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Histone methylation plays a crucial role in tumorigenesis. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that regulates chromatin structure and gene expression. EZH2 inhibitors (EZH2is) have been shown to be effective in treating hematologic malignancies, while their effectiveness in solid tumors remains limited. One of the major challenges in the treatment of solid tumors is their hypoxic tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) is a key hypoxia responder that interacts with EZH2 to promote tumor progression. Here we discuss the implications of the relationship between EZH2 and hypoxia for expanding the application of EZH2is in solid tumors.
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The clean and efficient utilization of municipal solid waste (MSW) has attracted increasing concerns in recent years. Pyrolysis of MSW is one of the promising options due to the production of high-value intermediates and the inhibition of pollutants at reducing atmosphere. Herein, the formation behavior of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) during MSW pyrolysis and incineration was experimentally investigated and compared. The influence of reaction temperature, CaO addition, and redox atmosphere on PCDD/Fs formation were compared and discussed. The results showed as the pyrolysis temperature increased, the mass concentration and international toxicity equivalence quantity of PCDD/Fs initially peaked at â¼750 °C before declining. Most of the generated PCDD/Fs were concentrated in the liquid and gaseous products, accounting for â¼90% of the total. Among liquid products, octachlorodibenzo-p-dioxin (O8CDD), 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,6,7,8-heptachlorodibenzofuran (H7CDF) were the most crucial mass concentration contributors, while in gas products, high-chlorinated PCDD/Fs, such as O8CDD, octachlorodibenzofuran (O8CDF) and 1,2,3,4,6,7,8-H7CDF were predominant. Compared to incineration, the formation of PCDD/Fs was 7-20 times greater than that from pyrolysis. This discrepancy can be attributed to the hydrogen-rich and oxygen-deficient atmosphere during pyrolysis, which effectively inhibited the Deacon reaction and the formation of C-Cl bonds, thereby reducing the active chlorine in the system. The addition of in-situ CaO additives also decreased the active chlorine content in the system, bolstering the inhibiting of PCDD/Fs formation during MSW pyrolysis.
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Compostos de Cálcio , Incineração , Oxirredução , Óxidos , Dibenzodioxinas Policloradas , Pirólise , Dibenzodioxinas Policloradas/química , Dibenzodioxinas Policloradas/análise , Compostos de Cálcio/química , Óxidos/química , Dibenzofuranos Policlorados/química , Temperatura , Resíduos Sólidos , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/química , Benzofuranos/químicaRESUMO
The present study utilized rice husk biomass as a carrier to synthesize rice husk biochar loaded with iron and nickel. Mono-metallic and bimetallic catalysts were prepared for the removal of toluene as the tar model. The efficiency of the catalysts for the removal of toluene was investigated, and finally, the removal mechanisms of mono-metallic and bimetallic catalysts for toluene were revealed. The experimental results showed that the bimetallic-loaded biochar catalysts had excellent toluene removal performance, which was closely related to the ratio of loaded Fe and Ni. Among them, the catalyst DBC-Fe2.5 %-Ni2.5 % (2.5 wt% iron loading and 2.5 wt% nickel loading) obtained through secondary calcination at 700 °C achieved the highest toluene removal efficiency of 92.76 %. The elements of Fe and Ni in the catalyst were uniformly dispersed on the surface and in the pores of the biochar, and the catalyst had a layered structure with good adsorption. Under the interaction of Fe and Ni, the agglomeration and sintering of Ni were reduced, and the surface acidity of the catalyst was increased, the surface acidity was favorable for toluene removal. The ironnickel catalyst did not form significant alloys when calcined at 400 °C, whereas strong metal interactions occurred at 700 °C, resulting in the formation of Fe0.64Ni0.36 alloy and NiFe2O4 alloy. This NiFe alloy had abundant active sites to enhance the catalytic cracking of toluene and provide lattice oxygen for the reaction. Furthermore, the functional groups on the catalyst surface also had an impact on toluene removal. The catalyst prepared in this paper reduces the cost of tar removal, can be applied to the removal of industrial pollutant tars, reduces the pollution of the environment, and provides theoretical guidance and technical reference for the efficient removal of tar.
