Ctenophora, compromising approximately 200 described species, is an important lineage for understanding metazoan evolution and is of great ecological and economic importance. Ctenophore diversity includes species with unique colloblasts used for prey capture, smooth and striated muscles, benthic and pelagic lifestyles, and locomotion with ciliated paddles or muscular propulsion. However, ancestral states of traits are debated and relationships among many lineages are unresolved. Here, using 27 newly sequenced ctenophore transcriptomes, publicly available data, and methods to control systematic error we establish the placement of Ctenophora as the sister group to all other animals and refine phylogenetic relationships within ctenophores. Molecular clock analyses suggest modern ctenophore diversity originated approximately 350MYA ± 88 MY, conflicting with previous hypotheses of approximately 65 MYA. We recover Euplokamis dunlapae, a species with striated muscles, as the sister lineage to other sampled ctenophores. Ancestral state reconstruction shows the most recent common ancestor of extant ctenophores was pelagic, possessed tentacles, was bioluminescent, and did not have separate sexes. Our results imply at least two transitions from a pelagic to a benthic lifestyle within Ctenophora, suggesting such transitions were more common in animal diversification than appreciated.
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.
Dietary intake/status of the trace mineral Se may affect the risk of developing hypertensive conditions of pregnancy, i.e. pre-eclampsia and pregnancy-induced hypertension (PE/PIH). In the present study, we evaluated Se status in UK pregnant women to establish whether pre-pregnant Se status or Se supplementation affected the risk of developing PE/PIH. The samples originated from the SPRINT (Selenium in PRegnancy INTervention) study that randomised 230 UK primiparous women to treatment with Se (60 μg/d) or placebo from 12 weeks of gestation. Whole-blood Se concentration was measured at 12 and 35 weeks, toenail Se concentration at 16 weeks, plasma selenoprotein P (SEPP1) concentration at 35 weeks and plasma glutathione peroxidase (GPx3) activity at 12, 20 and 35 weeks. Demographic data were collected at baseline. Participants completed a FFQ. UK pregnant women had whole-blood Se concentration lower than the mid-range of other populations, toenail Se concentration considerably lower than US women, GPx3 activity considerably lower than US and Australian pregnant women, and low baseline SEPP1 concentration (median 3·00, range 0·90–5·80 mg/l). Maternal age, education and social class were positively associated with Se status. After adjustment, whole-blood Se concentration was higher in women consuming Brazil nuts (P= 0·040) and in those consuming more than two seafood portions per week (P= 0·054). A stepwise logistic regression model revealed that among the Se-related risk factors, only toenail Se (OR 0·38, 95 % CI 0·17, 0·87, P= 0·021) significantly affected the OR for PE/PIH. On excluding non-compliers with Se treatment, Se supplementation also significantly reduced the OR for PE/PIH (OR 0·30, 95 % CI 0·09, 1·00, P= 0·049). In conclusion, UK women have low Se status that increases their risk of developing PE/PIH. Therefore, UK women of childbearing age need to improve their Se status.
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