Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 379 records · Page 21Linked to original sources

bioRxiv2025

Structural basis for membrane microdomain formation by a human Stomatin complex

Biological membranes are not just passive barriers--they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 [A] cryo-electron microscopy structure of the human Stomatin complex in a native membrane environment. We find that Stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a [~]12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits C16 symmetry, the C-terminal domains adopt two alternating conformations, producing a symmetry-broken hydrophobic {beta}-barrel pore with local C8 symmetry. The membrane beneath the complex remains flat despite surrounding curvature, indicating localized membrane stiffening. The structure reveals a conserved network of inter-subunit salt bridges that stabilize the assembly. These findings provide a molecular framework for how Stomatin oligomers shape membrane architecture and mechanics, offering new insight into their roles in mechanotransduction and diseases such as nephrotic syndrome.

biophysics↗

bioRxiv2025

Macrophage Migration Inhibitory Factor Suppresses Natural Killer Cell Response and Promotes Hypoimmunogenic Stem Cell Engraftment Following Spinal Cord Injury

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor, could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders.

cell biology↗

bioRxiv2025

Development, validation, and evidence of frequent exchange of mating type HD alleles of Puccinia striiformis f. sp. tritici provide an insight into highly genetic diversity

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a worldwide destructive wheat disease. It possesses the potential to generate novel virulence races through sexual reproduction, which is the primary cause of its extensive epidemics. Mating type (MAT) of Pst lacks direct experimental evidence to account for the role of sexual recombination on high genetic diversity in evolution. Herein, we developed 11 pairs of HD alleles of Pst MAT genes, and 2 pairs HD alleles of P. striiformis f. sp. hordei (Psh, the causal agent of barley stripe rust) MAT genes. HD alleles in Pst are different from those in Psh. We tested that mating system of Pst is tetrapolar responsible for sexual genetic recombination via HD genes by experiments of selfing and sexual hybridization on alternate (secondary) hosts. Multiple HD gene types and HD gene recombination types were detected in Chinese natural Pst populations of 200 Pst isolates and 13 Psh isolates from 92 sampling sites in 11 provinces, supporting that sexual reproduction accounts for frequent emergence of new races and high genetic diversity of Pst population in northwestern oversummering variable region (hotspot) than other stripe rust-occurring regions in China. Overall, these results provide an insight into diverse types and frequent exchange of Ps MAT alleles, revealing the important role of sexual recombination via MAT alleles in virulence variation, high genetic diversity and epidemics of Pst, and also provide a basis for wheat stripe rust control in those regions where sexual reproduction occurs. Author summaryHeteroecism of the wheat stripe rust pathogen Puccinia striiformis f. sp. tritici (Pst) was discovered a decade ago. The significance of sexual reproduction in maintaining genetic diversity has emerged as a pressing concern in contemporary scientific discourse. In this study, we elucidated the presence of multiple HD gene types (HD1 linked to HD2) in Puccinia striiformis f. sp. tritici (Pst), distinguishing it from P. striiformis f. sp. hordei. Through biological experiments on sexual reproduction, we demonstrated that the mating system of Pst is tetrapolar. Furthermore, we observed that sexual reproduction, particularly selfing (individual race) and crossing (between two races), facilitates sexual recombination via HD genes, leading to pathogenic variation and a high level of genetic diversity. We established a model illustrating sexual reproduction of Pst by selfing and crossing, respectively. In China, we have observed that the Pst population exhibits a diverse range of HD gene types and HD gene recombination types. Notably, northwestern oversummering variable regions (hotspot) have a higher number of HD genes compared to other epidemic region. Population structure and cluster analyses based on HD genes indicate that Pst populations in Tibet and Xinjiang are distinct from those in other inland regions. These findings provide valuable insights into comprehending the intricate interplay between sexual reproduction and genetic diversity of Pst, thereby elucidating the reasons behind the high genetic diversity of the Chinese Pst population.

microbiology↗

bioRxiv2025

Quantifying cancer- and drug-induced changes in Shannon information capacity of RTK signaling

