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Reinforced cellular responses to endoplasmic reticulum (ER) stress are caused by a variety of pathological conditions including cancers. Human rhomboid family-1 protein (RHBDF1), a multiple transmembrane protein located mainly on the ER, has been shown to promote cancer development, while the binding immunoglobulin protein (BiP) is a key regulator of cellular unfolded protein response (UPR) for the maintenance of ER protein homeostasis. In this study, we investigated the role of RHBDF1 in maintaining ER protein homeostasis in breast cancer cells. We showed that deleting or silencing RHBDF1in breast cancer cell lines MCF-7 and MDA-MB-231 caused marked aggregation of unfolded proteins in proximity to the ER. We demonstrated that RHBDF1 directly interacted with BiP, and this interaction had a stabilizing effect on the BiP protein. Based on the primary structural motifs of RHBDF1 involved in BiP binding, we found a pentapeptide (PE5) targeted BiP and inhibited BiP ATPase activity. SPR assay revealed a binding affinity of PE5 toward BiP (Kd= 57.7 μM). PE5 (50, 100, 200 μM) dose-dependently promoted ER protein aggregation and ER stress-mediated cell apoptosis in MCF-7 and MDA-MB-231 cells. In mouse 4T1 breast cancer xenograft model, injection of PE5 (10 mg/kg, s.c., every 2 days for 2 weeks) significantly inhibited the tumor growth with markedly increased ER stress and apoptosis-related proteins in tumor tissues. Our results suggest that the ability of RHBDF1 to maintain BiP protein stability is critical to ER protein homeostasis in breast cancer cells, and that the pentapeptide PE5 may serve as a scaffold for the development of a new class of anti-BiP inhibitors.

Objectives: Treatment effects in patients with laryngeal squamous cell carcinoma may vary significantly even among those with the same TNM stage. Routine preoperative blood and coagulation tests are economical and easily available hematological indicators. This study aimed to investigate the clinical predictive significance of pretreatment evaluation of plasma fibrinogen (FIB) level, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in patients with laryngeal carcinoma.Methods: Clinicopathological and demographic data from 203 patients who underwent surgery for laryngeal carcinoma were collected and analyzed. The optimal cutoff values for FIB, NLR, and PLR were determined using receiver operating characteristic curve analysis. Univariate and multivariate Cox regression analyses were used to study the relationship between blood markers and patient survival.Results: The optimal cutoff values for FIB, NLR, and PLR were 3.05 g/L, 2.41, and 110.94, respectively. Preoperative hyperfibrinemia (FIB >3.05 g/L) was an independent prognostic factor for overall survival (OS) and disease-free survival in patients with laryngeal carcinoma. An NLR >2.41 was associated with reduced OS in patients with laryngeal carcinoma, while PLR >110.94 had no effect on prognosis in these patients.Conclusions: Fibrinogen and NLR were valuable markers in predicting survival in patients with laryngeal carcinoma and may be used to inform clinicians in designing individual treatment strategies.

Background: The research on the association between the relative glycemic level postpercutaneous coronary intervention (PCI) and adverse prognosis in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients is relatively inadequate. Objective: The study aimed to identify whether the glycemic level post-PCI predicts adverse prognosis in NSTE-ACS patients. Methods: Patients (n=2465) admitted with NSTE-ACS who underwent PCI were enrolled. The relative glycemic level post-procedure was calculated as blood glucose level post-PCI divided by HbA1c level, which was named post-procedural glycemic index (PGI). The primary observational outcome of this study was major adverse cardiovascular events (MACE) [defined as a composite of all-cause death, non-fatal myocardial infarction (MI) and any revascularization]. Results: The association between PGI and MACE rate is presented as a U-shape curve. Higher PGIs [hazard ratio (HR): 1.669 (95% confidence interval (CI): 1.244-2.238) for the third quartile (Q3) and 2.076 (1.566-2.753) for the fourth quartile (Q4), p<;0.001], adjusted for confounding factors, were considered to be one of the independent predictors of MACE. The association between the PGI and the risk of MACE was more prominent in the non-diabetic population [HR (95%CI) of 2.356 (1.456-3.812) for Q3 and 3.628 (2.265-5.812) for Q4, p<0.001]. There were no significant differences in MACE risk between PGI groups in the diabetic population. Conclusion: Higher PGI was a significant and independent predictor of MACE in NSTE-ACS patients treated with PCI. The prognostic effect of the PGI is more remarkable in subsets without pre-existing diabetes than in the overall population. The predictive value of PGI was not identified in the subgroup with diabetes.

