Expression of the transcriptional regulator Egr-1 in experimental glomerulonephritis: Requirement for mesangial cell proliferation

Expression of the transcriptional regulator Egr-1 in experimental glomerulonephritis: Requirement for mesangial cell proliferation. The early growth response gene-1 (Egr-1), a zinc finger transcriptional regulator, was induced in a rat model of mesangioproliferative glomerulonephritis (GN). Northern blot analysis revealed a maximal 14.9-fold increase in glomerular Egr-1 mRNA at day 6 of GN. By immunohistochemistry Egr-1 protein expression was demonstrated to be mainly confined to glomerular mesangial cells (MC). To test whether Egr-1 directly regulates MC proliferation, cultured MCs were stimulated with platelet-derived growth factor (PDGF) after preincubation with different Egr-1 antisense oligonucleotides (ASOs). PDGF-induced Egr-1 mRNA levels were inhibited by up to 75% and protein levels by up to 91%. In addition Egr-1-specific ASOs blocked PDGF-induced rise in 3H-thymidine uptake by 83% and almost completely abrogated increase in MC number. We conclude that Egr-1 induction is of critical importance for PDGF-induced mitogenic signaling in MCs, and inhibition of Egr-1 in vivo may offer an approach to oppose glomerular MC proliferation in glomerular inflammatory disease

Neural correlates of the perception of dynamic versus static facial expressions of emotion

Aim: This study investigated brain areas involved in the perception of dynamic facial expressions of emotion

The effectiveness of daclatasvir based therapy in European patients with chronic hepatitis C and advanced liver disease

Daclatasvir; Eficàcia; Hepatitis CDaclatasvir; Eficacia; Hepatitis CDaclatasvir; Effectiveness; Hepatitis CBackground There is limited evidence for the effectiveness of daclatasvir in patients whose hepatitis C threatens their life expectancy. The Named Patient Program in Europe included patients with advanced chronic hepatitis C, a life expectancy of less than 12 months and no other treatment options. Methods A retrospective multi-country cohort of patients with chronic hepatitis C who received daclatasvir as part of the Named Patient Program in Austria, Denmark, Spain, Sweden, Switzerland and the United Kingdom. Treatment response was defined as a sustained virologic response (unquantifiable hepatitis C RNA) at 12 weeks post treatment. We summarised the characteristics of the patients in this cohort and estimated the rate of sustained virologic response for patients receiving daclatasvir and sofosbuvir with or without ribavirin using hierarchical Bayesian modelling. Results The 249 patients included had a median age of 56 years; most were male (78%), hepatitis C genotype 1 (75%), treatment experienced (65%) and with decompensated cirrhosis (59%). Many had had a liver transplant before receiving daclatasvir (40%). Of the 249 patients, 242 patients received daclatasvir and sofosbuvir and either reached 12 weeks post treatment or died during (n = 9) or after treatment (n = 4) or were lost to follow up during treatment (n = 1). The estimated rate of sustained virologic response at 12 weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis. Conclusions Daclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis.This work was supported by BMS

Развитие нестандартных форм занятости

Представлена характеристика и обобщены признаки нестандартных форм занятости, разнообразие которых связано с развитием и повышением доступности технологий, дано определение виртуальной занятости. Подчеркивается, что распространение нестандартных форм занятости является ответом рынка труда на происходящие изменения в экономик

6α-Acetoxy­gedunin

The title compound [systematic name: (1S,3aS,4aR,4bS,5S,6R,6aR,10aR,10bR,12aS)-5,6-bis­(acet­yloxy)-1-(3-fur­yl)-1,5,6,6a,7,10a,10b,11,12,12a-deca­hydro-4b,7,7,10a,12a-penta­methyl­oxireno[c]phenanthro[1,2-d]pyran-3,8(3aH,4bH)-dione], C30H36O9, is a limonoid-type triterpene isolated from Aglaia elaeagnoidea (A. Juss.) Benth. (Meliaceae) from Queensland, northern Australia. It contains the gedunin core of four trans-fused six-membered rings with an oxirane ring annelated to the fourth ring. A terminal 3-furyl unity and two acet­oxy groups in a mutual cis-disposition supplement the mol­ecule. A comparison between the gedunin cores of the title compound, the parent compound gedunin, and three further gedunin derivatives revealed considerable variations in their conformation stemming from the conformational lability of the first screw-boat ring and the third twist-boat ring. A sensitive measure for the third ring is one C—C—C—C torsion angle, which is 14.2 (2)° in the title compound, but varies in other cases from ca 20 to ca −40°. In the crystalline state, 6α-acetoxy­gedunin shows ten comparatively weak C—H⋯O inter­actions, with H⋯O distances in the range of 2.33–2.69 Å

Adipose triglyceride lipase activity is inhibited by long-chain acyl-coenzyme A

AbstractAdipose triglyceride lipase (ATGL) is required for efficient mobilization of triglyceride (TG) stores in adipose tissue and non-adipose tissues. Therefore, ATGL strongly determines the availability of fatty acids for metabolic reactions. ATGL activity is regulated by a complex network of lipolytic and anti-lipolytic hormones. These signals control enzyme expression and the interaction of ATGL with the regulatory proteins CGI-58 and G0S2. Up to date, it was unknown whether ATGL activity is also controlled by lipid intermediates generated during lipolysis. Here we show that ATGL activity is inhibited by long-chain acyl-CoAs in a non-competitive manner, similar as previously shown for hormone-sensitive lipase (HSL), the rate-limiting enzyme for diglyceride breakdown in adipose tissue. ATGL activity is only marginally inhibited by medium-chain acyl-CoAs, diglycerides, monoglycerides, and free fatty acids. Immunoprecipitation assays revealed that acyl-CoAs do not disrupt the protein–protein interaction of ATGL and its co-activator CGI-58. Furthermore, inhibition of ATGL is independent of the presence of CGI-58 and occurs directly at the N-terminal patatin-like phospholipase domain of the enzyme. In conclusion, our results suggest that inhibition of the major lipolytic enzymes ATGL and HSL by long-chain acyl-CoAs could represent an effective feedback mechanism controlling lipolysis and protecting cells from lipotoxic concentrations of fatty acids and fatty acid-derived lipid metabolites