Signaling pathways transmit and process information, enabling cells to respond accurately to external cues. Disease states like cancer can corrupt signal transmission, though the magnitude to which they reduce information capacity has not been quantified. Here we apply pseudo-random pulsatile optogenetic stimulation, live-cell imaging, and information theory to compare the information capacity of receptor tyrosine kinase (RTK) signaling pathways in EML4-ALK-driven lung cancer cells (STE-1) and non-transformed lung epithelial cells (BEAS-2B). The information rate through the RTK/ERK pathway in STE-1 cells was below 0.5 bit/hour but increased to 3 bit/hour after oncogene inhibition. Information was transmitted by only 50-70% of cells, whose channel capacity (maximum information rate) was estimated through in silico protocol optimization. Although oncogene inhibition increased the capacity of the RTK/ERK pathway in STE-1 cells (6 bit/hour), capacity remained lower than in BEAS-2B (11 bit/hour). The capacity of the parallel RTK/calcineurin pathway in BEAS-2B exceeded 15 bit/hour. This study highlights information capacity as a sensitive metric for identifying disease-associated dysfunction and evaluating effects of targeted interventions.

systems biology↗

bioRxiv2025

Sialin2 Functions as a Mammalian Nitrate Sensor to Sustain Mitochondrial Homeostasis

Nitrogen homeostasis is fundamental for cellular physiology, yet mammalian nitrate (NO3-) sensing mechanisms remain elusive. Here, we identify Sialin2--a proteolytic fragment of the nitrate transporter Sialin generated by cathepsin B (CTSB) cleavage-- as the first mammalian nitrate sensor. Microscale thermophoresis (MST) reveals Sialin2 as a high-affinity nitrate sensor, while Cryo-Electron Microscopy (Cryo-EM) uncovers its structural basis for signaling. We show that Sialin2 localizes to mitochondria and scaffolds liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) complexes to drive organelle-specific metabolic adaptation via spatiotemporally controlled AMPK activation, enhancing mitochondrial biogenesis, ATP production, and cell survival. Real-time tracking using the sCiSiNiS biosensor demonstrates nitrate signaling dynamics at physiological levels. This signaling axis redefines nitrate as a direct ligand activating receptor-like cascades, independent of classical nitric oxide synthesis. Our findings establish a paradigm of "inorganic salt signaling biology", wherein anions co-opt trafficking systems to achieve signaling specificity, offering therapeutic avenues for mitochondrial disorders.

cell biology↗

bioRxiv2025

Low level of viral intra-host diversity is associated with severe SFTS disease

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus that can cause severe clinical symptoms and high fatality. However, the dynamics of SFTSV intra-host diversity during infection and its association with disease severity remain unexplored. Here, we characterized SFTSV iSNVs in longitudinal clinical samples from patients with distinct clinical outcomes. Our analyses revealed that SFTSV intra-host diversity was associated with disease severity and showed distinct patterns in severe and mild cases. Severe cases exhibited paradoxically lower SFTSV intra-host diversity despite higher viral loads, likely driven by reduced selection pressure. Notably, iSNVs linked to viral replication emerged in severe cases, while iSNVs associated with immunity invasion arose in mild cases. Machine learning models showed that intra-host diversity can contribute to classification of SFTS by severity. Our findings, through the lens of within-host viral populations, highlight variations in viral-host interactions during SFTSV infection and provide potential biomarkers for predicting SFTS severity.

pathology↗

bioRxiv2025

Robust and Reliable de novo Protein Design: A Flow-Matching-Based Protein Generative Model Achieves Remarkably High Success Rates

Generative models have achieved significant progress in the field of protein design, particularly in the generation of tertiary structures. However, they still face several challenges, such as balancing the designability and diversity of the generated structures, generating specified structures under highly constrained conditions, and the most challenging aspect, direct functional design such as motifs and binders. We present OriginFlow, an efficient protein generative model that combines Stochastic Differential Equation (SDE) models and flow models based on flow matching. The generated structures exhibit state-of-the-art (SOTA) levels of designability, diversity, and novelty. Moreover, this model demonstrates outstanding performance in functional design aspects such as motifs, binders, and symmetric motif scaffolding. We performed binder design for multiple targets, and all results showed excellent affinity performance in AF3 complex predictions and MD experiments. Wet-lab validation was conducted on PD-L1, RBD, and VEGF targets, achieving 90% expression, solubility, and affinity. These results are significantly superior to all current AI binder design algorithms.

