Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys

<p>Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of macroautophagy/autophagy (especially mitophagy) in the protective effect of IPC in kidneys. IPC induced autophagy in renal tubular cells in mice and suppressed subsequent renal ischemia-reperfusion injury (IRI). The protective effect of IPC was abolished by pharmacological inhibitors of autophagy and by the ablation of <i>Atg7</i> from kidney proximal tubules. Pretreatment with BECN1/Beclin1 peptide induced autophagy and protected against IRI. These results suggest the dependence of IPC protection on renal autophagy. During IPC, the mitophagy regulator PINK1 (PTEN induced putative kinase 1) was activated. Both IPC and BECN1 peptide enhanced mitolysosome formation during renal IRI in mitophagy reporter mice, suggesting that IPC may protect kidneys by activating mitophagy. We further established an in vitro model of IPC by inducing ‘chemical ischemia’ in kidney proximal tubular cells with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Brief treatment with CCCP protected against subsequent injury in these cells and the protective effect was abrogated by autophagy inhibition. In vitro IPC increased mitophagosome formation, enhanced the delivery of mitophagosomes to lysosomes, and promoted the clearance of damaged mitochondria during subsequent CCCP treatment. IPC also suppressed mitochondrial depolarization, improved ATP production, and inhibited the generation of reactive oxygen species. Knockdown of <i>Pink1</i> suppressed mitophagy and reduced the cytoprotective effect of IPC. Together, these results suggest that autophagy, especially mitophagy, plays an important role in the protective effect of IPC.</p> <p><b>Abbreviations</b>: ACTB: actin, beta; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; BUN: blood urea nitrogen; CASP3: caspase 3; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; COX4I1: cytochrome c oxidase subunit 4I1; COX8: cytochrome c oxidase subunit 8; DAPI: 4ʹ,6-diamidino-2-phenylindole; DNM1L: dynamin 1 like; EGFP: enhanced green fluorescent protein; EM: electron microscopy; ER: endoplasmic reticulum; FC: floxed control; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; H-E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HSPD1: heat shock protein family D (Hsp60) member 1; IMMT/MIC60: inner membrane mitochondrial protein; IPC: ischemic preconditioning; I-R: ischemia-reperfusion; IRI: ischemia-reperfusion injury; JC-1: 5,5ʹ,6,6ʹ-tetrachloro-1,1ʹ,3,3ʹ-tetraethylbenzimidazolylcarbocyanine iodide; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mito-QC: mito-quality control; mRFP: monomeric red fluorescent protein; NAC: N-acetylcysteine; PINK1: PTEN induced putative kinase 1; PPIB: peptidylprolyl isomerase B; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RPTC: rat proximal tubular cells; SD: standard deviation; sIPC: simulated IPC; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling</p

Haze, public health and mitigation measures in China: A review of the current evidence for further policy response.

With rapid economic development, China has been plagued by choking air pollution in recent years, and the frequent occurrence of haze episodes has caused widespread public concern. The purpose of this study is to describe the sources and formation of haze, summarize the mitigation measures in force, review the relationship between haze pollution and public health, and to discuss the challenges, potential research directions and policy options. Haze pollution has both natural and man-made causes, though it is anthropogenic sources that are the major contributors. Accumulation of air pollutants, secondary formation of aerosols, stagnant meteorological conditions, and trans-boundary transportation of pollutants are the principal causes driving the formation and evolution of haze. In China, haze includes gaseous pollutants and fine particles, of which PM2.5 is the dominant component. Short and long-term exposure to haze pollution are associated with a range of negative health outcomes, including respiratory diseases, cardiovascular and cerebrovascular diseases, mental health problems, lung cancer and premature death. China has paid increasing attention to the improvement of air quality, and has introduced action plans and policies to tackle pollution, but many interventions have only temporary effects. There may be fierce resistance from industry groups and some government agencies, and often it is challenging to enforce relevant control measures and laws. We discuss the potential policy options for prevention, the need for wider public dialogue and the implications for scientific research

Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms

Abstract Background Acquired imatinib (IM) resistance is frequently characterized by Bcr-Abl mutations that affect IM binding and kinase inhibition in patients with chronic myelogenous leukemia (CML). Bcr-Abl-T315I mutation is the predominant mechanism of the acquired resistance to IM. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that nickel pyrithione (NiPT) potently inhibits the ubiquitin proteasome system via targeting the 19S proteasome-associated deubiquitinases (UCHL5 and USP14), without effecting on the 20S proteasome. In this present study, we investigated the effect of NiPT, a novel proteasomal deubiquitinase inhibitor, on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. Methods Cell viability was examined by MTS assay and trypan blue exclusion staining assay in KBM5, KBM5R, K562, BaF3-p210-WT, BaF3-p210-T315I cells, and CML patients’ bone marrow samples treated with NiPT. Cell apoptosis in CML cells was detected with Annexin V-FITC/PI and rhodamine-123 staining followed by fluorescence microscopy and flow cytometry and with western blot analyses for apoptosis-associated proteins. Expression levels of Bcr-Abl in CML cells were analyzed by using western blotting and real-time PCR. The 20S proteasome peptidase activity was measured using specific fluorogenic substrate. Active-site-directed labeling of proteasomal DUBs, as well as the phosphorylation of USP14 was used for evaluating the inhibition of the DUBs activity by NiPT. Mouse xenograft models of KBM5 and KBM5R cells were analyzed, and Bcr-Abl-related proteins and protein biomarkers related to proliferation, differentiation, and adhesion in tumor tissues were detected by western blots and/or immunohistological analyses. Results NiPT induced apoptosis in CML cells and inhibited the growth of IM-resistant Bcr-Abl-T315I xenografts in nude mice. Mechanistically, NiPT induced decreases in Bcr-Abl proteins, which were associated with downregulation of Bcr-Abl transcription and with the cleavage of Bcr-Abl protein by activated caspases. NiPT-induced ubiquitin proteasome system inhibition induced caspase activation in both IM-resistant and IM-sensitive CML cells, and the caspase activation was required for NiPT-induced Bcr-Abl downregulation and apoptotic cell death. Conclusions These findings support that NiPT can overcome IM resistance through both Bcr-Abl-dependent and Bcr-Abl-independent mechanisms, providing potentially a new option for CML treatment

GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment

Background: Mutations in GJB2 are the most common molecular defects responsible for autosomal recessive nonsyndromic hearing impairment (NSHI). The mutation spectra of this gene vary among different ethnic groups. Methods: In order to understand the spectrum and frequency of GJB2 mutations in the Chinese population, the coding region of the GJB2 gene from 2063 unrelated patients with NSHI was PCR amplified and sequenced. Results: A total of 23 pathogenic mutations were identified. Among them, five (p.W3X, c.99delT, c.155_c.158delTCTG, c.512_c.513insAACG, and p.Y152X) are novel. Three hundred and seven patients carry two confirmed pathogenic mutations, including 178 homozygotes and 129 compound heterozygotes. One hundred twenty five patients carry only one mutant allele. Thus, GJB2 mutations account for 17.9% of the mutant alleles in 2063 NSHI patients. Overall, 92.6% (684/739) of the pathogenic mutations are frame-shift truncation or nonsense mutations. The four prevalent mutations; c.235delC, c.299_c.300delAT, c.176_c.191del16, and c.35delG, account for 88.0% of all mutantalleles identified. The frequency of GJB2 mutations (alleles) varies from 4% to 30.4% among different regions of China. It also varies among different sub-ethnic groups. Conclusion: In some regions of China, testing of the three most common mutations can identify at least one GJB2 mutant allele in all patients. In other regions such as Tibet, the three most common mutations account for only 16% the GJB2 mutant alleles. Thus, in this region, sequencing of GJB2 would be recommended. In addition, the etiology of more than 80% of the mutant alleles for NSHI in China remains to be identified. Analysis of other NSHI related genes will be necessary.Version of Recor

Responses of calcareous sand foundations to variations of groundwater table and applied loads

The long-term settlement of calcareous sand foundations caused by daily periodic fluctuations has become a significant geological hazard, but effective monitoring tools to capture the deformation profiles are still rarely reported. In this study, a laboratory model test and an in situ monitoring test were conducted. An optical frequency domain reflectometer (OFDR) with high spatial resolution (1 mm) and high accuracy (±10-6) was used to record the soil strain responses to groundwater table and varied loads. The results indicated that the fiber-optic measurements can accurately locate the swelling and compressive zones. During the loading process, the interlock between calcareous sand particles was detected, which increased the internal friction angle of soil. The foundation deformation above the sliding surface was dominated by compression, and the soil was continuously compressed beneath the sliding surface. After 26–48 h, calcareous sand swelling occurred gradually above the water table, which was primarily dependent on capillary water. The swelling of the soil beneath the groundwater table was completed rapidly within less than 2 h. When the groundwater table and load remain constant, the compression creep behavior can be described by the Yasong-Wang model with R2 = 0.993. The daily periodically varying in situ deformation of calcareous sand primarily occurs between the highest and lowest groundwater tables, i.e. 4.2–6.2 m deep. The tuff interlayers with poor water absorption capacity do not swell or compress, but they produce compressive strain under the influence of deformed calcareous sand layers

