Aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders: progress of experimental models based on disease pathogenesis.

Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction. To date, no effective treatment exists as the exact causative mechanism remains unknown. Therefore, experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets. Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4, which is highly expressed on the membrane of astrocyte endfeet, most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes. These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders, such as aquaporin-4 loss, astrocytopathy, granulocyte and macrophage infiltration, complement activation, demyelination, and neuronal loss; however, they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders. In this review, we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro, ex vivo, and in vivo for neuromyelitis optica spectrum disorders, suggest potential pathogenic mechanisms for further investigation, and provide guidance on experimental model choices. In addition, this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders, offering further therapeutic targets and a theoretical basis for clinical trials.

Comprehensive metabolic profiling of dioxin-like compounds exposure in laying hens: Implications for toxicity assessment.

The evaluation of toxicity related to polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) is crucial for a comprehensive risk assessment in real-world exposure scenarios. This study employed a controlled feeding experiment to investigate the metabolic effects of dioxin-like compounds (DLCs) on laying hens via feed exposure. Diets enriched with two concentrations (1.17 and 5.13 pg toxic equivalents (TEQ)/g dry weight (dw)) were administered over 14 days, followed by 28 days of clean feed. Metabolomics analyses of blood samples revealed significant metabolic variations between PCDD/Fs and DL-PCBs exposed groups and controls, reflecting the induced metabolic disruption. Distinct changes were observed in sphingosine, palmitoleic acid, linoleate, linolenic acid, taurocholic acid, indole acrylic acid, and dibutyl phthalate levels, implying possible connections between PCDD/Fs and DL-PCBs toxic effects and energy-neuronal imbalances, along with lipid accumulation and anomalous amino acid metabolism, impacting taurine metabolism. Moreover, we identified three differential endogenous metabolites-L-tryptophan, indole-3-acetaldehyde, and indole acrylic acid-as potential ligands for the aryl hydrocarbon receptor (AhR), suggesting their role in mediating PCDD/Fs and DL-PCBs toxicity. This comprehensive investigation provides novel insights into the metabolic alterations induced by PCDD/Fs and DL-PCBs in laying hens, thereby enhancing our ability to assess risks associated with their exposure in human populations.

Gegen Qinlian Decoction reverses oxaliplatin resistance in colorectal cancer by inhibiting YTHDF1-regulated m6A modification of GLS1.

BACKGROUND: Colorectal cancer (CRC) and its chemoresistance pose significant threats to human health. Gegen Qinlian Decoction (GQD) is frequently employed alongside chemotherapy drugs for the treatment of CRC and various intestinal disorders. Despite its widespread use, there is limited research investigating the mechanisms through which GQD reverses chemoresistance. PURPOSE: This study investigated the mechanism by which GQD reverses oxaliplatin (OXA) resistance in CRC. METHODS: A YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-knockdown OXA-resistant cell line was constructed by lentivirus to clarify YTHDF1-mediated chemoresistance through the regulation of glutaminase 1 (GLS1). The efficacy of GQD in reversing OXA resistance in CRC in vitro was evaluated by Cell Counting Kit-8, western blotting, quantitative real-time polymerase chain reaction, and glutaminase activity assays. In vivo validation was performed by constructing tumor xenografts in nude mice with OXA-resistant cells. In addition, mouse feces were collected and a 16S rDNA assay was performed to assess the regulation of intestinal flora by GQD. RESULTS: Overexpression of YTHDF1 upregulated GLS1 expression and induced OXA-resistance in CRC. GQD induced apoptosis in LoVo/OXAR, increased OXA accumulation in LoVo/OXAR, inhibited expression of YTHDF1 and GLS1 when administered alone and in combination with OXA, and suppressed GLS1 activity to reverse drug resistance with good synergistic effects. GQD and OXA combination or GLS1 inhibitor alleviated OXA toxicity, reduced the volume of tumor xenografts in nude mice, inhibited YTHDF1 and GLS1 protein expression and GLS1 activity, adjusted the intestinal flora, and significantly reversed the increased Firmicutes/Bacteroidetes ratio. CONCLUSION: GQD has shown superior efficacy in reversing OXA-resistance and increasing sensitivity. These findings indicate that the therapy combined with GQD has potential utility in the treatment of OXA-resistant CRC.

