Studies of the Molecular Mechanism and Signaling Regulation of Autophagy in Saccharomyces Cerevisiae.

Autophagy is a highly conserved cellular degradation process in which portions of cytosol and organelles are sequestered into a double-membrane vesicle, an autophagosome, and delivered into a degradative organelle, the vacuole/lysosome, for breakdown and eventual recycling of the resulting macromolecules. Malfunction of autophagy has been linked to a wide range of human pathologies, including cancer, neurodegeneration and pathogen infection. Identification of many autophagy-related, ATG, genes in yeast that are essential to drive this cellular process, and the finding of orthologs in other organisms, reveals the conservation of the autophagic machinery in all eukaryotes. In addition to this, complex signaling cascades controlling autophagy have also begun to emerge, with TOR as a central but far from exclusive player. In this thesis, (1) we summarize our current knowledge about the machinery and molecular mechanism of autophagy. (2) We highlight the recent advances in identifying and understanding the core molecular machinery and signaling pathways that are involved in mammalian autophagy. (3) We elucidate a molecular mechanism for linking the degradative and recycling roles of autophagy. We show that in contrast to published studies Atg22 is not directly required for the breakdown of autophagic bodies within the lysosome/vacuole. Instead, we demonstrate that Atg22, Avt3 and Avt4 are redundant vacuolar effluxers, which mediate the efflux of leucine and other amino acids resulting from autophagic degradation. The release of autophagic amino acids allows the maintenance of protein synthesis and viability during nitrogen starvation. We propose a “recycling” model that includes the efflux of macromolecules from the lysosome/vacuole as the final step of autophagy. (4) We used genetic analyses to elucidate the mechanism by which the stress-responsive, cyclin-dependent kinase, Pho85 and its corresponding cyclins antagonistically modulate autophagy in Saccharomyces cerevisiae. When complexed with cyclins Pho80 and Pcl5, Pho85 negatively regulates autophagy through downregulating the protein kinase Rim15, and the transcription factors Pho4 and Gcn4. The cyclins Clg1, Pcl1 and Pho80, in concert with Pho85, positively regulate autophagy through promoting the degradation of Sic1, a negative regulator of autophagy that targets Rim15. Our results suggest a model in which Pho85 has opposing roles in autophagy regulation.Ph.D.Molecular, Cellular, and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/75834/1/zfyang_1.pd

Induction of defensive enzymes (isozymes) during defense against two different fungal pathogens in pear calli

Activities of defensive enzymes peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), polyphenol oxidase (PPO) and esterase (EST) and their isozymes in pear calli were studied to reveal their role in the defensive response to different fungal infections and to find some clues to enhance their antimicrobial properties. The results confirm the fact that the activities and isozymes of these five enzymes showed differences in response to different fungal infections. After the inoculation of two different fungi for the same calli, its defensive enzymes’ activities changed relatively when compared with those of the control and in Botryosphaeria berengriana f.sp. piricola (BBP)-infected calli, the enzymes’ activities changed more significantly than those of Monilinia fructigena Honcy (MFH). Meanwhile, more new isozymes were induced by BBP infection. These are in agreement with the fact that the BBP-infected calli decay was slower than that of the MFH. These results suggest that enhancing defensive enzymes’ activities and inducing new isozymes may be related to mitigating pathogen-induced oxidative damage which result in the decrease of calli decay, and this implies that antioxidant defense response may be involved in the mechanisms of plant against fungal pathogen.Keywords: Pear callus, fungi infection, defense enzyme, isozyme, biochemical defense mechanis

Railway axle box bearing fault identification using LCD-MPE and ELM-AdaBoost

. In this study, a new method for bearing fault diagnosis using local characteristic-scale decomposition multi-scale permutation entropy (LCD-MPE) and extreme learning machine AdaBoost (ELM-AdaBoost) algorithms is proposed. Vibration signals of railway axle box rolling bearings under 4 conditions (normal, outer race fault, inner race fault, and rolling element fault) were used as our research objects. The signals were de-noised using wavelet de-noising (WD) as a pre-filter, then the LCD was used to decompose the signal into a number of intrinsic scale components (ISCs). Then, the multi-scale permutation entropy (MPE) was extracted as the feature parameters. Finally, the extracted features were used as ELM-AdaBoost to achieve the automated fault diagnosis. Our results prove that our method is effective for an accurate diagnosis of railway axle box bearing faults. Furthermore, our fault diagnosis method is highly applicable in practical engineering

A real-world study of anlotinib as third-line or above therapy in patients with her-2 negative metastatic breast cancer