Research and application of key technology of intelligent coal caving in high gas fully-mechanized top coal caving face

At present, intelligent coal caving in high gas fully mechanized top coal caving face is facing many problems, mainly including poor recognition accuracy of coal gangue, incomplete control research on coal flow and gas concentration, cumbersome design and development of follow-up process, and slow response of control system.In order to solve these problems, this paper developed a cloud side collaborative intelligent coal caving control system based on 5G communication.The system includes 5G network, cloud server, edge processor, terminal execution equipment, etc.It has a high data transmission speed, control response speed and data processing capability.Based on the analysis of fully mechanized coal caving process parameters and intelligent coal caving process flow, elaborates the four key technologies of intelligent coal caving the coal gangue identification technology, big block coal identification and coal flow load balance technology, gas safety linkage control technology, and digital twin technology of coal caving following machine.The application test was carried out in Baode 81309 fully mechanized top coal caving face.After the intelligent fully mechanized top coal caving technology was adopted, the top coal recovery rate increased from 86% to 93%, the coal gangue rate decreased from 21% to 15%, the total production efficiency increased by 10%, and the number of coal caving operators decreased from 3 to 4 to 1 to 2.The cloud edge collaborative intelligent coal caving control system based on 5G communication developed in this paper and its key technologies can also be extended to other fully mechanized coal caving faces, which is of great value for reducing personnel and increasing efficiency and safe and efficient mining of coal mines

Accessibility and boarding technology for offshore wind power platforms in China: current status and future prospects

Objective Most offshore wind power platforms are unmanned, resulting in high operation and maintenance costs due to the complex operating environment, limited accessibility, and short time window for going offshore. Consequently, ensuring the safe and efficient transfer of personnel and materials between vessels and wind turbine generators has become a critical challenge in offshore wind power operation and maintenance. Methods Based on the operational context of offshore wind farms in China, the characteristics of five commonly used vessels for offshore wind power operation and maintenance were examined, including monohull, catamaran, trimaran, small waterplane area vessel, and service operation vessel. Then the current status, characteristics and influencing factors of the boarding technologies for offshore wind power platforms were analyzed, including those without motion compensation systems and with wave motion compensation systems, as well as helicopter-assisted boarding. Results Using an offshore wind farm in the South China Sea as a case study, three access options for operation and maintenance were compared and analyzed: catamarans, service operation vessels, and a fixed life support platform adjacent to the converter station. Considering accessibility and costs, it is recommended to adopt the option with a fixed life support platform adjacent to the converter station, supplemented by shuttle carriers for personnel transfer within the wind farm. Conclusion In response to the urgent needs of offshore wind power development and trends in modern science and technology, four key research directions are proposed: (1) boarding technologies and equipment for improved accessibility of far-sea/deep-sea floating wind farms; (2) intelligent operation and maintenance technologies and equipment for offshore wind power; (3) technologies and equipment for boarding using heavy lift drones and loading aircraft; (4) technical standards for boarding and accessibility of offshore wind power platforms. Additionally, leveraging the technical advantages of current electric vertical take-off and landing (eVTOL) aircraft, it is recommended to demonstrate the application of eVTOL in offshore wind farm boarding, operation and maintenance to promote the high-quality development of the entire offshore wind power industry chain

Genomic Variation in Rice: Genesis of Highly Polymorphic Linkage Blocks during Domestication

Genomic regions that are unusually divergent between closely related species or racial groups can be particularly informative about the process of speciation or the operation of natural selection. The two sequenced genomes of cultivated Asian rice, Oryza sativa, reveal that at least 6% of the genomes are unusually divergent. Sequencing of ten unlinked loci from the highly divergent regions consistently identified two highly divergent haplotypes with each locus in nearly complete linkage disequilibrium among 25 O. sativa cultivars and 35 lines from six wild species. The existence of two highly divergent haplotypes in high divergence regions in species from all geographical areas (Africa, Asia, and Oceania) was in contrast to the low polymorphism and low linkage disequilibrium that were observed in other parts of the genome, represented by ten reference loci. While several natural processes are likely to contribute to this pattern of genomic variation, domestication may have greatly exaggerated the trend. In this hypothesis, divergent haplotypes that were adapted to different geographical and ecological environments migrated along with humans during the development of domesticated varieties. If true, these high divergence regions of the genome would be enriched for loci that contribute to the enormous range of phenotypic variation observed among domesticated breeds.</p