Discovery of Bisamide-heterocycles as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure–activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50 = 17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278

Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport

A potent class of indolinyl-thiazole based inhibitors of cellular lipid uptake mediated by scavenger receptor, class B, type I (SR-BI) was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) in an assay measuring the uptake of the fluorescent lipid DiI from HDL particles. This class of compounds is represented by ML278 (17–11), a potent (average IC50 = 6 nM) and reversible inhibitor of lipid uptake via SR-BI. ML278 is a plasma-stable, noncytotoxic probe that exhibits moderate metabolic stability, thus displaying improved properties for in vitro and in vivo studies. Strikingly, ML278 and previously described inhibitors of lipid transport share the property of increasing the binding of HDL to SR-BI, rather than blocking it, suggesting there may be similarities in their mechanisms of action

Scoping Potential Routes to UK Civil Unrest via the Food System: Results of a Structured Expert Elicitation

We report the results of a structured expert elicitation to identify the most likely types of potential food system disruption scenarios for the UK, focusing on routes to civil unrest. We take a backcasting approach by defining as an end-point a societal event in which 1 in 2000 people have been injured in the UK, which 40% of experts rated as “Possible (20–50%)”, “More likely than not (50–80%)” or “Very likely (>80%)” over the coming decade. Over a timeframe of 50 years, this increased to 80% of experts. The experts considered two food system scenarios and ranked their plausibility of contributing to the given societal scenario. For a timescale of 10 years, the majority identified a food distribution problem as the most likely. Over a timescale of 50 years, the experts were more evenly split between the two scenarios, but over half thought the most likely route to civil unrest would be a lack of total food in the UK. However, the experts stressed that the various causes of food system disruption are interconnected and can create cascading risks, highlighting the importance of a systems approach. We encourage food system stakeholders to use these results in their risk planning and recommend future work to support prevention, preparedness, response and recovery planning

The importance of major mergers in the build up of stellar mass in brightest cluster galaxies at z=1

Recent independent results from numerical simulations and observations have shown that brightest cluster galaxies (BCGs) have increased their stellar mass by a factor of almost two between z~0.9 and z~0.2. The numerical simulations further suggest that more than half this mass is accreted through major mergers. Using a sample of 18 distant galaxy clusters with over 600 spectroscopically confirmed cluster members between them, we search for observational evidence that major mergers do play a significant role. We find a major merger rate of 0.38 +/- 0.14 mergers per Gyr at z~1. While the uncertainties, which stem from the small size of our sample, are relatively large, our rate is consistent with the results that are derived from numerical simulations. If we assume that this rate continues to the present day and that half of the mass of the companion is accreted onto the BCG during these mergers, then we find that this rate can explain the growth in the stellar mass of the BCGs that is observed and predicted by simulations. Major mergers therefore appear to be playing an important role, perhaps even the dominant one, in the build up of stellar mass in these extraordinary galaxies.Comment: 15 pages, 6 figures, accepted for publication in MNRAS. Reduced data will be made available through the ESO archiv

The Importance of Major Mergers in the Build Up of Stellar Mass in Brightest Cluster Galaxies at \u3cem\u3ez\u3c/em\u3e = 1

Recent independent results from numerical simulations and observations have shown that brightest cluster galaxies (BCGs) have increased their stellar mass by a factor of almost 2 between z ∼ 0.9 and z ∼ 0.2. The numerical simulations further suggest that more than half this mass is accreted through major mergers. Using a sample of 18 distant galaxy clusters with over 600 spectroscopically confirmed cluster members between them, we search for observational evidence that major mergers do play a significant role. We find a major merger rate of 0.38 ± 0.14 mergers per Gyr at z ∼ 1. While the uncertainties, which stem from the small size of our sample, are relatively large, our rate is consistent with the results that are derived from numerical simulations. If we assume that this rate continues to the present day and that half of the mass of the companion is accreted on to the BCG during these mergers, then we find that this rate can explain the growth in the stellar mass of the BCGs that is observed and predicted by simulations. Major mergers therefore appear to be playing an important role, perhaps even the dominant one, in the build up of stellar mass in these extraordinary galaxies

Serum albumin and mortality risk in a hyperendemic area of HCV infection in Japan

<p>Abstract</p> <p>Background</p> <p>Hypoalbuminemia has been shown to be associated with increased mortality. We reported a mass screening in 1990 of X town in Japan, which demonstrated a high prevalence of hepatitis C virus (HCV) infection. This follow-up study determined, through a period of 12 years, whether serum albumin levels impact on the life prognosis of the residents of X town.</p> <p>Results</p> <p>Of the 509 subjects, 69 had died and 55 had moved to other regions by 2002. Therefore, we analyzed 454 people for whom we could confirm life and death between 1990 and 2002. Albumin levels were assigned to two groups, low (<4.0 g/L, group A) and normal (≥4.0 g/L, group B). Of the 454 subjects analyzed, 25 were in group A and 429 in group B and the mortality was 68.0% (17/25 cases, P < 0.00001 vs. group B) and 12.1% (52/429), respectively. Mortality from hepatocellular carcinoma (HCC) was 66.7% in group A (6/9 cases, P = 0.01 vs. group B) and 15.8% (3/19) in group B. According to multivariate analysis, five factors - 50 years or older, low albumin level (<4.0 g/L), abnormal AST level, history of smoking, and absence of alcohol consumption - were associated with death. The adjusted odds ratios for these five factors were 20.65, 10.79, 2.58, 2.24 and 2.08, respectively, and each was statistically significant.</p> <p>Conclusions</p> <p>We show that the serum albumin level is an independent risk factor for mortality from all causes in the residents of X town and an important prognostic indicator. Improvement of hypoalbuminaemia should be considered for improvement of prognosis.</p

Retinoic Acid Mediates Regulation of Network Formation by COUP-TFII and VE-Cadherin Expression by TGFβ Receptor Kinase in Breast Cancer Cells

Tumor development, growth, and metastasis depend on the provision of an adequate vascular supply. This can be due to regulated angiogenesis, recruitment of circulating endothelial progenitors, and/or vascular transdifferentiation. Our previous studies showed that retinoic acid (RA) treatment converts a subset of breast cancer cells into cells with significant endothelial genotypic and phenotypic elements including marked induction of VE-cadherin, which was responsible for some but not all morphological changes. The present study demonstrates that of the endothelial-related genes induced by RA treatment, only a few were affected by knockdown of VE-cadherin, ruling it out as a regulator of the RA-induced endothelial genotypic switch. In contrast, knockdown of the RA-induced gene COUP-TFII prevented the formation of networks in Matrigel but had no effect on VE-cadherin induction or cell fusion. Two pan-kinase inhibitors markedly blocked RA-induced VE-cadherin expression and cell fusion. However, RA treatment resulted in a marked and broad reduction in tyrosine kinase activity. Several genes in the TGFβ signaling pathway were induced by RA, and specific inhibition of the TGFβ type I receptor blocked both RA-induced VE-cadherin expression and cell fusion. Together these data indicate a role for the TGFβ pathway and COUP-TFII in mediating the endothelial transdifferentiating properties of RA