The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular ...calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
ABSTRACT
Innovations in genomics have enabled the development of low‐cost, high‐resolution, single nucleotide polymorphism (SNP) genotyping arrays that accelerate breeding progress and support basic ...research in crop science. Here, we developed and validated the SoySNP618K array (618,888 SNPs) for the important crop soybean. The SNPs were selected from whole‐genome resequencing data containing 2,214 diverse soybean accessions; 29.34% of the SNPs mapped to genic regions representing 86.85% of the 56,044 annotated high‐confidence genes. Identity‐by‐state analyses of 318 soybeans revealed 17 redundant accessions, highlighting the potential of the SoySNP618K array in supporting gene bank management. The patterns of population stratification and genomic regions enriched through domestication were highly consistent with previous findings based on resequencing data, suggesting that the ascertainment bias in the SoySNP618K array was largely compensated for. Genome‐wide association mapping in combination with reported quantitative trait loci enabled fine‐mapping of genes known to influence flowering time, E2 and GmPRR3b, and of a new candidate gene, GmVIP5. Moreover, genomic prediction of flowering and maturity time in 502 recombinant inbred lines was highly accurate (>0.65). Thus, the SoySNP618K array is a valuable genomic tool that can be used to address many questions in applied breeding, germplasm management, and basic crop research.
To accelerate breeding progress and support basic research in soybean, the customized SoySNP618K array contains 618,888 SNPs selected from > 2,000 diverse, re‐sequenced soybean genomes. SoySNP618K is a valuable genomic tool to address questions in applied breeding, germplasm management, and basic research.
A practical protocol for the preparation of quinoxaline‐2,3(1H,4H)‐diones through direct C(sp2)−H hydroxylation of quinoxalin‐2(1H)‐ones in recyclable DL‐α‐Tocopherol methoxypolyethylene glycol ...succinate solution (2 wt% in water) (TPGS‐750‐M/H2O) was developed. The target products were exclusively generated and could be collected through extraction and recrystallization.
Background and aims
Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI ...classification schemes based on standardized gross sampling protocols of HCC are available at present.
Methods
119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG.
Results
The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%,
p
= 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%,
p
= 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (
p
< 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (
p
< 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS.
Conclusions
SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.
As a new material with excellent mechanical properties and good stability, slide‐ring gels have attracted attention and research. However, they cannot be widely used due to their relatively ...complicated synthesis. Herein, we use 6‐acrylamidomethylether‐modified α‐cyclodextrin (αCDAAmMe) and PEG20000 diacrylate (PEG20000DA) to construct a polypseudorotaxane. Then, the polypseudorotaxane reacts with acrylamide via a photo‐initiated polymerization in situ to conveniently obtain a slide‐ring hydrogel with good elastic property and high recovery property. The hydrogel can be easily stretched to 22.5 times of its original length but recovered rapidly and almost reversibly. These results enable the application of hydrogel to make an intrinsically stretchable and compressible supercapacitor after doping ions and the adhesion of commercially available carbon nanotube (CNT) paper as electrodes, giving the ionic conductivity of 17.0 mS cm−1 (comparable to that of the commercial PVA/H3PO4 electrolyte) and the capacitance of 0.87 μF cm−2 (at the scan speed of 100 mV s−1), and its capacitance can be further enhanced under stretching.
At a stretch: A highly elastic slide‐ring hydrogel with good recovery was obtained by a two‐step method. The threading of 6‐acrylamidomethylether‐modified α‐cyclodextrins (αCDAAmMe) on the PEG20000 diacrylate (PEG20000DA) produces a polypseudorotaxane, then the polypseudorotaxane co‐polymerizes with the acrylamide monomer via a photo‐initiated polymerization. The hydrogel can be used to construct a stretchable supercapacitor after doping with 1 m Li2SO4 and the adhesion of carbon nanotube (CNT) paper as electrodes.
