Biology subjects

Leng, S.

Publications and source records attributed to Leng, S..

12 recordsLinked to original sources

bioRxiv2026

Artificial Intelligence Models for Classifying Wrist Ligament Injuries Using Synthetically-Generated Joint Proximity Maps from Finite Element Models

Background/PurposeDiagnosing wrist ligament injuries is challenging; early detection and treatment are important to prevent osteoarthritis progression. Interosseous proximity maps, a proxy measure for joint space, can be generated from volumetric imaging data and may provide important information about wrist health. Artificial intelligence (AI) could enhance accuracy of noninvasive diagnosis based on imaging-derived metrics. This work demonstrates feasibility of AI training using synthetic proximity map data generated from finite element models (FEMs). MethodsPersonalized wrist FEMs for two asymptomatic participants were created from four-dimensional computed tomography-derived anatomic and kinematic data. Monte Carlo sampling varied 22 ligament material properties and simulated 7,500 unique injury scenarios generating 9,000,000 labeled red, green, and blue (RGB) images of interosseous proximity vector fields from FEM-derived motions. Images were associated with 17 descriptive metrics, including gross wrist angles and bone surface pairs, and used to develop mixed-input convolutional neural networks (CNNs). Model performance was evaluated for identifying specific ligament injuries. ResultsAverage area under receiver operating characteristic curve (AUROC) for CNNs was 0.757 across all injury types and kinematics. In a subset with clinically-relevant functional angles, the average AUROC was 0.824. Best-performing individual ligament AUROCs ranged from 0.807 to 0.999. Sensitivities and specificities exceeded 0.99 for some ligament injury simulations under specific wrist angles and bone surface pairs. ConclusionThis study demonstrates the feasibility of using synthetic data from FEMs to train AI models for classifying wrist ligament injuries. Proximity-based RGB images may be a relevant biomarker of ligamentous injury.

biophysics↗

bioRxiv2026

Paternal inheritance of a vulnerable opioid-taking phenotype in female rats

Risk for opioid use disorder (OUD) is substantially heritable, yet its genetic architecture remains only partly understood. This study examined oxycodone intake in two nearly isogenic rat strains, Wistar Kyoto More Immobile (WMI) and Less Immobile (WLI), and their reciprocal female F1 offspring. The parental strains differ in depression-like behavior and substance use vulnerability, with WMI rats consuming more oxycodone than WLI controls. Voluntary consumption was measured with an operant licking self-administration protocol that delivered 60 l drug per reward. Across four experimental stages, oxycodone concentrations increased from 0.025 to 0.1 mg/ml, and session durations increased from 1 to 4 hours. Female offspring showed a parent-of-origin effect. F1 females sired by WMI fathers (WLIxWMI) displayed accelerated escalation during the transition from 1-hour to 4-hour sessions in Stage 2 and consumed more oxycodone than reciprocal WMIxWLI females across expanded-access stages. This vulnerability was associated with increased licking during the drug-unavailable timeout period. In WMI and reciprocal WMIxWLI female, consumption was regulated by the drugs subjective value, as measured by lick microstructure, during Stages 1 and 2. This relationship was absent in WLIxWMI females during Stage 2. Together, these findings suggest that paternal WMI lineage is associated with a rapid transition to high oxycodone intake and cue-directed drug seeking, and identify a parent-of-origin effect that may contribute to female vulnerability to addiction.

animal behavior and cognition↗

bioRxiv2026

Dietary Microplastics Engage Gut Mechanosensory-Endocrine Signaling to Disrupt Bone Homeostasis

Background and AimsMicroplastics are pervasive environmental contaminants increasingly detected in food and water supplies; however, their effects on gastrointestinal physiology and systemic health remain poorly understood. We investigated whether chronic dietary microplastic exposure alters colonic neuroendocrine signaling and skeletal health. MethodsFemale and male C57BL/6J mice were fed purified basal, high-fat/high-cholesterol, or high-fiber diets with or without a physiological relevant polystyrene microplastic mixture ([~]1.7 mg/kg; particle sizes 0.49 - 5.0 {micro}m) for 12 weeks. Colonic cellular responses were evaluated using ELISA, histology, immunofluorescence, and single-nuclei RNA sequencing. Fecal microbiota transplantation was performed to assess microbial contributions to microplastic-induced phenotypes. Bone microarchitecture was assessed by micro-computed tomography. Human bone specimens were analyzed for microplastic content, and primary osteoblast mineralization assays were performed. ResultsDietary microplastic exposure increased chromogranin A-positive enteroendocrine cells and enhanced serotonergic signaling in the colon without evidence of intestinal inflammation or lineage reprogramming. Single-nuclei transcriptomic analysis identified compartment-specific serotonergic and mechanosensory adaptations in epithelial and enteric neuronal populations. Transfer of microbiota from microplastic-exposed donors to control recipients recapitulated increased enteroendocrine cell abundance. Chronic microplastic ingestion induced sex- and diet-dependent reductions in trabecular bone loss and architecture without systemic inflammatory activation. Microplastics were detected in human mineralized bone, and microplastic exposure impaired osteoblast mineralization in a donor-dependent manner. ConclusionsChronic ingestion of microplastics remodels gut neuroendocrine signaling through microbiota-dependent mechanisms and impairs skeletal homeostasis in the absence of overt inflammation. These findings identify a previously unrecognized gut-bone pathway through which dietary microplastic exposure may influence host physiology.

