Preoperative prediction model of lymph node metastasis in the inguinal and femoral region based on radiomics and artificial intelligence.

OBJECTIVE: To predict preoperative inguinal lymph node metastasis in vulvar cancer patients using a machine learning model based on imaging features and clinical data from pelvic magnetic resonance imaging (MRI). METHODS: 52 vulvar cancer patients were divided into a training set (n=37) and validation set (n=15). Clinical data and MRI images were collected, and regions of interest were delineated by experienced radiologists. A total of 1688 quantitative imaging features were extracted using the Radcloud platform. Dimensionality reduction and feature selection were applied, resulting in a radiomics signature. Clinical characteristics were screened, and a combined model integrating the radiomics signature and significant clinical features was constructed using logistic regression. Four machine learning classifiers (K nearest neighbor, random forest, adaptive boosting, and latent dirichlet allocation) were trained and validated. Model performance was evaluated using the receiver operating characteristic curve and the area under the curve (AUC), as well as decision curve analysis. RESULTS: The radiomics score significantly differentiated between lymph node metastasis positive and negative patients in both the training and validation sets. The combined model demonstrated excellent discrimination, with AUC values of 0.941 and 0.933 in the training and validation sets, respectively. The calibration curve and decision curve analysis confirmed the model's high predictive accuracy and clinical utility. Among the machine learning classifiers, latent dirichlet allocation and random forest models achieved AUC values >0.7 in the validation set. Integrating all four classifiers resulted in a total model with an AUC of 0.717 in the validation set. CONCLUSION: Radiomics combined with artificial intelligence can provide a new method for prediction of inguinal lymph node metastasis of vulvar cancer before surgery.

Annexin A family: A new perspective on the regulation of bone metabolism.

Osteoblast-mediated bone formation and osteoclast-mediated bone resorption are critical processes in bone metabolism. Annexin A, a calcium-phospholipid binding protein, regulates the proliferation and differentiation of bone cells, including bone marrow mesenchymal stem cells, osteoblasts, and osteoclasts, and has gradually become a marker gene for the diagnosis of osteoporosis. As calcium channel proteins, the annexin A family members are closely associated with mechanical stress, which can target annexins A1, A5, and A6 to promote bone cell differentiation. Despite the significant clinical potential of annexin A family members in bone metabolism, few studies have reported on these mechanisms. Therefore, based on a review of relevant literature, this article elaborates on the specific functions and possible mechanisms of annexin A family members in bone metabolism to provide new ideas for their application in the prevention and treatment of bone diseases, such as osteoporosis.

Mefunidone alleviates silica-induced inflammation and fibrosis by inhibiting the TLR4-NF-κB/MAPK pathway and attenuating pyroptosis in murine macrophages.

AIMS: Silicosis is the most common and severe type of pneumoconiosis, imposing a substantial disease burden and economic loss on patients and society. The pathogenesis and key targets of silicosis are not yet clear, and there are currently no effective treatments available. Therefore, we conducted research on mefunidone (MFD), a novel antifibrotic drug, to explore its efficacy and mechanism of action in murine silicosis. METHODS: Acute 7-day and chronic 28-day silicosis models were constructed in C57BL/6J mice by the intratracheal instillation of silica and subsequently treated with MFD to assess its therapeutic potential. The effects of MFD on silica-induced inflammation, pyroptosis, and fibrosis were further investigated using immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: In the 7-day silica-exposed mouse models, MFD treatment significantly alleviated pulmonary inflammation and notably reduced macrophage infiltration into the lung tissue. RNA-sequencing analysis of silica-induced iBMDMs followed by gene set enrichment analysis revealed that MFD profoundly influenced cytokine-cytokine receptor interactions, chemokine signaling, and the toll-like receptor signaling pathways. MFD treatment also markedly reduced the secretion of inflammatory cytokines and chemokines from silica-exposed iBMDMs. Moreover, MFD effectively downregulated the activation of the TLR4-NF-κB/MAPK signaling pathway induced by silica and mitigated the upregulation of pyroptosis markers. Additionally, MFD treatment significantly suppressed the activation of fibroblasts and alveolar epithelial cells co-cultured with silica-exposed mouse macrophages. Ultimately, in the 28-day silica-exposed mouse models, MFD administration led to a substantial reduction in the severity of pulmonary fibrosis. CONCLUSION: MFD mitigates silica-induced pulmonary inflammation and fibrosis in mice by suppressing the TLR4-NF-κB/MAPK signaling pathway and reducing pyroptotic responses in macrophages. MFD could potentially emerge as a novel therapeutic agent for the treatment of silicosis.

