[Causal association between depression and stress urinary incontinence: A two-sample bidirectional Mendelian randomization study].

OBJECTIVE: To investigate the causal correlation between depression and stress urinary incontinence (SUI) using Mendelian randomization (MR) analysis. METHODS: We searched the FinnGen Consortium database for genome-wide association studies (GWAS) on depression and obtained 23 424 case samples and 192 220 control samples, with the GWAS data on SUI provided by the UK Biobank, including 4 340 case samples and 458 670 control samples. We investigated the correlation between depression and SUI based on the depression data collected from the Psychiatric Genomics Consortium (PGC). We employed inverse-variance weighting as the main method for the MR study, and performed sensitivity analysis to verify the accuracy and stability of the findings. RESULTS: Analysis of the data from the UK Biobank and FinnGen Consortium showed that depression was significantly correlated with an increased risk of SUI (P=0.005), but not SUI with the risk of depression (P=0.927). And analysis of the PGC data verified the correlation of depression with the increased risk of SUI (P=0.043). CONCLUSION: Depression is associated with an increased risk of SUI, while SUI does not increase the risk of depression.

Exploring the Molecular Mechanisms of Herbs in the Treatment of Hyperlipidemia Based on Network Pharmacology and Molecular Docking.

Many herbs have been shown to safely and successfully treat hyperlipidemia. However, the molecular mechanisms underlying their treatment remain unclear. In this study, 103 prescriptions for the treatment of hyperlipidemia containing 146 herbs were screened. Cluster analyses identified a core prescription comprising five herbs, namely, Crataegus pinnatifida (Shan Zha), Cassiae semen (Jue Ming Zi), Alisma orientale (Sam.) Juz. (Ze Xie), Salvia miltiorrhiza (Dan Shen), and Radix Polygoni Multiflori (He Shou Wu), in combination for the treatment of hyperlipidemia. Next, 9, 62, 5, 132, and 34 potential targets for each of the core herbs and a total of 512 hyperlipidemia-related protein targets were detected. Finally, 40 targets shared by core herbs and hyperlipidemia were identified. IL6, AKT1, IL1B, PTGS2, VEGFA, PPARG, and NOS3 were the seven proteins that were found to be most important in the treatment of hyperlipidemia. Interestingly, the Kyoto Encyclopedia of Genes and Genomes pathway indicated that these targets were mainly enriched in the lipid and atherosclerosis pathway and the cancer pathway. In addition, core target proteins such as AKT1, PTGS2, and PPARG have been demonstrated to play critical roles in hyperlipidemia and pancreatic cancer. Significant affinity between bioactive chemicals and proteins involved in cancer pathways was found by molecular docking. Molecular docking results showed that AKT1, PTGS2, and PPARG exhibited good binding ability with three bioactive chemicals, including 3-beta-hydroxymethyllenetanshiquinone, danshexinkum d, and physciondiglucoside. The treatment of hyperlipidemia by herbs may be mediated through the modulation of proteins associated with the cancer pathway. This study helps to provide a theoretical basis for future combined therapy for hyperlipidemia and cancer. [Figure: see text].

Polyphenol improve the foaming properties of soybean isolate protein: Structural, physicochemical property changes and application in angel cake.

With the increasing demand for food foaming, how to enhance the foaming properties of protein has gradually become the research focus. This work studied the effect of synephrine (SY) on foaming properties, structure properties, and physicochemical properties of soybean protein isolate (SPI). When the mass ratio of SY to SPI was 1:2, compared with SPI alone, the foam capacity and foam stability of the SY-SPI complex were significantly enhanced. Optical microscopy and confocal laser scanning microscope showed that the improvement in foaming performance was mainly due to the reduction of bubble size and uniform protein distribution. Circular dichroism spectrum and fluorescence spectra indicated that the hydrogen bond of SPI was destroyed and blue shifted with the addition of SY. What's more, the absolute value of Zeta potential, solubility, and hydrophobicity all increased, while the particle size decreased. As a result of molecular docking, surface hydrogen bonds, Van der Waals forces and hydrophobic interactions are the main driving forces. The addition of SY and SPI improved the specific volume and texture of angel cake. This study shows that SY has the potential to be developed into a new type of blowing agent.

Loss of ZNF408 attenuates STING-mediated immune surveillance in breast carcinogenesis.

Understanding the mechanism of cancer immune surveillance is crucial for precision medicine and effective immunotherapy. We report here that ZNF408, encoded by a gene linked to familial exudative vitreoretinopathy (FEVR) and autosomal recessive retinitis pigmentosa (RP), is physically associated with the SETD1A/COMPASS complex mediating histone H3 lysine 4 (H3K4) methylation in breast cancer cells. Integrative epigenomic and transcriptomic analyses reveal that ZNF408 and SETD1A share overlapped chromatin landscape and coordinately activate a cohort of genes, among which STING1 is critical in innate immune responses. ZNF408-SETD1A complex enhances STING1 expression and promotes STING-mediated anti-tumor immune responses both in vitro and in vivo. Importantly, ZNF408 expression is positively correlated with that of STING1 and negatively correlated with the histological grade of breast cancer. Our study uncovers a role for ZNF408 in cancer immune surveillance, supporting further investigations for therapeutic targeting of ZNF408-SETD1A-STING1 axis in breast carcinogenesis and other ZNF408-associated diseases including FEVR and RP.

Thermotropic "Plumber's Nightmare" - A Tight Liquid Organic Double Framework.

Gyroid, double diamond and the body-centred "Plumber's nightmare" are the three most common bicontinuous cubic phases in lyotropic liquid crystals and block copolymers. While the first two are also present in solvent-free thermotropics, the latter had never been found. Containing six-fold junctions, it was unlikely to form in the more common phases with rod-like cores normal to the network columns, where a maximum of four branches can join at a junction. The solution has therefore been sought in side-branched mesogens that lie in axial bundles joined at their ends by flexible "hinges". But for the tightly packed double framework, geometric models predicted that the side-chains should be very short. The true Plumber's nightmare reported here, using fluorescent dithienofluorenone rod-like mesogen, has been achieved with, indeed, no side chains at all, but with 6 flexible end-chains. Such molecules normally form columnar phases, but the key to converting a complex helical column-forming mesogen into a framework-forming one was the addition of just one methyl group to each pendant chain. A geometry-based explanation is given.

Feasibility study on heterotrophic utilization of galactose by Chlorella sorokiniana and promotion of galactose utilization through mixed carbon sources culture.

BACKGROUND: The development of alternative carbon sources is important for reducing the cost of heterotrophic microalgae cultivation. Among cheap feedstocks, galactose is one of the most abundant sugars and can be easily obtained from many natural biomasses. However, it is generally difficult to be utilized by microalgae. In addition, the mechanism of its low utilization efficiency in heterotrophic cultivation is still unknown. RESULTS: Among seven tested carbon sources, only glucose and acetate could be efficiently utilized by C. sorokiniana in heterotrophic cultivation while there were no apparent signs of utilization of other carbohydrates, including galactose, in regular heterotrophic cultivation. However, galactose could be utilized in cultures with high inoculation sizes. This confirmed that C. sorokiniana has a complete pathway for transporting and assimilating galactose under dark conditions, but the rate of galactose utilization is quite low. In addition, the galactose utilization was greatly enhanced in mixotrophic cultures, which indicated that galactose utilization could be enhanced by additional pathways that can enhance cell growth. Based on above results, a mixed carbon source culture strategy was proposed to improve the utilization rate of galactose, and a significant synergistic effect on cell growth was achieved in cultures using a mixture of galactose and acetate. CONCLUSIONS: This study indicated that the galactose metabolism pathway may not be inherently deficient in Chlorophyta. However, its utilization rate was too low to be detected in regular heterotrophic cultivation. Mixed carbon source culture strategy was confirmed effective to improve the utilization rate of galactose. This study contributes to a deeper understanding of the utilization ability of difficultly utilized substrates in the heterotrophic cultivation of microalgae, which is of great significance for reducing the cost of heterotrophic cultivation of microalgae.

