Restored UBE2C expression in islets promotes ß-cell regeneration in mice by ubiquitinating PER1.

Insulin deficiency may be due to the reduced proliferation capacity of islet ß-cell, contributing to the onset of diabetes. It is therefore imperative to investigate the mechanism of the ß-cell regeneration in the islets. NKX6.1, one of the critical ß-cell transcription factors, is a pivotal element in ß-cell proliferation. The ubiquitin-binding enzyme 2C (UBE2C) was previously reported as one of the downstream molecules of NKX6.1 though the exact function and mechanism of UBE2C in ß-cell remain to be elucidated. Here, we determined a subpopulation of islet ß-cells highly expressing UBE2C, which proliferate actively. We also discovered that ß-cell compensatory proliferation was induced by UBE2C via the cell cycle renewal pathway in weaning and high-fat diet (HFD)-fed mice. Moreover, the reduction of ß-cell proliferation led to insulin deficiency in ßUbe2cKO mice and, therefore, developed type 2 diabetes. UBE2C was found to regulate PER1 degradation through the ubiquitin-proteasome pathway via its association with a ubiquitin ligase, CUL1. PER1 inhibition rescues UBE2C knockout-induced ß-cell growth inhibition both in vivo and in vitro. Notably, overexpression of UBE2C via lentiviral transduction in pancreatic islets was able to relaunch ß-cell proliferation in STZ-induced diabetic mice and therefore partially alleviated hyperglycaemia and glucose intolerance. This study indicates that UBE2C positively regulates ß-cell proliferation by promoting ubiquitination and degradation of the biological clock suppressor PER1. The beneficial effect of UBE2C on islet ß-cell regeneration suggests a promising application in treating diabetic patients with ß-cell deficiency.

Trilemma among energy, economic and environmental efficiency: Can dilemma of EEE address simultaneously in era of COP 21?

Economic growth is a prerequisite for development while energy is the engine for growth process. In the era of globalization, production cost heavily dependent on energy intensity and efficiency with keeping environmental conditions intact. Therefore, the structuring of a significant environmental index is pre-requisition of the world with energy intensity, energy efficiency. For this objective, this study employs 18-years data set between 2000 and 2018 of Organization for Economic Co-operation and Development (OECD) to form a universal aspect of economics, environmental index, and energy efficiency (EEE). The data envelopment analysis (DEA) and arithmetic mean aggregation in the formation of mathematical aggregation mechanisms are applied for empirical analysis. According to the results, Iceland maintained an overall high rank regarding energy efficiency, energy intensity, and environment followed by Greece, New Zeeland, and Norway. In this investigation, Ireland followed by the UK and the USA are the lowest performer regarding energy and environment. Thus, the study concludes that energy (efficiency & intensity) and environment hold complex relations and needs a special set of policies to address them collectively and it is expected that this study can be used as valuable information for the policymaking process.

High prevalence of HIV-1 transmitted drug resistance among therapy-naïve Burmese entering travelers at Dehong ports in Yunnan, China.

BACKGROUND: The overall success of Human immunodeficiency virus type 1 (HIV-1) antiretroviral therapy (ART) was heavily challenged upon the occurrence of drug resistance. Dehong Prefecture witnessed not only the first report of HIV-1 infection but also the experimental adoption of antiviral treatment in China. The transmission and epidemic of HIV-1 in Dehong is impacted by cross-border activities. The characteristics of HIV-1 drug resistance among therapy-naïve Burmese entering travelers in Yunnan and their speculated origin are still not clarified. METHODS: Two hundred ninety-eight HIV-1 infected Burmese entering travelers at Dehong ports were recruited between 2003 and 2012. The partial HIV-1 pol gene fragments were amplified and sequenced for the analysis of drug-resistance mutations (DRMs). Phylogenetic analysis on gag-pol gene was conducted to elucidate phylogenetic and evolutionary characteristics of these drug resistant strains. RESULTS: It was figured out that the occurrence ratio of HIV-1 drug resistance among HIV-1 infected entering travelers from Myanmar was up to 12.8%. The resistant mutations covered several types, including one type of PI mutations (L33F), six types of NRTI mutations and seven types of NNRTI. Close genetic relationship was observed in the phylogenetic analysis on gag-pol gene among the drug resistant strains respectively from Dehong, other Yunnan areas, neighboring provinces (Guangxi) and neighboring countries (Thailand and Myanmar). CONCLUSIONS: The findings in this study revealed that HIV drug resistant locus is spreading from the population who is receiving drug-resistance treatment to the new infectors, which indicates the urgency of surveillance work on drug resistance among the migrant population with high risks of HIV infection.

[Significance of TSLC1 gene methylation and TSLC1 protein expression in the progression of cervical lesions].

