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We present a new scheme for Majorana modes in systems with nonsymmorphic-symmetry-protected band degeneracy. We reveal that when the gapless fermionic excitations are encoded with conventional superconductivity and magnetism, which can be intrinsic or induced by proximity effect, topological superconductivity and Majorana modes can be obtained. We illustrate this outcome in a system which respects the space group P4/nmm and features a fourfold-degenerate fermionic mode at (π,  π) in the Brillouin zone. We show that in the presence of conventional superconductivity, different types of topological superconductivity, i.e., first-order and second-order topological superconductivity, with coexisting fragile Wannier obstruction in the latter case, can be generated in accordance with the different types of magnetic orders; Majorana modes are shown to exist on the boundary, at the corner and in the vortices. To further demonstrate the effectiveness of our approach, another example related to the space group P4/ncc based on this scheme is also provided. Our study offers insights into constructing topological superconductors based on bulk energy bands and conventional superconductivity and helps to find new material candidates and design new platforms for realizing Majorana modes.

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Background: Young children are susceptible to enterovirus (EV) infections, which cause significant morbidity in this age group. Objective: This study investigated the characteristics of virus strains and the epidemiology of EVs circulating among young children in Taiwan from 2011 to 2020. Methods: Children diagnosed with EV infections from 2011 to 2020 were identified from the routine national health insurance data monitoring disease system, real-time outbreak and disease surveillance system, national laboratory surveillance system, and Statistics of Communicable Diseases and Surveillance Report, a data set (secondary data) of the Taiwan Centers for Disease and Control. Four primary outcomes were identified: epidemic features, characteristics of sporadic and cluster cases of EV infections, and main cluster institutions. Results: From 2011 to 2020, between 10 and 7600 person-times visited the hospitals for EV infections on an outpatient basis daily. Based on 2011 to 2020 emergency department EV infection surveillance data, the permillage of EV visits throughout the year ranged from 0.07‰ and 25.45‰. After typing by immunofluorescence assays, the dominant type was coxsackie A virus (CVA; 8844/12,829, 68.9%), with most constituting types CVA10 (n=2972), CVA2 (n=1404), CVA6 (n=1308), CVA4 (n=1243), CVA16 (n=875), and CVA5 (n=680); coxsackie B virus CVB (n=819); echovirus (n=508); EV-A71 (n=1694); and EV-D68 (n=10). There were statistically significant differences (P<.001) in case numbers of EV infections among EV strains from 2011 to 2020. Cases in 2012 had 15.088 times the odds of being EV-A71, cases in 2014 had 2.103 times the odds of being CVA, cases in 2015 had 1.569 times the odds of being echovirus, and cases in 2018 had 2.274 times the odds of being CVB as cases in other years. From 2011 to 2020, in an epidemic analysis of EV clusters, 57 EV clusters were reported. Clusters that tested positive included 53 (53/57, 93%) CVA cases (the major causes were CVA6, n=32, and CVA10, n=8). Populous institutions had the highest proportion (7 of 10) of EV clusters. Conclusions: This study is the first report of sporadic and cluster cases of EV infections from surveillance data (Taiwan Centers for Disease and Control, 2011-2020). This information will be useful for policy makers and clinical experts to direct prevention and control activities to EV infections that cause the most severe illness and greatest burden to the Taiwanese.

