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In this work, we consider numerical methods for solving a class of block three-by-three saddle point problems, which arise from finite element methods for solving time-dependent Maxwell equations and a class of quadratic programs. We present a variant of Uzawa method with two variable parameters for the saddle point problems. These two parameters can be updated easily in each iteration, similar to the evaluation of the two iteration parameters in the conjugate gradient method. We show that the new iterative method converges to the unique solution of the saddle point problems under a reasonable condition. Numerical experiments highlighting the performance of the proposed method for problems are presented.

Cantharidin (CTD), a natural compound derived from Mylabris , is widely used in traditional Oriental medicine for its potent anticancer properties. However, its clinical application is restricted due to its high toxicity, particularly towards the liver. This review provides a concise understanding of the hepatotoxic mechanisms of CTD and highlights novel therapeutic strategies to mitigate its toxicity while enhancing its anticancer efficacy. We systematically explore the molecular mechanisms underlying CTD-induced hepatotoxicity, focusing on the involvement of apoptotic and autophagic processes in hepatocyte injury. We further discuss the endogenous and exogenous pathways implicated in CTD-induced liver damage and potential therapeutic targets. This review also summarizes the structural modifications of CTD derivatives and their impact on anticancer activity. Additionally, we delve into the advancements in nanoparticle-based drug delivery systems that hold promise in overcoming the limitations of CTD derivatives. By offering valuable insights into the hepatotoxic mechanisms of CTD and outlining potential avenues for future research, this review contributes to the ongoing efforts to develop safer and more effective CTD-based therapies.

PurposeInsomnia has become one of the foremost health concerns among workers. Despite a significant number of epidemiological studies have reported on the correlation between insomnia and job stress, comprehensive evidence remains insufficient. Therefore, this research seeks to provide evidence with greater reliability, through summarizing relevant contemporary literature via a meta-analysis.MethodsLiterature from across Europe and Asia that was of both a prospective and cross-sectional design was included, if well-controlled odds ratios were available. The meta-analysis was undertaken in accordance with the guidelines devised by PRISMA, including tests for publication bias and heterogeneity.ResultsHigh job stress was associated with a greater risk of suffering from insomnia (random OR = 1.73, 95% CI 1.46–2.05), and the correlation between effort-reward imbalance and insomnia was statistically significant (random OR = 2.63, 95% CI 1.22–5.69). Higher demand was correlated to a relatively greater risk of insomnia (random OR = 1.35, 95% CI 1.20–1.51), while the pooled effect of low control was not found to be statistically significant. The summary random odds ratio of heavy workload was 2.76, and a pooled odds ratio of 1.67 (fixed, 95% CI 1.11–2.52) was calculated in low social support. With regard to the overall population, work-family conflict was correlated with insomnia (random OR = 2.32, 95% CI 1.53–3.51). The subgroup analysis provided comparable outcomes, for both males (fixed OR = 1.97, 95% CI 1.50–2.57) and females (random OR = 2.80, 95% CI 1.30–6.05). Egger’s regression indicated that publication bias may be apparent in the syntheses of effort-reward imbalance, low social support, and work-family conflict (p < 0.05). Heterogeneity was caused by design, measuring the exposure or outcome, in addition to the region where the research was conducted.ConclusionsThe correlation between insomnia and higher levels of job stress, effort-reward imbalance, high demand, heavy workload, and low social support was determined. Publication bias and heterogeneity were partially observed. Furthermore, future studies with improved methodologies and a focus on mechanisms are anticipated.

Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation‐induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial‐mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes. This review discussed the molecular mechanisms of cancer resistance to radiotherapy and chemotherapy including enhanced DNA damage repair, reduced intracellular accumulation of drugs, drug inactivation, changes in drug targets, apoptosis‐growth balance disruption. We also focused on the roles of oncogenes and tumor suppressor genes in therapeutic resistance. Some anticancer drugs targeting oncogenes associated with therapeutic resistance were summarized.

