblast dysfunction. Elucidating the molecular mechanisms underlying synovial tissue impairment in OA is crucial for developing targeted therapeutic interventions. Huoxuezhitongsan (HXZTS), a traditional Chinese medicine formula, has shown promising therapeutic effects in treating OA, but its mechanisms of action on synovial tissue remain unclear. MethodThis study integrated network pharmacology, bioinformatics analysis, molecular docking, and experimental validation to elucidate the potential targets, pathways, and mechanisms by which HXZTS exert therapeutic effects on osteoarthritic synovial tissue. ResultsNetwork analysis identified 21 active ingredients and 111 common targets of HXZTS for OA, with key compounds like quercetin, {beta}-sitosterol, and stigmasterol. Enrichment analysis revealed HXZTS modulates inflammation through TNF, IL-17, and MAPK signaling pathways, oxidative stress, apoptosis, angiogenesis, and metabolic regulation. Molecular docking demonstrated strong binding affinities of HXZTS compounds with targets like AKT1, TNF, TP53, IL6, and VEGFA. RT-qPCR validation confirmed the downregulation of inflammatory mediators like IL6 and PTGS2, alongside the upregulation of genes associated with potential cartilage repair effects, such as MMP1 and MMP3, upon HXZTS treatment. ConclusionsHXZTS exerts therapeutic effects on osteoarthritic synovial tissue through a multifaceted mechanism involving modulation of inflammation, oxidative stress, apoptosis, angiogenesis, and metabolic regulation. These findings provide insights into the potential application of HXZTS as a complementary or alternative therapeutic approach for managing OA and a foundation for developing novel targeted therapies.

bioinformatics↗

bioRxiv2025

The Shape of Chemical Space

The concept of chemical space is critical in cheminformatics, medicinal chemistry, and machine learning applications. Despite this, the high dimensionality of molecular representations greatly complicates its sampling, analysis, and visualization. A popular approach to overcome problem is to project these representations to a "human-manageable" subspace, usually containing only two dimensions. Non-linear dimensionality reduction techniques are by far the preferred strategy, following the reasoning that their flexibility can accommodate any arbitrary distribution originally present in the high-dimensional space. However, this ignores the elevated computational cost of these methods and the difficulty in tuning their hyper-parameters. Here, we show that basic properties of the metrics used in the original space can be used to infer the shape of the chemical space, which in turns suggests an optimal strategy to project chemical information to lower dimensions. The key insight is to realize that, no matter the set of molecules, their fingerprint representation can be considered to lie on a hyper-spherical surface. The smooth nature of this manifold means that we can use clustering to identify locally-dense sectors of chemical space, and selectively project them simply using linear (hyper-parameter free) methods, like principal component analysis. This approach surpasses non-linear techniques in several neighborhood preservation metrics, while only requiring a fraction of the computational cost. This pipeline is implemented in our N-Ary Mapping Interface (NAMI: https://github.com/mqcomplab/NAMI), which we tested in the visualization of 10 million molecules.

bioinformatics↗

bioRxiv2025

The Implications of Alternative Splicing Regulation for Maximum Lifespan

Mammalian maximum lifespan (MLS) varies over a hundred-fold, yet the molecular mechanisms underlying this diversity remain unclear. We present a cross-species analysis of alternative splicing (AS) across six tissues in 26 mammals, identifying hundreds of conserved AS events significantly associated with MLS, with the brain containing twice as many tissue-specific events as peripheral tissues. MLS-AS events are enriched in pathways related to mRNA processing, stress response, neuronal functions, and epigenetic regulation, and are largely distinct from genes whose expression correlates with MLS, indicating that AS captures unique lifespan-related signals. The brain exhibits certain associations divergent from peripheral tissues and reduced overlap with body mass (BM)-associated splicing; neither is observed at the gene expression level. While MLS- and age-associated AS events show limited overlap, the shared events are enriched in intrinsically disordered protein regions, suggesting a role in protein flexibility and stress adaptability. Furthermore, MLS-associated AS events display stronger RNA-binding protein (RBP) motif coordination than age-associated ones, highlighting a more genetically programmed adaptation for lifespan determination, in contrast to the more variable splicing changes seen with chronological aging. These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering new insights into the molecular basis of longevity.