Diabetes is a disorder of glucose metabolism, and over 90% are type 2 diabetes. Diabetic cardiomyopathy (DCM) is one of the type 2 diabetes complications, usually accompanied by changes in myocardial ...structure and function, together with cardiomyocyte apoptosis. Our study investigated the effect of curcumin on regulating oxidative stress (OS) and apoptosis in DCM. In vivo, diabetes was induced in an experimental rat model by streptozoticin (STZ) together with high‐glucose and high‐fat (HG/HF) diet feeding. In vitro, H9c2 cardiomyocytes were cultured with high‐glucose and saturated free fatty acid palmitate. Curcumin was orally or directly administered to rats or cells, respectively. Streptozoticin ‐induced diabetic rats showed metabolism abnormalities and elevated markers of OS (superoxide dismutase SOD, malondialdehyde MDA, gp91phox, Cyt‐Cyto C), enhanced cell apoptosis (Bax/Bcl‐2, Cleaved caspase‐3, TUNEL‐positive cells), together with reduced Akt phosphorylation and increased Foxo1 acetylation. Curcumin attenuated the myocardial dysfunction, OS and apoptosis in the heart of diabetic rats. Curcumin treatment also enhanced phosphorylation of Akt and inhibited acetylation of Foxo1. These results strongly suggest that apoptosis was increased in the heart of diabetic rats, and curcumin played a role in diabetic cardiomyopathy treatment by modulating the Sirt1‐Foxo1 and PI3K‐Akt pathways.
Pulmonary endometriosis is a rare form of thoracic endometriosis. We herein describe a 29-year-old woman with recurrent hemoptysis associated with her menstrual cycle. The patient had a 4-month ...history of catamenial hemoptysis without thoracic pain, respiratory embarrassment, cough, fever, night sweating, or loss of appetite. Chest computed tomography revealed exudation shadows in the right lower pulmonary lobe and small fiber lesions in the right middle lobe and left lung. Thoracoscopic wedge resection of the right lower pulmonary lobe was performed, and the pathological result was pulmonary endometriosis. No evidence of hemoptysis during menstruation was found following the operation.
DBSCAN is the most famous density based clustering algorithm which is one of the main clustering paradigms. However, there are many redundant distance computations among the process of DBSCAN ...clustering, due to brute force Range-Query used to retrieve neighbors for each point in DBSCAN, which yields high complexity (O(n 2 )) and low efficiency. Thus, it is unsuitable and not applicable for large scale data. In this paper, an improved DBSCAN based on neighbor similarity is proposed, which utilizes and Cover Tree to retrieve neighbors for each point in parallel, and the triangle inequality to filter many unnecessary distance computations. From the experiments conducted on large scale data sets, it is demonstrated that the proposed algorithm greatly speedup the original DBSCAN, and outperform the main improvements of DBSCAN. Comparing with ρ-approximate DBSCAN, which is the current fastest but approximate version of DBSCAN, the proposed algorithm has two advantages: one is faster and the other is that the result is accurate.
Nanobody (Nb) is a promising vector for targeted drug delivery. This study aims to identify an Nb that can specifically target the lung by binding human pulmonary surfactant protein A (SP-A). Human ...lung frozen tissue sections were used for 3 rounds of biospanning of our previously constructed Nb library for rat SP-A to establish a sub-library of Nb, which specifically bound human lung tissues. Phage-ELISA was performed to screen the sub-library to identify Nb4, which specifically bound human SP-A. The binding affinity Kd of Nb4 to recombinant human SP-A was 7.48 × 10
M. Nb4 (19 kDa) was stable at 30 °C-37 °C and pH 7.0-7.6 and specifically bound the SP-A in human lung tissue homogenates, human lung A549 cells, and human lung tissues, whereas didn't react with human liver L-02 cells, kidney 293T cells, and human tissues from organs other than the lung. Nb4 accumulated in the lung of nude mice 5 minutes after a tail vein injection of Nb4 and was excreted 3 hours. Short-term exposure (one month) to Nb4 didn't cause apparent liver and kidney toxicity in rats, whereas 3-month exposure resulted in mild liver and kidney injuries. Nb4 may be a promising vector to specifically deliver drugs to the lung.
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