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The regulation of PD-L1 is the key question, which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. However, besides the transcription level, the protein stability of PD-L1 is closely correlated with its function and has drawn increasing attention. In this study, EZH2 inhibition enhances PD-L1 expression and protein stability, and the deubiquitinase ubiquitin-specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition transcriptionally upregulates USP22 expression, and upregulated USP22 further stabilizes PD-L1. Importantly, a combination of EZH2 inhibitors with anti-PD-1 immune checkpoint blockade therapy improves the tumor microenvironment, enhances sensitivity to immunotherapy, and exerts synergistic anticancer effects. In addition, knocking down USP22 can potentially enhance the therapeutic efficacy of EZH2 inhibitors on colon cancer. These findings unveil the novel role of EZH2 inhibitors in tumor immune evasion by upregulating PD-L1, and this drawback can be compensated by combining ICI immunotherapy. Therefore, these findings provide valuable insights into the EZH2-USP22-PD-L1 regulatory axis, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor-based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment.
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Antígeno B7-H1 , Neoplasias Colorretais , Proteína Potenciadora do Homólogo 2 de Zeste , Estabilidade Proteica , Ubiquitina Tiolesterase , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Humanos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Camundongos , Estabilidade Proteica/efeitos dos fármacos , Linhagem Celular Tumoral , Ubiquitinação , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Modelos Animais de Doenças , Microambiente Tumoral/efeitos dos fármacosAssuntos
Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Estudos Retrospectivos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Feminino , Masculino , Injeções Subcutâneas , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Idoso , Resultado do Tratamento , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Esquema de MedicaçãoRESUMO
The emergence of the wide-band-gap semiconductor Ga2O3 has propelled it to the forefront of solar blind detection activity owing to its key features. Although various architectures and designs of Ga2O3-based solar blind photodetectors have been proposed, their performance still falls short of commercial standards. In this study, we demonstrate a method to enhance the performance of a simple metal-semiconductor-metal-structured Ga2O3-based solar blind photodetector by exciting acoustic surface waves. Specifically, we demonstrate that under a bias voltage of 100 mV and a radio frequency signal of 20 dBm, the responsivity and detectivity can increase from 2.78 to 1.65 × 104 A/W and from 8.35 × 1014 to 2.66 × 1016 jones, respectively, rivaling a commercial photomultiplier tube. The over 5 × 103-fold enhancement in responsivity could be attributed to the acousto-photoelectric coupling mechanism. Furthermore, since surface acoustic waves can also serve as signal receivers, such photodetectors offer the prospect of dual-mode detection. Our findings reveal a promising pathway for achieving high-performance Ga2O3-based electronics and optoelectronics.
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The treatment and disposal of waste biomass and plastics are of great importance to achieve both waste management and resource recycling. In this work, pyrolysis of biomass and plastic blends were investigated to identify the influence of temperature and in situ CaO addition on the production of hydrogen-rich, HCl-free, and low tar content fuel gases. The results show that the increase in temperature and the use of CaO significantly improved both the quantity and quality of the fuel gas and mitigated the formation of tar compounds and HCl. Moreover, H2 yield was significantly improved from 0.30 to 3.68 mmol/g with the increase in temperature from 550 to 850 °C. Also, the use of in situ CaO significantly increased the H2 yield by 28-88%. The H2/CO ratio was also enhanced from 0.35 to 1.50 with the temperature increase and CaO addition. Tar removal efficiency reached approximately 70.09% with the use of CaO at 850 °C. The produced HCl gas could be effectively absorbed by CaO through dechlorination reactions to form CaClOH at a highest mitigation efficiency of 92.37%. The results could be used to develop clean and efficient treatment technologies of waste biomass and plastics.
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Vascular smooth muscle cells (SMCs) can adapt to changes in cellular geometric cues; however, the underlying mechanisms remain elusive. Using 2D micropatterned substrates to engineer cell geometry, it is found that in comparison with an elongated geometry, a square-shaped geometry causes the nuclear-to-cytoplasmic redistribution of DNA methyltransferase 1 (DNMT1), hypermethylation of mitochondrial DNA (mtDNA), repression of mtDNA gene transcription, and impairment of mitochondrial function. Using irregularly arranged versus circumferentially aligned vascular grafts to control cell geometry in 3D growth, it is demonstrated that cell geometry, mtDNA methylation, and vessel contractility are closely related. DNMT1 redistribution is found to be dependent on the phosphoinositide 3-kinase and protein kinase B (AKT) signaling pathways. Cell elongation activates cytosolic phospholipase A2, a nuclear mechanosensor that, when inhibited, hinders AKT phosphorylation, DNMT1 nuclear accumulation, and energy production. The findings of this study provide insights into the effects of cell geometry on SMC function and its potential implications in the optimization of vascular grafts.
