Type VII secretion system extracellular protein B targets STING to evade host anti-Staphylococcus aureus immunity.

Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.

Exploring the immune characteristions of CRKP pneumonia at single-cell level.

The immune dysregulation associated with carbapenem-resistant Klebsiella pneumoniae (CRKP) severity was investigated through single-cell RNA sequencing (scRNA-seq) of 5 peripheral blood samples from 3 patients with moderate and severe CRKP pneumonia. Additionally, scRNA-seq datasets from two individuals with COVID-19 were included for comparative analysis. The dynamic characterization and functional properties of each immune cell type were examined by delineating the transcriptional profiles of immune cells throughout the transition from moderate to severe conditions. Overall, most immune cells in CRKP patients exhibited a robust interferon-α response and inflammatory reaction compared to healthy controls, mirroring observations in COVID-19 patients. Furthermore, cell signatures associated with NK cells, macrophages, and monocytes were identified in CRKP progression including PTPRCAP for NK cells, C1QB for macrophages, and S100A12 for both macrophages and monocytes. In summary, this study offers a comprehensive scRNA-seq resource for illustrating the dynamic immune response patterns during CRKP progression, thereby shedding light on the associations between CRKP and COVID-19.

The Potential Role of Virus Infection in the Progression of Thyroid Cancer.

Multiple factors have engaged in the progression of thyroid cancer (TC). Recent studies have shown that viral infection can be a critical factor in the pathogenesis of TC. Viruses, such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may play an essential role in the occurrence, development, and even prognosis in TC. This review mainly explored the potential role of viral infection in the progress of TC. The possible mechanisms could be recognizing the host cell, binding to the receptors, affecting oncogenes levels, releasing viral products to shape a beneficial environment, interacting with immune cells to induce immune evasion, and altering the pituitary-thyroid axis. Thus, comprehensive knowledge may provide insights into finding molecular targets for diagnosing and treating virus-related TC.

Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-ß-Ketosulfones.

A novel and efficient method for functionalizing organosulfones has been established, utilizing a visible-light-driven intermolecular radical cascade cyclization of α-allyl-ß-ketosulfones. This process employs fac-Ir(ppy)3 as the photoredox catalyst and α-carbonyl alkyl bromide as the oxidizing agent. Via this approach, the substrates experience intermolecular addition of α-carbonyl alkyl radicals to the alkene bonds, initiating a sequence of C-C bond formations that culminate in the production of organosulfone derivatives. Notably, this technique features gentle reaction conditions and an exceptional compatibility with a wide array of functional groups, making it a versatile and valuable addition to the field of organic synthesis.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

First-Principles Predictions of MoS2-WS2 In-Plane Heterostructures for Sensing Dissolved Gas Species in Oil-Immersed Transformers.

This work from first-principles insight uses a MoS2-WS2 in-plane heterostructure as a potential sensing material for detection of CO and C2H2, two typical dissolved gases in oil-immersed transformers, in order to evaluate the operation status. The adsorption performance of the MoS2-WS2 heterostructure upon two gas species is assessed via three adsorption sites and compared with isolated MoS2 and WS2. Results indicate that MoS2-WS2 performs with a much stronger binding force and charge-transfer for adsorptions of CO and C2H2 in comparison to the isolated counterpart, which gives rise to more obvious deformation in the electronic property of MoS2-WS2 as well as a much larger resistance-based sensing response. The recovery time of MoS2-WS2 for desorption of CO and C2H2 molecules is also appropriate to allow the reusability of such a sensor. The findings in this work uncover the admirable sensing potential of transition metal dichalcogenides (TMDs)-based heterostructures upon oil dissolved gases, which opens up a new way to explore novel 2D nanomaterials as resistive gas sensors for dissolved gas analysis in electrical oil-immersed transformers.

Identification of PavHB16 gene in Prunus avium and validation of its function in Arabidopsis thaliana.

Sweet cherry (Prunus avium L.) is one of the most economically important fruits in the world. However, severe fruit abscission has brought significant challenges to the cherry industry. To better understand the molecular regulation mechanisms underlying excessive fruit abscission in sweet cherry, the fruit abscission characteristics, the anatomical characteristics of the abscission zone (AZ), as well as a homeodomain-Leucine Zipper gene family member PavHB16 function were analyzed. The results showed that the sweet cherry exhibited two fruit abscission peak stages, with the "Brooks" cultivar demonstrating the highest fruit-dropping rate (97.14%). During these two fruit abscission peak stages, both the retention pedicel and the abscising pedicel formed AZs. but the AZ in the abscising pedicel was more pronounced. In addition, a transcription factor, PavHB16, was identified from sweet cherry. The evolutionary analysis showed that there was high homology between PavHB16 and AtHB12 in Arabidopsis. Moreover, the PavHB16 protein was localized in the nucleus. Overexpression of PavHB16 in Arabidopsis accelerated petal shedding. In the PavHB16-overexpressed lines, the AZ cells in the pedicel became smaller and denser, and the expression of genes involved in cell wall remodeling, such as cellulase 3 gene (AtCEL3), polygalacturonase 1 (AtPG1), and expandin 24(AtEXPA24) were upregulated. The results suggest that PavHB16 may promote the expression of genes related to cell wall remodeling, ultimately facilitating fruit abscission. In summary, this study cloned the sweet cherry PavHB16 gene and confirmed its function in regulating sweet cherry fruit abscission, which provided new data for further study on the fruit abscission mechanism. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01443-8.

Screening and identification of hub genes for ischemic cardiomyopathy and construction and validation of a clinical prognosis model using bioinformatics analysis.

Background: Myocardial ischemia and hypoxia may result in myocardial cell necrosis, scar formation, and hyperplasia. We aim to explore the differentially expressed genes (DEGs) in ischemic cardiomyopathy (ICM), construct and identify a clinical prognosis model using bioinformatics methods, so as to screen potential biomarkers of ICM to provide a basis for the early diagnosis and treatment of ICM. Methods: Based on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, R language was used to screen DEGs in healthy myocardial (n=5) and ICM myocardial tissues (n=12). DEGs were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI). Receiver operating characteristic (ROC) curves were drawn to verify the target genes. Results: A total of 259 genes with significantly changed fold change (FC) values were obtained through conditional screening, including up-regulated genes and down-regulated genes. The first two hub genes [interleukin-6 (IL-6) and Ras homologous gene family member A (RHOA)] with the largest degree value among the above up-regulated and down-regulated genes were selected and their expression values were combined in the gene chip to draw the ROC curve based on the pROC package of R language. The area under the ROC curve (AUC) values of IL-6 and RHOA were 0.956 and 0.995, respectively. The expression levels of Sqstm1, Nos2, IL-6, RHOA, and Zfp36 genes in the ICM group are lower than those in the blank control group and the difference was statistically significant (P<0.05). RHOA and Stat3 were identified as the key genes controlling the occurrence and development of ICM. Conclusions: ICM is closely related to the changes of extracellular matrix (ECM) and oxidoreductase activity. The IL-6 and RHOA are expected to become potential targets for ICM treatment.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.

Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.

Complete response after treatment of breast cancer with isolated liver metastasis: a case report.

Background: Breast cancer has a high incidence and is prone to metastasis, while isolated liver metastasis is rare. A growing body of evidence supports the effectiveness of treating breast cancer with anti-human epidermal growth factor receptor-2 (HER2) therapy in combination with chemotherapy. However, little is known about its impact on metastatic liver disease. There is also a lack of consensus on managing liver metastases from breast cancer, and no studies have been conducted on managing the disappearance of liver metastases after treatment. Case Description: In May 2021, a 51-year-old female patient with HER2-positive breast cancer with isolated liver metastases had immunohistochemistry of estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2 (3+) for both her primary lesion and liver metastases. After undergoing 17 cycles of anti-HER2 therapy and chemotherapy, the patient expressed a desire for surgery. Then a preoperative examination was performed, which revealed the disappearance of both the primary breast lesion and the liver metastases. Immediately afterwards, a left mastectomy was performed, and postoperative pathology showed a complete response to the breast tumor. As for the liver, where the metastatic lesions disappeared, no relevant study has reported how to deal with this situation. Finally, after a hospital-wide discussion, the patient was given trastuzumab maintenance therapy. Until now, no obvious signs of recurrence or metastasis have been observed during regular follow-ups. Conclusions: This case suggests that maintenance therapy may be the best option for patients with breast cancer whose liver metastases disappear by medication. Also, it can be inferred that in HER2-positive metastatic breast cancer (MBC), patients with isolated liver metastases may be more likely to achieve a cure-like outcome. Nevertheless, more cases and follow-up information are needed to support these views.

MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.

OBJECTIVES: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress. METHODS: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo. RESULTS: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models. DISCUSSION: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

Factors influencing self-regulatory fatigue in patients undergoing chemotherapy for gynecologic cancer: a cross-sectional study.

Objective: To understand the current status of self-regulatory fatigue among gynecologic cancer chemotherapy patients and explore influencing factors. Methods: Using convenient sampling, a total of 232 gynecological cancer chemotherapy patients from two tertiary hospitals in Zhengzhou, Henan, China, were selected as study subjects from February 2023 to April 2023. General information questionnaire, Self-Regulatory Fatigue Scale (SRF-S), Strategies Used by People to Promote Health (SUPPH) Scale, Connor-Davidson resilience scale (CD-RISC) and Perceived Social Support Scale (PSSS) were employed for data collection. The data were analyzed using SPSS 26.0 software. Chi-square test and binary logistic regression were executed to explore the correlates of self-regulatory fatigue, the significance level (α) was set at 0.05. Results: The self-regulatory fatigue score of the 232 patients was 44 (36, 56). Binary logistic regression analyses revealed significant associations, demonstrating that residing in urban areas (OR=0.241, P=0.015), having no comorbidities (OR=0.158, P=0.015), increased perceived social support (OR=0.937, P=0.001), strong self-efficacy (OR=0.959, P=0.021), and heightened psychological resilience (OR=0.895, P<0.001) acted as protective factors against self-regulatory fatigue (P < 0.05). Conclusion: Patients residing in rural areas, having more than two comorbidities, lower self-efficacy and psychological resilience levels, and lower perceived social support are indicative of higher levels of self-regulatory fatigue. Identifying these influencing factors can provide references and support for developing individualized support and intervention measures to improve patients' physical and mental well-being.

Ocular A-to-I RNA editing signatures associated with SARS-CoV-2 infection.

Ophthalmic manifestations have recently been observed in acute and post-acute complications of COVID-19 caused by SARS-CoV-2 infection. Our precious study has shown that host RNA editing is linked to RNA viral infection, yet ocular adenosine to inosine (A-to-I) RNA editing during SARS-CoV-2 infection remains uninvestigated in COVID-19. Herein we used an epitranscriptomic pipeline to analyze 37 samples and investigate A-to-I editing associated with SARS-CoV-2 infection, in five ocular tissue types including the conjunctiva, limbus, cornea, sclera, and retinal organoids. Our results revealed dramatically altered A-to-I RNA editing across the five ocular tissues. Notably, the transcriptome-wide average level of RNA editing was increased in the cornea but generally decreased in the other four ocular tissues. Functional enrichment analysis showed that differential RNA editing (DRE) was mainly in genes related to ubiquitin-dependent protein catabolic process, transcriptional regulation, and RNA splicing. In addition to tissue-specific RNA editing found in each tissue, common RNA editing was observed across different tissues, especially in the innate antiviral immune gene MAVS and the E3 ubiquitin-protein ligase MDM2. Analysis in retinal organoids further revealed highly dynamic RNA editing alterations over time during SARS-CoV-2 infection. Our study thus suggested the potential role played by RNA editing in ophthalmic manifestations of COVID-19, and highlighted its potential transcriptome impact, especially on innate immunity.

Liver Involvement is Associated with Higher Risk of Rapidly Progressive Interstitial Lung Disease and Mortality in Anti-Melanoma Differentiation-Associated Gene 5 Antibody- Positive Dermatomyositis.

Purpose: This study aimed to assess liver involvement and investigate its correlation with rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5 positive) DM patients. Patients and Methods: This retrospective study included 159 patients diagnosed with anti-MDA5 positive DM or anti-synthetase syndrome (ASyS). Clinical features and laboratory findings were compared between patients with anti-MDA5 positive DM and patients with ASyS. In the anti-MDA5 positive DM cohort, clinical features and laboratory findings between patients with liver involvement and without liver involvement were further compared. The effects of liver involvement on the overall survival (OS) and development of RP-ILD were also analyzed using Kaplan-Meier method and Cox regression analysis. Results: Levels of serum aspartate aminotransferase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γGT) and alkaline phosphatase (ALP) were all significantly higher in patients with anti-MDA5 positive DM than those in patients with ASyS. In our cohort of anti-MDA5 positive DM patents, 31 patients (34.4%) were complicated with liver involvement. Survival analysis revealed that serum ferritin >1030.0 ng/mL (p<0.001), ALT >103.0 U/l (p<0.001), AST >49.0 U/l (p<0.001), γGT >82.0 U/l (p<0.001), ALP >133.0 U/l (p<0.001), lactate dehydrogenase (LDH)>474.0 U/l (p<0.001), plasma albumin (ALB) <35.7 g/l (p<0.001) and direct bilirubin (DBIL) >2.80 µmol/l (p=0.002) predicted poor prognosis. The incidence of RP-ILD increased remarkably in patients with liver involvement compared to patients without liver involvement (58.1% vs 22.0%, p=0.001). Multivariate analysis revealed that elevated serum ALT level was an independent risk factor for mortality (HR 6.0, 95% CI 2.3, 16.2, p<0.001) and RP-ILD (HR 5.9, 95% CI 2.2, 15.9, p<0.001) in anti-MDA5 positive DM patents. Conclusion: Liver involvement is common in patients with anti-MDA5 positive DM. Elevated serum ALT level was an independent risk factor for RP-ILD and mortality in patients with anti-MDA5 positive DM.

Dependency-aware deep generative models for multitasking analysis of spatial omics data.

Spatially resolved transcriptomics (SRT) technologies have significantly advanced biomedical research, but their data analysis remains challenging due to the discrete nature of the data and the high levels of noise, compounded by complex spatial dependencies. Here, we propose spaVAE, a dependency-aware, deep generative spatial variational autoencoder model that probabilistically characterizes count data while capturing spatial correlations. spaVAE introduces a hybrid embedding combining a Gaussian process prior with a Gaussian prior to explicitly capture spatial correlations among spots. It then optimizes the parameters of deep neural networks to approximate the distributions underlying the SRT data. With the approximated distributions, spaVAE can contribute to several analytical tasks that are essential for SRT data analysis, including dimensionality reduction, visualization, clustering, batch integration, denoising, differential expression, spatial interpolation, resolution enhancement and identification of spatially variable genes. Moreover, we have extended spaVAE to spaPeakVAE and spaMultiVAE to characterize spatial ATAC-seq (assay for transposase-accessible chromatin using sequencing) data and spatial multi-omics data, respectively.

Unveiling potential therapeutic targets for diabetes-induced frozen shoulder through Mendelian randomization analysis of the human plasma proteome.

INTRODUCTION: This study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms. RESEARCH DESIGN AND METHODS: We employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein-protein interaction network. RESULTS: Our MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p<3.03E-5). According to colocalization analysis, parathyroid hormone-related protein (PTHLH) was moderately correlated with the genetic variance of frozen shoulder (posterior probability=0.68), while secreted frizzled-related protein 4 was highly correlated with the genetic variance of frozen shoulder (posterior probability=0.97). Additionally, nine plasma proteins were activated during diabetes-associated pathologies. Subsequent MR analysis of nine diabetic target proteins with four frozen shoulder causal proteins indicated that insulin receptor subunit alpha, interleukin-6 receptor subunit alpha, interleukin-1 receptor accessory protein, glutathione peroxidase 7, and PTHLH might contribute to the onset and progression of frozen shoulder induced by diabetes. CONCLUSIONS: Our study identified a causal relationship between diabetes and frozen shoulder, highlighting the pathological pathways through which diabetes influences frozen shoulder.

Nitrogen migration and transformation during re-suspension and photo-induction in landscape water replenished by reclaimed water.

Sediment re-suspension plays a crucial role in releasing endogenous nitrogen and greenhouse gases in shallow urban waters. However, the impacts of repeated re-suspension and photo-induced processes on migration and transformation from endogenous nitrogen, as well as the emission of greenhouse gases, remain unclear. This study simulated three conditions: re-suspension (Rs), re-suspension combined with ultravioletirradiation (Rs + UV), and ultraviolet irradiation (UV). The findings revealed that both repeated sediment re-suspension and exposure to UV light altered the characteristics of surface sediments. Decrease of convertible nitrogen in sediments, leading to the release of ion-exchangeable nitrogen (IEF-N) into NH4+-N and NO3--N, influenced greenhouse gas production differently under various conditions. The study observed the highest concentration of dissolved N2O in under UV irradiation, positively correlated with NO2--N and NO3--N. Re-suspension increased the turbidity of the overlying water and accelerated nitrification, resulting in the highest NO3--N concentration and the lowest dissolved N2O concentration. Additionally, in the Rs + UV dissolved N2O maintained the higher concentrations than in Rs, with greatest amount of N conversion in surface sediments, and a 59.45% reduction in IEF-N. The production of N2O during re-suspension was mainly positively correlated with NH4+-N in the overlying water. Therefore, this study suggest that repeated re-suspension and light exposure significantly influence nitrogen migration and transformation processes in sediment, providing a theoretical explanation for the eutrophication of water and greenhouse gas emissions.

m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure.

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

Design, synthesis and structure-activity relationship of 1,8-naphthalimide derivatives as highly potent hCYP1B1 inhibitors.

Human cytochrome P450 1B1 enzyme (hCYP1B1), a member of hCYP1 subfamily, plays a crucial role in multiple diseases by participating in many metabolic pathways. Although a suite of potent hCYP1B1 inhibitors have been previously reported, most of them also act as aryl hydrocarbon receptor (AhR) agonists that can up-regulate the expression of hCYP1B1 and then counteract their inhibitory potential in living systems. This study aimed to develop novel efficacious hCYP1B1 inhibitors that worked well in living cells but without AhR agonist effects. For these purposes, a series of 1,8-naphthalimide derivatives were designed and synthesized, and their structure-activity relationships (SAR) as hCYP1B1 inhibitors were analyzed. Following three rounds SAR studies, several potent hCYP1B1 inhibitors were discovered, among which compound 3n was selected for further investigations owing to its extremely potent anti-hCYP1B1 activity (IC50 = 0.040 nM) and its blocking AhR transcription activity in living cells. Inhibition kinetic analyses showed that 3n potently inhibited hCYP1B1 via a mix inhibition manner, showing a Ki value of 21.71 pM. Docking simulations suggested that introducing a pyrimidine moiety to the hit compound (1d) facilitated 3n to form two strong interactions with hCYP1B1/heme, viz., the C-Br⋯π halogen bond and the N-Fe coordination bond. Further investigations demonstrated that 3n (5 µM) could significantly reverse the paclitaxel (PTX) resistance in H460/PTX cells, evidenced by the dramatically reduced IC50 values, from 632.6 nM (PTX alone) to 100.8 nM (PTX plus 3n). Collectively, this study devised a highly potent hCYP1B1 inhibitor (3n) without AhR agonist effect, which offered a promising drug candidate for overcoming hCYP1B1-associated drug resistance.