bioengineering↗

bioRxiv2025

A Versatile Marker-Free Genome Engineering Platform to Overcome Homologous Recombination Bias in Microbes: A Case Study in Synechococcus elongatus UTEX 2973

The single crossover occurring via homologous recombination is a common phenomenon exited among most microbes like Escherichia, Clostridium, Streptococcus, Lactobacillus, and cyanobacteria, threatening the stability of engineered strains. Among them, fast-growing cyanobacterium Synechococcus elongatus UTEX 2973 (Syn2973) is an attractive photosynthetic chassis for CO2 bioconversion. To address the challenge of homologous recombination, we constructed two endogenous plasmid-based shuttle vectors, pSES and pSEL, enabling stable DNA delivery without reliance on homologous recombination. In parallel, two robust counter-selection systems were developed based on sepT2 and rpsL, which, in combination with positive selection markers, significantly improved the screening efficiency of double-crossover mutants. Building upon these tools, we established three marker-free platforms: (i) T4CROSS, which employs two plasmids and four rounds of single crossover; (ii) TRIPLEARM, which uses a single plasmid containing three homologous arms for three rounds of single crossover; and (iii) CRISPRARM, which integrates CRISPR/Cpf1-mediated genome editing with homologous recombination. All three methods successfully repaired mutations in the pilMNOQ pilus gene cluster in Syn2973, restoring natural competence with high efficiency and positive selection rates. As proof of concept, we employed the CRISPRARM platform for a three-step sequential engineering of the sucrose biosynthetic pathway. The final engineered strain produced 7.12 g{middle dot}L-1 of sucrose within four days.

synthetic biology↗

bioRxiv2025

Systemic trafficking of mRNA lipid nanoparticle vaccine following intramuscular injection generates potent tissue-specific T cell response

The mRNA lipid nanoparticles (LNPs) represent a new generation of vaccine carriers designed to elicit potent immune responses against infectious diseases and cancer. Despite the clinical success and rapid advancements in mRNA LNP technologies, the trafficking patterns of LNPs after intramuscular (i.m.) administration and the subsequent tissue-specific immunological effects have not been systematically characterized. Here, we report that trafficking of mRNA LNPs to different organs following i.m. injection is crucial for the induction of tissue-specific immunity beyond systemic immune response, particularly in tissue-resident CD8+ T cell generation, which is important for localized defense. By fine-tuning the composition of mRNA LNPs, trafficking patterns to systemic organs can be modulated, which can alter the resulting tissue-specific immune response. Formulations with a greater ability to enter the bloodstream can preferentially localize and transfect cells in specific organs like the liver, elicit stronger tissue-specific CD8+ T cell immune responses, and achieve enhanced efficacy in a liver tumor model. These findings highlight the potential to tailor mRNA LNP compositions to modulate trafficking following i.m. injection, thereby providing novel strategies for designing tissue-specific vaccines. Such strategies are particularly valuable for organ-specific diseases like cancer and infectious diseases, where tissue targeting and long-lasting immunity are essential for therapeutic success.

bioengineering↗

bioRxiv2025

Deciphering ESR1-driven transcription in human endometrial stromal cells via transcriptome, cistrome, and integration with chromatin landscape