Anaerobic methane oxidation is coupled to the reduction of electron acceptors, such as sulfate, and contributes to their biogeochemical cycling in the environment. However, whether arsenate acts as an alternative electron acceptor of anaerobic methane oxidation and how this influences global arsenic transformations remains elusive. Here, we present incubations of arsenate-contaminated wetland soils from seven provinces in China. Using isotopically labelled methane, we find that anaerobic methane oxidation was linked to arsenate reduction at a rate approaching the theoretical arsenic/methane stoichiometric ratio of 4. In microcosm incubations with natural wetland soils, we find that the coupled pathway of anaerobic methane oxidation and arsenate reduction contributed 26 to 49% of total arsenic release from soils, with arsenic in the more soluble and toxic form arsenite. Comparative gene quantification and metagenomic sequencing suggest that the coupled pathway was facilitated by anaerobic methanotrophs, either independently or synergistically with arsenate-reducing bacteria through reverse methanogenesis and respiratory arsenate reduction. Further bioinformatic analyses show that genes coding for reverse methanogenesis and respiratory arsenate reduction are universally co-distributed in nature. This suggests that coupling of anaerobic methane oxidation and arsenate reduction is a potentially global but previously overlooked process, with implications for arsenic mobilization and environmental contamination.

Cancer stem cells (CSCs) are the most intractable subpopulation of triple-negative breast cancer (TNBC) cells, which have been associated with a high risk of relapse and poor prognosis. However, eradication of CSCs continues to be difficult. Here, we integrate the multiomics data of a TNBC cohort (n = 360) to identify vital markers of CSCs. We discover that EMSY, inducing a BRCAness phenotype, is preferentially expressed in breast CSCs, promotes ALDH+cells enrichment, and is positively correlated with poor relapse-free survival. Mechanistically, EMSY competitively binds to the Jmjc domain, which is critical for KDM5B enzyme activity, to reshape methionine metabolism, and to promote CSC self-renewal and tumorigenesis in an H3K4 methylation-dependent manner. Moreover, EMSY accumulation in TNBC cells sensitizes them to PARP inhibitors against bulk cells and methionine deprivation against CSCs. These findings indicate that clinically relevant eradication of CSCs could be achieved with a strategy that targets CSC-specific vulnerabilities in amino acid metabolism.

Fibrosis is deemed to be a pivotal determinant of the long-term prognosis in non-alcoholic fatty liver disease (NAFLD). We aimed to develop a novel nomogram-based non-invasive model to accurately predict significant fibrosis in patients with NAFLD. We designed a prospective cohort study including 207 patients with biopsy-proven NAFLD. Detailed anthropometric and fibrosis-related laboratory parameters were collected. A nomogram was established based on variables that were independently associated with significant fibrosis identified by the logistic regression model. Then it was compared with aspartate aminotransferase-to-platelet ratio index (APRI), NAFLD fibrosis score (NFS), FIB-4 and BARD score. Diagnostic accuracy was assessed according to area under the receiver operator characteristic curve (AUROC), sensitivity, specificity, positive and negative predictive values, and decision curve analysis. Variables included in the nomogram were: waist-to-height ratio, hyaluronic acid, procollagen-III-peptide, chitinase-3-like protein 1, and cytokeratine-18 neoepitope M65. The discrimination ability of the nomogram (AUROC?=?0.829, 95%CI 0.755–0.904) was significantly superior to APRI (AUROC?=?0.670, 95%CI 0.563–0.777), NFS (AUROC?=?0.601, 95%CI 0.480–0.722), FIB-4 (AUROC?=?0.624, 95%CI 0.511–0.736) and BARD (AUROC?=?0.579, 95%CI 0.459–0.699) for significant fibrosis (all p?

