Adaptations for gas exchange enabled the elongation of lepidopteran proboscises.

The extensive biodiversification of butterflies and moths (Lepidoptera) is partly attributed to their unique mouthparts (proboscis [Pr]) that can span in length from less than 1 mm to over 280 mm in Darwin's sphinx moths. Lepidoptera, similar to other insects, are believed to inhale and exhale respiratory gases only through valve-like spiracles on their thorax and abdomen, making gas exchange through the narrow tracheae (Tr) challenging for the elongated Pr. How Lepidoptera overcome distance effects for gas transport to the Pr is an open question that is important to understanding how the Pr elongated over evolutionary time. Here, we show with scanning electron microscopy and X-ray imaging that distance effects on gas exchange are overcome by previously unreported micropores on the Pr surface and by superhydrophobic Tr that prevent water loss and entry. We find that the density of micropores decreases monotonically along the Pr length with the maxima proportional to the Pr length and that micropore diameters produce a Knudsen number at the boundary between the slip and transition flow regimes. By numerical estimation, we further show that the respiratory gas exchange for the Pr predominantly occurs via diffusion through the micropores. These adaptations are key innovations vital to Pr elongation, which likely facilitated lepidopteran biodiversification and the radiation of angiosperms by coevolutionary processes.

The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial.

AIMS: The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown. METHODS AND RESULTS: The dal-ACUTE study randomized 300 patients (1 : 1) to dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% (P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-ß1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-ß1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-ß1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. CONCLUSIONS: High-density lipoprotein raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.

Rationale and design of dal-VESSEL: a study to assess the safety and efficacy of dalcetrapib on endothelial function using brachial artery flow-mediated vasodilatation.

OBJECTIVE: Dalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme, the efficacy and safety of dalcetrapib is assessed in coronary heart disease (CHD) patients in the dal-VESSEL study (ClinicalTrials.gov identifier: NCT00655538), the design and methods of which are presented here. RESEARCH DESIGN AND STUDY METHOD: Men and women with CHD or CHD risk equivalent, with HDL-C levels <50 mg/dL were recruited for a 36-week, double-blinded, placebo-controlled trial. After a pre-randomisation phase of up to 8 weeks, patients received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. Brachial flow-mediated dilatation (FMD) measured by B-mode ultrasound represents endothelial function and is a validated marker for early atherosclerosis and cardiovascular disease risk. MAIN OUTCOME MEASURES: The primary efficacy outcome is change from baseline in brachial FMD after 12 weeks. The primary safety endpoint is 24-hour ambulatory blood pressure monitoring (ABPM) assessed at week 4. Secondary endpoints include brachial FMD at 36 weeks, ABPM at 12 and 36 weeks, lipid profile, CETP mass and activity, and markers of inflammation, oxidation, and cardiovascular risk. Clinical endpoints are assessed as a composite endpoint for the dal-HEART Program. CURRENT STATUS: In 19 European clinical centres, 476 subjects met inclusion criteria and have entered the study. In conclusion, the dal-VESSEL study is the largest multicentre trial with brachial FMD ever performed. The study assesses efficacy and safety of dalcetrapib on endothelial function, blood pressure, lipids, and clinical outcomes in CHD patients with below average HDL-C and will therefore provide vital information regarding its potential role in the preventative treatment of CHD risk.

The three-dimensional architecture of the class I ligase ribozyme.

The class I ligase ribozyme catalyzes a Mg(++)-dependent RNA-ligation reaction that is chemically analogous to a single step of RNA polymerization. Indeed, this ribozyme constitutes the catalytic domain of an accurate and general RNA polymerase ribozyme. The ligation reaction is also very rapid in both single- and multiple-turnover contexts and thus is informative for the study of RNA catalysis as well as RNA self-replication. Here we report the initial characterization of the three-dimensional architecture of the ligase. When the ligase folds, several segments become protected from hydroxyl-radical cleavage, indicating that the RNA adopts a compact tertiary structure. Ribozyme folding was largely, though not completely, Mg(++) dependent, with a K(1/2[Mg]) < 1 mM, and was observed over a broad temperature range (20 degrees C -50 degrees C). The hydroxyl-radical mapping, together with comparative sequence analyses and analogy to a region within 23S ribosomal RNA, were used to generate a three-dimensional model of the ribozyme. The predictive value of the model was tested and supported by a photo-cross-linking experiment.