Biomechanical effects of different instrumented segments and trunk shifts on distal adjacent segments after congenital scoliosis posterior hemivertebrectomy: Preliminary results of a single case.

Objective: The present study aims to discuss the biomechanical effects of the sagittal vertical axis and different instrumented segments on distal adjacent segments after congenital scoliosis posterior hemivertebrectomy. Method: A case of congenital scoliosis caused by hemivertebra was selected for the reconstruction of the preoperative and postoperative 3D computed tomography data of the full spine. A finite element model of different fusion lengths and postoperative trunk shift (TS) values was established using the finite element method to compare the biomechanical effects of different models on the distal adjacent segment. Result: In the L1-L3 and T12-L1-L3-L4 fusion modes, the horizontal shift of the 1st vertebra below the lowest instrumented vertebra (LIV) increased with the trunk shift (TS) expansion after operation, and the imbalance between the left and right vertical stress of the 1st intervertebral disc below the LIV increased. With the decrease in fused segments in cases of TS = 10 mm and TS = 5 mm, the 1st vertebra below the LIV was subjected to a greater unbalanced force in the horizontal direction, and the 1st intervertebral disc below the LIV was subjected to a smaller imbalance between the left and right vertical stress after operation. Conclusion: When treating congenital scoliosis with hemivertebrectomy and pedicle screw fixation, fused segments can be properly extended and the postoperative TS shortened with a view of reducing the imbalance between the left and right stress of the 1st intervertebral disc below the LIV as well as the horizontal shift of the 1st vertebra below the LIV.

Disclosing Topographical and Chemical Patterns in Confined Films of High-Molecular-Weight Block Copolymers under Controlled Solvothermal Annealing.

The microphase separation of high-molecular-weight block copolymers into nanostructured films is strongly dependent on the surface fields. Both, the chain mobility and the effective interaction parameters can lead to deviations from the bulk morphologies in the structures adjacent to the substrate. Resolving frustrated morphologies with domain period L0 above 100 nm is an experimental challenge. Here, solvothermal annealing was used to assess the contribution of elevated temperatures of the vapor Tv and of the substrate Ts on the evolution of the microphase-separated structures in thin films symmetric of polystyrene-b-poly(2vinylpyridine) block copolymer (PS-PVP) with L0 about 120 nm. Pronounced topographic mesh-like and stripe patterns develop on a time scale of min and are attributed to the perforated lamella (PL) and up-standing lamella phases. By setting Tv/Ts combinations it is possible to tune the sizes of the resulting PL patterns by almost 10%. Resolving chemical periodicity using selective metallization of the structures revealed multiplication of the topographic stripes, i.e., complex segregation of the component within the topographic pattern, presumably as a result of morphological phase transition from initial non-equilibrium spherical morphology. Reported results reveal approaches to tune the topographical and chemical periodicity of microphase separation of high-molecular-weight block copolymers under strong confinement, which is essential for exploiting these structures as functional templates.

The effect and mechanism of patchouli alcohol on cognitive dysfunction in AD mice induced by Aß1-42 oligomers through AMPK/mTOR pathway.

Alzheimer's disease (AD) is a neurodegenerative brain disorder that progressively impairs long-term and working memory. The function and mechanism of PA(Patchouli alcohol) in improving AD in the external treatment of encephalopathy remain unclear. This study aimed to investigate the therapeutic effect of PA on AD using an Aß1-42 induced AD mouse model with LPS(Lipopolysaccharide) stimulation of BV2 microglial cells. Additionally, we aimed to explore the potential mechanism of PA in enhancing autophagy and reducing neuroinflammation through the AMPK (AMP-activated protein kinase)/mTOR (Mammaliam target of rapamycin) signaling pathway. The Morris water maze was used to assess cognitive function, and cortical and hippocampal tissues were collected for further analysis of the corresponding signaling pathways and inflammatory changes through biological experiments. Our research findings demonstrate that PA has a significant positive impact on cognitive and memory impairments in mice that have been induced with Aß1-42-induced AD. Additionally, PA was also found to revert the activation of microglia induced by LPS. These effects may be attributed to the reduction of neuroinflammation and enhancement of the AMPK/mTOR autophagy pathway. Therefore, PA may serve as an effective therapeutic option to prevent or delay the progression of AD-associated memory dysfunction.