ObjectiveTo investigate ESR1 and estrogen-driven transcription in human endometrial stromal cells. DesignTelomerase-immortalized human endometrial stromal cells were engineered to activate ESR1 using the CRISPR activation system and treated with vehicle or E2. Primary endometrial stromal cells were treated with vehicle or decidualization cocktail. SubjectsBiopsies from two healthy, reproductive-aged volunteers with regular menstrual cycles and no history of gynecological malignancies. Main Outcome MeasuresBulk RNA-sequencing in ESR1-activated and E2-treated cells was compared to identify ligand-independent and -dependent ESR1 actions. Cut&Run was performed in ESR1-activated cells treated with E2 or vehicle to assess the ESR1 cistrome. H3K27ac HiChIP was conducted in primary endometrial stromal cells treated with vehicle or decidualization cocktail to identify hormonally induced chromatin interaction changes. ResultsAmong six tested guide RNAs, the ESR1-3 gRNA induced robust ESR1 activation, which restored E2 responsiveness in THESC. Bulk RNA-seq revealed ESR1-mediated E2-dependent and E2-independent transcriptional programs, regulating pathways involved in inflammation, proliferation, extracellular matrix organization, and cancer. Notably, 72% of differentially expressed genes (DEGs) overlapped with genes active in human endometrial tissue during the proliferative E2 dominant phase, supporting their physiological relevance. Cut&Run-seq identified genome-wide ESR1 binding sites, with most located at distal regulatory elements. To associate distal ESR1 binding sites with genes, we integrated H3K27ac HiChIP chromatin loops in hESC to identify distal ESR1 binding sites that loop to gene promoters. We identified genes regulated by ESR1/E2 through long-range chromatin looping that are involved in stromal cell decidualization, including FOXO1 and IL6R. Additionally, we identified genes implicated in endometrial cancer, including ERRFI1, NRIP1, and EPAS1, suggesting a role for stromal ESR1 driven endometrial pathologies. Functional assays confirmed that ESR1 promotes cell viability and, in the presence of E2, enhances migration. ConclusionsESR1 activation through CRISPR restores E2 responsiveness in endometrial stromal cells. Changes to chromatin architecture support gene expression changes that drive decidualization. Integration of ESR1/E2 transcriptome and cistrome with HiChIP data identifies its role in regulating inflammation, proliferation, and decidualization, as well as its implications in endometrial cancer. This model serves as a powerful tool to study estrogen signaling in endometrial stromal biology and related pathologies.

molecular biology↗

bioRxiv2025

Whole-Proteome Screening and Multi-Modal Profiling of Antigen-Specific CD4+ T Cells at Single-Cell Resolution

Systematic whole-proteome screening and comprehensive profiling of antigen-specific CD4+ T cells are crucial for advancing our understanding of CD4+ T cell immunity, yet such efforts remain technically challenging. Here, we present a high-throughput platform that employs large-scale class II single-chain trimer libraries to detect antigen-specific CD4+ T cells, while simultaneously profiling their antigen specificity, TCR/{beta} sequences, MHC restriction, whole transcriptomes, and patient/timepoint origins at single-cell resolution. We benchmarked SCTs against conventional pMHCs and validated the SCT library-based approach in direct ex vivo identification of antigen-specific CD4+ T cells in healthy donors. We then applied the platform to screen the entire SARS-CoV-2 receptor-binding domain in a longitudinal patient cohort, identifying 2,188 antigen-specific CD4+ T cells and revealing key features that define antigen immunogenicity. Extending to cancer, we performed whole-proteome screening of HPV-16 E6/E7 for TCR repertoire profiling in a precancerous cohort, uncovering functional heterogeneity of HPV-specific TCRs. By integrating high-throughput antigen screening with high-dimensional, multi-modal cellular characterization, our approach offers an unprecedented window into CD4+ T cell immunity across diverse disease contexts and empowers the development of new therapies.

bioengineering↗

bioRxiv2025

Single-Cell Pharmacogenomic Landscapes of Epigenetic Therapy in Gastric Cancer

Gene expression signatures ("molecular phenotypes") are extensively utilized in cancer research. To study how gastric cancer (GC) molecular phenotypes are shaped by cell-intrinsic genetic alterations interacting with cell-extrinsic therapeutic pressures, we performed direct capture Perturb-seq (dcPerturb-seq) to interrogate >200 GC-related genes across 4 distinct epigenetic drug classes in multiple gastric lines. We captured 17.7 million pharmocogenomic expression interactions in 625,866 cells representing baseline and post-therapeutic molecular phenotypes. This single-cell pharmacogenomic compendium confirmed previously known gene-driven molecular phenotypes, elucidated poorly characterized genes, and uncovered novel gene dosage-molecular phenotype relationships. Molecular phenotypes in post-therapeutic surviving cells revealed diverse gene perturbation-associated pathways causing convergent drug resistance (EMT plasticity, cell cycle alterations, metabolic reprogramming), highlighting combinatorial strategies for restoring sensitivity. Mapping of in vitro molecular phenotypes to primary human GCs imparted prognostic information and insights into spatial heterogeneity. Comparative analysis of gene perturbations across therapies and lines revealed both conserved and context-specific molecular alterations. Our results illustrate how Perturb-seq approaches can systematically map diverse cancer-associated molecular phenotypes across multiple gene/drug/cell line interactions, yielding translational insights.