The SARS (severe acute respiratory syndrome) outbreak was caused by a coronavirus (CoV) named the SARS-CoV. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant activation of the innate immune response. Here, we identify several mechanisms by which a SARS-CoV open reading frame (ORF) activates intracellular stress pathways and targets the innate immune response. We show that ORF8b forms insoluble intracellular aggregates dependent on a valine at residue 77. Aggregated ORF8b induces endoplasmic reticulum (ER) stress, lysosomal damage, and subsequent activation of the master regulator of the autophagy and lysosome machinery, Transcription factor EB (TFEB). ORF8b causes cell death in epithelial cells, which is partially rescued by reducing its ability to aggregate. In macrophages, ORF8b robustly activates the NLRP3 inflammasome by providing a potent signal 2 required for activation. Mechanistically, ORF8b interacts directly with the Leucine Rich Repeat domain of NLRP3 and localizes with NLRP3 and ASC in cytosolic dot-like structures. ORF8b triggers cell death consistent with pyroptotic cell death in macrophages. While in those cells lacking NLRP3 accumulating ORF8b cytosolic aggregates cause ER stress, mitochondrial dysfunction, and caspase-independent cell death.

Recent advances in next-generation sequencing (NGS) technologies have triggered the rapid accumulation of publicly available multi-omics datasets. The application of integrated omics to explore robust signatures for clinical translation is increasingly emphasized, and this is attributed to the clinical success of immune checkpoint blockades in diverse malignancies. However, effective tools for comprehensively interpreting multi-omics data are still warranted to provide increased granularity into the intrinsic mechanism of oncogenesis and immunotherapeutic sensitivity. Therefore, we developed a computational tool for effective Immuno-Oncology Biological Research (IOBR), providing a comprehensive investigation of the estimation of reported or user-built signatures, TME deconvolution, and signature construction based on multi-omics data. Notably, IOBR offers batch analyses of these signatures and their correlations with clinical phenotypes, long non-coding RNA (lncRNA) profiling, genomic characteristics, and signatures generated from single-cell RNA sequencing (scRNA-seq) data in different cancer settings. Additionally, IOBR integrates multiple existing microenvironmental deconvolution methodologies and signature construction tools for convenient comparison and selection. Collectively, IOBR is a user-friendly tool for leveraging multi-omics data to facilitate immuno-oncology exploration and to unveil tumor-immune interactions and accelerating precision immunotherapy.

Obstructive sleep apnea (OSA) has been demonstrated to be associated with renal injury. However, the cellular and molecular mechanisms by which chronic intermittent hypoxia (CIH), a hallmark of OSA, contributes to renal injury remain poorly understood. Twelve male Sprague-Dawley rats were randomized into normoxic control (NC) and CIH groups ( n  = 6 each), with CIH exposure for 12 weeks. Renal injury was evaluated by Hematoxylin and Eosin staining and a modified Jablonski score. Single-nucleus RNA sequencing (snRNA-seq) was performed. Data analysis included clustering of cells, differential gene expression analysis, and functional enrichment through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Histopathological analysis revealed renal injury with renal tubular epithelial cell edema, necrosis in the CIH group compared to NC. A total of 42,581 cells (19,655 cells from NC group and 22,926 cells from CIH group) were retained after quality control, with 13 distinct renal cell populations identified. CIH exposure resulted in an increased proportion of podocytes, while mesangial cells were reduced compared to the NC group. CIH exposure altered the transcriptomic landscape, with differentially expressed genes (DEGs) observed across multiple cell types. Functional enrichment analysis indicated that CIH-induced DEGs were associated with suppressed metabolic and signaling pathways in proximal tubule and loop of Henle epithelial cells, activation of apoptotic and sodium reabsorption pathways in distal convoluted tubule cells, and enhanced inflammatory and phagocytic signaling in mononuclear phagocytes. Our study provides a high-resolution atlas of CIH-induced transcriptional changes in the rat kidney. The findings reveal cell type-specific responses and pathways potentially contributing to OSA-associated renal injury, offering novel insights into pathogenesis and potential therapeutic targets for preventing renal damage in OSA patients.

