Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk:Rationale and design of the ODYSSEY DM-INSULIN trial

Aims: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. Methods: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening. ≥. 70. mg/dL (1.81. mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24. weeks of alirocumab 75. mg every 2. weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C. ≥. 70. mg/dL at week 8 underwent a blinded dose increase to 150. mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. Results: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. Conclusion: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy

Spacelike Singularities and Hidden Symmetries of Gravity

We review the intimate connection between (super-)gravity close to a spacelike singularity (the "BKL-limit") and the theory of Lorentzian Kac-Moody algebras. We show that in this limit the gravitational theory can be reformulated in terms of billiard motion in a region of hyperbolic space, revealing that the dynamics is completely determined by a (possibly infinite) sequence of reflections, which are elements of a Lorentzian Coxeter group. Such Coxeter groups are the Weyl groups of infinite-dimensional Kac-Moody algebras, suggesting that these algebras yield symmetries of gravitational theories. Our presentation is aimed to be a self-contained and comprehensive treatment of the subject, with all the relevant mathematical background material introduced and explained in detail. We also review attempts at making the infinite-dimensional symmetries manifest, through the construction of a geodesic sigma model based on a Lorentzian Kac-Moody algebra. An explicit example is provided for the case of the hyperbolic algebra E10, which is conjectured to be an underlying symmetry of M-theory. Illustrations of this conjecture are also discussed in the context of cosmological solutions to eleven-dimensional supergravity.Comment: 228 pages. Typos corrected. References added. Subject index added. Published versio

The Early Royal Society and Visual Culture

Recent studies have fruitfully examined the intersection between early modern science and visual culture by elucidating the functions of images in shaping and disseminating scientific knowledge. Given its rich archival sources, it is possible to extend this line of research in the case of the Royal Society to an examination of attitudes towards images as artefacts –manufactured objects worth commissioning, collecting and studying. Drawing on existing scholarship and material from the Royal Society Archives, I discuss Fellows’ interests in prints, drawings, varnishes, colorants, images made out of unusual materials, and methods of identifying the painter from a painting. Knowledge of production processes of images was important to members of the Royal Society, not only as connoisseurs and collectors, but also as those interested in a Baconian mastery of material processes, including a “history of trades”. Their antiquarian interests led to discussion of painters’ styles, and they gradually developed a visual memorial to an institution through portraits and other visual records.AH/M001938/1 (AHRC

Cigarette Smoke Affects Keratinocytes SRB1 Expression and Localization via H2O2 Production and HNE Protein Adducts Formation

Scavenger Receptor B1 (SR-B1), also known as HDL receptor, is involved in cellular cholesterol uptake. Stratum corneum (SC), the outermost layer of the skin, is composed of more than 25% cholesterol. Several reports support the view that alteration of SC lipid composition may be the cause of impaired barrier function which gives rise to several skin diseases. For this reason the regulation of the genes involved in cholesterol uptake is of extreme significance for skin health. Being the first shield against external insults, the skin is exposed to several noxious substances and among these is cigarette smoke (CS), which has been recently associated with various skin pathologies. In this study we first have shown the presence of SR-B1 in murine and human skin tissue and then by using immunoblotting, immunoprecipitation, RT-PCR, and confocal microscopy we have demonstrated the translocation and the subsequent lost of SR-B1 in human keratinocytes (cell culture model) after CS exposure is driven by hydrogen peroxide (H2O2) that derives not only from the CS gas phase but mainly from the activation of cellular NADPH oxidase (NOX). This effect was reversed when the cells were pretreated with NOX inhibitors or catalase. Furthermore, CS caused the formation of SR-B1-aldheydes adducts (acrolein and 4-hydroxy-2-nonenal) and the increase of its ubiquitination, which could be one of the causes of SR-B1 loss. In conclusion, exposure to CS, through the production of H2O2, induced post-translational modifications of SR-B1 with the consequence lost of the receptor and this may contribute to the skin physiology alteration as a consequence of the variation of cholesterol uptake

Comparative analysis of the transcriptome across distant species

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters