A Well-Hung Horse: Sired by Knowledge and Imagination

For more than a century, historians of science have been spinning a philosophical roulette wheel, pondering which is more important in the creative process: imagination or knowledge. The most original scientists (and artists) in our day discover newness by blending existing knowledge with imaginative thinking

Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia

A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors, was able to remove LDL cholesterol from plasma at a nearly normal rate. We conclude that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation. These data underscore the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings. (N Engl J Med 1984; 311: 1658–64.). © 1984, Massachusetts Medical Society. All rights reserved

Identification of the Acyltransferase that Octanoylates Ghrelin, an Appetite-Stimulating Peptide Hormone

SummaryGhrelin is a 28 amino acid, appetite-stimulating peptide hormone secreted by the food-deprived stomach. Serine-3 of ghrelin is acylated with an eight-carbon fatty acid, octanoate, which is required for its endocrine actions. Here, we identify GOAT (Ghrelin O-Acyltransferase), a polytopic membrane-bound enzyme that attaches octanoate to serine-3 of ghrelin. Analysis of the mouse genome revealed that GOAT belongs to a family of 16 hydrophobic membrane-bound acyltransferases that includes Porcupine, which attaches long-chain fatty acids to Wnt proteins. GOAT is the only member of this family that octanoylates ghrelin when coexpressed in cultured endocrine cell lines with prepro-ghrelin. GOAT activity requires catalytic asparagine and histidine residues that are conserved in this family. Consistent with its function, GOAT mRNA is largely restricted to stomach and intestine, the major ghrelin-secreting tissues. Identification of GOAT will facilitate the search for inhibitors that reduce appetite and diminish obesity in humans

Richard G.W. Anderson (1940–2011) and the birth of receptor-mediated endocytosis

On March 19, 2011, the discipline of cell biology lost a creative force with the passing of Richard G.W. Anderson, Professor and Chairman of the Department of Cell Biology at the University of Texas Southwestern Medical School. An unabashed chauvinist for cell biology, Dick served for many years on the editorial board of The Journal of Cell Biology and the Council of the American Society for Cell Biology. He died of glioblastoma multiforme six days before his 71st birthday

Goal-directed versus outcome-based financial incentives for weight loss among low-income patients with obesity: rationale and design of the Financial Incentives foR Weight Reduction (FIReWoRk) randomised controlled trial.

IntroductionObesity is a major public health challenge and exacerbates economic disparities through employment discrimination and increased personal health expenditures. Financial incentives for weight management may intensify individuals' utilisation of evidence-based behavioural strategies while addressing obesity-related economic disparities in low-income populations. Trials have focused on testing incentives contingent on achieving weight loss outcomes. However, based on social cognitive and self-determination theories, providing incentives for achieving intermediate behavioural goals may be more sustainable than incentivising outcomes if they enhance an individual's skills and self-efficacy for maintaining long-term weight loss. The objective of this paper is to describe the rationale and design of the Financial Incentives foR Weight Reduction study, a randomised controlled trial to test the comparative effectiveness and cost-effectiveness of two financial incentive strategies for weight loss (goal directed vs outcome based) among low-income adults with obesity, as well as compared with the provision of health behaviour change resources alone.Methods and analysisWe are recruiting 795 adults, aged 18-70 years with a body mass index ≥30 kg/m2, from three primary care clinics serving residents of socioeconomically disadvantaged neighbourhoods in New York City and Los Angeles. All participants receive a 1-year commercial weight loss programme membership, self-monitoring tools (bathroom scale, food journal and Fitbit Alta HR), health education and monthly check-in visits. In addition to these resources, those in the two intervention groups can earn up to $750 over 6 months for: (1) participating in an intensive weight management programme, self-monitoring weight and diet and meeting physical activity guidelines (goal-directed arm); or (2) a ≥1.5% to ≥5% reduction in baseline weight (outcome-based arm). To maximise incentive efficacy, we incorporate concepts from behavioural economics, including immediacy of payments and framing feedback to elicit regret aversion. We will use generalised mixed effect models for repeated measures to examine intervention effects on weight at 6, 9 and 12 months.Ethics and disseminationHuman research protection committees at New York University School of Medicine, University of California Los Angeles (UCLA) David Geffen School of Medicine and Olive-View-UCLA Medical Center granted ethics approval. We will disseminate the results of this research via peer-reviewed publications, conference presentations and meetings with stakeholders.Trial registration numberNCT03157713

Doping and temperature dependence of electron spectrum and quasiparticle dispersion in doped bilayer cuprates

Within the t-t'-J model, the electron spectrum and quasiparticle dispersion in doped bilayer cuprates in the normal state are discussed by considering the bilayer interaction. It is shown that the bilayer interaction splits the electron spectrum of doped bilayer cuprates into the bonding and antibonding components around the $(\pi,0)$ point. The differentiation between the bonding and antibonding components is essential, which leads to two main flat bands around the $(\pi,0)$ point below the Fermi energy. In analogy to the doped single layer cuprates, the lowest energy states in doped bilayer cuprates are located at the $(\pi/2,\pi/2)$ point. Our results also show that the striking behavior of the electronic structure in doped bilayer cuprates is intriguingly related to the bilayer interaction together with strong coupling between the electron quasiparticles and collective magnetic excitations.Comment: 9 pages, 4 figures, updated references, added figures and discussions, accepted for publication in Phys. Rev.