cancer biology↗

bioRxiv2025

DNA Methylation in Sex Chromosomes and Genes under Selection Underpins the Emergence of Sexual Size Dimorphism

Sexual size dimorphism (SSD) refers to the differences in body size between males and females. Epigenetics such as methylation contribute to shaping phenotypes, nevertheless, their role in SSD is still unclear. Here, we used Cynoglossus semilaevis, a species with larger females known as female-biased SSD, as a model to investigate the role of methylation in the emergence and regulation of SSD. Methylomes and transcriptomes were constructed in four tissues (brain, liver, muscle, and gonad) from three key life stages: juveniles (3-months post fertilization), male mature stage (1-year post fertilization; ypf), and female mature stage (3 ypf). In 1 ypf and 3 ypf females showed lower methylation, while the number of differentially methylated regions between sexes increased during the lifetime. Genes at the top of the growth hormone/insulin-like growth factor (GH/IGF) axis and hypothalamus-pituitary-gonadal axis (gh1, igf1, gnrhr2r-like, err{gamma}, etc.) showed differential methylation between sexes, consistent with sex-related differences in growth. The female-specific W chromosome showed higher methylation than the autosomes or the Z chromosome. Genes of the IGF signaling network that negatively regulate growth and located on W chromosome were hyper-methylated than their Z homologs. Furthermore, genes with a faster evolutionary rate in C. semilaevis exhibited lower methylation levels than the background genes, suggesting an important evolutionary role for DNA methylation in shaping SSD. Our results provide a comprehensive depiction of methylation regulation of SSD in vertebrates, and improve our understanding of how methylation regulation can help organisms to respond to natural selection, and allocate resources between the sexes.

developmental biology↗

bioRxiv2025

Expanding the chicken gut virome: Uncovering viral diversity, host interactions, and regional variations across the intestinal tract

Chicken gastrointestinal virome comprises a complex and diverse viral community with significant implications for host health and microbiome function. We analyzed 3,312 publicly available chicken gut metagenomic datasets to establish the chicken gastrointestinal virome collection (CGVD), which includes 39,380 non-redundant viral operational taxonomic units (vOTUs); notably, 84.90% (33,433/39,380) represent novel sequences absent from current databases. Over half of the CGVD vOTUs were classified as bacteriophages, predominantly from the order Caudovirales. The predicted hosts were mainly prokaryotes, particularly Bacillota and Bacteroidota, revealing a multifaceted landscape of virus-host interactions. Many vOTUs infected multiple bacterial phyla, indicating high adaptability and broad ecological impact. In addition, lifestyle prediction showed that 28.28% (11,137 /39,380) of the vOTUs in CGVD were identified as lytic phages. Functional annotation demonstrated that viral genes contribute to key metabolic processes, including nucleotide and amino acid metabolism, thereby facilitating viral replication and host adaptation. The detection of auxiliary metabolic genes and carbohydrate-active enzymes underscores the role of viruses in modulating the gut microbiome. Although antibiotic resistance genes and mobile genetic elements were present, their contribution to horizontal gene transfer appears limited. Additionally, marked regional differences in virome composition were observed between the small and large intestines, particularly in the abundance of families such as Siphoviridae and Myoviridae. CGVD not only highlights the key role of viruses in shaping the chicken gut microbiome and influencing microbial dynamics and metabolic pathways, but also provides new resources and insights for future research.

microbiology↗

bioRxiv2025

Transfer Learning and Permutation-Invariance improving Predicting Genome-wide, Cell-Specific and Directional Interventions Effects of Complex Systems

