Front cover (paperback): South wall of a mural depicting Detroit Industry, 1932-33 (fresco), Rivera, Diego (1886-1957)/Detroit Institute of Arts, USA/Gift of Edsel B. Ford/Bridgeman Images. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cold Spring Harbor xiv Foreword The year 2015 marked the sesquicentennial anniversary of Gregor Mendel's landmark 1865 presentation of his paper "Experiments on Plant Hybridization," which laid the groundwork for modern genetics. Seminal discoveries throughout the 20th century followed, not least of which was the demonstration that chromatin carried traits, the formalization of the concept of the gene as the hereditary unit, the discovery of DNA as the hereditary material, the discovery of the double helix structure of DNA, and the elucidation of many mechanisms now known to operate to express and protect the hereditary material in its nuclear, cellular, and organismal context. The year also marked the 125th anniversary of Cold Spring Harbor Laboratory as well as the 80th Cold Spring Harbor Laboratory Symposium on Quantitative Biology, the preeminent and storied series of landmark meetings initiated by Reginald Harris in 1933. It therefore seemed fitting to focus this year's Symposium on 21st Century Genetics: Genes at Work to provide a current synthesis of genetic mechanisms and genome/chromosome biology. The decision to plan the 2015 Symposium on this theme reflects the enormous research progress achieved in recent years, and it was intended to provide a broad synthesis of the current state of the field, setting the stage for future discoveries and application. Opening night speakers included Robert Tjian (HHMI and UC Berkeley) on probing transcription regulation by single-molecule imaging; Denis Duboule (EPF Lausanne, Switzerland), who spoke about long-range regulation during development and evolution; Ron Evans (Salk Institute for Biological Studies) on nuclear receptors-feast, famine, and physiology; and Angelika Amon (Massachusetts Institute of Technology), who addressed the effects of aneuploidy on cellular fitness and tumorigenesis. Svante Pääbo (Max Planck Institute for Evolutionary Anthropology, Germany) addressed The Genetic Legacy of Neanderthals in an outstanding Dorcas Cummings Lecture for Laboratory friends, neighbors, and Symposium participants in advance of the annual dinner parties. Susan Gasser provided a masterful Summary at the conclusion of the Symposium immediately before the final banquet. This Symposium was attended by almost 350 scientists from universities around the country and the world, and the program included 65 invited presentations and 135 poster presentations. To disseminate the latest results and discussion of the Symposium to a wider audience, attendees were able to share many of the Symposium talks with their colleagues who were unable to attend using the Leading Strand video archive.

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MV O 2 ) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MV O 2 and LV mechanical efficiency increased (22.4؎2.8% to 30.9؎3.4% (P<0.05). In contrast, dobutamine significantly increased MV O 2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MV O 2 , resulting in an increased myocardial mechanical efficiency in dogs with HF. F ree fatty acids (FFAs) are the primary energy substrate of the myocardium; however, they are not as efficient as glucose and lactate. 1 Studies in isolated rat hearts, 1 dogs, 2 pigs, 3 and humans 4 show that external power is reduced for a given myocardial oxygen consumption (MV O 2 ) when the heart has elevated FFA oxidation. Abnormalities of energy metabolism may contribute to the poor left ventricular (LV) function that characterizes heart failure (HF). 5,6 Patients with HF designated as New York Heart Association (NYHA) class II-III have greater myocardial FFA oxidation and lower carbohydrate oxidation compared with healthy individuals. 7 Impaired carbohydrate oxidation may contribute to mechanical dysfunction in the failing heart, as suggested by improved contractile function and efficiency in HF patients when carbohydrate oxidation is stimulated with dichloroacetate 8 or intracoronary pyruvate. 9 It has been suggested that pharmacological inhibition of myocardial FFA oxidation improves LV function without an increase in MV O 2 , and thus increases LV mechanical efficiency. 5 Ranolazine inhibits FFA ␤-oxidation and significantly improves treadmill time to onset of angina and 1-mm STsegment depression in patients with chronic stable angina. 10,11 The purpose of this investigation was to measure MV O 2 , LV function, and mechanical efficiency during short-term treatment with ranolazine. We used dobutamine, a positive inotropic agent that should not improve the mechanical efficiency, as a comparator. In addition, the net myocardial uptake of FFAs, glucose, and lactate was assessed. Materials and MethodsThe canine model of chronic HF was previously described in detail. 12,13 Chronic LV dysfunction and failure were produced by multiple sequential intracoronary embolizations, which results in loss of viable myocardium. 12 Eight healthy dogs (Hodgins Kennel, Howell, Mich) underwent microembolizations to induce HF. This study was approved by the Henry Ford Health System Institutional Animal Care and Use Committee.Dogs were anesthetized 12,13 and catheters placed in the femoral vein, coronary sinus, and left ventricle under fluoroscopic guidance, and LV pressure was measured. Cardiac function and coronary flow measurements were made 12,13 and arterial and coronary sinus (cs) blood samples drawn at baseline and after 30 minutes of treatment with either ranolazine (0.5 mg/kg bolus, followed by a constant infusion of 1.0 mg ·...