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Músculo Liso Vascular , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-akt/metabolismo , Músculo Liso Vascular/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Metilação de DNA/genética , Mitocôndrias/metabolismo , Metabolismo EnergéticoRESUMO
Bicyclol (BIC) has been widely used to treat drug-induced liver injury (DILI), however, it still has the problems of low solubility and bioavailability. Besides, the metabolic characteristics of BIC remain unclear. In the current study, we identified the metabolite of BIC in rat plasma, urine and feces, and evaluated the efficacy and safety of these metabolites. Based on the fragmentation behavior, we totally identified 11 metabolites and 7 metabolites in plasma, 8 metabolites in urine and 8 metabolites in feces. Notably, M1-M3, M6, M7, M10 and M11 were identified for the first time. M7 was the most abundant metabolite in the rat plasma. The metabolic pathways mainly involved demethylation, dealkylation, hydrolysis, methylation, oxidation and glucuronidation. In addition, the efficacy and safety of BIC's metabolites were evaluated by network pharmacology and molecular docking combined with toxicity prediction. The analysis of network pharmacology indicated that BIC's metabolites against DILI through the MAPK signaling pathway and Hepatitis B pathway. The molecular docking results showed that the binding energy of 5 compounds that docked with "7nuw" and 10 compounds that docked with "4tjz" was lower than BIC. 11 compounds possessed higher solubility and lower toxicity than BIC in prediction. Thus, the identification and evaluation of BIC's metabolites contributed to a better understanding of pharmacological mechanism of BIC and the high-value metabolites of high efficacy, safety and solubility provided a basis for drug development.
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Farmacologia em Rede , Espectrometria de Massas em Tandem , Animais , Compostos de Bifenilo , Cromatografia Líquida de Alta Pressão/métodos , Fezes/química , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodosRESUMO
It is vital to supply necessary electric power during natural disasters and in deprived regions. A novel heat collector is proposed to improve the capacity of the stove-powered thermoelectric generator (SPTEG). Enclosed combustion walls are constructed with four W-shape copper plates, and act as a whole to be an exceptional heat collector, which was not previously reported in TEG studies. Forty TE modules are installed and two DC-DC converters are employed to stabilize the electric power. Owing to the novel heat collector, the generated electric power reaches 0.024 W/K per unit temperature difference for an individual TE module, which is 200% higher than the previous record (0.008 W/K) when forty TE modules are incorporated. The proposed SPTEG is able to generate a net electric power of 119 W, which is considerably larger than the previous record (75.2 W). The corresponding TE efficiency reaches 3.12%, which is measured at a temperature difference of 140 °C. The startup performance, power load feature, and cooling water flow rate of the SPTEG are studied in detail. Furthermore, one-dimensional theoretical analyses are conducted to explore the SPTEG performance. The theoretical electric power agrees well with the experimental data when DC-DC converters are not involved. Applying DC-DC converters to stabilize the electric power will alter the impendence of the SPTEG, resulting in much lower electric power output than that without DC-DC converters.
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BACKGROUND: Mechanical forces play crucial roles in neointimal hyperplasia after vein grafting; yet, our understanding of their influences on vascular smooth muscle cell (VSMC) activation remains rudimentary. METHODS: A cuff mouse model was used to study vein graft hyperplasia. Fifteen percent to 1 Hz uniaxial cyclic stretch (arterial strain), 5% to 1 Hz uniaxial cyclic stretch or a static condition (venous strain) were applied to the cultured VSMCs. Metabolomics analysis, cell proliferation and migration assays, immunoblotting, co-immunoprecipitation, mutagenesis, pull-down and surface plasmon resonance assays were employed to elucidate the potential molecular mechanisms. RESULTS: RNA-sequencing in vein grafts and the controls identified changes in metabolic pathways and downregulation of mitochondrial protein MFN2 (mitofusin 2) in the vein grafts. Exposure of VSMCs to 15% stretch resulted in MFN2 downregulation, mitochondrial fragmentation, metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, and cell proliferation and migration, as compared with that to a static condition or 5% stretch. Metabolomics analysis indicated an increased generation of fructose 1,6-bisphosphate, an intermediate in the glycolytic pathway converted by PFK1 (phosphofructokinase 1) from fructose-6-phosphate, in cells exposed to 15% stretch. Mechanistic study revealed that MFN2 physically interacts through its C-terminus with PFK1. MFN2 knockdown or exposure of cells to 15% stretch promoted stabilization of PFK1, likely through interfering the association between PFK1 and the E3 ubiquitin ligase TRIM21 (E3 ubiquitin ligase tripartite motif [TRIM]-containing protein 21), thus, decreasing the ubiquitin-protease-dependent PFK1 degradation. In addition, study of mechanotransduction utilizing pharmaceutical inhibition indicated that the MFN2 downregulation by 15% stretch was dependent on inactivation of the SP1 (specificity protein 1) and activation of the JNK (c-Jun N-terminal kinase) and ROCK (Rho-associated protein kinase). Adenovirus-mediated MFN2 overexpression or pharmaceutical inhibition of PFK1 suppressed the 15% stretch-induced VSMC proliferation and migration and alleviated neointimal hyperplasia in vein grafts. CONCLUSIONS: MFN2 is a mechanoresponsive protein that interacts with PFK1 to mediate PFK1 degradation and therefore suppresses glycolysis in VSMCs.