bioinformatics↗

bioRxiv2025

A single-cell spatial transcriptomic census of human skin anatomy

The skin is the largest human organ and a site of significant disease burden, yet its cellular and molecular organization across the body are largely undefined. Here, we construct a spatially-resolved single-cell atlas of 1.2 million cells from normal adult human skin to localize 45 cell types across 15 anatomic sites. We define principles of organ-wide cell composition, including axes of cell diversity and specialization, and distinguish site-enriched cell types. Each body site is comprised of 10 multicellular neighborhoods that define cell-cell communication. Notably, we identify a perivascular neighborhood enriched for immune-stromal crosstalk with features resembling a homeostatic immune niche similar to skin-associated lymphoid tissue. Finally, mapping these neighborhoods onto skin disease reveals pathogenic neighborhood disruptions, including pan-disease immune alterations in the perivascular neighborhood. We present a framework charting the skins multiscale spatial organization across a molecular to macroanatomic scale. This work advances our understanding of organ-wide skin cellular organization and communication, and its architectural disruption in disease. HIGHLIGHTSO_LIHuman skin MERFISH spatial atlas of 1.2 million cells from 114 samples and 22 donors C_LIO_LICellular diversity varies along a central to peripheral body site spatial axis C_LIO_LI10 multicellular neighborhoods define skin microanatomy and homeostatic interactions C_LIO_LIHuman skin diseases feature spatial and transcriptional neighborhood remodeling C_LI

genomics↗

bioRxiv2025

Inferring Personalized Cell-Cell Communication Networks in Colorectal Cancer with Individualized Causal Discovery

Understanding tumor heterogeneity at the resolution of individualized cell-cell communication networks (CCCNs) remains a major computational challenge in precision oncology. Existing inference methods largely rely on population-level correlation and thus fail to capture patient-specific signaling patterns across diverse cell types. To address this limitation, we developed an integrative computational framework combining the nested hierarchical Dirichlet process (nHDP) model for identifying hierarchically structured gene expression modules, with instance-specific Greedy Fast Causal Inference (iGFCI) for inferring individualized CCCNs (iCCCNs) in colorectal cancer (CRC). Applied to large-scale single-cell RNA-seq data from over 625,000 cells, our model successfully decomposed complex gene expression modules GEMs, potentially representing the cell lineage and cellular signaling states, and uncovered iCCCNs across detailed cell subtypes. We further used TCGA bulk RNA-seq data with survival data to validate the clinical relevance of these individualized gene expression module causal interactions, demonstrating their potential as robust prognostic signatures in CRC. Finally, we used principled causal inference methods to search for ligand-receptor pairs that mediate cell-cell communication. This framework enables mechanistic insights into immune evasion. Our computational method represents a significant advance toward realizing personalized oncology, enabling precise patient stratification and identification of actionable biomarkers for improved therapeutic targeting in cancers.

bioinformatics↗

bioRxiv2025

Novel Calcin peptides from Scorpion Venom Exhibit Humidity-Dependent Expression and Ryanodine Receptor Activation

Scorpions are venomous animals of considerable pharmacological potential, traditionally used in East Asia to treat cardiovascular and autoimmune diseases. However, geographical variations in the expression of their venom components remain poorly understood. We performed transcriptome profiling on scorpion samples collected from eight distinct climatic and environmental regions in East Asia, we successfully identified two distinct scorpion species: Uroctonus mordax and Mesobuthus martensii. Furthermore, we identified two novel calcins from the venoms of these species, with their expression levels showing a significant correlation to environmental humidity. Functional assays revealed that these calcins differentially potentiate [3H]ryanodine binding to RyR isoforms and induce a persistent subconductance state, suggesting distinct mechanisms of action. Our findings suggest biogeographical variation in venom composition between species and suggest that environmental humidity as a key factor influencing calcin expression. These results expand the structural diversity of the calcin family and provide a mechanistic basis for the medicinal application and ecological adaptation of scorpion venom.

molecular biology↗