SUMMARYThe regulation of energy homeostasis is fundamental to all organisms. The Drosophila fat body serves as a repository for both triglycerides and glycogen, combining the energy storage functions of mammalian adipose and hepatic tissues, respectively. Here we show that mutation of the Drosophila adipokinetic hormone receptor (AKHR), a functional analog of the mammalian glucagon receptor, leads to abnormal accumulation of both lipid and carbohydrate. As a consequence of their obese phenotypes, AKHR mutants are markedly starvation resistant. We show that AKHR is expressed in the fat body, and, intriguingly, in a subset of gustatory neurons that mediate sweet taste. Genetic rescue experiments establish that the metabolic phenotypes arise exclusively from the fat body AKHR expression. Behavioral experiments demonstrate that AKHR mutants are neither sedentary nor hyperphagic, suggesting the metabolic abnormalities derive from a genetic propensity to retain energy stores. Taken together, our results indicate that a single endocrine pathway contributes to both lipid and carbohydrate catabolism in the Drosophila fat body.

ABSTRACT:In this review, the utility of Drosophila melanogaster as a model organism for research in metabolism will be demonstrated. Importantly, many metabolic pathways are conserved in both man and the fly. Recent work has highlighted that these conserved molecular pathways have the potential to give rise to similar phenotypes. For example, it has proven possible to generate obese and diabetic Drosophila; conversely, genetic manipulation can also generate lean and hypoglycemic phenotypes. From conserved circulating hormones to key enzymes, the fly is host to a variety of homologous, metabolically active signaling mechanisms. The world of Drosophila research has not only a rich history of developing techniques for exquisite genetic manipulation, but also continues to develop genetic methodologies at an exciting rate. Many of these techniques add to the cadre of experimental tools available for the use of the fly as a model organism for studying carbohydrate and lipid homeostasis. This review is written for the pediatric-scientist with little background in Drosophila, with the goal of relaying the potential of this model organism for contributing to a better understanding of diseases affecting today's children.

The thermal cycloaromatization reactions of hex-3-ene-l,5diynes to form 1,4-didehydrobenzene intermediates were first studied in our laboratories several years ago.1"4 5678Such intermediates are now thought to play a critical role in the DNA-cleaving activity of an emerging class of powerful antitumor antibiotics. The isolation of natural products such as the esperamicins, calicheamicins, and dynemicins has stimulated numerous synthetic, mechanistic, and biological activity studies.5,6 The renaissance of research in this area has prompted us to return to the chemistry of a variety of substituted enediyne systems in the hope of discovering new types of dehydroaromatic biradical intermediates. Our first goal was the synthesis and thermal reactions of the extended enediyne system (Z,Z)-deca-3,7-diene-l,5,9-triyne (1). We present experimental evidence that heating 1 leads to 2,6didehydronaphthalene.7,8The stereospecific synthesis of the requisite dienetriynes utilized standard nickel-9 and palladium-catalyzed10,11 coupling metho-(1)

IntroductionThe aim of this study was to use multiple data sources to update information on gastrointestinal perforations (GIPs) during tocilizumab (TCZ) treatment in patients with rheumatoid arthritis (RA).MethodsReporting rates of GIP events were estimated from three distinct patient data sets: a TCZ-IV RA clinical trial all-exposure population, a global TCZ postmarketing safety database population, and a US healthcare claims database population of patients with RA, including patients who received TCZ, anti-tumor necrosis factor (aTNF) agents, or abatacept.ResultsThe clinical trial, global postmarketing, and healthcare claims populations provided 17,906, 382,621, and 3268 patient-years (PYs) of TCZ exposure, respectively. GIP incidence rates [95% confidence interval (CI)] were 1.9 (1.3–2.7), 1.2 (1.1–1.3), and 1.8 (0.7–4.0; specific definition) to 2.8 (1.3–5.2; sensitive definition) per 1000 PYs for the clinical trial, postmarketing, and healthcare claims populations, respectively. The GIP incidence rate (95% CI) for the comparator aTNF healthcare claims population ranged from 0.6 (0.3–1.2) to 0.9 (0.5–1.5) per 1000 PYs, for an absolute rate difference between TCZ and aTNFs of 1.2 (−0.3 to 2.5) to 1.9 (0.0–3.7) per 1000 PYs, corresponding to a number needed to harm between 533 and 828.ConclusionThe TCZ GIP event rates from multiple data sources were consistent with previously reported rates, did not increase over time, and were significantly associated with the number of prior biologics. Comparison of GIP incidence rates among patients with prior biologic exposure suggests that, for every 1000 patients treated with TCZ per year, an additional 1–2 GIP events might occur compared with patients treated with aTNFs.FundingRoche.

Results. Patients had stunted growth at baseline (mean height SD score ؊2.2). During tocilizumab treatClinicalTrial.gov identifier: NCT00642460. Istituto Giannina Gaslini has received research support for the PRINTO network from Bristol