The association between thyroid differentiation score and survival outcomes in papillary thyroid carcinoma.

BACKGROUND: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in PTC. The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts. METHODS: Two independent cohorts of PTC patients were used: 1) the Cancer Genome Atlas (TCGA) thyroid cancer study (N=372), 2) MD Anderson Cancer Center (MDACC) cohort (N=111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was also explored. The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. RESULTS: In both cohorts, TDS was associated with tumor and nodal stage at diagnosis as well as tumor driver mutation status. High TDS was associated with longer PFI on univariable analyses across cohorts. After adjusting for overall stage, TDS remained significantly associated with PFI in the MDACC cohort only (aHR 0.67, 95%CI 0.52-0.85). In subgroup analyses stratified by tumor driver mutation status, higher TDS was most consistently associated with longer PFI in BRAFV600E-mutated tumors across cohorts after adjusting for overall stage (TCGA: aHR 0.60, 95% CI: 0.33-1.07; MDACC: aHR 0.59, 95% CI: 0.42-0.82). For OS, increasing TDS was associated with longer OS in the overall MDACC cohort (aHR=0.78, 95% CI:0.63-0.96), where the median duration of follow-up was 12.9 years. CONCLUSION: TDS quantifies the spectrum of differentiation status in PTC and may serve as a potential prognostic biomarker in PTC, mostly promisingly in BRAFV600E-mutated tumors.

A single-centre study on abnormal antinuclear antibodies in children caused by intravenous infusion of gamma globulin.

Objective: To clarify the impact of intravenous infusion of gamma globulin (IVIg) on antinuclear antibodies (ANAs) in children. Methods: A retrospective analysis was performed on the data of children with nonspecific autoantibody-related diseases whose antinuclear antibody (ANA) and autoantibody profiles were detected in our hospital from January to March 2022. A total of 108 patients with a clear history of IVIg infusion within 28 days composed the IVIg group, and 1201 patients without a history of IVIg infusion composed the non-IVIg group. Results: All patients in the IVIg group had either positive ANAs or positive autoantibodies. Anti-SSA, anti-Ro52 and anti-AMA Mi2 were the top three autoantibodies in the IVIg group. The proportions of patients who were positive for either of these three autoantibodies in the IVIg group were significantly greater than those in the non-IVIg group (all P<0.5). Spearman correlation analysis revealed that the signal intensities of anti-SSA and anti-Ro52 were negatively correlated with the number of days of ANA detection after IVIg infusion (P<0.05). Multiple logistic analyses revealed that a greater total dosage of IVIg, greater IVIg per kilogram of body weight, and fewer ANA detection days after IVIg infusion were independent risk factors for positive anti-SSA and anti-Ro52 results. Conclusions: It is recommended that if rheumatic diseases are suspected, ANA detection should be carried out beforeIVIg infusion. But for patients who are positive for at least one of these three autoantibodies after IVIg infusion, doctors should first consider adoptive antibodies.

Paxlovid reduces the 28-day mortality of patients with COVID-19: a retrospective cohort study.

PURPOSE: In this study, we aim to explore the efficacy of paxlovid on reducing mortality of COVID-19 patients in clinical setting, especially whether paxlovid modifies the risk of death in these severe and critical patients. METHODS: Our retrospective cohort study was conducted on the medical records of patients, consecutively admitted for COVID-19 to five hospitals in Chongqing, China from Dec 8, 2022 to Jan 20, 2023. Based on whether patients received paxlovid during their hospitalization, patients were grouped as paxlovid group and non-paxlovid group. We used 1:1 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between groups. Statistical analysis were performed by SPSS 23.0. The differences in 28-day mortality between these two groups and its influencing factors were the main results we focused on. RESULTS: There were 1018 patients included in our study cohort. With 1:1 ratio PSM, each of the paxlovid group and non-paxlovid group included 237 patients. The results showed that patients using paxlovid have a lower 28-day mortality in overall population either before PSM (OR 0.594, 95% CI 0.385-0.917, p = 0.019) or after PSM (OR 0.458, 95% CI 0.272-0.774, p = 0.003) with multivariable adjusted logistic regression models. Meanwhile, in severe subgroup, it showed similar findings.With paxlovid treatment, it showed a significantly lower 28-day mortality in severe subgroup both before PSM (28% vs.41%, p = 0.008) and after PSM (19% vs.32%, p = 0.007). CONCLUSION: Paxlovid can significantly reduce the risk of 28-day mortality in overall population and severe subgroup patients.This study distinguished the severe subgroup patients with COVID-19 who benefit more from paxlovid treatment.