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Glucocorticoid-induced osteoporosis (GIOP) commonly accelerates bone loss, increasing the risk of fractures and osteonecrosis more significantly than traditional menopausal osteoporosis. The extracellular environment influenced by glucocorticoids heightens fracture and osteonecrosis risks. Fraxin (Fra), a key component of the traditional Chinese herbal remedy Cortex Fraxini, is known for its wide-ranging pharmacological effects, but its impact on GIOP remains unexplored. This investigation aims to delineate the effects and underlying mechanisms of Fra in combating dexamethasone (Dex)-induced ferroptosis and GIOP. We established a mouse model of GIOP via intraperitoneal injections of Dex and cultured osteoblasts with Dex treatment for in vitro analysis. We evaluated the impact of Fra on Dex-treated osteoblasts through assays such as C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses via Western blot and immunofluorescence. The influence of Fra on bone microarchitecture of GIOP in mice was assessed using microcomputerized tomography, hematoxylin and eosin staining, double-labeling with Calcein-Alizarin Red S, and immunohistochemistry at imaging and histological levels. Based on our data, Fra prevented Dex-induced ferroptosis and bone loss. In vitro, glutathione levels increased and malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species decreased. Fra treatment also increases nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and COL1A1 expression and promotes bone formation. To delve deeper into the mechanism, the findings revealed that Fra triggered the activation of Nrf2/GPX4 signaling. Moreover, the use of siRNA-Nrf2 blocked the beneficial effect of Fra in osteoblasts cultivated with Dex. Fra effectively combats GIOP by activating the Nrf2/GPX4 signaling pathway to inhibit ferroptosis.

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INTRODUCTION: Developing an effective stroke prevention strategy is crucial for elderly atrial fibrillation (AF) patients with dementia. This is due to the limited and inconsistent evidence available on this topic. In this nationwide, population-based cohort study, we aim to compare the effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin in AF patients with dementia. PATIENTS AND METHODS: We identified AF patients with dementia, aged 50 years or older, from Taiwan's National Health Insurance Research Database between 2010 and 2019. The primary outcome was a composite of hospitalizations due to ischemic stroke, acute myocardial infarction, intracranial hemorrhage, or major bleeding, as well as all-cause mortality. We used 1:1 propensity score matching and Cox proportional hazard models to adjust for confounding factors when comparing outcomes between warfarin and DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) users or warfarin and each individual DOAC. RESULTS: There were 2952 patients in the DOAC-warfarin matched cohort. The apixaban-, dabigatran-, edoxaban-, and rivaroxaban-warfarin matched cohorts had 2346, 2554, 1684, and 2938 patients, respectively. The DOAC group, when compared to warfarin, was associated with a lower risk of both the composite outcome (hazard ratio (HR), 0.81; 95% confidence interval (CI) 0.69-0.95) and ischemic stroke (HR 0.65; 95% CI 0.48-0.87). Apixaban (HR 0.79; 95% CI 0.66-0.94), dabigatran (HR 0.64; 95% CI 0.53-0.77), and rivaroxaban (HR 0.82; 95% CI 0.70-0.97) were also associated with a lower risk of the composite outcome. DISCUSSION AND CONCLUSION: Compared to warfarin, DOACs, whether as a group or apixaban, dabigatran, or rivaroxaban individually, were associated with a reduced risk of the composite outcome in elderly patients with concurrent AF and dementia.

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Liver injury is closely related to poor outcomes in sepsis patients. Current studies indicate that sepsis is accompanied by metabolic disorders, especially those related to lipid metabolism. It is highly important to explore the mechanism of abnormal liver lipid metabolism during sepsis. As a key regulator of glucose and lipid metabolism, angiopoietin-like 8 (ANGPTL8) is involved in the regulation of multiple chronic metabolic diseases. In the present study, severe liver lipid deposition and lipid peroxidation were observed in the early stages of lipopolysaccharide (LPS) induced liver injury. LPS promotes the expression of ANGPTL8 both in vivo and in vitro. Knockout of Angptl8 reduced hepatic lipid accumulation and lipid peroxidation, improved fatty acid oxidation and liver function, and increased the survival rate of septic mice by activating the PGC1α/PPARα pathway. We also found that the expression of ANGPTL8 induced by LPS depends on TNF-α, and that inhibiting the TNF-α pathway reduces LPS-induced hepatic lipid deposition and lipid peroxidation. However, knocking out Angptl8 improved the survival rate of septic mice better than inhibiting the TNF-α pathway. Taken together, the results of our study suggest that ANGPTL8 functions as a novel cytokine in LPS-induced liver injury by suppressing the PGC1α/PPARα signaling pathway. Therefore, targeting ANGPTL8 to improve liver lipid metabolism represents an attractive strategy for the management of sepsis patients.

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As key performance indicators, the water absorption and mechanical strength of ceramics are highly associated with sintering temperature. Lower sintering temperatures, although favorable for energy saving in ceramics production, normally render the densification degree and water absorption of as-prepared ceramics to largely decline and increase, respectively. In the present work, 0.5 wt.% MnO2, serving as an additive, was mixed with aluminosilicate ceramics using mechanical stirring at room temperature, achieving a flexural strength of 58.36 MPa and water absorption of 0.05% and lowering the sintering temperature by 50 °C concurrently. On the basis of the results of TG-DSC, XRD, MIP, and XPS, etc., we speculate that the MnO2 additive promoted the elimination of water vapor in the ceramic bodies, effectively suppressing the generation of pores in the sintering process and facilitating the densification of ceramics at a lower temperature. This is probably because the MnO2 transformed into a liquid phase in the sintering process flows into the gap between grains, which removed the gas inside pores and filled the pores, suppressing the generation of pores and the abnormal growth of grains. This study demonstrated a facile and economical method to reduce the porosity and enhance the densification degree in the practical production of aluminosilicate ceramics.

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The lycid genus Ponyalis Fairmaire, 1899 is reviewed. Six new species are described from China, including P.longicornis sp. nov., P.truncata sp. nov., P.dabieshanensis sp. nov., P.hainanensis sp. nov., P.quadricollimima sp. nov., and P.zhejiangensis sp. nov. Nine previously known species, including P.alternata (Pic, 1927), P.fukiensis (Bocak, 1999), P.gracilis (Bocak, 1999), P.himalejica (Bourgeois, 1885), P.klapperichi (Bocak, 1999), P.laticornis Fairmaire, 1899, P.nigrohumeralis (Pic, 1939), P.quadricollis (Kiesenwetter, 1874), and P.variabilis Li, Bocak & Pang, 2015 are illustrated with images of the habitus and aedeagi to make the comparisons with the new species. In addition, a distribution map and an identification key to all 24 species of Ponyalis are provided.

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In this study, the effects of micro-positive pressure formed by covering with a semipermeable membrane in the heating phase of dairy manure composting on greenhouse gas emissions and the mechanism of reducing methane emissions by the archaeal community were investigated. A large-scale experiment was conducted with semipermeable membrane-covered composting (SMC), forced aeration composting (FAC), and traditional static composting (TSC) groups. The results showed that the oxygen concentration and methanogen abundance were key factors in regulating methane emissions. In the heating phase of SMC, the micro-positive pressure could enhance the O2 utilization rate and heating rate, resulting in Methanobrevibacter and Methanobacterium greatly decreasing, and the abundance of mcrA decreased by 90.03%, while that of pmoA did not increase. Compared with FAC and TSC, the cumulative methane emissions in SMC decreased by 51.75% and 96.04%, respectively. Therefore, the micro-positive pressure could effectively reduce greenhouse gas emissions by inhibiting the growth of methanogens.

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Spatial confinement of organic pollutants and reactive oxygen species (e.g., SO4•- and •OH) with ultrashort lifetime inside the scale of chemical theoretical diffusion could provide a greatly promising strategy to overcome the limitation of mass transfer in the heterogeneous Fenton-like oxidation process. Herein, we first reported spatial confinement of cobalt nanoparticles in N-doped carbon nanorods (Co-NCNRs), by encapsulating Co nanoparticles into N-doped carbon nanorods, in activating CaSO3 for antibiotic degradation. Compared to Na2SO3 and NaHSO3, CaSO3 could slowly and persistently discharge SO32- due to its low solubility, thus avoiding the depletion of the generated SO3•- and •OH under the high concentration of sulfite ions. Fully physical characterizations confirmed that the 3D hydrogel was mostly transformed into the nanorod structure of Co-NCNRs at 550 °C. Co atoms were successfully nanoconfined into N-doped carbon nanorods, which contributes to mass transfer and prevents the agglomeration of Co nanoparticles, thus enhancing its catalytic activity and stability in activating CaSO3 for water decontamination. The catalytic performance, kinetic research, influences of inorganic anions, pH, and degradation mechanism of chlortetracycline degradation catalyzed by the Co-NCNRs/CaSO3 system have been studied in detail. This work not only proposed a facile method for synthesis of nanoconfined catalyst but also provided an excellent Co-NCNRs/CaSO3 system for wastewater treatment.

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INTRODUCTION: The potential influence of age at menarche (AM) on cognitive aging remains inadequate, partly because of the difficulties presented by multiple confounders. To address this issue, Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on cognitive aging. METHODS: Using the publicly accessible Taiwan Biobank, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM as instrumental variables to estimate the effects of instruments on cognitive function assessed with the Mini-Mental State Examination (MMSE). We employed several MR methods, including two-stage least squares, inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and constrained maximum likelihood (cML) MR methods, to ensure the stability and reliability of the results. RESULTS: MR analyses indicated no significant causal relationship between genetically determined AMs and total and subdomain MMSE scores, except the G5 subdomain (ßIVW = 0.156, 95% confidence interval [CI]: 0.005, 0.307; ßcML = 0.161, 95% CI: 0.014, 0.309). However, in a leave-one-out sensitivity analysis, we found a significant relationship between AM and cognitive aging after eliminating rs157863 and rs6758290, thus demonstrating the potential pleiotropic effects of these two SNPs. After these two SNPs were eliminated, we found a significant causal relationship between AM and overall MMSE scores (ßIVW = 0.425, 95% CI: 0.011, 0.839), though. CONCLUSION: Evidence from the present MR study did not fully support a causal relationship between AM and cognitive function decline in later life. Potential pleiotropic effects of the genes underlying these two traits are worthy of further investigation.

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Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) is an ultra-rare autosomal recessive neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. Here, we report the generation and characterization of human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of three unrelated SSADHD patients - one female and two males with the CRISPR-corrected isogenic controls. These individuals are clinically diagnosed and are being followed in a longitudinal clinical study.

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Introduction: Diabetes and obesity are momentous risk factors threatening people's lives and health. Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss. Co-agonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss. Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it. Methods: The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro. The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys. The OGTTs were performed in Sprague­Dawley (SD) rats. The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic (db/db) mice for 4 weeks. The effects of anti-obesity and improving metabolism of DR10627 were evaluated by repeated administration of DR10627 in diet-induced obesity (DIO) mice for 57 days. Results: DR10627 had the capacity to activate both GLP-1R and GIPR in vitro. The terminal half-life of DR10627 was found to be approximately 4.19-5.8 h in cynomolgus monkeys. DR10627 had a great improvement in oral glucose tolerance in SD rats. Moreover, DR10627 had a potent glucose-lowering effect in db/db mice, and the hypoglycemic effect of 18 nmol/kg DR10627 was better than that of 50 nmol/kg liraglutide. In addition, 10 and 30 nmol/kg DR10627 possessed the ability of potentiating the weight-loss, lipid-lowing efficacy and improving metabolism to a greater extent than 80 nmol/kg liraglutide. Conclusion: Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and db/db mice, and substantial body weight reduction and metabolism improvement in DIO mice. DR10627 is a promising agent deserving further investigation for the treatment of type 2 diabetes and obesity.

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BACKGROUND: Atrial fibrillation (AF) is associated with circulating inflammation. Short-chain fatty acids (SCFAs) derived from gut microbiota (GM) regulate leukocyte function and inhibit the release of inflammatory cytokines, which are partly mediated by the G-protein-coupled receptor 43 (GPR43) signaling. This study aimed to investigate the expression of GPR43/NOD-like receptors family pyrin domain containing 3 (NLRP3) in leukocytes and the interaction with intestinal SCFAs levels in AF patients. METHODS: Expressions of GPR43 and NLRP3 mRNA in peripheral blood leukocytes from 23 AF patients and 25 non-AF controls were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Expressions of leukocyte GPR43 and NLRP3 protein were evaluated by western blot analysis. The levels of plasma IL-1ß were measured by enzyme-linked immunosorbent assay (ELISA). The fecal SCFAs levels based on GC/MS metabolome of corresponding 21 controls and 14 AF patients were acquired from our published dataset. To evaluate the expression of NLRP3 and GPR43 and the release of IL-1ß, human THP-1 cells were stimulated with or without SCFAs (acetate, propionate, and butyrate), lipopolysaccharide (LPS), and nigericin in vitro, respectively. RESULTS: Compared to the controls, the mRNA expression in peripheral leukocytes was significantly reduced in AF patients (P = 0.011) coupled with the increase in downstream leukocyte NLRP3 mRNA expression (P = 0.007) and plasma IL-1ß levels (P < 0.001), consistent with changes in GPR43 and NLRP3 protein expression. Furthermore, leukocyte GPR43 mRNA levels were positively correlated with fecal GM-derived acetic acid (P = 0.046) and negatively correlated with NLRP3 mRNA expression (P = 0.024). In contrast to the negative correlation between left atrial diameter (LAD) and GPR43 (P = 0.008), LAD was positively correlated with the leukocyte NLRP3 mRNA levels (P = 0.024). Subsequent mediation analysis showed that 68.88% of the total effect of intestinal acetic acid on AF might be mediated by leukocyte GPR43/NLRP3. The constructed GPR43-NLRP3 score might have a predictive potential for AF detection (AUC = 0.81, P < 0.001). Moreover, SCFAs treatment increased GPR43 expression and remarkably reduced LPS/nigericin-induced NLRP3 expression and IL-1ß release in human THP-1 cells in vitro. CONCLUSIONS: Disrupted interactions between GPR43 and NLRP3 expression in peripheral blood leukocytes, associated with reduced intestinal GM-derived SCFAs, especially acetic acid, may be involved in AF development and left atrial enlargement by enhancing circulating inflammation.

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Background: Litchi (Litchi chinensis) is an important sub-tropical fruit in the horticulture market in China. Breeding for improved fruit characteristics is needed for satisfying consumer demands. Budding is a sustainable method for its propagation. During our ongoing breeding program, we observed a litchi mutant with flat leaves and sharp fruit peel cracking in comparison to the curled leaves and blunt fruit peel cracking fruits of the mother plant. Methods: To understand the possible molecular pathways involved, we performed a combined metabolome and transcriptome analysis. Results: We identified 1,060 metabolites in litchi leaves and fruits, of which 106 and 101 were differentially accumulated between the leaves and fruits, respectively. The mutant leaves were richer in carbohydrates, nucleotides, and phenolic acids, while the mother plant was rich in most of the amino acids and derivatives, flavonoids, lipids and organic acids and derivatives, and vitamins. Contrastingly, mutant fruits had higher levels of amino acids and derivatives, carbohydrates and derivatives, and organic acids and derivatives. However, the mother plant's fruits contained higher levels of flavonoids, scopoletin, amines, some amino acids and derivatives, benzamidine, carbohydrates and derivatives, and some organic acids and derivatives. The number of differentially expressed genes was consistent with the metabolome profiles. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway-enriched gene expressions showed consistent profiles as of metabolome analysis. Conclusion: These results provide the groundwork for breeding litchi for fruit and leaf traits that are useful for its taste and yield.

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BACKGROUND: Colon cancer (CC) has a high incidence rate. Radical resection is the main treatment method for CC; however, liver metastasis (LM) often occurs post-surgery. The liver contains both innate and adaptive immune cells that monitor and remove abnormal cells and pathogens. Before LM, tumor cells secrete cytokines and exosomes to adjust the immune microenvironment of the liver, thus forming an inhibitory immune microenvironment for colonization by circulating tumor cells. This indicates that the immune state of patients with CC plays a crucial role in the occurrence and progression of LM. AIM: To observe and analyze the relationship between immune status and expression of tumor factors in patients with LM of CC, and to provide a scientific intervention method for promoting the patient prognosis. METHODS: A retrospective analysis was performed. The baseline data of 100 patients with CC and 100 patients with CC who suffered from postoperative LM and were admitted to our hospital from May 2021 to May 2023 were included in the non-occurrence and occurrence groups, respectively. The immune status of the patients and the expression of tumor factor-related indicators in the two groups were compared, and the predictive value of the indicators for postoperative LM in patients with CC was analyzed. RESULTS: Compared with the non-occurrence group, the expression of serum carcinoembryonic antigen (CEA), CA19-9, CA242, CA72-4 and CA50 in patients in the occurrence group were significantly higher, while the expression of CD3+, CD4+, CD8+, natural killer (NK) and CD4+/CD25 in patients in the occurrence group were significantly lower (P < 0.05). No significant difference was observed in other baseline data between groups (P > 0.05). Multivariate logistic regression model analysis revealed that the expressions of CEA, CA19-9, CA242, CA72-4, CA50, CD3+, CD4+, CD8+, NK, and CD4+/CD25 were associated with the LM in patients with CC. High expressions of serum CEA, CA19-9, CA242, CA72-4 and CA50, and low expressions of CD3+, CD4+, CD8+, NK, and CD4+/CD25 in patients with CC were risk factors for LM (OR > 1, P < 0.05). The receiver operating characteristic curve showed that the area under curve for CEA, CA19-9, CA242, CA72-4, CA50, CD3+, CD4+, CD8+, NK, and CD4+/CD25 in the prediction of LM in patients with CC were all > 0.80, with a high predictive value. CONCLUSION: The expression of tumor factors and immune state-related indices in patients with CC is closely associated with the occurrence of LM.

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Livestock manure often contains various pollutants. The aim of this study was to investigate how adding amoxicillin (AMX), Cu, and both AMX and Cu (ACu) affected humification during composting and the microbial mechanisms involved. The cellulose degradation rates were 16.96%, 10.86%, and 9.01% lower, the humic acid contents were 18.71%, 12.89%, and 16.78% lower, and the humification degrees were 24.72%, 24.16%, and 15.73% lower for the AMX, Cu, and ACu treatments, respectively, than the control. Adding AMX and Cu separately or together inhibited humic acid formation and decreased the degree of humification, but the degree of humification was decreased less by ACu than by AMX or Cu separately. The ACu treatment decreased the number of core bacteria involved in humic acid formation and decreased carbohydrate and amino acid metabolism during the maturing period, and thereby delayed humic acid formation and humification. The results support composting manure containing AMX and Cu.

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BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent form of malignancy globally. Disulfidptosis is novel programmed cell death pathway based on disulfide proteins, may have a positive impact on the development of LUAD treatment strategies. OBJECTIVE: To investigate the impact of disulfidptosis-related genes (DRGs) on the prognosis of LUAD, developed a risk model to facilitate the diagnosis and prognostication of patients. We also explored ACTN4 (DRGs) as a new therapeutic biomarker for LUAD. METHODS: We investigated the expression patterns of DRGs in both LUAD and noncancerous tissues. To assess the prognostic value of the DRGs, we developed risk models through univariate Cox analysis and lasso regression. The expression and function of ACTN4 was evaluated by qRT-PCR, immunohistochemistry and in vitro experiments. The TIMER examined the association between ACTN4 expression and immune infiltration in LUAD. RESULTS: Ten differentially expressed DRGs were identified. And ACTN4 was identified as potential risk factors through univariate Cox regression analysis (P< 0.05). ACTN4 expression and riskscore were used to construct a risk model to predict overall survival in LUAD, and high-risk demonstrated a significantly higher mortality rate compared to the low-risk cohort. qRT-PCR and immunohistochemistry assays indicated ACTN4 was upregulated in LUAD, and the upregulation was associated with clinicopathologic features. In vitro experiments showed the knockdown of ACTN4 expression inhibited the proliferation in LUAD cells. The TIMER analysis demonstrated a correlation between the expression of ACTN4 and the infiltration of diverse immune cells. Elevated ACTN4 expression was associated with a reduction in memory B cell count. Additionally, the ACTN4 expression was associated with m6A modification genes. CONCLUSIONS: Our study introduced a prognostic model based on DRGs, which could forecast the prognosis of patients with LUAD. The biomarker ACTN4 exhibits promise for the diagnosis and management of LUAD, given its correlation with tumor immune infiltration and m6A modification.