PRRX1-fused mesenchymal neoplasm: A novel PRRX1::NCOA1 fusion transcript.

PRRX1-fused mesenchymal neoplasm is a recently identified, rare subcutaneous soft tissue neoplasm that is characterized by fusion of PRRX1 (exon 1) with NCOA1 (exon 13) in the majority of reported cases. Although initially considered to be fibroblastic, a possibility of neural or neuroectodermal differentiation has been suggested in a subset of cases. We report a 26-year-old female with a 4.0 cm painless mass located in the subcutis of the left thigh. Microscopically, the tumor was well-circumscribed and multinodular and was composed of relatively monomorphic ovoid to spindle cells arranged in loose fascicles, trabeculae, and cords within alternating myxoid and fibrous matrix, and vascularized stroma. Mitotic figures were scarce and necrosis was not observed. By immunohistochemistry, the neoplastic cells demonstrated focal co-expression of S100 protein and SOX10 and were negative for epithelial membrane antigen, smooth muscle actin, desmin, CD34, STAT6, HMB45, Melan-A, and MUC4. The expression of Rb1 was retained. Targeted RNA-sequencing identified a novel transcript fusion of PRRX1 (exon 1)::NCOA1 (exon 15), which was further confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. The tumor was narrowly excised and no tumor recurrence or metastasis was identified after 13 months of follow-up. In summary, we report a new case of PRRX1-fused mesenchymal neoplasm, expanding the molecular genetic spectrum and providing further support for possible neural or neuroectodermal differentiation of this emerging soft tissue tumor entity.

Inhibiting the CB1 receptor in CIH-induced animal model alleviates colon injury.

Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)-induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1ß, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. KEY POINTS: •CIH leads to overexpression of CB1 receptor in colon tissue. •CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. •Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery.

Low muscle density in children with osteogenesis imperfecta using opportunistic low-dose chest CT: a case-control study.

BACKGROUND: The aim of the study was to investigate the muscle differences in children with osteogenesis imperfecta (OI) using opportunistic low-dose chest CT and to compare different methods for the segmentation of muscle in children. METHODS: This single center retrospective study enrolled children with OI and controls undergoing opportunistic low-dose chest CT obtained during the COVID pandemic. From the CT images, muscle size (cross-sectional area) and density (mean Hounsfield Units [HU]) of the trunk muscles were measured at the mid-T4 and the mid-T10 level using two methods, the fixed thresholds and the Gaussian mixture model. The Bland-Altman method was also used to compute the strength of agreement between two methods. Comparison of muscle results between OI and controls were analyzed with Student t tests. RESULTS: 20 children with OI (mean age, 9.1 ± 3.3 years, 15 males) and 40 age- and sex-matched controls were enrolled. Mean differences between two methods were good. Children with OI had lower T4 and T10 muscle density than controls measured by the fixed thresholds (41.2 HU vs. 48.0 HU, p < 0.01; 37.3 HU vs. 45.9 HU, p < 0.01). However, children with OI had lower T4 muscle size, T4 muscle density, T10 muscle size and T10 muscle density than controls measured by the Gaussian mixture model (110.9 vs. 127.2 cm2, p = 0.03; 44.6 HU vs. 51.3 HU, p < 0.01; 72.6 vs. 88.0 cm2, p = 0.01; 41.6 HU vs. 50.3 HU, p < 0.01, respectively). CONCLUSIONS: Children with OI had lower trunk muscle density indicating that OI might also impair muscle quality. Moreover, the fixed thresholds may not be suitable for segmentation of muscle in children.