Enhancing the Antitumor Efficacy of Oncolytic Adenovirus Through Sonodynamic Therapy-Augmented Virus Replication.

The therapeutic efficacy of oncolytic adenoviruses (OAs) relies on efficient viral transduction and replication. However, the limited expression of coxsackie-adenovirus receptors in many tumors, along with the intracellular antiviral signaling, poses significant obstacles to OA infection and oncolysis. Here, we present sonosensitizer-armed OAs (saOAs) that potentiate the antitumor efficacy of oncolytic virotherapy through sonodynamic therapy-augmented virus replication. The saOAs could not only efficiently infect tumor cells via transferrin receptor-mediated endocytosis but also exhibit enhanced viral replication and tumor oncolysis under ultrasound irradiation. We revealed that the sonosensitizer loaded on the viruses induced the generation of ROS within tumor cells, which triggered JNK-mediated autophagy, ultimately leading to the enhanced viral replication. In mouse models of malignant melanoma, the combination of saOAs and sonodynamic therapy elicited a robust antitumor immune response, resulting in significant inhibition of melanoma growth and improved host survival. This work highlights the potential of sonodynamic therapy in enhancing the effectiveness of OAs and provides a promising platform for fully exploiting the antitumor efficacy of oncolytic virotherapy.

Application of dezocine patient-controlled epidural analgesia in postoperative analgesia in patients with total myomectomy.

BACKGROUND: Uterine fibroids are common benign gynecological conditions. Patients who experience excessive menstruation, anemia, and pressure symptoms should be administered medication, and severe cases require a total hysterectomy. This procedure is invasive and causes severe postoperative pain, which can affect the patient's postoperative sleep quality and, thus, the recovery process. AIM: To evaluate use of dezocine in patient-controlled epidural analgesia (PCEA) for postoperative pain management in patients undergoing total myomectomy. METHODS: We selected 100 patients undergoing total abdominal hysterectomy for uterine fibroids and randomized them into two groups: A control group receiving 0.2% ropivacaine plus 0.06 mg/mL of morphine and an observation group receiving 0.2% ropivacaine plus 0.3 mg/mL of diazoxide in their PCEA. Outcomes assessed included pain levels, sedation, recovery indices, PCEA usage, stress factors, and sleep quality. RESULTS: The observation group showed lower visual analog scale scores, shorter postoperative recovery indices, fewer mean PCEA compressions, lower cortisol and blood glucose levels, and better polysomnographic parameters compared to the control group (P < 0.05). The cumulative incidence of adverse reactions was lower in the observation group than in the control group (P < 0.05). CONCLUSION: Dezocine PCEA can effectively control the pain associated with total myomectomy, reduce the negative impact of stress factors, and have less impact on patients' sleep, consequently resulting in fewer adverse effects.

Insertion with long target duplication in polymyxin B-induced resistant mutant of Salmonella.

OBJECTIVES: A Salmonella enterica subsp. diarizonae (hereafter S. diarizonae) clinical strain S499 demonstrated unique genomic features. The strain S499 was treated with polymyxin B in vitro to investigate the mechanism of resistance. METHODS: S499 was treated with polymyxin B by increasing concentration gradually to obtain a resistant mutant S499V. Whole genomes of the two strains were sequenced using Illumina HiSeq X-10 and PacBio RS II platforms. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to compare the gene expression. RESULTS: The chromosome of strain S499 contained a 40-kb DNA region that was replicated after treatment with polymyxin B and generated a triple tandem DNA repeat region in the chromosome of mutant strain S499V. This repeat region in S499V was flanked by IS1 and contained pmrD, pmrG, and arnBCADTEF operon. In comparison to the homologous 40-kb DNA region of strain S499, a few genes in the repeat DNA region of strain S499V contained truncating mutations that generate two open reading frames (ORFs). The expression of pmrD, pmrG, and arnT was significantly upregulated in S499V. CONCLUSION: The duplication and overexpression of pmrD, pmrG, and arnT operon may be responsible for the polymyxin B resistance of mutant strain S499V.

Ferroelectric polarization and magnetic structure at domain walls in a multiferroic film.