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Mecanotransdução Celular , Músculo Liso Vascular , Fosfofrutoquinase-1/metabolismo , Animais , Proliferação de Células , Células Cultivadas , GTP Fosfo-Hidrolases/genética , Hiperplasia/metabolismo , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Von Willebrand Factor (VWF) can promote platelet adhesion to the post-atherosclerotic regions to initiate thrombosis. The synthesis and secretion of VWF are important functions of endothelial cells (ECs). However, the mechanism through which blood flow regulates endothelial secretion of VWF remains unclear. We utilized a parallel-plate flow apparatus to apply fluid shear stress to human umbilical vein endothelial cells (HUVECs). Compared with pulsatile shear stress that mimics laminar flow in the straight parts of arteries or upstream of atherosclerotic stenosis sites, short-term exposure to oscillatory shear stress (OS) that mimics disturbed flow increased VWF secretion independent of affecting synaptosomal-associated protein 23 (SNAP23) expression and promoted the translocation of SNAP23 to the cell membrane. Vimentin associated with SNAP23, and this association was enhanced by OS or histamine. Acrylamide, a reagent that disrupts vimentin intermediate filaments, prevented histamine/OS-induced SNAP23 translocation, as well as VWF secretion. Immunofluorescence analysis revealed that the polarity of the vimentin intermediate filament network decreased after stimulation with histamine or OS. In addition, inhibition of protein kinase A (PKA) or G protein coupled receptor 68 (GPR68) eliminated the histamine/OS-induced phosphorylation of vimentin at Ser38 and secretion of VWF. Furthermore, syntaxin 7 might assist with the translocation of SNAP23 to the cell membrane, thus playing a role in promoting VWF secretion. The GPR68/PKA/vimentin signaling pathway may represent a novel mechanism for the regulation of SNAP23-mediated VWF secretion by ECs under OS and provide strategies for the prevention of atherosclerosis-related thrombosis.
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Trombose , Fator de von Willebrand , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Histamina/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Filamentos Intermediários/metabolismo , Mecanotransdução Celular , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estresse Mecânico , Trombose/metabolismo , Vimentina/metabolismo , Fator de von Willebrand/metabolismoRESUMO
In order to utilize waste heat from passenger vehicles by a thermoelectric generator (TEG), a lab-scale TEG with a sufficient low-pressure drop was designed and tested. The waste heat from a 2.0 L petrol engine was simulated by using an air-circulation channel with an adjustable electric heater and a speed control motor. The TEG consisted of an integrated molding designed aluminum-finned heat collector, twenty thermoelectric modules, and a set of water-cooled heat sinks. Experiments were conducted in terms of power load feature, pressure drop, heat collection efficiency, thermoelectric efficiency and overall efficiency. It was found that the hot-end temperature was much lower (46.9%) than the flue gas temperature because the trade-off between fin area and pressure drop had to be considered. The obtained maximum electric power was 36.4 W, and the corresponding pressure drop was 36 Pa. The corresponding heat collection efficiency was 46.5%, and the thermoelectric efficiency was 2.88%, which agreed well with the theoretical prediction of 3.38%. As a result, an overall efficiency of 1.21% was reached. The present work firstly demonstrated a waste-heat-recovering TEG prototype with a balanced overall efficiency of over 1%, and a pressure drop of less than 50 Pa. On the other hand, the maximum electric power was difficult to fully extract. The charging power to a battery with a maximum power point tracking direct current-direct current converter was experimentally verified to work at a much higher conversion efficiency (15.3% higher) than regular converters.
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Objective: This study aimed to explore the association between base excess (BE) and the risk of 30-day mortality among patients with acute kidney injury (AKI) in the intensive care unit (ICU). Methods: This retrospective study included patients with AKI from the Medical Information Mart for Intensive Care (MIMIC)-IV database. We used a multivariate Cox proportional-hazards model to obtain the hazard ratio (HR) for the risk of 30-day mortality among patients with AKI. Furthermore, we utilized a Cox proportional-hazard model with restricted cubic splines (RCS) to explore the potential non-linear associations. Results: Among the 14,238 ICU patients with AKI, BE showed a U-shaped relationship with risk of 30-day mortality for patients with AKI, and higher or lower BE values could increase the risk. Compared with normal base excess (-3~3 mEq/L), patients in different groups (BE ≤ -9 mEq/L, -9 mEq/L < BE ≤ -3 mEq/L, 3 mEq/L < BE ≤ 9 mEq/L, and BE > 9 mEq/L) had different HRs for mortality: 1.57 (1.40, 1.76), 1.26 (1.14, 1.39), 0.97 (0.83, 1.12), 1.53 (1.17, 2.02), respectively. The RCS analyses also showed a U-shaped curve between BE and the 30-day mortality risk. Conclusion: Our results suggest that higher and lower BE in patients with AKI would increase the risk of 30-day mortality. BE measured at administration could be a critical prognostic indicator for ICU patients with AKI and provide guidance for clinicians.
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Chlorinated contaminants are a cause of significant concern in the development of municipal solid waste (MSW) thermal treatment techniques. This study investigates the efficacy of two calcium (Ca)-based in-furnace additives, calcium oxide (CaO), and calcined dolomite (CD), at reducing the levels of chlorinated contaminants during MSW thermal treatment. The results reveal that Ca-based additives could effectively reduce the chlorine (Cl) content by more than 76.8% and 37.3% in the gas and tar phases, respectively. The total concentration and the international total equivalent (I-TEQ) value of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) were significantly higher under the incineration condition than pyrolysis and gasification conditions. Adding CaO could reduce the total concentration and the I-TEQ value of PCDD/Fs by more than 43.4% and 36.7%, respectively. The reduction effect on PCDD/Fs was more significant in the gaseous phase and the tar phase than the solid phase. CD was more effective than CaO at reducing the chlorinated contaminants, including hydrogen chloride, Cl in the tar phase, and PCDD/Fs. Thus, adding Ca-based sorbents in the furnace during MSW pyrolysis and gasification can effectively reduce PCDD/Fs generation. Based on the experimental results, the mechanism of Ca-based sorbents on the high-temperature homogeneous reaction of PCDD/Fs formation was analysed.
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Poluentes Atmosféricos , Benzofuranos , Dibenzodioxinas Policloradas , Poluentes Atmosféricos/análise , Benzofuranos/análise , Cálcio , Dibenzofuranos , Dibenzofuranos Policlorados , Incineração , Resíduos SólidosRESUMO
The production of clean and efficient energy from municipal solid waste (MSW) is extremely urgent matter due to an increasing energy demand and environmental concerns. In this study, a high steam parameter (520 °C, 7.9 MPa) circulating fluidized bed (CFB) MSW incineration system, equipped with a mechanical, biological treatment and external heat exchanger systems, was introduced and a comparative study with a typical mechanical grate (450 °C, 5.3 MPa) incineration system and conventional CFB (485 °C, 5.3 MPa) incineration system was carried out from a life-cycle, environmental and exergetic perspective which could assess different energy and material outputs based on real operating data. Moreover, the potential system optimization of this advanced CFB system was proposed. The results showed that the advanced CFB system was more environmentally friendly and resource-efficient than conventional MSW incineration systems. The recovery of material should be given priority over energy recovery. According to the assessment of the environment, and energy and material recovery, a process improvement with an incinerated refuse-derived fuel and a semi-compost produced by MBT as a soil conditioner was highly recommended.