With the advent of precision medicine, single-drug treatments may not fully satisfy the pursuit of precision medicine. However, single-drug treatments have accumulated a large amount of data and a considerable number of deep learning models. In this context, using transfer learning to effectively leverage the existing vast amount of single-compound intervention effect data to build models that can accurately predict the intervention effects of complex systems is highly worth investigating. In this study, we used a deep model based on permutation-invariance as the core module, pre-trained on a large amount of single-compound intervention data in cell lines, and fine-tuned on a small amount of complex system (like natural products) intervention data in cell lines, resulting in a predictive model named SETComp (the Concat version with ~200M parameters and the Add version with ~173M parameters). The two versions of SETComp achieved an accuracy of 93.86% and 92.70%, respectively, on the complex system-cell-gene association test set, improving by 5.82% to 27.59% compared to the baseline. When predicting the intervention effects of those complex systems the model had never encountered before, the accuracy increased by up to 24.83% compared to the baseline. In our in vitro validation, up to 88.65% of the predictions were confirmed to be correct, and the models output showed a significant positive correlation with the real-world foldchange. We further observed SETComps potential in various biomedical scenarios, achieving good performance in applications such as mechanism uncovering, repositioning, and compound synergy discovery.

systems biology↗

bioRxiv2025

Integration of the hammerhead ribozyme into structured RNAs to measure ligand-binding events for riboswitch candidates and aptamers

Some structured RNAs, such as riboswitches and aptamers, can bind their cognate ligands and have been used in biosensors and gene expression control elements. However, current methods for detecting ligand binding to structured RNAs are either severely limited or inconvenient. In this study, we design a multi-base pair bridge to integrate a hammerhead ribozyme into structured RNAs to detect ligand binding events. The experimental results demonstrate that the length of the bridge has a significant effect on the cleavage of the ribozyme; optimal cleavage can be achieved with three to six base pairs in the bridge. The dissociation constant (KD) values obtained through this method are in agreement with those determined by in-line probing techniques, and 1 pmol of allosteric ribozyme RNA is sufficient for measurement. We apply this method to evaluate the binding affinity of the riboswitch candidate Motif_9307. Our findings indicate that this motif has no binding affinity for S-adenosylmethionine or several other tested ligands, which is consistent with the results of the in-line probing experiments. Notably, our method reveals an increase in cleavage activity when yeast extract is added as a mixture of ligands, suggesting that the ligand of Motif_9307 is present in the extract. In conclusion, we develop an alternative approach for measuring ligand binding events associated with riboswitch candidates and aptamers.

molecular biology↗

bioRxiv2025

Non-invasive skin topical delivery of hyaluronan

Hyaluronic acid (HA), a key glycosaminoglycan in the skin extracellular matrix, diminishes with aging, leading to dryness, wrinkles, and loss of elasticity. While subcutaneous HA injection remains the standard treatment, it is invasive and associated with complications. Here, we developed a zwitterionic polymer-based nanogel system (HA/OP) for noninvasive transdermal HA delivery. The nanogels, formed by complexing HA with poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OP), exhibited pH-responsive behavior, remaining stable at weakly acidic skin surface pH ([~]5) but dissociating in neutral dermal environments. HA/OP nanogels efficiently permeated the stratum corneum via sebum-assisted enrichment and para-corneocyte transport, followed by transcytosis and enhanced paracellular penetration mediated by myosin light-chain kinase (MLCK) upregulation. This enabled deep HA deposition in the dermis and subcutaneous tissue, significantly improving skin hydration and reducing wrinkles in hairless mice without irritation. Our findings present a safe, needle-free strategy for topical HA delivery, addressing a major unmet need in cosmetic and dermatological applications.

bioengineering↗

bioRxiv2025

Mechanistic basis for protection against fatty liver disease by CIDEB loss-of-function mutations

Background & AimsSomatic and germline CIDEB mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether CIDEB suppression would be an effective therapy against fatty liver disease remain unclear. Methods21 CIDEB somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace Cideb mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional Cideb knockout mice were generated to study Cideb in liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (Cideb/Atgl and Cideb/Ppara) tested mechanisms underlying Cideb loss. ResultsMost CIDEB mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with some, but not all fatty liver inducing diets. Cideb KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific Cideb deletion could ameliorate disease after MASLD establishment, modeling the impact of therapeutic siRNAs. Cideb loss protected livers via increased {beta}-oxidation, specifically through ATGL and PPARa activation. ConclusionsCideb deletion is more protective in some types of fatty liver disease. {beta}-oxidation is an important component of the Cideb protective mechanism. CIDEB inhibition represents a promising approach, and somatic mutations in CIDEB might predict the patient populations that might benefit the most.

physiology↗