ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10⁻⁹) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10⁻⁹). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60–0.81], P = 2.2 × 10⁻⁶) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37–0.76], P = 4.5 × 10⁻⁴) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40–0.68], P = 1.7 × 10⁻⁶) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.     

Ultrastructure of Coelomocytes in Sphaerolaimus gracilis de Man, 1876 (Nematoda)

The structure of coelomocytes in the adenophorean aquatic nematode Sphaerolaimus gracilis de Man 1876 was studied with light and electron microscopes. Acid phosphatase and catalase activities were demonstrated by electron microscopy. Two pairs of coelomocytes occurred laterally posterior to the esophagointestinaljunction. The anterior pair of the coelomocytes, with the renette cell and gonad, lay in either the left or the right lateral side of the body. The posterior pair of coelomocytes was in the opposite side of the body, usually posterior to the renette. A long, thin, cell-extension-like structure appeared to originate from the coelomocytes. Coelomocytes were characterized by specialized organelles (CC-organelle) and large vacuoles. The CC-organelle contained crystalline structures like those in peroxisomes. Acid phosphatase and catalase activities were detected in the matrix of CC-organelles and catalase activity in the vacuoles. It was assumed that vacuoles originate from the CC-organelles. Coelomocytes showed pinocytotic activities, and numerous vesicles were observed between the cell membranes and the vacuoles.     

Assay technologies facilitating drug discovery for ADP-ribosyl writers,readers and erasers

ADP-ribosylation is a post-translational modification catalyzed by writer enzymes – ADP-ribosyltransferases. The modification is part of many signaling events, can modulate the function and stability of target proteins, and often results in the recruitment of reader proteins that bind to the ADP-ribosyl groups. Erasers are integral actors in these signaling events and reverse the modification. ADP-ribosylation can be targeted with therapeutics and many inhibitors against writers exist, with some being in clinical use. Inhibitors against readers and erasers are sparser and development of these has gained momentum only in recent years. Drug discovery has been hampered by the lack of specific tools, however many significant advances in the methods have recently been reported. We discuss assays used in the field with a focus on methods allowing efficient identification of small molecule inhibitors and profiling against enzyme families. While human proteins are focused, the methods can be also applied to bacterial toxins and virus encoded erasers that can be targeted to treat infectious diseases in the future.