SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway.

SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson's disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway

Detecting Variability in Massive Astronomical Time-series Data. II. Variable Candidates in the Northern Sky Variability Survey

We present variability analysis of data from the Northern Sky Variability Survey (NSVS). Using the clustering method, which defines variable candidates as outliers from large clusters, we cluster 16,189,040 light curves having data points at more than 15 epochs as variable and non-variable candidates in 638 NSVS fields. Variable candidates are selected depending on how strongly they are separated from the largest cluster and how rarely they are grouped together in eight-dimensional space spanned by variability indices. All NSVS light curves are also cross-correlated with IRAS , AKARI, Two Micron All Sky Survey, Sloan Digital Sky Survey (SDSS), and GALEX objects, as well as known objects in the SIMBAD database. The variability analysis and cross-correlation results are provided in a public online database, which can be used to select interesting objects for further investigation. Adopting conservative selection criteria for variable candidates, we find about 1.8 million light curves as possible variable candidates in the NSVS data, corresponding to about 10% of our entire NSVS sample. Multi-wavelength colors help us find specific types of variability among the variable candidates. Moreover, we also use morphological classification from other surveys such as SDSS to suppress spurious cases caused by blending objects or extended sources due to the low angular resolution of the NSVS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98631/1/1538-3881_143_3_65.pd

HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation

SummaryThe terminal stages of pulmonary development, called sacculation and alveologenesis, involve both differentiation of distal lung endoderm progenitors and extensive cellular remodeling of the resultant epithelial lineages. These processes are coupled with dramatic expansion of distal airspace and surface area. Despite the importance of these late developmental processes and their relation to neonatal respiratory diseases, little is understood about the molecular and cellular pathways critical for their successful completion. We show that a histone deacetylase 3 (Hdac3)-mediated epigenetic pathway is critical for the proper remodeling and expansion of the distal lung saccules into primitive alveoli. Loss of Hdac3 in the developing lung epithelium leads to a reduction of alveolar type 1 cell spreading and a disruption of lung sacculation. Hdac3 represses miR-17-92 expression, a microRNA cluster that regulates transforming growth factor β (TGF-β) signaling. De-repression of miR-17-92 in Hdac3-deficient lung epithelium results in decreased TGF-β signaling activity. Importantly, inhibition of TGF-β signaling and overexpression of miR-17-92 can phenocopy the defects observed in Hdac3 null lungs. Conversely, loss of miR-17-92 expression rescues many of the defects caused by loss of Hdac3 in the lung. These studies reveal an intricate epigenetic pathway where Hdac3 is required to repress miR-17-92 expression to allow for proper TGF-β signaling during lung sacculation

Raw Garlic Consumption and Risk of Liver Cancer: A Population-Based Case-Control Study in Eastern China.

Although the major risk factors for liver cancer have been established, preventive factors for liver cancer have not been fully explored. We evaluated the association between raw garlic consumption and liver cancer in a large population-based case-control study in Eastern China. The study was conducted in Jiangsu, China, from 2003 to 2010. A total of 2011 incident liver cancer cases and 7933 randomly selected population-controls were interviewed. Epidemiological data including raw garlic intake and other exposures were collected, and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were assayed. Overall, eating raw garlic twice or more per week was inversely associated with liver cancer, with an adjusted odds ratio (aOR) of 0.77 (95% confidence interval (CI): 0.62-0.96) compared to those ingesting no raw garlic or less than twice per week. In stratified analyses, high intake of raw garlic was inversely associated with liver cancer among Hepatitis B surface antigen (HBsAg) negative individuals, frequent alcohol drinkers, those having history of eating mold-contaminated food or drinking raw water, and those without family history of liver cancer. Marginal interactions on an additive scale were observed between low raw garlic intake and HBsAg positivity (attributable proportion due to interaction (AP) = 0.31, 95% CI: -0.01-0.62) and heavy alcohol drinking (AP = 0.28, 95% CI: 0.00-0.57). Raw garlic consumption is inversely associated with liver cancer. Such an association shed some light on the potential etiologic role of garlic intake on liver cancer, which in turn might provide a possible dietary intervention to reduce liver cancer in Chinese population

Mcm5 Represses Endodermal Migration through Cxcr4a-itgb1b Cascade Instead of Cell Cycle Control

Minichromosome maintenance protein 5 (MCM5) is a critical cell cycle regulator; its role in DNA replication is well known, but whether it is involved in the regulation of organogenesis in a cell cycle-independent way, is far from clear. In this study, we found that a loss of mcm5 function resulted in a mildly smaller liver, but that mcm5 overexpression led to liver bifida. Further, the data showed that mcm5 overexpression delayed endodermal migration in the ventral–dorsal axis and induced the liver bifida. Cell cycle analysis showed that a loss of mcm5 function, but not overexpression, resulted in cell cycle delay and increased cell apoptosis during gastrulation, implying that liver bifida was not the result of a cell cycle defect. In terms of its mechanism, our data proves that mcm5 represses the expression of cxcr4a, which sequentially causes a decrease in the expression of itgb1b during gastrulation. The downregulation of the cxcr4a-itgb1b cascade leads to an endodermal migration delay during gastrulation, as well as to the subsequent liver bifida during liver morphogenesis. In conclusion, our results suggest that in a cell cycle-independent way, mcm5 works as a gene expression regulator, either partially and directly, or indirectly repressing the expression of cxcr4a and the downstream gene itgb1b, to coordinate endodermal migration during gastrulation and liver location during liver organogenesis