CT-determined low skeletal muscle index predicts poor prognosis in patients with colorectal cancer.

BACKGROUND: Sarcopenia is highly prevalent among patients with colorectal cancer (CRC). Computed tomography (CT)-based assessment of low skeletal muscle index (SMI) is widely used for diagnosing sarcopenia. However, there are conflicting findings on the association between low SMI and overall survival (OS) in CRC patients. The objective of this study was to investigate whether CT-determined low SMI can serve as a valuable prognostic factor in CRC. METHODS: We collected data from patients with CRC who underwent radical surgery at our institution between June 2020 and November 2021. The SMI at the third lumbar vertebra was calculated using CT scans, and the cutoff values for defining low SMI were determined using receiver operating characteristic curves. Univariate and multivariate analyses were performed to assess the associations between clinical characteristics and postoperative major complications. RESULTS: A total of 464 patients were included in the study, 229 patients (46.7%) were classified as having low SMI. Patients with low SMI were older and had a lower body mass index (BMI), a higher neutrophil to lymphocyte ratio (NLR), and higher nutritional risk screening 2002 (NRS2002) scores compared to those with normal SMI. Furthermore, patients with sarcopenia had a higher rate of major complications (10.9% vs. 1.3%; p < 0.001) and longer length of stay (9.09 ± 4.86 days vs. 8.25 ± 3.12 days; p = 0.03). Low SMI and coronary heart disease were identified as independent risk factors for postoperative major complications. Moreover, CRC patients with low SMI had significantly worse OS. Furthermore, the combination of low SMI with older age or TNM stage II + III resulted in the worst OS in each subgroup analysis. CONCLUSIONS: CT-determined low SMI is associated with poor prognosis in patients with CRC, especially when combined with older age or advanced TNM stage.

[Pedigree Analysis of Hereditary Coagulation Factor XII Deficiency Caused by Compound Heterozygous Mutation p.Gly175Cys and p.Gly542Ser of F12 Gene].

OBJECTIVE: To analyze the clinical phenotype and gene mutation of a genetic coagulation factor XII (FXII) deficiency pedigree and explore the molecular pathogenesis. METHODS: The activated partial thromboplastin time (APTT) and FXII activity (FXII:C) were detected by clotting method. The FXII antigen (FXII:Ag) was tested with ELISA. All exons and flanks of F12 gene were determined by Sanger sequencing. ClustalX-2.1-win, PROVEAN and Swiss-Pdb Viewer software were used to analyze the conservatism of amino acids at the mutant site, forecast whether the mutant amino acids were harmful and confirm the influence of the mutation on protein structure. RESULTS: The APTT of the proband prolonged to 71.3 s. The FXII:C and FXII:Ag were decreased to 5% and 6%, respectively. There were two heterozygous missense mutations c.580G>T and c.1681G>A detected in exon 7 and exon 14 of F12 gene, resulting in p.Gly175Cys and p.Gly542Ser, severally. Proband's father carried the p.Gly175Cys heterozygous mutation, while mother, brother and daughter had the p.Gly542Ser heterozygous mutation. Software analysis showed that both Gly175 and Gly542 were conserved, the two mutations were harmful and when mutations had occurred, the corresponding sites affected the protein local structure. CONCLUSION: The p.Gly175Cys and p.Gly542Ser compound heterozygous mutations are the molecular pathogenesis of the hereditary coagulation FXII deficiency pedigree. The p.Gly175Cys mutation has been detected for the first time in the world.

Population differentiation and dynamics of five pioneer species of Gaultheria from the secondary forests in subtropical China.

