Identification of Novel Regulatory Cholesterol Metabolite, 5-Cholesten, 3β,25-Diol, Disulfate

Oxysterol sulfation plays an important role in regulation of lipid metabolism and inflammatory responses. In the present study, we report the discovery of a novel regulatory sulfated oxysterol in nuclei of primary rat hepatocytes after overexpression of the gene encoding mitochondrial cholesterol delivery protein (StarD1). Forty-eight hours after infection of the hepatocytes with recombinant StarD1 adenovirus, a water-soluble oxysterol product was isolated and purified by chemical extraction and reverse-phase HPLC. Tandem mass spectrometry analysis identified the oxysterol as 5-cholesten-3β, 25-diol, disulfate (25HCDS), and confirmed the structure by comparing with a chemically synthesized compound. Administration of 25HCDS to human THP-1-derived macrophages or HepG2 cells significantly inhibited cholesterol synthesis and markedly decreased lipid levels in vivo in NAFLD mouse models. RT-PCR showed that 25HCDS significantly decreased SREBP-1/2 activities by suppressing expression of their responding genes, including ACC, FAS, and HMG-CoA reductase. Analysis of lipid profiles in the liver tissues showed that administration of 25HCDS significantly decreased cholesterol, free fatty acids, and triglycerides by 30, 25, and 20%, respectively. The results suggest that 25HCDS inhibits lipid biosynthesis via blocking SREBP signaling. We conclude that 25HCDS is a potent regulator of lipid metabolism and propose its biosynthetic pathway

Enhanced tensile ductility and strength of electrodeposited ultrafine-grained nickel with a desired bimodal microstructure

This work aims to use surfactant-assisted direct current electrodeposition technique to prepare four types of bimodal nickel, under different current densities. Bimodal Ni is obtained with different grain size and spatial distribution of CG and UFG areas showing a big disparity in mechanical properties. As a result of small population of coarse-grained surrounded by quite a lot of ultrafine-grained forming a unique shell-and-core bimodal structure, bimodal one present the best comprehensive mechanical properties with an ultrahigh tensile strength (similar to 847 MPa) and a considerable plastic strain (similar to 16.7%). Deformation initial, bimodal structures display more positive strain hardening to meaningful strains than unimodal structure of UFG and CG. Particularly bimodal one work-hardening rate is the highest thanks to its structure (UFG occupy 76.7% in total number fraction) and the distribution of growth twins. Growth twins in this article are referred to Sigma 3(111) coherent twins playing an important role in improving high strength, enhancing uniform plastic deformation ability

Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca^(2+) entry in glomerular mesangial cells

Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca^(2+) entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein. Activation of SOCE blunted high-glucose-increased Smad1 protein content. Treatment of human MCs with ANG II at 1 µM for 15 min, high glucose for 3 days, or TGF-β1 at 5 ng/ml for 30 min increased the level of phosphorylated Smad1. However, the phosphorylation of Smad1 by those stimuli was significantly attenuated by activation of SOCE. Knocking down Smad1 reduced, but expressing Smad1 increased, the amount of Col IV protein. Furthermore, activation of SOCE significantly attenuated high-glucose-induced Col IV protein production, and blockade of SOCE substantially increased the abundance of Col IV. To further verify those in vitro findings, we downregulated SOCE specifically in MCs in mice using small-interfering RNA (siRNA) against Orai1 (the channel protein mediating SOCE) delivered by the targeted nanoparticle delivery system. Immunohistochemical examinations showed that expression of both Smad1 and Col IV proteins was significantly greater in the glomeruli with positively transfected Orai1 siRNA compared with the glomeruli from the mice without Orai1 siRNA treatment. Taken together, our results indicate that SOCE negatively regulates the Smad1 signaling pathway and inhibits Col IV protein production in MCs

Self-Assembled Polymeric Micellar Nanoparticles as Nanocarriers for Poorly Soluble Anticancer Drug Ethaselen