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BACKGROUND: Pheochromocytoma (PCC) is a rare neuroendocrine tumor. Angiogenesis is primary contributing factor for tumorigenesis. Cytochrome c oxidase 4I2 (COX4I2) has been confirmed to take part in the progression of cancer. Hypoxia-inducible factor 1A (HIF1A) is the main regulatory factor for the steady-state response of hypoxia, involved in metabolism and angiogenesis. In this study, we intended to explore the functions of COX4I2 in PCC and the effect mechanism between HIF1A and COX4I2. MATERIALS AND METHODS: The RNA-sequencing and immunohistochemistry tested COX4I2 expression in highly vascular PCC. Small interfering RNA (siRNA) was used to reduce the mRNA expression of COX4I2, and a small molecule inhibitor was utilized to reduce the protein expression of HIF1A. Culturing cells in 1% O2environment was performed to activate HIF1A. Western blot was applied to quantify the expression of target genes at the protein levels. The supernatant from PCC cells and fibroblasts acted as the conditioned medium. We conducted the tube formation and transwell assays in human vascular endothelial cells (HUVECs) to determine angiogenesis, the binding of COX4I2 promoter and HIF1A was evaluated by the dual luciferase reporter assay. RESULTS: COX4I2 had been rigorously shown to be overexpressed in highly vascular PCC. Knockdown of COX4I2 in PCC cells (MPC) did not significantly impact angiogenesis, while knockdown of COX4I2 in fibroblast (3T3) notably inhibited angiogenesis. RNA sequencing suggested that the expression of 11 vascular markers, such as CD34 and angiogenesis associated pathways in 3T3, decreased with knockdown of COX4I2. HIF1A had been shown to enhance the mRNA expression of COX4I2 through transcriptional regulation. Activation and inhibition of HIF1A resulted in upregulation and downregulation of COX4I2, respectively. The HIF1A inhibitor demonstrated a reduction in angiogenesis. CONCLUSION: COX4I2 is overexpressed in highly vascular PCC and contributes to angiogenesis in fibroblasts. Mechanistically, HIF1A transcriptional regulation enhances COX4I2 and its effects on angiogenesis in PCC. COX4I2 might serve as a vascular marker and represent a potential target for vascular therapy.

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BACKGROUND: Cyclin-dependent kinase (CDK) 7 is aberrantly overexpressed in many types of cancer and is an attractive target for cancer therapy due to its dual role in transcription and cell cycle progression. Moreover, CDK7 can directly modulate the activities of estrogen receptor (ER), which is a major driver in breast cancer. Breast cancer cells have exhibited high sensitivity to CDK7 inhibition in pre-clinical studies. METHODS: In this review, we provide a comprehensive summary of the latest insights into CDK7 biology and recent advancements in CDK7 inhibitor development for breast cancer treatment. We also discuss the current application of CDK7 inhibitors in different molecular types of breast cancer to provide potential strategies for the treatment of breast cancer. RESULTS: Significant progress has been made in the development of selective CDK7 inhibitors, which show efficacy in both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer (HR+). Moreover, combined with other agents, CDK7 inhibitors may provide synergistic effects for endocrine therapy and chemotherapy. Thus, high-quality studies for developing potent CDK7 inhibitors and investigating their applications in breast cancer therapy are rapidly emerging. CONCLUSION: CDK7 inhibitors have emerged as a promising therapeutic strategy and have demonstrated significant anti-cancer activity in different subtypes of breast cancer, especially those that have been resistant to current therapies.

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