Background Early clinical screening and prevention can reduce the incidence and severity of early childhood caries (ECC). With the development of social media, TikTok and Douyin were used as important tools for ECC popularization and early screening. The purpose of this study was to evaluate the educational impact from the integrity, accuracy and quality of ECC-related short videos on TikTok and Douyin. Methods We searched for short videos related to ECC on the mobile application TikTok and Douyin on April 15, 2024. The search keywords were as follows: “Early childhood caries” on TikTok in both English and Japanese, and Chinese search on Douyin. The first 100 short videos were selected as samples for each group. we applied an instrument called DISCERN, which consisted of 3 sections and a total of 16 questions to evaluate the quality of each short video, and used a checklist to rate the content of videos. The accuracy of the content was evaluated based on the Children's Caries Risk Assessment and Management Guidelines. Results A total of 115 short videos were assessed for the useful information quality of ECC, including 78 Chinese, 26 English, and 11 Japanese. The score for the content quality of short videos showed that each of the three groups assigned the highest scores to the sections on symptoms and treatment, with Chinese short videos achieving the top ratings. The DISCERN scores for useful short videos in each group were 33.10 ± 3.49 in Chinese, 29.54 ± 2.37 in English, and 28.27 ± 2.61 in Japanese, respectively. Compared with English and Japanese videos, Chinese videos had the highest DISCERN score with significant differences ( p  < 0.05). Meanwhile, in Chinese short videos, healthcare professionals or organizations uploaded videos with higher DISCERN scores, which were more comprehensive and extensive than those uploaded by private users. Conclusions It is necessary for more healthcare professionals and institutions to join in to improve the quality of content on short video platforms and solve more health problems for patients through short videos.

Fracture networks play a more significant role in conducting fluid flow and solute transport in fractured rock masses, comparing with that of the rock matrix. Accurate estimation of the permeability of fracture networks would help researchers and engineers better assess the performance of projects associated with fluid flow in fractured rock masses. This study provides a review of previous works that have focused on the estimation of equivalent permeability of two-dimensional (2-D) discrete fracture networks (DFNs) considering the influences of geometric properties of fractured rock masses. Mathematical expressions for the effects of nine important parameters that significantly impact on the equivalent permeability of DFNs are summarized, including (1) fracture-length distribution, (2) aperture distribution, (3) fracture surface roughness, (4) fracture dead-end, (5) number of intersections, (6) hydraulic gradient, (7) boundary stress, (8) anisotropy, and (9) scale. Recent developments of 3-D fracture networks are briefly reviewed to underline the importance of utilizing 3-D models in future research.

PurposeColchicine, a multipotent anti-inflammatory drug, has been reported to alleviate cardiac remodeling and improve cardiac function after acute myocardial infarction (AMI). However, the underlying mechanism remains incompletely understood. Because neutrophils extracellular traps (NETs) enhance inflammation and participate in myocardial ischemia injury, and colchicine can inhibit NETosis, we thus aimed to determine whether colchicine exerts cardioprotective effects on AMI via suppressing NETs.MethodsAdult C57BL/6 mice were subjected to permanent ligation of the left anterior descending coronary artery and treated with colchicine (0.1 mg/kg/day) or Cl-amidine (10 mg/kg/day) for 7 or 28 days after AMI. Cardiac function was evaluated by echocardiography, and NETs detected by immunofluorescence. ROS production was detected using 2′,7′-dichlorodihydrofluorescein diacetates (DCFH-DA) fluorometry. Intracellular Ca2+ concentration was assessed by a fluorometric ratio technique.ResultsWe found that colchicine treatment significantly increased mice survival (89.8% in the colchicine group versus 67.9% in control, n = 32 per group; log-rank test, p < 0.05) and improved cardiac function at day 7 (left ventricular ejection fraction (LVEF): 28.0 ± 9.2% versus 12.6 ± 3.9%, n = 8 per group; p < 0.001) and at day 28 (LVEF: 26.2 ± 7.2% versus 14.8 ± 6.7%, n = 8 per group; p < 0.001) post-AMI. In addition, the administration of colchicine inhibited NETs formation and inflammation. Furthermore, colchicine inhibited NETs formation by reducing NOX2/ROS production and Ca2+ influx. Moreover, prevention of NETs formation with Cl-amidine significantly alleviated AMI-induced cardiac remodeling.ConclusionsColchicine inhibited NETs and cardiac inflammation, and alleviated cardiac remodeling after acute myocardial infarction.