BACKGROUND: The influence of native secondary succession associated with anthropogenic disturbance on the biodiversity of the forests in subtropical China remains uncertain. In particular, the evolutionary response of small understory shrubs, particularly pioneer species inhabiting continuously disturbed habitats, to topographic heterogeneity and climate change is poorly understood. This study aimed to address this knowledge gap by focusing on the Gaultheria crenulata group, a clade of small pioneer shrubs in subtropical China. RESULTS: We examined the genetic structure and demographic history of all five species of the G. crenulata group with two maternally inherited chloroplast DNA (cpDNA) fragments and two biparentally inherited low-copy nuclear genes (LCG) over 89 natural populations. We found that the genetic differentiation of this group was influenced by the geomorphological boundary between different regions of China in association with Quaternary climatic events. Despite low overall genetic diversity, we observed an isolation-by-distance (IBD) pattern at a regional scale, rather than isolation-by-environment (IBE), which was attributed to ongoing human disturbance in the region. CONCLUSION: Our findings suggest that the genetic structure of the G. crenulata group reflects the interplay of geological topography, historical climates, and anthropogenic disturbance during the Pliocene-Pleistocene-Holocene periods in subtropical China. The observed IBD pattern, particularly prominent in western China, highlights the role of limited dispersal and gene flow, possibly influenced by physical barriers or decreased connectivity over geographic distance. Furthermore, the east-to-west trend of gene flow, potentially facilitated by the East Asian monsoon system, underscores the complex interplay of biotic and abiotic factors shaping the genetic dynamics of pioneer species in subtropical China's secondary forests. These findings can be used to assess the impact of environmental changes on the adaptation and persistence of biodiversity in subtropical forest ecosystems.

Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer.

Background: Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions. Materials and methods: A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions. Results: The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS. Conclusion: A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.

Optimizing cell therapy by sorting cells with high extracellular vesicle secretion.

Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. Here, we utilize a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach is applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibit distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintain high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improves heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.

Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor.

OBJECTIVE: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a thyroid hormone receptor-beta is the only Food and Drug Administration approved therapy. As such, there is a critical need to improve our understanding of gene expression regulation and signaling transduction in MASLD to develop new therapies. Matrin-3 is a DNA- and RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor (CAR). METHODS: Matrin-3 floxed and liver-specific knockout mice were fed either a chow diet or 60 kcal% high-fat diet (HFD) for up to 16 weeks. The mice were euthanized for different analysis including liver histology, lipid levels, and gene expression. Bulk RNA-seq, bulk ATAC-seq, and single-nucleus Multiome were used to examine changes of transcriptome and chromatin accessibility in the liver. Integrative bioinformatics analysis of our data and publicly available datasets and different biochemical assays were performed to identify underlying the molecular mechanisms mediating matrin-3's effects. Liver-tropic adeno-associated virus was used to restore the expression of CAR for lipid, acute phase genes, and histological analysis. RESULTS: Matrin-3 expression is induced in the steatotic livers of mice. Liver-specific matrin-3 deletion exacerbated HFD-induced steatosis, acute phase response, and inflammation in the liver of female mice. The transcriptome and chromatin accessibility were re-programmed in the liver of these mice with signatures indicating that CAR signaling is dysregulated. Mechanistically, matrin-3 interacts with CAR mRNA, and matrin-3 deficiency promotes CAR mRNA degradation. Consequently, matrin-3 deletion impaired CAR signaling by reducing CAR expression. Matrin-3 levels positively correlate with CAR expression in human livers. Ces2a and Il1r1 were identified as new target genes of CAR. Interestingly, we found that CAR discords with the expression of its target genes including Cyp2b10 and Ces2a in response to HFD, indicating CAR signaling is dysregulated by HFD despite increased CAR expression. Dysregulated CAR signaling upon matrin-3 deficiency reduced Ces2a and de-repressed Il1r1 expression. CAR restoration partially abrogated the dysregulated gene expression, exacerbated hepatic steatosis, acute phase response, and inflammation in liver-specific matrin-3 knockout mice fed a HFD. CONCLUSIONS: Our findings demonstrate that matrin-3 is a key upstream regulator maintaining CAR signaling upon metabolic stress, and the matrin-3-CAR axis limits hepatic steatosis and stress response signaling that may give insights for therapeutic intervention.