OBJECTIVE: To study the expression and significance of tumor suppressor in lung cancer 1 (TSLC1) gene methylation, the expression of TSLC1 protein in cervix cancer and precancerous lesions as well as their relationship with HR-HPV DNA infection. METHODS: The clinicopathological data of 92 cases of different cervical lesions during March 2011 to August 2012 treated in our hospital were collected. There were pathologically confirmed 10 cases of normal cervix, 26 cases of cervical intraepithelial neoplasia (CIN) I, 20 cases of CIN II, 15 cases of CIN III, and 21 cases of cervical cancer. Methylation-specific polymerase chain reaction (MSP) was used to detect the TSLC1 gene methylation status in cervical lesions, immunohistochemistry (SP) was used to detect the expressions of TSLC1 protein in cervical lesions, and the second generation hybrid capture (HC2) method was used to detect the high-risk HPV in cervical lesions. RESULTS: The expression rate of TSLC1 gene methylation in normal cervical tissue, CIN I, CIN II, CIN III and SCC were 10.0%, 30.8%, 55.0%, 60.0%, 66.7%, respectively, showing a statistically significant difference (P = 0.004). The positive expression rate of TSLC1 protein in normal cervical tissue, CIN I, CIN II, CIN III and SCC were 100.0%, 80.8%, 65.0%, 33.3%, and 23.8%, respectively, with a significant difference (P = 0.004). In the progression from CIN to invasive cervical cancer, there was no significant correlation between TSLC1 gene methylation and HR-HPV DNA infection (P = 0.919), TSLC1 protein expression and HR-HPV DNA infection (P = 0.664). The correlation analysis showed a negative correlation between TSLC1 gene methylation and TSLC1 protein expression (r = -0.674, P < 0.001). CONCLUSIONS: TSLC1 gene promoter methylation may be an early event in the cervical carcinogenesis, become an early sensitive marker, and serve the early prevention and prognostic prediction for cervical cancer.

Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet ß cells in various mouse models of diabetes with distinct age of initiation.

During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the ß cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of islet ß cells. Cre-LoxP systems were used to generate islet cell type-specific (α, ß, or δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing, thereinto ß-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing (scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled ß cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of ß cells and some of which transdifferentiated into a or δ cells in both youth- and adulthood-initiated mice while this phenomenon was barely observed in HFD models. ß cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into ß cells in STZ-treated mice (both youth- and adulthood-initiated). In addition to the re-dedifferentiation of ß cells, it is also highly likely that these "α or δ" cells transdifferentiated from pre-existing ß cells could also re-trans-differentiate into insulin-producing ß cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of ß cells. Our findings shed light on how islet ß cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.

mTORC2 Facilitates Liver Regeneration Through Sphingolipid-Induced PPAR-α-Fatty Acid Oxidation.

BACKGROUND & AIMS: During liver regeneration after partial hepatectomy, the function and metabolic pathways governing transient lipid droplet accumulation in hepatocytes remain obscure. Mammalian target of rapamycin 2 (mTORC2) facilitates de novo synthesis of hepatic lipids. Under normal conditions and in tumorigenesis, decreased levels of triglyceride (TG) and fatty acids (FAs) are observed in the mTORC2-deficient liver. However, during liver regeneration, their levels increase in the absence of mTORC2. METHODS: Rictor liver-specific knockout and control mice underwent partial hepatectomy, followed by measurement of TG and FA contents during liver regeneration. FA metabolism was evaluated by analyzing the expression of FA metabolism-related genes and proteins. Intraperitoneal injection of the peroxisome proliferator-activated receptor α (PPAR-α) agonist, p53 inhibitor, and protein kinase B (AKT) activator was performed to verify the regulatory pathways involved. Lipid mass spectrometry was performed to identify the potential PPAR-α activators. RESULTS: The expression of FA metabolism-related genes and proteins suggested that FAs are mainly transported into hepatocytes during liver regeneration. The PPAR-α pathway is down-regulated significantly in the mTORC2-deficient liver, resulting in the accumulation of TGs. The PPAR-α agonist WY-14643 rescued deficient liver regeneration and survival in mTORC2-deficient mice. Furthermore, lipidomic analysis suggested that mTORC2 deficiency substantially reduced glucosylceramide (GluCer) content. GluCer activated PPAR-α. GluCer treatment in vivo restored the regenerative ability and survival rates in the mTORC2-deficient group. CONCLUSIONS: Our data suggest that FAs are mainly transported into hepatocytes during liver regeneration, and their metabolism is facilitated by mTORC2 through the GluCer-PPAR-α pathway, thereby establishing a novel role for mTORC2 in lipid metabolism.

Efficacy of orlistat in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

In the present meta-analysis, the efficacy and safety of orlistat in the treatment of non-alcoholic fatty liver (NAFLD) and non-alcoholic steatohepatitis (NASH) were evaluated. PubMed, Embase, the Cochrane Library, Web of Science, and Wan Fang data were searched for controlled trials of orlistat in patients with NAFLD or NASH, published before August 2017. Three randomized controlled trials and four single-arm trials were included. The involved participants with NAFLD or NASH (330 patients) were analyzed for clinical outcomes including alteration in hepatic histological variables and biomarkers of liver function. Improvements were observed in levels of alanine aminotransferase [standard mean difference (SMD)=-1.41; P=0.01], aspartate aminotransferase (SMD=-2.06; P=0.0005), γ-glutamyl transpeptidase (SMD=-1.91; P=0.05), glucose [mean difference (MD)=-0.51; P=0.01], triglycerides (MD=-0.93; P=0.01), homeostasis model assessment of insulin resistance index (MD=-1.05; P=0.04) and body mass index (MD=-1.97; P=0.02), but not in liver fibrosis score (SMD=-0.14; P=0.71). On sub-analyses of the different patient groups, no significant differences were observed in patients with NASH. Taken together, these findings demonstrate that orlistat could serve as a therapeutic drug to improve biochemical indicators of liver damage, but not as first-choice drug for the management of NAFLD or NASH; thus suggesting a novel palliative drug only for the treatment of NAFLD.