A series of monomethoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) diblock copolymers were synthesized, and mPEG-PLA micelle was fabricated and used as a nanocarrier for solubilization and delivery of a promising anticancer drug ethaselen. Ethaselen was efficiently encapsulated into the micelles by the dialysis method, and the solubility of ethaselen in water was remarkably increased up to 82 μg/mL before freeze-drying. The mean diameter of ethaselen-loaded micelles ranged from 51 to 98 nm with a narrow size distribution and depended on the length of PLA block. In vitro hemolysis study indicated that mPEG-PLA copolymers and ethaselen-loaded polymeric micelles had no hemolytic effect on the erythrocyte. The enhanced antitumor efficacy and reduced toxic effect of ethaselen-loaded polymeric micelle when compared with ethaselen-HP-β-CD inclusion were observed at the same dose in H22human liver cancer cell bearing mouse models. These suggested that mPEG-PLA polymeric micelle nanoparticles had great potential as nanocarriers for effective solubilization of poorly soluble ethaselen and further reducing side effects and toxicities of the drug

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Spine decomposition and Llog⁡LL\log L criterion for superprocesses with non-local branching mechanisms

In this talk, I will describe a pathwise spine decomposition for superprocesses with both local and non-local branching mechanisms under a martingale change of measure. This result complements the related results obtained in Evans (1993), Kyprianou et al. (2012) and Liu, Ren and Song (2009) for superprocesses with purely local branching mechanisms and in Chen, Ren and Song (2016) and Kyprianou and Palau (2016) for multitype superprocesses. As an application of this decomposition, we obtain necessary/sufficient conditions for the limit of the fundamental martingale to be non-degenerate. In particular, we obtain extinction properties of superprocesses with non-local branching mechanisms as well as a Kesten-Stigum $LlogL$ theorem for the fundamental martingale.Non UBCUnreviewedAuthor affiliation: Peking UniversityFacult

Boundary singularity problem of some nonlinear elliptic equations

Let L be a uniformly elliptic operator in . We investigate limit properties of solutions to the boundary singularity problem of non-linear equation Lu=u[alpha], 1Superdiffusion Trace Nonlinear elliptic equation Boundary singularity problem Green function Poisson kernel

An Accent Marking Algorithm of English Conversion System Based on Morphological Rules

Facing the English conversion system, the existing accent marking algorithms cannot acquire the morphological rules of English, making the accent marking inaccurate, inefficient, and time-consuming. To solve these problems, this paper puts forward an accent marking algorithm of English conversion system based on morphological rules. Specifically, the English audios in a self-developed English corpus were classified by the speaker classification software based on hidden Markov model, as well as audio classification technology, producing the morphological rules of English. After that, the English accents were marked by the maximum entropy model in the English conversion system. The proposed method was proved accurate and efficient in accent marking through experiments. The research results provide a good reference for marking the accents in English conversion system

Herbal Formula Gegen-Qinlian Decoction for Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials

Background. Herbal formula Gegen-Qinlian Decoction (GQD) has been widely used in China for the treatment of type 2 diabetes mellitus (T2DM), but its efficacy and safety are unclear. Method. The studies were identified from the PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure database, Wanfang database, and VIP database using the keywords “Gegenqinlian” or “Gegen-Qinlian” or “Gegen-Qin-Lian” or “Ge Gen Qin Lian.” Relevant studies were selected according to predefined inclusion and exclusion criteria. Study selection, data extraction, and validation were carried out by, at least, two reviewers with disagreements being settled by discussion. Results. After literature search, a total of 26 randomized controlled trials were included with a total of 2553 patients. There was evidence that compared with metformin, the combination of GQD and metformin significantly reduced the fasting plasma glucose levels (MD −1.79, 95% CI (−2.31, −1.27), p<0.00001); 2-hour postprandial plasma glucose levels (MD −1.72, 95% CI (−2.12, −1.31), p<0.00001); and glycosylated hemoglobin levels (MD −1.26, 95% CI (−1.80, −0.72), p<0.00001), and no serious side effects were identified. Conclusion. These data suggest that GQD may be an effective herbal formula in treating T2DM without serious side effects. The addition of GQD also enhances the hypoglycemic effects of metformin. However, the evidence remains weak due to methodological flaws, which may amplify the therapeutic benefit of GQD