physiology↗

bioRxiv2026

Neutrophil-targeted delivery of circSCMH1 unlocks an acute anti-thromboinflammatory function to restore microvascular perfusion in stroke

ObjectivesFutile recanalization (FR) after endovascular thrombectomy (EVT) is driven by neutrophil-mediated thromboinflammation, yet conventional neuroprotectants fail to address the spatiotemporal complexity of stroke injury. This study aimed to identify the clinical link between circSCMH1, traditionally viewed as a late-stage repair molecule, and FR, while evaluating its hyperacute anti-inflammatory potential via a neutrophil-targeted delivery system. MethodsWe analyzed thrombi and plasma from LVO-AIS patients stratified by functional outcomes. We engineered neutrophil-targeted lipid nanoparticles (circSCMH1@pepLNP) for delivery in a mouse transient middle cerebral artery occlusion model. Therapeutic outcomes were evaluated through infarct volume measurement, histological assessment of NETosis, and intravital two-photon microscopy to monitor real-time neutrophil dynamics and capillary stalling. ResultsClinical analyses showed circSCMH1 was significantly downregulated in FR patients, with its levels negatively correlated with NET burden. Furthermore, circSCMH1-negative neutrophils exhibited a higher propensity for NETosis within the thrombus microenvironment. In mice, circSCMH1@pepLNP achieved specific neutrophil delivery, significantly reduced infarct volume, and suppressed the expression of citrullinated histone H3 and neutrophil elastase. Intravital two-photon and laser speckle imaging further confirmed that this intervention attenuated neutrophil adhesion, increased migratory velocity, and alleviated capillary stalling, thereby restoring cortical microvascular perfusion. ConclusionsOur findings associate neutrophil-specific circSCMH1 downregulation with clinical FR in LVO-AIS. Targeted intracellular delivery reveals an acute anti-thromboinflammatory function that complements established reparative properties, proposing a novel adjunctive approach for EVT to address the spatiotemporal complexity of stroke and improve clinical outcomes.

neuroscience↗

bioRxiv2026

Acute wood smoke exposure is associated with cell-specific hippocampal transcriptomic responses in an accelerated ovarian failure mouse model

BackgroundWildfire events are increasing in frequency and intensity, and it is well-known that aging individuals are more susceptible to air pollution exposures, and that air pollution exposures result in neurological sequelae. Despite this, it is unclear how declining levels of ovarian hormones that naturally occur in aging females influence brain vulnerability to air pollution. Menopause and the menopausal transition represent a period of profound physiological change that affects cardiovascular, neurological, and immune health. MethodsWe tested whether perimenopausal-like hormonal status amplifies hippocampal responses to acute wood smoke (WS) using an ovary-intact, 4-vinylcyclohexene diepoxide (VCD) model of moderate accelerated ovarian failure (AOF) in female C57BL/6 mice. Animals were exposed to HEPA-filtered air (FA) or WS for 4 h/day over 2 consecutive days ([~]0.5 mg/m3). Exposure characterization confirmed a complex mixture of combustion products with significant levels of both trace metals and gas release during WS exposure. ResultsSpatial transcriptomics (10x Visium; (n=4 sections/group) with automated cell-type annotation identified astrocytes, GABAergic and glutamatergic neurons, oligodendrocytes, revealed cell type-specific transcriptional alterations following WS exposure. Distinct transcriptional patterns were observed across all identified neuronal and glial cell populations. ConclusionTogether, these findings define a cell type-resolved transcriptional framework linking WS exposure and ovarian hormone decline and identify potential cellular pathways relevant to hippocampal vulnerability.

pharmacology and toxicology↗

bioRxiv2025

Chromosomal Topological Domain Formation Modulates Transcription and the Coupling of Neighboring Genes in Escherichia coli

