Neisseria gonorrhoeae is a common sexually transmitted pathogen that significantly impacts female fertility, neonatal health, and transmission of HIV worldwide. N. gonorrhoeae usually causes ...localized inflammation of the urethra and cervix by inducing production of IL-1beta and other inflammatory cytokines. Several NLR (nucleotide-binding domain, leucine-rich repeat) proteins are implicated in the formation of pro-IL-1beta-processing complexes called inflammasomes in response to pathogens. We demonstrate that NLRP3 (cryopyrin, NALP3) is the primary NLR required for IL-1beta/IL-18 secretion in response to N. gonorrhoeae in monocytes. We also show that N. gonorrhoeae infection promotes NLRP3-dependent monocytic cell death via pyronecrosis, a recently described pathway with morphological features of necrosis, including release of the strong inflammatory mediator HMBG1. Additionally, N. gonorrhoeae activates the cysteine protease cathepsin B as measured by the breakdown of a cathepsin B substrate. Inhibition of cathepsin B shows that this protease is an apical controlling step in the downstream activities of NLRP3 including IL-1beta production, pyronecrosis, and HMGB1 release. Nonpathogenic Neisseria strains (Neisseria cinerea and Neisseria flavescens) do not activate NLRP3 as robustly as N. gonorrhoeae. Conditioned medium from N. gonorrhoeae contains factors capable of initiating the NLRP3-mediated signaling events. Isolated N. gonorrhoeae lipooligosaccharide, a known virulence factor from this bacterium that is elaborated from the bacterium in the form of outer membrane blebs, activates both NLRP3-induced IL-1beta secretion and pyronecrosis. Our findings indicate that activation of NLRP3-mediated inflammatory response pathways is an important venue associated with host response and pathogenesis of N. gonorrhoeae.
Issues of water scarcity, food crisis, and ecological degradation pose great challenges to the sustainable development of Central Asia. In this study, a bi-level chance-constrained programming (BCCP) ...method is developed for planning water-food-ecology (WFE) nexus system of the Amu Darya River basin, where the efficiency of water-trading mechanism and the impact of uncertain water-availability are examined. This is the first attempt for planning WFE nexus system by incorporating chance-constrained programming (CCP) within a bi-level optimization framework. BCCP can reflect the risk of violating probabilistic constraint under uncertainty as well as balance the tradeoff between two-level decision makers in the WFE nexus system. Under trading scheme, multiple scenarios in association with different food demand, ecological-water requirement, and water availability are examined. Major findings are: (i) compared with that under non-trading, system benefits would increase 3.9, 20.4% under trading scenarios, disclosing that water trading is an effective mechanism for the study basin; (ii) when food demand increases 10.5%, water allocated to ecological use would decrease 0.9, 2.7% under all scenarios, revealing that agriculture can squeeze ecological water; (iii) both system benefit and water allocation would increase with p level, implying there is a tradeoff between system benefit and system-failure risk. These findings can gain insight into the interaction between two-level stakeholders and objectives as well as provide decision support for WFE nexus synergetic management.
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•A BCCP method is developed to plan WFE nexus system for the first time.•The challenges of hierarchical structure and random uncertainty can be tackled.•BCCP-WFE can alleviate water scarcity, food crisis and ecological degradation.•With the introduction of water trading, system benefit would increase 3.9, 20.4%.
Rapidly increased coal consumption has caused dramatically pollutants and carbon dioxide (CO2) emissions, such that utilizing renewable energy to substitute high pollutant and carbon fuels is crucial ...to fulfill sustainable development. In this study, an interval possibilistic-stochastic programming (IPSP) method that is capable of dealing with multiple uncertainties existed in the real-world mixed energy system (MES) is developed. Then, the IPSP method is applied to planning MES in the City of Qingdao (China) that aims to encourage developing renewable energies based on subsidy policy. Solutions under varied subsidies for stimulating renewable energies in association with different probabilities and α levels have been generated, which can help determine the optimized electricity generation and supply that could hedge appropriately against system violation risk. Compared to the results without subsidy, renewable energies with subsidy policy can increase by 2.4, 3.2 % and the share of renewable energies would raise to 17.5% at the end of planning horizon. The findings can provide useful information for the other municipal-scale MES planning issues to facilitate policy enactment of renewable energy, improvement of energy supply security, as well as accomplishment of planning environmental and sustainable MES.
•An interval possibilistic-stochastic programming (IPSP) method is developed.•IPSP can handle multiple uncertainties under different probabilities and α levels.•The IPSP method is applied to planning mixed energy system (MES) of Qingdao, China.•Solutions under various subsidies for stimulating renewable energy are analyzed.•Results can facilitate policy enactment of renewable energy and improve MES security.
Summary
The role of protein intake in bone has been controversial. Our case-control study among Chinese elderly concluded that a higher consumption of protein, even substituted for fat, is associated ...with lowered hip fracture risk. Differences in protein sources, amino acids composition, gender, and calcium sufficiency may explain the inconsistency.
Purpose
The aim of the study was to investigate the association of dietary protein intakes with hip fracture risk among Chinese elderly.
Methods
This was a 1:1 age and sex matched cross-sectional study of case-control design among 1070 pairs of elderly Chinese people aged 55 to 80 years. Patients who were newly diagnosed (within 2-week) hip fracture by X-ray were recruited from four hospitals in Guangdong Province of China. Dietary intakes were evaluated by a validated food frequency questionnaire for total protein, protein from different sources, amino acids profiles, and estimated renal acid load in diet.