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Incineração , Eliminação de Resíduos , Animais , Estágios do Ciclo de Vida , Resíduos Sólidos/análiseRESUMO
Purpose: To evaluate the association of prior to intensive care unit (ICU) statin use with the clinical outcomes in critically ill patients with acute kidney injury (AKI). Materials and Methods: Patients with AKI were selected from the Medical Information Mart for Intensive Care IV (version 1.0) database for this retrospective observational study. The primary outcome was 30-day intensive care unit (ICU) mortality. A 30-day in-hospital mortality and ICU length of stay (LOS) were considered as secondary outcomes. Comparison of mortality between pre-ICU statin users with non-users was conducted by the multivariate Cox proportional hazards model. Comparison of ICU LOS between two groups was implemented by multivariate linear model. Three propensity score methods were used to verify the results as sensitivity analyses. Stratification analyses were conducted to explore whether the association between pre-ICU statin use and mortality differed across various subgroups classified by sex and different AKI stages. Results: We identified 3,821 pre-ICU statin users and 9,690 non-users. In multivariate model, pre-ICU statin use was associated with reduced 30-day ICU mortality rate [hazard ratio (HR) 0.68 (0.59, 0.79); p < 0.001], 30-day in-hospital mortality rate [HR 0.64 (0.57, 0.72); p < 0.001] and ICU LOS [mean difference -0.51(-0.79, -0.24); p < 0.001]. The results were consistent in three propensity score methods. In subgroup analyses, pre-ICU statin use was associated with decreased 30-day ICU mortality and 30-day in-hospital mortality in both sexes and AKI stages, except for 30-day ICU mortality in AKI stage 1. Conclusion: Patients with AKI who were administered statins prior to ICU admission might have lower mortality during ICU and hospital stay and shorter ICU LOS.
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Background: The beneficial effects of colchicine on cardiovascular disease have been widely reported in recent studies. Previous research demonstrated that colchicine has a certain protective effect on ischemic myocardium and has the potential to treat myocardial ischemia reperfusion injury (MIRI). However, the potential targets and pharmacological mechanism of colchicine to treat MIRI has not been reported. Methods: In this study, we used network pharmacology and experimental verification to investigate the pharmacological mechanisms of colchicine for the treatment of MIRI. Potential targets of colchicine and MIRI related genes were screened from public databases. The mechanism of colchicine in the treatment of MIRI was determined by protein-protein interaction (PPI), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Additionally, we evaluated the effect of colchicine on H9C2 cell activity using CCK-8 assays, observed the effect of colchicine on H9C2 cell apoptosis via flow cytometry, and further verified the expression of key targets after colchicine treated by Western blot. Results: A total of 626 target genes for colchicine and 1549 MIRI disease targets were obtained. 138 overlapping genes were determined as potential targets of colchicine in treating MIRI. the PPI network analysis demonstrated that the targets linked to MIRI were ALB, TNF, ACTB, AKT1, IL6, TP53, IL1B, CASP3 and these targets showed nice affinity with colchicine in molecular docking experiments. The results of GO analysis and KEGG pathway enrichment demonstrated that the anti-MIRI effect of colchicine involves in apoptotic signaling pathway. Further tests suggested that colchicine can protect H9C2 cell from Hypoxia/Reoxygenation (H/R) injury through anti-apoptotic effects. Western blot results demonstrated that colchicine can inhibited MIRI induced apoptosis of H9C2 cell by enhancing the decreased levels of Caspase-3 in myocardial injure model induced by H/R and activating the PI3K/AKT/eNOS pathway. Conclusions: we performed network pharmacology and experimental evaluation to reveal the pharmacological mechanism of colchicine against MIRI. The results from this study could provide a theoretical basis for the development and clinical application of colchicine.
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Jarosite is an important scavenger for arsenic (As) due to its strong adsorption capacity and ability to co-precipitate metal(loid)s in acid mine drainage (AMD) environments. When subjected to natural organic matter (NOM), metastable jarosite may undergo dissolution and transformation, affecting the mobility behavior of As. Therefore, the present study systematically explored the dissolution and transformation of jarosite, and the consequent redistribution of coprecipitated As(V) under anoxic condition in the presence of a common phenolic acid-gallic acid (GA). The results suggested that As(V) incorporating into the jarosite structure stabilized the mineral and inhibited the dissolution process. Jarosite persisted as the dominant mineral phase at pH 2.5 up to 60 d, though a large amount of structural Fe(III) was reduced by GA. However, at pH 5.5, jarosite mainly transformed to ferrohexahydrite (FeSO4·6H2O) with GA addition, while the principal end-product was goethite in GA-free system. The dissolution process enhanced As(V) mobilization into aqueous and surface-complexed phase at pH 2.5, while co-precipitated fraction of As(V) remained dominant under pH 5.5 condition. Result of XPS indicated that no reduction of As(V) occurred during the interaction between GA and As(V)-bearing jarosite, which would limit the toxicity to the environment. The reductive process involved that GA promoted the dissolution of jarosite via the synergistic effect of ligand and reduction, following by GA and release As(V) competing for active sites on mineral surface. The findings demonstrated that phenolic groups in NOM can exert great influence on the stability of jarosite and partitioning behavior of As(V).