Domain walls affect significantly ferroelectric and magnetic properties of magnetoelectric multiferroics. The stereotype is that the ferroelectric polarization will reduce at the domain walls due to the incomplete shielding of depolarization field or the effects of gradient energy. By combining transmission electron microscopy and first-principles calculations, we demonstrate that the ferroelectric polarization of tail-to-tail 180° domain walls in ε-Fe2O3 is regulated by the bound charge density. A huge enhancement (43%) of ferroelectric polarization is observed in the type I domain wall with a low bound charge density, while the ferroelectric polarization is reduced to almost zero at the type II domain wall with a high bound charge density. The magnetic coupling across the type I and type II ferroelectric domain walls are antiferromagnetic and ferromagnetic, respectively. Revealing mechanisms for enhancing ferroelectric polarization and magnetic behaviors at ferroelectric domain walls may promote the fundamental research and potential applications of magnetoelectric multiferroics.

Peptide-TLR7/8a-Coordinated DNA Vaccines Elicit Enhanced Immune Responses against Infectious Diseases.

DNA vaccines represent an innovative approach for the immunization of diverse diseases. However, their clinical trial outcomes are constrained by suboptimal transfection efficiency and immunogenicity. In this work, we present a universal methodology involving the codelivery of Toll-like receptor 7/8 agonists (TLR7/8a) and antigen gene using TLR7/8a-conjugated peptide-coated poly(ß-amino ester) (PBAE) nanoparticles (NPs) to augment delivery efficiency and immune response. Peptide-TLR7/8a-coated PBAE NPs exhibit advantageous biophysical attributes, encompassing diminutive particle dimensions, nearly neutral ζ potential, and stability in the physiological environment. This synergistic approach not only ameliorates the stability of plasmid DNA (pDNA) and gene delivery efficacy but also facilitates subsequent antigen production. Furthermore, under optimal formulation conditions, the TLR7/8a-conjugated peptide coated PBAE NPs exhibit a potent capacity to induce robust immune responses. Collectively, this nanoparticulate gene delivery system demonstrates heightened transfection efficacy, stability, biodegradability, immunostimulatory effect, and low toxicity, making it a promising platform for the clinical advancement of DNA vaccines.

Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 µM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, a high serum succinate level was independently associated with higher rates of disease progression (OR 13.087, 95%CI (2.819-60.761)) and mortality (HR 3.418, 95% CI (1.308-8.927)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused by BLM. In vitro, succinate promoted the activation of lung fibroblasts by activating ERK pathway through GPR91. In summary, succinate is a promising biomarker for diagnosis and prognosis of IPF. The accumulation of succinate may promote fibroblast activation through GPR91 and pulmonary fibrosis.

Phase-Stabilized Nickel-Molybdenum Electrocatalyst by Samarium Doping for Hydrogen Evolution in Alkaline Water Electrolysis.

Although the nickel-molybdenum electrocatalyst exhibits excellent activity in the alkaline hydrogen evolution reaction (HER), its stability is poor mainly due to molybdenum leaching. This work reports that doping samarium into nickel-molybdenum electrocatalyst effectively suppresses molybdenum leaching by forming a stable phase consisting of Sm, Mo, and O elements. The resulting electrode displays no noticeable activity degradation during the long-term testing (> 850 h) under a current density of 500 mA cm-2 in 1 м KOH. This enhanced stability is ascribed to the formation of a robust phase within the HER potential windows in alkaline electrolytes, as evidenced by the Pourbaix diagram. Furthermore, the samarium-modified electrocatalyst exhibits increased activity, with the overpotential decreasing by ≈59 mV from 159 to 100 mV at 500 mA cm-2 compared to the unmodified counterpart. These remarkable properties stem from samarium doping, which not only facilitates the formation of a stable phase to inhibit molybdenum leaching but also adjusts the electronic properties of molybdenum to enhance water dissociation.

Smoking-Attributable Health Care Expenditures for US Adults With Chronic Lower Respiratory Disease.

Importance: Cigarette smoking is a primary risk factor for chronic lower respiratory disease (CLRD) and is associated with worse symptoms among people with CLRD. It is important to evaluate the economic outcomes of smoking in this population. Objective: To estimate smoking prevalence and cigarette smoking-attributable health care expenditures (SAHEs) for adults with CLRD in the US. Design, Setting, and Participants: This cross-sectional study used data from the 2014-2018 and 2020 National Health Interview Surveys (NHIS) and the 2020 Medical Expenditure Panel Survey. The final study population, stratified by age 35 to 64 years and 65 years or older, was extracted from the 2014-2018 NHIS data. The data analysis was performed between February 1 and March 31, 2024. Exposures: Cigarette smoking, as classified into 4 categories: current smokers, former smokers who quit less than 15 years ago, former smokers who quit 15 or more years ago, and never smokers. Main Outcomes and Measures: Smoking-attributable health care expenditures were assessed using a prevalence-based annual cost approach. Econometric models for the association between cigarette smoking and health care utilization were estimated for 4 types of health care services: inpatient care, emergency department visits, physician visits, and home health visits. Results: In the 2014-2018 NHIS study sample of 13 017 adults, 7400 (weighted 62.4%) were aged 35 to 64 years, 5617 (weighted 37.6%) were 65 years or older, and 8239 (weighted 61.9%) were female. In 2020, among 11 211 222 adults aged 35 to 64 with CLRD, 3 508 504 (31.3%) were current smokers and 3 496 790 (31.2%) were former smokers. Total SAHEs in 2020 for this age group were $13.6 billion, averaging $2752 per current smoker and $1083 per former smoker. In 2020, 7 561 909 adults aged 65 years or older had CLRD, with 1 451 033 (19.2%) being current smokers and 4 104 904 (54.3%) being former smokers. Total SAHEs in 2020 for the older age group were $5.3 billion, averaging $1704 per current smoker and $682 per former smoker. In sum, SAHEs for adults with CLRD aged 35 years or older amounted to $18.9 billion in 2020. Conclusions and Relevance: In this cross-sectional study of adults with CLRD, cigarette smoking was associated with a substantial health care burden. The higher per-person SAHEs for current smokers compared with former smokers suggest potential cost savings of developing targeted smoking cessation interventions for this population.

Shexiang Baoxin Pill enriches Lactobacillus to regulate purine metabolism in patients with stable coronary artery disease.

BACKGROUND: It has been clinically confirmed that the Shexiang Baoxin Pill (SBP) dramatically reduces the frequency of angina in patients with stable coronary artery disease (SCAD). However, potential therapeutic mechanism of SBP has not been fully explored. PURPOSE: The study explored the therapeutic mechanism of SBP in the treatment of SCAD patients. METHODS: We examined the serum metabolic profiles of patients with SCAD following SBP treatment. A rat model of acute myocardial infarction (AMI) was established, and the potential therapeutic mechanism of SBP was explored using metabolomics, transcriptomics, and 16S rRNA sequencing. RESULTS: SBP decreased inosine production and improved purine metabolic disorders in patients with SCAD and in animal models of AMI. Inosine was implicated as a potential biomarker for SBP efficacy. Furthermore, SBP inhibited the expression of genes involved in purine metabolism, which are closely associated with thrombosis, inflammation, and platelet function. The regulation of purine metabolism by SBP was associated with the enrichment of Lactobacillus. Finally, the effects of SBP on inosine production and vascular function could be transmitted through the transplantation of fecal microbiota. CONCLUSION: Our study reveals a novel mechanism by which SBP regulates purine metabolism by enriching Lactobacillus to exert cardioprotective effects in patients with SCAD. The data also provide previously undocumented evidence indicating that inosine is a potential biomarker for evaluating the efficacy of SBP in the treatment of SCAD.

Phase 1/2 multicenter trial of acalabrutinib in Chinese patients with relapsed/refractory mantle cell lymphoma.

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1-24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL.

Association between tobacco product use and respiratory health and asthma-related interference with activities among U.S. Adolescents.

Tobacco use adversely affects long-term respiratory health. We examined the relationship between sole and dual tobacco product use and both respiratory health and respiratory-related quality of life during adolescence in the U.S. Using adolescent data (baseline age 12-17) from Waves 4.5 (data collected from December 2017-December 2018) and 5 (data collected from December 2018-November 2019) of the Population Assessment of Tobacco and Health Study, we examined the associations between combustible (i.e., cigarette or cigar), vaped, and dual (i.e., both cigar/cigarette and e-cigarette) tobacco/nicotine use at baseline and two respiratory symptoms (all adolescents, n = 11,748) and new asthma diagnosis (adolescents with no baseline diagnosis, n = 9,422) at follow-up. Among adolescents with asthma (Wave 5, n = 2,421), we estimated the association between current tobacco use and the extent to which asthma interfered with daily activities. At follow-up, 12.3 % of adolescents reported past 12-month wheezing/whistling, 17.4 % reported past 12-month dry cough, and 1.9 % reported newly diagnosed asthma. Baseline current cigarette/cigar smoking was associated with subsequent wheezing/whistling and baseline report of another tobacco product use pattern was associated with subsequent asthma diagnosis. Among adolescents with asthma, 5.7 % reported it interfering with activities some of the time and 3.1 % reported interference most/all of the time in the past 30 days. Past 30-day sole cigarette/cigar smoking and dual use was positively associated with asthma-related interference with activities compared to never tobacco use and sole e-cigarette use. Combustible and dual tobacco use pose direct risk to respiratory health and indirect risk to quality of life through respiratory health.

Dishevelled Segment Polarity Protein 3 (DVL3) Induced by Bacterial LPS Promotes the Proliferation and Migration of Prostate Cancer Cells through the TLR4 Pathway.

BACKGROUND: Chronic inflammation is associated with various malignant tumors. Bacterial lipopolysaccharides (LPSs) play a significant part in the event and development of prostate cancer. Dishevelled segment polarity protein 3 (DVL3) is a shared component of the Wnt/ß-catenin and Notch signaling pathways, which are involved in tumor progression, chemoresistance, and maintenance of stem cell-like properties. According to reports, prostatic cancer cell invasion and proliferation are mediated by toll-like receptor 4 (TLR4). However, the role and regulation of DVL3 in prostate cancer and its relationship with TLR4 remain unclear. METHODS: Survival curves were plotted to evaluate the relationship between DVL3 expression and prognosis in patients with prostate cancer. DVL3 was silenced in PC3 and DU145 cells using small interfering RNAs (siRNAs). Subsequently, cell counting kit-8 (CCK-8) assay, colony formation assay, transwell migration assay, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were performed to investigate the role of DVL3 in cell proliferation and migration in vitro. The protein markers of potential pathways were analyzed via western blotting. RESULTS: DVL3 expression was linked to prognosis in patients with prostate cancer; In particular, patients with high DVL3 expression had a poor prognosis. LPS stimulation increased (p < 0.01) the expression of DVL3 in PC3 cells. DVL3 regulated tumor cell proliferation and migration by mediating the increase (p < 0.01) in TLR4 expression. Knockout of TLR4 validated that TLR4 played a crucial role in LPS-induced DVL3 expression. Silencing of DVL3 decreased (p < 0.01) the LPS-induced proliferation and migration of PC3 cells. CONCLUSIONS: Bacterial LPS-induced DVL3 promoted the multiplication and migration of prostate cancer cells through the TLR4 pathway. This study offers a valuable reference for the development and clinical application of targeted drugs for prostate cancer.

Genomic characterization of dryland adaptation in endangered Anxi cattle in China.

Local species exhibit distinctive indigenous characteristics while showing unique productive and phenotypic traits. However, the advent of commercialization has posed a substantial threat to the survival of indigenous species. Anxi cattle, an endangered native breed in China, have evolved unique growth and reproductive characteristics in extreme desert and semidesert ecosystems. In this study, we conducted a genomic comparison of 10 Anxi cattle genomes with those of five other global populations/breeds to assess genetic diversity and identify candidate genomic regions in Anxi cattle. Population structure and genetic diversity analyses revealed that Anxi cattle are part of the East Asian cattle clade, exhibiting higher genetic diversity than commercial breeds. Through selective sweep analysis, we identified specific genetic variations linked to the environmental adaptability of Anxi cattle. Notably, we identified several candidate genes, including CERS3 involved in regulating skin permeability and antimicrobial functions, RBFOX2 associated with cardiac development, SLC16A7 participated in the regulation of pancreatic endocrine function, and SPATA3 related to reproduction. Our findings revealed the distinctive genomic features of Anxi cattle in dryland environments, provided invaluable insights for further research and breed preservation, and had important significance for enriching the domestic cattle breeding gene bank.

miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence.

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

Pyroptosis-related signatures predict immune characteristics and prognosis in IPF.

The purpose of this work was to use integrated bioinformatics analysis to screen for pyroptosis-related genes (PRGs) and possible immunological phenotypes linked to the development and course of IPF. Transcriptome sequencing datasets GSE70866, GSE47460 and GSE150910 were obtained from GEO database. From the GSE70866 database, 34 PRGs with differential expression were found in IPF as compared to healthy controls. In addition, a diagnostic model containing 4 genes PRGs (CAMP, MKI67, TCEA3 and USP24) was constructed based on LASSO logistic regression. The diagnostic model showed good predictive ability to differentiate between IPF and healthy, with ROC-AUC ranging from 0.910 to 0.997 in GSE70866 and GSE150910 datasets. Moreover, based on a combined cohort of the Freiburg and the Siena cohorts from GSE70866 dataset, we identified ten PRGs that might predict prognosis for IPF. We constructed a prognostic model that included eight PRGs (CLEC5A, TREM2, MMP1, IRF2, SEZ6L2, ADORA3, NOS2, USP24) by LASSO Cox regression and validated it in the Leuven cohort. The risk model divided IPF patients from the combined cohort into high-risk and low-risk subgroups. There were significant differences between the two subgroups in terms of IPF survival and GAP stage. There is a close correlation between leukocyte migration, plasma membrane junction, and poor prognosis in a high-risk subgroup. Furthermore, a high-risk score was associated with more plasma cells, activated NK cells, monocytes, and activated mast cells. Additionally, we identified HDAC inhibitors in the cMAP database that might be therapeutic for IPF. To summarize, pyroptosis and its underlying immunological features are to blame for the onset and progression of IPF. PRG-based predictive models and drugs may offer new treatment options for IPF.

Cypermethrin induces Sertoli cell apoptosis through endoplasmic reticulum-mitochondrial coupling involving IP3R1-GRP75-VDAC1.

A widely used type II pyrethroid pesticide cypermethrin (CYP) is one of endocrine disrupting chemicals (EDCs) with anti-androgenic activity to induce male reproductive toxicology. However, the mechanisms have not been fully elucidated. This study was to explore the effects of CYP on apoptosis of mouse Sertoli cells (TM4) and the roles of endoplasmic reticulum (ER)-mitochondria coupling involving 1,4,5-trisphosphate receptor type1-glucose-regulated protein 75-voltage-dependent anion channel 1 (IP3R1-GRP75-VDAC1). TM4 were cultured with different concentrations of CYP. Flow cytometry, calcium (Ca2+) fluorescent probe, transmission electron microscopy and confocal microscopy, and western blot were to examine apoptosis of TM4, mitochondrial Ca2+, ER-mitochondria coupling, and expressions of related proteins. CYP was found to increase apoptotic rates of TM4 significantly. CYP was shown to significantly increase expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase (PARP). Concentration of mitochondrial Ca2+ was increased by CYP treatment significantly. CYP significantly enhanced ER-mitochondria coupling. CYP was shown to increase expressions of IP3R, Grp75 and VDAC1 significantly. We suggest that CYP induces apoptosis in TM4 cells by facilitating mitochondrial Ca2+ overload regulated by ER-mitochondria coupling involving IP3R1-GRP75-VDAC1. This study identifies a novel mechanism of CYP-induced apoptosis in Sertoli cells.

Gradient tungsten-doped Bi3TiNbO9 ferroelectric photocatalysts with additional built-in electric field for efficient overall water splitting.

Bi3TiNbO9, a layered ferroelectric photocatalyst, exhibits great potential for overall water splitting through efficient intralayer separation of photogenerated carriers motivated by a depolarization field along the in-plane a-axis. However, the poor interlayer transport of carriers along the out-of-plane c-axis, caused by the significant potential barrier between layers, leads to a high probability of carrier recombination and consequently results in low photocatalytic activity. Here, we have developed an efficient photocatalyst consisting of Bi3TiNbO9 nanosheets with a gradient tungsten (W) doping along the c-axis. This results in the generation of an additional electric field along the c-axis and simultaneously enhances the magnitude of depolarization field within the layers along the a-axis due to strengthened structural distortion. The combination of the built-in field along the c-axis and polarization along the a-axis can effectively facilitate the anisotropic migration of photogenerated electrons and holes to the basal {001} surface and lateral {110} surface of the nanosheets, respectively, enabling desirable spatial separation of carriers. Hence, the W-doped Bi3TiNbO9 ferroelectric photocatalyst with Rh/Cr2O3 cocatalyst achieves an efficient and durable overall water splitting feature, thereby providing an effective pathway for designing excellent layered ferroelectric photocatalysts.