BACKGROUND Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P = 0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878.)

Buckling-driven assembly of 3D mesostructures from releasable multilayers offers versatile design options for unique applications.

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A transition-metal-free direct α-C-H amination of ketones has been developed using commercially available ammonium iodide as the catalyst and sodium percarbonate as the co-oxidant. A wide range of ketone ((hetero)aromatic or nonaromatic ketones) and amine (primary/secondary amines, anilines, or amides) substrates undergo cross-coupling to generate synthetically useful α-amino ketones. The mechanistic studies indicated that a radical pathway might be involved in the reaction process. The utility of the method is highlighted through a concise one-step synthesis of the pharmaceutical agent amfepramone.

The first Fe-facilitated decarboxylative cross-coupling reaction between α-oxocarboxylic acids and acrylic acids in aqueous solution has been developed. This transformation is characterized by its wide substrate scope and good functional group compatibility utilizing inexpensive and easily accessible reagents, thus providing an efficient and expeditious approach to an important class of α,β-unsaturated carbonyls frequently found in bioactive compounds. The synthetic potential of the coupled products is also demonstrated in subsequent functionalization reactions. Preliminary mechanism studies suggest that a free radical pathway is involved in this process: the generation of an acyl radical from α-oxocarboxylic acid via the excision of carbon dioxide followed by the addition of an acyl radical to the α-position of the double bond in acrylic acid then delivers the α,β-unsaturated carbonyl adduct through the extrusion of another carbon dioxide.