Results
Daily average intakes of total protein were 58.1±27.0 (women) and 65.7±31.8 (men) g/d for cases, and 66.8±21.5 (women) and 72.1±24.4 (men) for controls (
p
<0.001). Multivariable regression indicated that, compared with the lowest quartile, the highest quartile of consumption of energy adjusted total protein OR: 0.360 (0.206~0.630) for women and 0.381 (0.153~0.949) for men and animal protein 0.326 (0.183, 0.560) for women and 0.335 (0.136~0.828) for men was significantly associated with the lowered risk of hip fracture in a dose-response manner (all
p
for trend <0.05). A significant hip fracture risk reduction was observed in women with higher intakes of sulfur amino acids OR: 0.464 (0.286~0.753) and aromatic amino acids 0.537 (0.326~0.884) but not in men. Subgroup analysis suggested that these associations were more evident in elderly with lower body mass index and dietary calcium intake less than 400 mg/d.
Conclusions
A higher level of protein intake, even substituted for fat, is associated with lowered hip fracture risk.
Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could ...therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo 3,2-b quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.
Epigenetic modifications are a driving force in carcinogenesis. However, their role in cancer metastasis remains poorly understood. The present study investigated the role of DNA methylation in the ...cervical cancer metastasis. Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and of the inhibition of metastasis by DNMT3B interference. Using methyl-DNA immunoprecipitation coupled with microarray analysis, we found that the protein tyrosine phosphatase receptor type R (PTPRR) was silenced through DNMT3B-mediated methylation in the cervical cancer. PTPRR inhibited p44/42 MAPK signaling, the expression of the transcription factor AP1, human papillomavirus (HPV) oncogenes E6/E7 and DNMTs. The methylation status of PTPRR increased in cervical scrapings (n=358) in accordance with disease severity, especially in invasive cancer. Methylation of the PTPRR promoter has an important role in the metastasis and may be a biomarker of invasive cervical cancer.
TOC: A composite gel polymer electrolyte based on hydroxyethyl cellulose (HEC) and poly (vinylidene fluoride) (PVDF) with sandwich-like architecture exhibiting high safety, good mechanical property ...is prepared and characterized.
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•A new composite HEC-PVDF gel polymer electrolyte with sandwich-like structure is prepared.•Its mechanical strength is largely improved compared with that of hydroxyethyl cellulose.•Its ionic conductivity and lithium ion transference number are greatly increased.•Li//LiFePO4 cell based this gel polymer electrolyte exhibits excellent performance.
A sandwich structure-like PVDF/HEC/PVDF polymer membrane is reported as host for matrix of gel polymer electrolytes for lithium ion batteries. The inner HEC (hydroxyethyl cellulose) layer is compact, and can avoid micro short-circuits. The producibility of the composite membrane is guaranteed due to the simple and efficient electro-spinning process for manufacturing the PVDF (poly(vinylidene fluoride)) layer and low-cost and eco-friendly HEC layer. This structure integrates the advantages of the HEC and PVDF, and it presents high uptake of liquid electrolyte (135.4%), excellent retention of liquid electrolyte, high ionic conductivity (0.88mScm−1 at ambient temperature), low activation energy for lithium movement (0.016eV), and high lithium ion transference number (t+=0.57), all properties are superior to those of the pure HEC membrane and commercial polyolefin separator (Celgard 2730). With the PVDF/HEC/PVDF gel polymer electrolyte as the electrolyte and separator, the assembled Li//LiFePO4 cell exhibits a notably high discharge capacity (140mAhg−1) over 140 cycles. The PVDF and HEC components are non-combustible, which is in sharp contrast with the combustible polymers for the commercial separators. These results show that this kind of sandwiched gel polymer electrolyte is promising for scale-up of lithium ion batteries especially those needing high safety and reliability.
In this study, a copula‐based particle filter (CopPF) approach was developed for sequential hydrological data assimilation by considering parameter correlation structures. In CopPF, multivariate ...copulas are proposed to reflect parameter interdependence before the resampling procedure with new particles then being sampled from the obtained copulas. Such a process can overcome both particle degeneration and sample impoverishment. The applicability of CopPF is illustrated with three case studies using a two‐parameter simplified model and two conceptual hydrologic models. The results for the simplified model indicate that model parameters are highly correlated in the data assimilation process, suggesting a demand for full description of their dependence structure. Synthetic experiments on hydrologic data assimilation indicate that CopPF can rejuvenate particle evolution in large spaces and thus achieve good performances with low sample size scenarios. The applicability of CopPF is further illustrated through two real‐case studies. It is shown that, compared with traditional particle filter (PF) and particle Markov chain Monte Carlo (PMCMC) approaches, the proposed method can provide more accurate results for both deterministic and probabilistic prediction with a sample size of 100. Furthermore, the sample size would not significantly influence the performance of CopPF. Also, the copula resampling approach dominates parameter evolution in CopPF, with more than 50% of particles sampled by copulas in most sample size scenarios.
Key Points
A copula‐based particle filter approach is developed for hydrological data assimilation
Synthetic experiments and real‐case studies demonstrate performance of the CopPF method
Results suggest that CopPF provides greater opportunities to access new samples which in turn lead to more accurate predictions
We aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).
It was a ...Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m2 i.v. day 1, and 5-FU 1000 mg/m2/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib.
In total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8–8.4 months), and the median overall survival was 11.8 months (95% CI 10.6–18.7 months). Major toxic effects included hand–foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases.
Combination of sorafenib, cisplatin (80 mg/m2) and 5-FU (3000 mg/m2) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.
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