DNA nanomachines have received great interest due to their potential to mimic various natural biomolecular machines. Intracellular pH sensing and imaging are of great significance to understand cellular behaviors and disease diagnostics. In this work, we report the novel molecular switching of a self-assembled 3D DNA triangular prism nanomachine (TPN) for pH sensing and imaging in living cells. The TPN was self-assembled in quantitative yields by hybridization with two DNA triangles and three I-strands (containing i-motif sequences). At acidic conditions, the TPN was compressed due to the I-strand that formed an intramolecular i-tetraplex, which was in between the fluorophores Cy3 and Cy5, resulting in a significant fluorescence resonance energy transfer (FRET) signal. At neutral or weakly alkaline conditions, the TPN adopted an extended state due to the random coil form of the I-strand, leading to spatial separation of the two fluorophores and the FRET being blocked. The TPN was fully reversible and could rapidly respond to the pH changes, entered into living cells automatically via an endocytic pathway, monitored spatiotemporal pH changes during endocytosis, maintained its structural integrity after escape from lysosomes, still had the ability for pH sensing, and also visualized pH fluctuations under varying stimuli in living cells. We foresee that this TPN can become a generic platform for a pH-related cell biology study and in disease diagnostics.

Background: Intraplaque angiogenesis, the process of generating new blood vessels mediated by endothelial cells, contributes to plaque growth, intraplaque hemorrhage, and thromboembolic events. Platelet-derived Exosomes (PLT-EXOs) affect angiogenesis in multiple ways. The ability of miR-126, one of the best-characterized miRNAs that regulates angiogenesis, carried by PLT-EXOs to influence angiogenesis via the regulation of the proliferation and migration of endothelial cells is unknown. In this study, we aimed to investigate the effects of PLT-EXOs on angiogenesis by Human Umbilical Vein Endothelial Cells (HUVECs). Methods: We evaluated the levels of miR-126 and angiogenic factors in PLT-EXOs from Acute Coronary Syndrome (ACS) patients and healthy donors by real-time Polymerase Chain Reaction (PCR) and western blotting. We incubated HUVECs with PLT-EXOs and measured cell proliferation and migration with the Cell Counting Kit-8 assay and scratch assay, respectively. We also investigated the expression of miR-126 and angiogenic factors in HUVECs after exposure to PLT-EXOs by western blotting and real-time PCR. Results: PLT-EXOs from ACS patients contained higher levels of miR-126 and angiogenic factors, including Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), and Transforming Growth Factor Beta 1 (TGF-β1), than those from healthy donors (p<0.05). Moreover, the levels of exosomal miR-126 and angiogenic factors were increased after stimulation with thrombin (p<0.01). HUVEC proliferation and migration were promoted by treatment with activated PLT-EXOs (p<0.01); they were accompanied by the over-expression of miR-126 and angiogenic factors, including VEGF, bFGF, and TGF-β1 (p<0.01). Conclusion: Activated PLT-EXOs promoted the proliferation and migration of HUVECs, and the overexpression of miR-126 and angiogenic factors, thereby elucidating potential new therapeutic targets for intraplaque angiogenesis.

The accurate determination and quantification of H2O2and glucose are necessary for diagnosis and bioengineering. Herein, we have reported a novel method for the rapid and selective detection of H2O2and glucose using g-C3N4–MnO2nanocomposite. In this method, the fluorescence of graphitic-C3N4(g-C3N4) was quenched by MnO2, which was attributed to fluorescence resonance energy transfer (FRET) between g-C3N4nanosheets and the deposited MnO2. When H2O2was introduced, the MnO2was reduced to Mn2+, which led to the elimination of FRET and the recovery of the quenched fluorescence. This H2O2detection system was also suitable for glucose detection since H2O2is one of the main products in the oxidation reaction of glucose catalyzed by glucose oxidase. Therefore, our method has a great application prospect in diabetes research and clinical diagnosis. Additionally, the fluorescence was linear with the concentration of H2O2in the range of 0 to 130 μM, with the detection limit of 1.5 μM, and also showed a good linear relationship with glucose in the range of 0 to 150 μM, with the detection limit of 1.5 μM. In addition to a wide linear response, the proposed sensor showed advantageous characteristics, such as easy preparation, low cost, high selectivity, rapid detection, and turn-on fluorescence response. Therefore, our proposed strategy would provide a new general strategy to develop low-cost, sensitive biological and clinical diagnostic methods.

ABSTRACTOvarian cancer is the third most common cancer in the female reproductive organs and epithelial ovarian cancer has the highest lethality of all gynecological cancers. Pomegranate fruit juice (PFJ) has been shown to inhibit the growth of several types of cancer other than ovarian cancer. In this study, we exposed the ovarian cancer cell line A2780 to PFJ and two of its components (ellagic acid and luteolin). MTT and wound healing assays demonstrated that all three treatments suppressed the proliferation and migration of the ovarian cancer cells. In addition, western blotting and ELISA assays showed that the expression levels of MMP2 and MMP9 gradually decreased after treatment with increasing concentrations of ellagic acid and luteolin. To confirm our findings in the in vitroexperiments, we used another ovarian cancer cell line, ES-2, in nude mice experiments. All three treatments inhibited tumor growth without obvious side-effects. Furthermore, compared with the control group, the expression levels of MMP2 and MMP9 were depressed. Ellagic acid induced a greater effect than luteolin, suggesting that ellagic acid might be a promising candidate for further preclinical testing for treatment of human ovarian cancer.

To evaluate the prevalence, clinical characteristics, and risk of cardiac events in patients with nonobstructive coronary artery disease (CAD).

The effect of obesity on restenosis in patients who undergo percutaneous coronary intervention (PCI) has not been fully understood. We undertook a meta-analysis for the effects of body mass index (BMI) on repeat revascularization in these patients.

To investigate the preferred and actual participation levels of colorectal cancer patients and their families in treatment decision-making.

In this paper, we take secondary forest, orchard, and woodland soils of rubber in different planting years as a research subject and analyze the influence of different land use on soil organic matter. The results show that land use has significant influence on soil organic matter components (p <0.01). We conducted a survey and sampling on 10 age classes of Hainan Dongfang Daguangba (3, 8, 13, 18,23,29,33,35,38,42 years old) rubber plantation plots soil layer (0 cm-20 cm, 20 cm-40 cm), and conducted in-house testing analysis of its organic matter content, and achieved preliminary exploration that soil organic matter content of different land use patterns in Dongfang City in Hainan: secondary forest> orchard> rubber plantation. These differences are mainly due to the litter under different tillage quantity, quality and variety of management measures. While orchards and rubber plantation have used different tillage method, as a plantation by human, it was greatly influenced by human.

This small study has determined the effect of vitamin C on myocardial reperfusion in patients undergoing elective percutaneous coronary intervention (PCI). This study was to explore whether antioxidant vitamin C infusion before the procedure is able to affect the incidence of periprocedural myocardial injury (PMI) in patients undergoing PCI.

Decreased estimated glomerular filtration rate (eGFR) is a strong predictor of both mortality and subsequent cardiac events after percutaneous coronary intervention. The safety and efficacy of drug-eluting (DESs) versus bare-metal stents (BMSs) in this population have not been evaluated adequately.

Myocardial necrosis occurs frequently in elective percutaneous coronary intervention (PCI) and is associated with subsequent major adverse cardiovascular events (MACEs). This study assessed the protective effect of remote ischemic preconditioning (RIPC) in patients undergoing successful drug-eluting stent implantation with normal baseline troponin values.

To assess the association between fasting plasma glucose (FPG) and all-cause mortality across the spectrum of coronary artery disease (CAD).