COVID­19 vaccine: recent advancements and future prospects.

Nowadays, although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic has been handled with long-term management globally, the virus strains keep continuous evolution in an uncertain direction. The newly emerged JN.1 dominated the globally circulating variants in a short time and resulted in increasing hospitalizations. Up to 2024, variant vaccines with the composition of XBB sub-lineage were available due to the coordinated efforts of developers and regulatory agencies. The development of updated vaccines is still needed and the regular availability of coronavirus disease 2019 (COVID-19) vaccines should be timely guaranteed. The current landscape of COVID-19 vaccines and the strategies for accelerating vaccine development and approval are reviewed. Proposals to enhance variants monitoring and the establishment of the strain recommendation mechanism are made. This review provides suggestions about platform technology designation and application, real-world data leveraging and modification to regulatory pathways both for the post-pandemic era of SARS-CoV-2 and for the future unknown pathogen pandemic.

Defactinib inhibits FAK phosphorylation and regulates psoriasis via attenuating hyperproliferation of keratinocytes.

Excessive proliferation of keratinocytes is a crucial pathological risk feature of psoriasis. Focal adhesion kinase (FAK) is a non-receptor protein that primarily regulates cell proliferation and migration. However, the expression and regulatory mechanism of FAK in psoriasis remains unclear. This study aimed to investigate the regulation of FAK in psoriasis and examined the potential impact of FAK inhibitor on psoriasis. A small molecular selective FAK inhibitor, defactinib, was used to evaluate the effect of FAK on psoriasis in in vitro and in vivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasis mice and human keratinocytes cells were used to study the potential roles and mechanisms of FAK in psoriasis. FAK phosphorylation has been weakly detected in normal intact skin and is markedly elevated upon IMQ treatment. By reducing FAK phosphorylation (p-FAK), defactinib treatment could attenuate psoriasiform inflammation and epidermal hyperplasia in IMQ-treated mice compared with IMQ-induced mice treated with the vehicle. In in vitro studies, resiquimod (R848) increased (p-FAK) and promoted cell proliferation in human keratinocytes cells, while defactinib reversed this effect. Mechanistically, defactinib can alleviate the proliferation via JNK/YB1 pathway in vitro and in vivo. Defactinib significantly attenuates psoriasiform inflammation and epidermal hyperproliferation through the inhibition of the FAK-mediated axis. The downregulation of phosphorylated FAK then suppressed the activation of JNK/YB1 protein signaling pathway in psoriasis. Our work highlights targeting FAK as a potentially effective strategy for the treatment of psoriasis.

Effect of Transcutaneous Electrical Nerve Stimulation Based on Wrist-Ankle Acupuncture Theory for Pain Relief during Non-Anesthetic Colonoscopy: A Randomized Controlled Trial.

BACKGROUND: Colonoscopy is essential for diagnosing colorectal diseases but can cause pain during the procedure. This study explores the analgesic effects of Transcutaneous Electrical Nerve Stimulation based on Wrist-Ankle Acupuncture theory (TENS-WAA) in non-anesthetic colonoscopy. METHODS: This prospective study included 120 participants undergoing non-anesthetic colonoscopies. The trial group receiving low-frequency, high-intensity TENS-WAA adjusted to the maximum tolerable current, while the control group received minimal current. Primary outcome was the retrospective pain VAS score. Secondary outcomes included time, heart rate, and credibility/expectancy questionnaire (CEQ) scores (ChiCTR2300076524). RESULTS: Participants who received TENS-WAA intervention reported significantly lower pain VAS scores than the control group (estimated median difference -1.1, 95% CI: -2 to -0.4, P=0.002). Male participants in the trial group experienced significantly lower pain scores than the control group (mean difference -1.4, 95% CI: -2.41 to -0.39, P=0.008). Additionally, the trial group also had significantly lower heart rates (P<0.001) and higher CEQ scores (P=0.001) than the control group. No adverse events were reported. CONCLUSION: TENS-WAA effectively reduces pain during non-anesthetized colonoscopy, especially in male participants, providing a promising non-invasive analgesic method.

Single-cell RNA sequencing data analysis utilizing multi-type graph neural networks.

Single-cell RNA sequencing (scRNA-seq) is the sequencing technology of a single cell whose expression reflects the overall characteristics of the individual cell, facilitating the research of problems at the cellular level. However, the problems of scRNA-seq such as dimensionality reduction processing of massive data, technical noise in data, and visualization of single-cell type clustering cause great difficulties for analyzing and processing scRNA-seq data. In this paper, we propose a new single-cell data analysis model using denoising autoencoder and multi-type graph neural networks (scDMG), which learns cell-cell topology information and latent representation of scRNA-seq data. scDMG introduces the zero-inflated negative binomial (ZINB) model into a denoising autoencoder (DAE) to perform dimensionality reduction and denoising on the raw data. scDMG integrates multiple-type graph neural networks as the encoder to further train the preprocessed data, which better deals with various types of scRNA-seq datasets, resolves dropout events in scRNA-seq data, and enables preliminary classification of scRNA-seq data. By employing TSNE and PCA algorithms for the trained data and invoking Louvain algorithm, scDMG has better dimensionality reduction and clustering optimization. Compared with other mainstream scRNA-seq clustering algorithms, scDMG outperforms other state-of-the-art methods in various clustering performance metrics and shows better scalability, shorter runtime, and great clustering results.

A nomogram prediction of gingival recession in mandibular incisors of orthodontic-orthognathic treated skeletal class III malocclusion with or without PAOO: A retrospective cohort study.

Background: To assess the alterations in gingival thickness and the occurrence gingival recession subsequent to orthodontic-orthognathic treatment of mandibular incisors in skeletal Class III and identify risk factors associated with gingival recession. Methods: In this retrospective cohort study, we enrolled 33 patients exhibiting skeletal Class III malocclusion, totaling 131 mandibular incisors, who were undergoing orthodontic- orthognathic treatment that did not involve extraction of mandibular teeth. The subjects were categorized into surgery group (S; n = 17; ANB = -5.55 ± 3.26; IOFTN = 4.60 ± 0.51, scores ranging: 4.3-5.3) and non-surgery group (NS; n = 16; ANB = -3.00 ± 4.08; IOFTN = 4.63 ± 0.50, scores ranging: 4.3-5.4), based on if they had history of Periodontally Accelerated Osteogenic Orthodontics surgery (S) or not (NS). Patients in S group received orthognathic surgery about 1-1.5 years after Periodontally Accelerated Osteogenic Orthodontics surgery. Alterations in gingival thickness, gingival recession, and keratinized gingival width were compared before and after orthodontic-orthognathic treatment. Logistic regression analysis was used to construct a gingival recession prediction model and draw nomograms. Results: After orthodontic-orthognathic treatment, the gingival thickness and keratinized gingival width in NS group decreased by 0.15 ± 0.21 mm and 0.74 ± 0.91 mm, whereas those in the S group increased by 0.32 ± 0.28 mm and 2.09 ± 1.51 mm (P < 0.05). After orthodontic-orthognathic, the percentage of gingival recession increased by 47.62 % in NS group, which was 14.77 times that of S group (P < 0.05). Multivariate regression analysis indicated that skeletal Class III patients with a gingival thickness below 0.72 mm, an alveolar bone height exceeding 2.36 mm, and an alveolar bone thickness under 0.45 mm might be at elevated risk for developing gingival recession following orthodontic - orthognathic therapy. Conclusions: Drawing on the findings of our investigation, we concluded the risk of gingival recession of mandibular anterior teeth increased after orthodontic-orthognathic treatment in skeletal Class III, whereas Periodontally Accelerated Osteogenic Orthodontics surgery could significantly improve the periodontal phenotype and prevent gingival recession.

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Metal-organic framework derived crystalline nanocarbon for Fenton-like reaction.

Nanoporous carbons with tailorable nanoscale texture and long-range ordered structure are promising candidates for energy, environmental and catalytic applications, while the current synthetic methods do not allow elaborate control of local structure. Here we report a salt-assisted strategy to obtain crystalline nanocarbon from direct carbonization of metal-organic frameworks (MOFs). The crystalline product maintains a highly ordered two-dimensional (2D) stacking mode and substantially differs from the traditional weakly ordered patterns of nanoporous carbons upon high-temperature pyrolysis. The MOF-derived crystalline nanocarbon (MCC) comes with a high level of nitrogen and oxygen terminating the 2D layers and shows an impressive performance as a carbocatalyst in Fenton-like reaction for water purification. The successful preparation of MCC illustrates the possibility to discover other crystalline heteroatom-doped carbon phases starting from correctly designed organic precursors and appropriate templating reactions.

Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis.

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

Ursolic Acid Alleviates Mitotic Catastrophe in Podocyte by Inhibiting Autophagic P62 Accumulation in Diabetic Nephropathy.

The glomerular podocyte, a terminally differentiated cell, is crucial for the integrity of the glomerular filtration barrier. The re-entry of podocytes into the mitotic phase results in injuries or death, known as mitotic catastrophe (MC), which significantly contributes to the progression of diabetic nephropathy (DN). Furthermore, P62-mediated autophagic flux has been shown to regulate DN-induced podocyte injury. Although previous studies, including ours, have demonstrated that ursolic acid (UA) mitigates podocyte injury by enhancing autophagy under high glucose conditions, the protective functions and potential regulatory mechanisms of UA against DN have not been fully elucidated. For aiming to investigate the regulatory mechanism of podocyte injuries in DN progression, and the protective function of UA treatment against DN progression, we utilized db/db mice and high glucose (HG)-induced podocyte models in vivo and in vitro, with or without UA administration. Our findings indicate that UA treatment reduced DN progression by improving biochemical indices. P62 accumulation led to Murine Double Minute gene 2 (MDM2)-regulated MC in podocytes during DN, which was ameliorated by UA through enhanced P62-mediated autophagy. Additionally, the overexpression of NF-κB p65 or TNF-α abolished the protective effects of UA both in vivo and in vitro. Overall, our results provide strong evidence that UA could be a potential therapeutic agent for DN, regulated by inhibiting podocyte MC through the NF-κB/MDM2/Notch1 pathway by targeting autophagic-P62 accumulation.

EC-YOLO: Improved YOLOv7 Model for PCB Electronic Component Detection.

Electronic components are the main components of PCBs (printed circuit boards), so the detection and classification of ECs (electronic components) is an important aspect of recycling used PCBs. However, due to the variety and quantity of ECs, traditional target detection methods for EC classification still have problems such as slow detection speed and low performance, and the accuracy of the detection needs to be improved. To overcome these limitations, this study proposes an enhanced YOLO (you only look once) network (EC-YOLOv7) for detecting EC targets. The network uses ACmix (a mixed model that enjoys the benefits of both self-attention and convolution) as a substitute for the 3 × 3 convolutional modules in the E-ELAN (Extended ELAN) architecture and implements branch links and 1 × 1 convolutional arrays between the ACmix modules to improve the speed of feature retrieval and network inference. Furthermore, the ResNet-ACmix module is engineered to prevent the leakage of function data and to minimise calculation time. Subsequently, the SPPCSPS (spatial pyramid pooling connected spatial pyramid convolution) block has been improved by replacing the serial channels with concurrent channels, which improves the fusion speed of the image features. To effectively capture spatial information and improve detection accuracy, the DyHead (the dynamic head) is utilised to enhance the model's size, mission, and sense of space, which effectively captures spatial information and improves the detection accuracy. A new bounding-box loss regression method, the WIoU-Soft-NMS method, is finally suggested to facilitate prediction regression and improve the localisation accuracy. The experimental results demonstrate that the enhanced YOLOv7 net surpasses the initial YOLOv7 model and other common EC detection methods. The proposed EC-YOLOv7 network reaches a mean accuracy (mAP@0.5) of 94.4% on the PCB dataset and exhibits higher FPS compared to the original YOLOv7 model. In conclusion, it can significantly enhance high-density EC target recognition.

Profibrotic role of the SOX9-MMP10-ECM biosynthesis axis in the tracheal fibrosis after injury and repair.