Chromosomal topology and transcription are tightly coupled, yet the quantitative impact of topological constraints on transcription, supercoiling, and the potential coupling between neighboring genes in vivo remains unclear. In this work, we constructed synthetic chromosomal domains in Escherichia coli that contained two genes inside a topology-controllable domain and a third gene outside. Using three-color single-molecule fluorescence in situ hybridization (smFISH), we measured transcription output from the three genes in individual cells under conditions in which gene orientation, domain formation state, and global chromosomal supercoiling density were varied. We found that topological domain formation repressed transcription, diminished gene orientation-dependent differences in transcription, and modulated the supercoiling sensitivity of genes located both within and near the domain. Relaxing global negative supercoiling through gyrase inhibition broadly repressed transcription; increasing global negative supercoiling level through topoisomerase I inhibition repressed highly expressed genes, while activating lowly expressed ones. Besides single-gene effects, we also observed an intrinsic coupling between neighboring genes with a non-monotonic dependence on the underlying supercoiling state, which shifted with domain topology and gene syntax. Our results establish chromosome topology as a major regulator of both transcription levels and the coupling between adjacent genes.

biophysics↗

bioRxiv2025

Metabolomic, Lipidomic, and Enterohormone Changes in the Progression from MASLD to MASH

Background & AimsMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) represent progressive stages of liver disease, with distinct metabolic and cellular alterations. This study investigates the progression from MASLD to MASH through metabolomics, lipidomics, and assessment of hormones. MethodsMale C57BL/6NTac mice were fed a high-fat diet for 16 weeks to induce MASLD and for 29 weeks to develop MASH. Aged-matched controls on a normal diet were used for comparison. Histology confirmed the progression of MASLD to MASH. We performed metabolomic and lipidomic profiling of liver, colon, and stool samples to identify metabolic and lipid alterations. Plasma enteroendocrine hormones and cytokines were quantified. Immunofluorescence was performed to assess enteroendocrine cells changes in the colon and the association of serotonin (5-HT) with fibronectin in the liver. ResultsMetabolomic and lipidomic analysis revealed significant alterations at different stages of the disease. Specifically, cholic acid was increased across the liver, colon, and stool in both MASLD and MASH mice compared to controls. Compared to the control group, MASLD mice exhibited an increase in enteroendocrine hormones, GLP-1, GIP, and PYY, whereas no changes were observed in MASH mice. Comparing MASLD to MASH livers, we found hepatic 5-HT levels were increased in MASH mice compared to MASLD mice. The MASH liver also exhibited a colocalization between fibronectin and 5-HT, suggesting a potential role of 5-HT in liver fibrosis. ConclusionsOur study provides novel insights into the progressive metabolic and hormonal changes from MASLD to MASH. The increase in cholic acid and differential enteroendocrine hormone responses highlight the complex interactions between the gut and liver in metabolic liver diseases. These findings suggest that enteroendocrine hormones may play a role in the progression of MASLD to MASH as well as liver fibrosis, offering potential therapeutic avenues for targeting the gut-liver axis in metabolic liver diseases.

cell biology↗

bioRxiv2025

Synthesizing unmodified, supercoiled circular DNA molecules in vitro

Supercoiled (Sc) circular DNA, such as plasmids, has shown therapeutic potential since the 1990s, but is limited by bacterial modifications, unnecessary DNA sequences, and contaminations that may trigger harmful responses. To overcome these challenges, we have developed two novel scalable biochemical methods to synthesize unmodified Sc circular DNA. Linear DNA with two loxP sites in the same orientation is generated via PCR or rolling circle amplification. Cre recombinase then converts this linear DNA into relaxed circular DNA. After T5 exonuclease removes unwanted linear DNA, topoisomerases are employed to generate Sc circular DNA. We have synthesized EGFP-FL, a 2,002 bp mini-circular DNA carrying essential EGFP expression elements. EGFP-FL transfected human HeLa and mouse C2C12 cells with much higher efficiency than E. coli-derived plasmids. These new biochemical methods can produce unmodified Sc circular DNA, in length from 196 base pairs to several kilobases and in quantities from micrograms to milligrams, providing a promising platform for diverse applications.

biochemistry↗

bioRxiv2024

Diabetes alters neuroeconomically dissociable forms of mental accounting

Those with diabetes mellitus are at high-risk of developing psychiatric disorders, yet the link between hyperglycemia and alterations in motivated behavior has not been explored in detail. We characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on a naturalistic neuroeconomic foraging paradigm called Restaurant Row. Mice made self-paced choices while on a limited time-budget accepting or rejecting reward offers as a function of cost (delays cued by tone-pitch) and subjective value (flavors), tested daily in a closed-economy system across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy that overprioritized high-value rewards. We discovered these foraging behaviors were driven by impairments in multiple decision-making systems, including the ability to deliberate when engaged in conflict and cache the value of the passage of time in the form of sunk costs. Surprisingly, diabetes-induced changes in behavior depended not only on the type of choice being made but also the salience of reward-scarcity in the environment. These findings suggest complex relationships between glycemic regulation and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt fundamentally distinct computational processes and could give rise to psychiatric vulnerabilities.

neuroscience↗

bioRxiv2023

Sex and heredity are determinants of oral oxycodone self-administration in 36 Inbred Rat Strains: correlations with behavioral tests ofanxiety and novelty-seeking

Oxycodone abuse begins with prescription oral oxycodone, yet vulnerability factors determining abuse are largely undefined. We evaluated genetic vulnerability in a rat model of oral oxycodone self-administration (SA): increasing oxycodone concentration/session (0.025-0.1mg/ml; 1,4,16-h) followed by extinction and reinstatement. Active licks and oxycodone intake were greater in females than males during 4-h and 16-h sessions (p< 0.001). Each sex increased intake during 16-h vs 4-h sessions (p<2e-16), but a subset of strains dramatically augmented intake at 16-h (p=0.0005). Heritability (h2) of active licks/4-h at increasing oxycodone dose ranged from 0.30-0.53. Under a progressive ratio schedule, breakpoints were strain-dependent (p<2e-16). Cued reinstatement was greater in females (p<0.001). Naive rats were assessed by elevated plus maze (EPM), open field (OF) and novel object interaction (NOI). We correlated these behaviors with 28 parameters of oxycodone SA. Anxiety-defining EPM traits were most associated with SA in both sexes, whereas more OF and NOI traits were SA-associated in males. Sex and heredity are major determinants of motivation to take and seek oxycodone; intake augments dramatically during extended access in specific strains; and pleiotropic genes affect anxiety and multiple SA parameters.

genetics↗

bioRxiv2021

Inhibition of Kallikrein-related peptidases 7 restrains pancreatic tumor growth through induction of ferroptosis

Pancreatic cancer is one of the most aggressive and lethal malignancies with extremely poor prognosis, and KLK7 was considered as a potential therapeutic target. In this study, we analyzed the expression of KLK7 in TCGA and GTEx databases and found that KLK7 had a negative correlation to long-term survival rate (>1.5 years) of pancreatic cancer patients. Compound 42 is a coumarinic derivative, a suicide substrate inhibitor of KLK7, which has been proved to inhibit the proliferation of PANC-1 cells in vitro effectively in our previous study. In this study, we further investigated the inhibition ability of Compound 42 in tumor formation and development in CDX and PDX tumor models of pancreatic cancer subsequently. Besides, we studied the inhibitory mechanism of Compound 42 and the result showed that Compound 42 arrested the pancreatic cancer cell cycle in G0/G1 phase and induced ferroptosis through down-regulation of GPX4 protein level and accumulation of iron ion. Thus, these experiments demonstrate that Compound 42, suppressing pancreatic cancer in vivo, is expected to become a novel drug for pancreatic cancer treatment.

molecular biology↗

bioRxiv2019

Bacteriological Monitoring and Evaluation of Cleaning-disinfection of Computer-related Equipment in an Obstetric and Gynecology Hospital

It is already known that computer keyboards and mouses in hospitals are contaminated with different kinds of bacteria. However, the mouse pad has been neglected with regard to both research and regular cleaning and disinfection in hospitals. In our study, we monitored and evaluated the bacteriology degrees of 74 computers keyboards, mouses and mouse pads from six departments. The results showed that before cleaning-disinfection, the contamination rate of the mouse pad ranked second following the keyboards. Enterococcus Faecium was cultured from the mouse pads. The computer-related equipment in the wards and outpatient rooms were much more contaminated than that in the operating rooms. Acinetobacter spp. was only isolated from the doctors computers. After cleaning-disinfection, 4 strains of MRSA were isolated from the keyboards and the mouses, one and 3 were cultured at day 3 and day 5 after cleaning-disinfection, respectively. One strain of Pseudomonas Aeruginosa was isolated from the mouses at day 3 after cleaning-disinfection. These demonstrated that the bacterial contamination of the mouse pads must be as emphasized as that of the keyboards and mouses. Furthermore, It is better to clean and disinfect the computer-related equipment(keyboards, mouses, mouse pads) at least once a day.

scientific communication and education↗