Stress hyperglycemia (SH) in a setting of acute myocardial infarction increases the risk of in-hospital mortality. The relationship between SH and in-hospital stent thrombosis (ST) is rare. The aim of our study was to assess the impact of SH on in-hospital ST and prognosis in nondiabetic patients with ST-segment elevation myocardial infarction (STEMI) undergoing a primary percutaneous coronary intervention (p-PCI).

To examine whether obesity has a similar effect on long-term prognosis between men and women undergoing a percutaneous coronary intervention (PCI).

Plackett-Burman design was employed for screening culture conditions for cellulase production by Penicillium decumbens in submerged fermentation. The results showed that wheat bran was the most significant factor influencing Filter Paper Activity (FPA) of the cellulase, followed by cellulose microcrystalline and initial pH, which could be further optimized for improving the cellulase activity. The effects of pH and temperature on FPA assay were investigated, and optimal FPA could be obtained at pH 4.5 and 60 ℃. The stabilities of endo-glucanase (EG), exo-glucanase (CBH) and β-glucosidase (BG) were investigated and compared with that of FPA under different pH and temperature. The results indicated that CBH and FPA were more sensitive to pH and temperature than EG and BG and the stability of CBH was very similar to that of FPA under the conditions.

Nowadays, the utilization of the by-product glycerol has become a common problem with the large amount of biodiesel production. This paper studied the conversion of the by-product glycerol of biodiesel production by Klebsiella pneumonia to 1,3-propanediol. The crude glycerol could be used directly without refining by a lactate dehydrogenase deficient K. pneumoniae and the lactic acid concentration was very low. In the fed-batch fermentation of 7L fermenter, 93.3g/l 1,3-propanediol was obtained and lactic acid concentration was just 2g/l. Analysis showed that D-type lactic acid synthesis was reduced obviously. The fermentation also was scaled up on the 42L fermenter. 1,3-propanediol and 2,3-Butanediol concentration reached 81.5g/l and 33.8g/l, respectively. No lactic acid was detected. The demonstration fermentation in 5000L fermenter was also successfully performed. The final 1,3-propanediol concentration and productivity was 87g/l and 1.2g/(lh). This work was considered useful to the integrated production of biodiesel and 1,3-propanediol.

Energy conservation guides and supports people to save energy of existing buildings energy through policy guidance and painstaking ideological work. Through demonstration projects, a set of building energy efficiency market transformation model has been formed. This paper introduces the overview of the building, room function, the air conditioning system, maintenance of the structure as the fundamental basis for energy saving. On this basis, suitable energy-saving proposals and measures for the building are proposed.

Despite achieving very low levels of low-density lipoprotein cholesterol (LDL-C), many patients continue to show disease progression. We sought to characterize the clinical factors that correlate with nonculprit lesion plaque progression in patients with LDL-C level less than 1.8 mmoll.

Microbial oxidation of organic compounds can promote arsenic release by reducing soil-associated arsenate to the more mobile form arsenite. While anaerobic oxidation of methane has been demonstrated to reduce arsenate, it remains elusive whether and to what extent aerobic methane oxidation (aeMO) can contribute to reductive arsenic mobilization. To fill this knowledge gap, we performed incubations of both microbial laboratory cultures and soil samples from arsenic-contaminated agricultural fields in China. Incubations with laboratory cultures showed that aeMO could couple to arsenate reduction, wherein the former bioprocess was carried out by aerobic methanotrophs and the latter by a non-methanotrophic bacterium belonging to a novel and uncultivated representative of Burkholderiaceae. Metagenomic analyses combined with metabolite measurements suggested that formate served as the interspecies electron carrier linking aeMO to arsenate reduction. Such coupled bioprocesses also take place in the real world, supported by a similar stoichiometry and gene activity in the incubations with natural paddy soils, and contribute up to 76.2% of soil-arsenic mobilization into pore waters in the top layer of the soils where oxygen was present. Overall, this study reveals a previously overlooked yet significant contribution of aeMO to reductive arsenic mobilization.

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