Fibroblast activation and extracellular matrix (ECM) deposition play an important role in the tracheal abnormal repair process and fibrosis. As a transcription factor, SOX9 is involved in fibroblast activation and ECM deposition. However, the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear. We investigated the role of SOX9 in TGF-ß1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast (RTF) cells. SOX9 overexpression adenovirus (Ad-SOX9) and siRNA were transfected into RTF cells. We found that SOX9 expression was up-regulated in RTF cells treated with TGF-ß1. SOX9 overexpression activated fibroblasts and promoted ECM deposition. Silencing SOX9 inhibited cell proliferation, migration, and ECM deposition, induced G2 arrest, and increased apoptosis in RTF cells. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) assays identified MMP10, a matrix metalloproteinase involved in ECM deposition, as a direct target of SOX9, which promotes ECM degradation by increasing MMP10 expression through the Wnt/ß-catenin signaling pathway. Furthermore, in vivo, SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis, as manifested by reduced tracheal stenosis. In conclusion, our findings indicate that SOX9 can drive fibroblast activation, cell proliferation, and apoptosis resistance in tracheal fibrosis via the Wnt/ß-catenin signaling pathway. The SOX9-MMP10-ECM biosynthesis axis plays an important role in tracheal injury and repair. Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

Analysis of an adult diabetes mellitus caused by a rare mutation of the gene: A case report.

BACKGROUND: This study presents the clinical and genetic mutation characteristics of an unusual case of adult-onset diabetes mellitus occurring in adolescence, featuring a unique mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. Data Access Statement: Research data supporting this publication are available from the NN repository at www.NNN.org/download/. CASE SUMMARY: The methodology employed entailed meticulous collection of comprehensive clinical data from the probands and their respective family members. Additionally, high-throughput sequencing was conducted to analyze the PPARG genes of the patient, her siblings, and their offspring. The results of this investigation revealed that the patient initially exhibited elevated blood glucose levels during pregnancy, accompanied by insulin resistance and hypertriglyceridemia. Furthermore, these strains displayed increased susceptibility to diabetic kidney disease without any discernible aggregation patterns. The results from the gene detection process demonstrated a heterozygous mutation of guanine (G) at position 284 in the coding region of exon 2 of PPARG, which replaced the base adenine (A) (exon2c.284A>Gp.Tyr95Cys). This missense mutation resulted in the substitution of tyrosine with cysteine at the 95th position of the translated protein. Notably, both of her siblings harbored a nucleotide heterozygous variation at the same site, and both were diagnosed with diabetes. CONCLUSION: The PPARG gene mutation, particularly the p.Tyr95Cys mutation, may represent a newly identified subtype of maturity-onset diabetes of the young. This subtype is characterized by insulin resistance and lipid metabolism disorders.

Fence-type Molecular Electrocatalysts for High-Performance Lithium-Sulfur Batteries.

Improving the slow redox kinetics of sulfur species and shuttling issues of soluble intermediates induced from the multiphase sulfur redox reactions are crucial factors for developing the next-generation high-energy-density lithium-sulfur (Li-S) batteries. In this study, we successfully constructed a novel molecular electrocatalyst through in situ polymerization of bis(3,4-dibromobenzene)-18-crown-6 (BD18C6) with polysulfide anions on the cathode interface. The crown ether (CE)-based polymer acts as a spatial "fence" to precisely control the unique redox characteristics of sulfur species, which could confine sulfur substance within its interior and interact with lithium polysulfides (LiPSs) to optimize the reaction barrier of sulfur species. The "fence" structure and the double-sided Li+ penetrability of the CE molecule may also prevent the CE catalytic sites from being covered by sulfur during cycling. This new fence-type electrocatalyst mitigates the "shuttle effect", enhances the redox activity of sulfur species, and promotes the formation of three-dimensional stacked lithium sulfide (Li2S) simultaneously. It thus enables lithium-sulfur batteries to exhibit superior rate performance and cycle stability, which may also inspire development facing analogous multiphase electrochemical energy-efficient conversion process.

Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.

AIMS/HYPOTHESIS: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. METHODS: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). RESULTS: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. CONCLUSIONS/INTERPRETATION: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. DATA AVAILABILITY: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).