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The intramembrane protease PARL acts as a crucial mitochondrial safeguard by cleaving the mitophagy regulators PINK1 and PGAM5. Depending on the stress level, PGAM5 can either stimulate cell survival or cell death. In contrast to PINK1, which is constantly cleaved in healthy mitochondria and only active when the inner mitochondrial membrane is depolarized, PGAM5 processing is inversely regulated. However, determinants of PGAM5 that indicate it as a conditional substrate for PARL have not been rigorously investigated, and it is unclear how uncoupling the mitochondrial membrane potential affects its processing compared to that of PINK1. Here, we show that several polar transmembrane residues in PGAM5 distant from the cleavage site serve as determinants for its PARL-catalyzed cleavage. Our NMR analysis indicates that a short N-terminal amphipathic helix, followed by a kink and a C-terminal transmembrane helix harboring the scissile peptide bond are key for a productive interaction with PARL. Furthermore, we also show that PGAM5 is stably inserted into the inner mitochondrial membrane until uncoupling the membrane potential triggers its disassembly into monomers, which are then cleaved by PARL. In conclusion, we propose a model in which PGAM5 is slowly processed by PARL-catalyzed cleavage that is influenced by multiple hierarchical substrate features, including a membrane potential-dependent oligomeric switch.Four pairs of undescribed enantiomeric isoquinoline alkaloids (6S/R-(N,N-diethylacetamido)yl-dihydrochelerythrine, 6R/S-acetonyl-9-hydroxy-dihydrochelerythrine, 6S/R-acroleinyl-dihydrochelerythrine, 6S/R-acetatemethyl-dihydrochelerythrine), five undescribed isoquinoline alkaloids (6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-hydroxy-dihydrochelerythrine, 9-methoxy-10-hydroxy-norchelerythrine, chelidoniumine A), together with 13 known isoquinoline alkaloids were isolated from an extract of the roots and rhizomes of Hylomecon japonica. The structures of the undescribed compounds were identified by NMR, HRESIMS, UV, IR, and their absolute configurations were defined via electronic circular dichroism data and optical rotation. All of the isolated compounds were tested for their anti-breast cancer activities in MCF-7 cells. Among them, the undescribed alkaloids 6S/R-acroleinyl-dihydrochelerythrine, 6,10-dimethoxydihydrochelerythrine, 6-ethoxy-ethaniminyl-dihydrochelandine, 9-methoxy-10-hydroxy-norchelerythrine and other known alkaloids 6-methoxydihydrosanguinarine, 6-acetaldehyde-dihyrochelerythrine, dihydrosanguinaline and 10-methoxy boconoline had good inhibitory effects on MCF-7 cells of breast cancer with an IC50 lower than 20 μM.The objective of this study was to visualize trends and current research status of hydrothermal biochar research through a bibliometric analysis by using CiteSpace software. The original article data were collected from the Web of Science core database published between 2009 and 2020. A visual analysis network of national co-authored, institutional co-authored and author co-authored articles was created, countries, institutions and authors were classified accordingly. By visualizing the cited literature and journal co-citation networks, the main subject distribution and core journals were identified respectively. By visualizing journal co-citations, the main research content was identified. Further the cluster analysis revealed the key research directions of knowledge structure. Keyword co-occurrence analysis and key occurrence analysis demonstrate current research hotspots and new research frontiers. Through the above analysis, the cooperation and contributions of hydrothermal biochar research at different levels, from researchers to institutions to countries to macro levels, were explored, the disciplinary areas of knowledge and major knowledge sources of hydrothermal biochar were discovered, and the development lineage, current status, hotspots and trends of hydrothermal biochar were clarified. The results obtained from the study can provide a reference for scholars to gain a deeper understanding of hydrothermal biochar.Di-(2-ethylhexyl) phthalate (DEHP) is one of the most extensively utilized plasticizers in the plastic manufacturing process. It is widely used in various fields due to its low cost and excellent effect. Although there is evidence that DEHP is harmful to animal and human health, DEHP-induced gill toxicity in aquatic organisms is inconclusive, and its mechanism has not been fully elucidated. Here, we investigated the effects of DEHP acute exposure on crucian carp gills at environmentally relevant concentrations of 20, 100, and 500 μg/L. Multi-omics profiling and biochemical assays were employed to characterize the potential toxicological mechanisms. The results showed that acute exposure to 100 and 500 μg/L of DEHP leads to oxidative stress in gills, as evidenced by overproduction of reactive oxygen species (ROS), increased antioxidant enzyme activity, and the transformation of glutathione from reduced to oxidized form, resulting in lipid peroxidation. Integrative analysis of transcriptomics and metabolomics indicated that increased purine metabolism was the potential source of increased ROS. selleckchem Moreover, lipid metabolism disorder, including arachidonic acid metabolism, induces inflammation. Further, DEHP causes the imbalance of the CYP enzyme system in the gill, and DEHP-induced gill toxicity in crucian carp was associated with interference with CYP450 homeostasis. Taken together, this study broadens the molecular understanding of the DEHP-induced gill toxicity in aquatic organisms and provides novel perspectives for assessing the effects of DEHP on target and non-target aquatic organisms in the environment.Metal-free carbonaceous