BackgroundAntiangiogenic agents provides an optional treatment strategy for patients with metastatic breast cancer. The present study was conducted to evaluate the efficacy and safety of anlotinib as third-line or above therapy for patients with HER-2 negative metastatic breast cancer.MethodsPatients with HER-2 negative metastatic breast cancer who have failed from prior therapy and treated with anlotinib monotherapy or combined with chemotherapy or immunotherapy from June 2018 to December 2020 were retrospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety.Results47 patients with HER-2 negative metastatic breast cancer received anlotinib monotherapy or combination therapy as third-line or above therapy. In the general population, 10 patients achieved PR, 25 patients had SD and 12 patients had PD. The overall ORR and DCR were 21.3% and 74.5%, respectively. Subgroup analysis suggested that there were no statistically significant differences in ORR and DCR with respect to HR status (positive vs. negative), treatment programs (monotherapy vs. combination) and treatment type in combination group (chemotherapy vs. immunotherapy). The patients who did not received previously anti-angiogenesis therapy had superior DCR (84.8% vs. 50.0%, P=0.012). Median PFS and OS were 5.0 months (95% CI=4.3-5.7) and 21.0 (95% CI=14.9-27.1) months, respectively. The PFS (6.5m vs. 3.5m, P=0.042)and OS (28.2m vs. 12.6m, P=0.040) were better in HR positive patients than HR negative patients. And simultaneously, patients who received anlotinib combination therapy obtained better PFS (5.5m vs. 3.0m, P=0.045). The incidence of Grade 3-4 adverse events(AEs) was 31.9%.ConclusionsAnlotinib monotherapy or combination therapy provide a viable third-line or above therapeutic strategy in patients with HER-2 negative metastatic breast cancer, a median PFS of 5.0 months was obtained with well tolerated toxicity

A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity

Macroautophagy (autophagy) is a critical cellular stress response; however, the signal transduction pathways controlling autophagy induction in response to stress are poorly understood. Here we reveal a new mechanism of autophagy control whose deregulation disrupts mitochondrial integrity and energy homeostasis in vivo. Stress conditions including hypoxia and exercise induce reactive oxygen species (ROS) through upregulation of a protein complex involving REDD1, an mTORC1 inhibitor and the pro-oxidant protein TXNIP. Decreased ROS in cells and tissues lacking either REDD1 or TXNIP increases catalytic activity of the redox-sensitive ATG4B cysteine endopeptidase, leading to enhanced LC3B delipidation and failed autophagy. Conversely, REDD1/TXNIP complex expression is sufficient to induce ROS, suppress ATG4B activity and activate autophagy. In Redd1−/− mice, deregulated ATG4B activity and disabled autophagic flux cause accumulation of defective mitochondria, leading to impaired oxidative phosphorylation, muscle ATP depletion and poor exercise capacity. Thus, ROS regulation through REDD1/TXNIP is physiological rheostat controlling stress-induced autophagy

RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity

Table tennis athlete’s psychological quality difference analysis

Sports a lot of influence on movement of psychological, to make sports person to maintain physical and mental health, this also is the purpose of this article research. Table tennis in the psychological quality of practitioners, the author of this paper pay attention to explore the effect of quality improvement, aims to analyze the movement in four dimensions of the quality of attention level of ascension effect, this paper USES the methods of experimental comparison and mathematical statistics, obtained based on the overall, based on the grouping, based on gender, based on a fixed number of year of the movement and pay attention to the quality dimension of single factor analysis of variance, the attention of the quality difference under different conditions is obtained and verified with table tennis as experimental subjects more with other sport subjects in the control group on pay attention to the quality improvement has more favorable effect

LncRNA 148400 Promotes the Apoptosis of Renal Tubular Epithelial Cells in Ischemic AKI by Targeting the miR−10b−3p/GRK4 Axis

Although recent studies have reported that long non-coding RNA (lncRNA) is involved in the development of ischemic acute kidney injury (AKI), the exact function and regulatory mechanism of lncRNAs in ischemic AKI remain largely unknown. Herein, we found that ischemic injury promoted the expression of lncRNA 148400 in mouse proximal tubule-derived cell line (BUMPT) and C57BL/6J mice. Furthermore, the lncRNA148400 mediates ischemic injury-induced apoptosis of BUMPT cells. Mechanistically, lncRNA 148400 sponged miR−10b−3p to promote apoptosis via GRK4 upregulation. Finally, knockdown of lncRNA 148400 alleviated the I/R-induced deterioration of renal function, renal tubular injury, and cell apoptosis. In addition, cleaved caspase−3 is increased via targeting the miR−10b−3p/GRK4 axis. Collectively, these results showed that lncRNA 148400/miR−10b−3p/GRK4 axis mediated the development of ischemic AKI

Amplitude of low-frequency fluctuations in first-episode, drug-naïve depressive patients: A 5-year retrospective study.

Despite different treatments and courses of illness, depressive symptoms appear similar in bipolar disorder (BD) and major depressive disorder (MDD), causing BD with an onset of depressive episode being frequently misdiagnosed as MDD, and leading to inappropriate treatment and poor clinical outcomes. Therefore, there is an urgent need to explore underlying neural basis to distinguish BD from MDD. The medical records of 80 first-episode, drug-naïve depressive patients with an initial diagnosis of MDD and illness duration of at least 5 years were reviewed retrospectively for this study. Fourteen bipolar depressed patients with a diagnosis conversion from MDD to BD, 14 patients with diagnosis of MDD, and 14 healthy subjects demographically matched with the BD group, were selected to participate in the study. Firstly, we examined whether there were differences among the three groups in whole brain fALFF during resting state. Secondly, clusters showing group differences in fALFF in any two groups were chosen as regions of interest (ROI) and then correlation between clinical features and fALFF values of ROIs were calculated. The BD group showed increased fALFF in bilateral putamen relative to both the MDD group and controls, while the MDD group exhibited decreased fALFF in left superior frontal gyrus (SFG) relative to both the BD group and controls (p < 0.05, corrected). Positive correlations between abnormality in the putamen and symptom severity were observed (significant for the MDD group, p = 0.043; marginally significant for the BD group, p = 0.060/0.076). These results implicate that abnormalities of key regions in the striatum and prefrontal areas may be trait markers for BD and MDD