Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

The B', CRF07_BC and CRF01_AE are the predominant HIV-1 subtypes in China. It is essential to determine their baseline susceptibility to HIV entry inhibitors before these drugs are used in China.The baseline susceptibility of 14 representative HIV-1 isolates (5 CRF07_BC, 4 CRF01_AE, and 5 B'), most of which were R5 viruses, obtained from drug-naïve patients to HIV entry inhibitors, including two fusion inhibitors (enfuvirtide and C34), two CCR5 antagonists (maraviroc and TAK779) and one CXCR4 antagonist (AMD3100), were determined by virus inhibition assay. The sequences of their env genes were amplified and analyzed. These isolates possessed similar susceptibility to C34, but they exhibited different sensitivity to enfuvirtide, maraviroc or TAK779. CRF07_BC isolates, which carried polymorphisms of A578T and V583I in the N-terminal heptad repeat and E630Q, E662A, K665S, A667K and S668N in the C-terminal heptad repeat of gp41, were about 5-fold less sensitive than B' and CRF01_AE isolates to enfuvirtide. Subtype B' isolates with a unique polymorphism site of F317W in V3 loop, were about 4- to 5-fold more sensitive than CRF07_BC and CRF01_AE isolates to maraviroc and TAK779. AMD3100 at the concentration as high as 5 µM exhibited no significant inhibitory activity against any of the isolates tested.Our results suggest that there are significant differences in baseline susceptibility to HIV entry inhibitors among the predominant HIV-1 subtypes in China and the differences may partly result from the naturally occurring polymorphisms in these subtypes. This study provides useful information for rational design of optimal therapeutic regimens for HIV-1-infected patients in China

Genetic Networks of Liver Metabolism Revealed by Integration of Metabolic and Transcriptional Profiling

Although numerous quantitative trait loci (QTL) influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s) and molecular pathways leading to those phenotypes is often elusive. One way to improve understanding of genetic architecture is to classify phenotypes in greater depth by including transcriptional and metabolic profiling. In the current study, we have generated and analyzed mRNA expression and metabolic profiles in liver samples obtained in an F2 intercross between the diabetes-resistant C57BL/6 leptinob/ob and the diabetes-susceptible BTBR leptinob/ob mouse strains. This cross, which segregates for genotype and physiological traits, was previously used to identify several diabetes-related QTL. Our current investigation includes microarray analysis of over 40,000 probe sets, plus quantitative mass spectrometry-based measurements of sixty-seven intermediary metabolites in three different classes (amino acids, organic acids, and acyl-carnitines). We show that liver metabolites map to distinct genetic regions, thereby indicating that tissue metabolites are heritable. We also demonstrate that genomic analysis can be integrated with liver mRNA expression and metabolite profiling data to construct causal networks for control of specific metabolic processes in liver. As a proof of principle of the practical significance of this integrative approach, we illustrate the construction of a specific causal network that links gene expression and metabolic changes in the context of glutamate metabolism, and demonstrate its validity by showing that genes in the network respond to changes in glutamine and glutamate availability. Thus, the methods described here have the potential to reveal regulatory networks that contribute to chronic, complex, and highly prevalent diseases and conditions such as obesity and diabetes

Demand-side approaches for limiting global warming to 1.5 °C

The Paris Climate Agreement defined an ambition of limiting global warming to 1.5 °C above preindustrial levels. This has triggered research on stringent emission reduction targets and corresponding mitigation pathways across energy economy and societal systems. Driven by methodological considerations, supply side and carbon dioxide removal options feature prominently in the emerging pathway literature, while much less attention has been given to the role of demand-side approaches. This special issue addresses this gap, and aims to broaden and strengthen the knowledge base in this key research and policy area. This editorial paper synthesizes the special issue’s contributions horizontally through three shared themes we identify: policy interventions, demand-side measures, and methodological approaches. The review of articles is supplemented by insights from other relevant literature. Overall, our paper underlines that stringent demand-side policy portfolios are required to drive the pace and direction of deep decarbonization pathways and keep the 1.5 °C target within reach. It confirms that insufficient attention has been paid to demand-side measures, which are found to be inextricably linked to supply-side decarbonization and able to complement supply-side measures. The paper also shows that there is an abundance of demand-side measures to limit warming to 1.5 °C, but it warns that not all of these options are “seen” or captured by current quantitative tools or progress indicators, and some remain insufficiently represented in the current policy discourse. Based on the set of papers presented in the special issue, we conclude that demand-side mitigation in line with the 1.5 °C goal is possible; however, it remains enormously challenging and dependent on both innovative technologies and policies, and behavioral change. Limiting warming to 1.5 °C requires, more than ever, a plurality of methods and integrated behavioral and technology approaches to better support policymaking and resulting policy interventions

Acyl-coenzyme A:cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7 alpha-hydroxylase in cultured rat hepatocytes and in vivo in the rat

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in clinical development as potential lipid-lowering and antiatherosclerotic agents. We investigated the effect of avasimibe (C1- 1011), a novel ACAT inhibitor, on bile acid synthesis and cholesterol 7α- hydroxylase in cultured rat hepatocytes and rats fed different diets. Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of β-migrating very low-density lipoproteins (βVLDL) (by 93% and 75% at 10 μmol/L) and reduced intracellular storage of cholesteryl esters. Avasimibe (3 μmol/L) increased bile acid synthesis (2.9- fold) after preincubation with βVLDL and cholesterol 7α-hydroxylase activity (1.7-and 2.6-fold, with or without βVLDL), the latter paralleled by a similar induction of its messenger RNA (mRNA). Hepatocytes treated with avasimibe showed a shift from storage and secretion of cholesteryl esters to conversion of cholesterol into bile acids. In rats fed diets containing different amounts of cholesterol and cholate, avasimibe reduced plasma cholesterol (by 52% to 71%) and triglyceride levels (by 28% to 62%). Avasimibe did not further increase cholesterol 7α-hydroxylase activity and mRNA in cholesterol-fed rats, but prevented down-regulation by cholate. Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7α-hydroxylase, 2 enzymes in the alternative pathway in bile acid synthesis. No increase in the ratio of biliary excreted cholesterol to bile acids was found, indicating that ACAT inhibition does not result in a more lithogenic bile. Avasimibe increases bile acid synthesis in cultured hepatocytes by enhancing the supply of free cholesterol both as substrate and inducer of cholesterol 7α- hydroxylase. These effects may partially explain the potent cholesterol- lowering effects of avasimibe in the rat

Increased lipogenesis and resistance of lipoproteins to oxidative modification in two patients with glycogen storage disease type 1a

We describe 2 patients with glycogen storage disease type la and severe hyperlipidemia without premature atherosclerosis. Susceptibility of low-density lipoproteins to oxidation was decreased, possibly related to the similar to40-fold increase in palmitate synthesis altering lipoprotein saturated fatty acid contents. These endings are potentially relevant for antihyperlipidemic treatment in patients with glycogen storage disease type la