catalysts have gained growing interest because of their excellence in organic pollutant degradation. However, most of them suffer from deactivation after use, and the origins have not been investigated or understood. In this study, the changes in the characteristics after multiple uses of a carbonaceous catalyst, i.e., oxygen-doped graphitic carbon nitride (O-gCN), were investigated to identify the key factors affecting its reactivity. The O-gCN was repeatedly used to remove an antibiotic (oxytetracycline, OTC) in the presence of peroxymonosulfate (PMS). OTC removal was significantly reduced as the O-gCN was repeatedly used. The reactivity of O-gCN used five times (O-gCN5) corresponded well with the decreased signals of DMPO-X, DMPO-O2•-, and TEMP-1O2 in electron paramagnetic resonance spectra. These signal changes were accompanied by a shift of the involved reactive species from 1O2 and OH• for O-gCN to 1O2 and SO4•- for O-gCN5. The changes in activity and involved reactive species were attributed to the changes in the properties of O-gCN, considering the negligible OTC adsorption and slight PMS consumption. The results of X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy showed a decrease in the degree of defects, graphene-like layers, and crystallinity in graphitic structures, but an increase in the fractions of N and O, for O-gCN5. However, the OTC degradation pathways and intermediates were not significantly different for O-gCN and O-gCN5. These results provide valuable information for developing strategies for the design, practical use, and regeneration of carbonaceous catalysts.Electrospray ionization (ESI) is the most common technique in liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) allowing for sensitive detection of polar compounds with online water concentration. The technique is popular in groundwater monitoring programs and has permitted great progress in the detection and quantification of polar pesticide transformation products (TP) in recent years. However, ESI is also known to be prone to matrix effects. The common solution to this potential bias is the use of labelled internal standards. Unfortunately, these are not available for all target compounds, which leads to the linkage of target compounds to non-homologue internal standards with unknown consequences for quantification in variable geochemical settings. We investigated these matrix effects for polar TP with a molecular mass range of 225-350 Da and logDpH7 between -0.27 and -1.7 as well as for parent compounds with logDpH3 between 0.84 and 3.22. The acquired internal standards were tested on a gradient of DOC, anions, conductivity and inorganic carbon with a set of ten carefully chosen groundwater samples. Internal standards that were measured in positive ionization mode proved to be insensitive to geochemical variations while those that were measured in negative ionization mode showed reduced response with increasing anion concentration. All pairs of internal standards and target analytes were investigated for deviating matrix effects using standard addition experiments. Positive ionization compounds and target compounds with deuterated homologues showed little deviation while non-homologue pairs in negative mode proved to be strongly biased. Although bias was up to factor five for some compounds it was remarkably stable over the entire gradient studied, suggesting an identical suppression mode at varying matrix levels for different compounds. We advocate the conduct of standard addition experiments if homologue internal standards are not available.
Inhaled corticosteroids (ICSs) have been used widely in the maintenance therapy of COPD. However, whether inhaled therapy containing ICSs can reduce the all-cause mortality risk and the possible benefited patient subgroups is unclear.
Does inhaled therapy containing ICSs reduce the all-cause mortality risk in patients with COPD compared with other inhaled therapies not containing ICSs?
We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for relevant randomized clinical trials (RCTs). Pooled results were calculated using Peto ORs with corresponding 95%CIs.
Sixty RCTs enrolling 103,034 patients were analyzed. Inhaled therapy containing ICSs (Peto OR, 0.90; 95%CI, 0.84-0.97), especially triple therapy (Peto OR, 0.73; 95%CI, 0.59-0.91), was associated with a reduction in the all-cause mortality risk among patients with COPD when compared with inhaled therapy without ICSs. Subgroup analyses revealed that treatment duration of > 6months (Peto OR, 0.90; 95%CI, 0.83-0.97), medium-dose ICSs.crd.york.ac.uk/prospero/.
Lung ultrasound (LUS) scanning is useful to diagnose and assess the severity of pulmonary lesions during COVID-19-related ARDS (CoARDS). A conventional LUS score is proposed to measure the loss of aeration during CoARDS. However, this score was validated during the pre-COVID-19 era in patients with ARDS in the ICU and does not consider the differences with CoARDS. An alternative LUS method is based on grading the percentage of extension of the typical signs of COVID-19 pneumonia on the lung surface (LUSext).
Is LUSext feasible in patients with COVID-19 at the onset of disease, and does it correlate with the volumetric measure of severity of COVID-19 pneumonia lesions at CT scan (CTvol)?
This observational study enrolled a convenience sampling of patients in the ED with confirmed COVID-19 whose condition demonstrated pneumonia at bedside LUS and CT scan. LUSext was visually quantified. All CT scan studies were analyzed retrospectively by a specifically designed software to calculate the CTvol. The correlation between LUSext and CTvol, and the correlations of each score with Pao
/Fio
ratio were calculated.
My Website: https://www.selleckchem.com/JAK.html
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