A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl) phenyl)-2-aminopropane, 5, and its des-alpha-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent 5-HT2A/2C agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [125I]-3-labeled 5-HT2A/2C sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate. The agonist properties of 5 and 6 were evaluated by measuring the accumulation of [3H]inositol monophosphate in cultured cells selectively expressing either 5-HT2A or 5-HT2C receptors. In comparison to serotonin (5-HT), compounds 3 (DOI), 5, and 6 were equally efficacious and full agonists at the 5-HT2C receptor. Similarly, 3 and 5 produced equivalent responses at the 5-HT2A receptor as compared to 5-HT. In contrast, 6, the alpha-desmethyl analog of 5, was only half as potent at stimulating inositol monophosphate accumulation at the 5-HT2A receptor. In conclusion, the title compound 5 and its alpha-desmethyl congener 6 appear to be the most potent of the so-called hallucinogenic amphetamine 5-HT agonists reported to date. Further, the reduced efficacy of 6 at the 5-HT2A receptor may offer at least a partial explanation for the observed higher in vivo potencies of alpha-methyl-substituted compounds in this series.

This study tested the hypothesis that an acute infusion of beta-hydroxybutyrate inhibits myocardial fatty acid uptake and oxidation in vivo. Anesthetized pigs were untreated (n = 6) or treated with an intravenous infusion of fat emulsion (n = 7) to elevate plasma free fatty acid levels. A third group received fat emulsion plus an intravenous infusion of beta-hydroxybutyrate (25 micromol.kg-1.min-1; n = 7) for 60 min. All animals received a continuous infusion of [3H]palmitate, and myocardial fatty acid oxidation was measured from the cardiac production of 3H2O. Plasma free fatty acid concentrations were elevated in the fat emulsion group (0.77 +/- 0.11 mM) compared with the untreated group (0.15 +/- 0.03 mM), which resulted in greater myocardial free fatty acid oxidation. In contrast, the group receiving beta-hydroxybutyrate in addition to fat emulsion had elevated beta-hydroxybutyrate concentration (0.87 +/- 0.11 vs. 0.04 +/- 0.01 mM), but suppressed fatty acid oxidation (0.053 +/- 0.013 micromol.g-1.min-1) (P < 0.05) compared with the fat emulsion group (0.116 +/- 0.029 micromol.g-1.min-1). There were no differences among the three groups in the tissue content for malonyl-CoA, acetyl-CoA, or free CoA or the activity of acetyl-CoA carboxylase; thus the inhibition of fatty acid oxidation by elevated beta-hydroxybutyrate did not appear to be due to malonyl-CoA inhibition of carnitine palmitoyl transferase-I or to an increase in the acetyl-CoA-to-free CoA ratio. In conclusion, fatty acid uptake and oxidation is blocked by an infusion of beta-hydroxybutyrate; this effect was not due to elevated myocardial malonyl-CoA content.

In the well-perfused heart, pyruvate carboxylation accounts for 3-6% of the citric acid cycle (CAC) flux, and CAC carbon is lost via citrate release. We investigated the effects of an acute reduction in coronary flow on these processes and on the tissue content of CAC intermediates. Measurements were made in an open-chest anesthetized swine model. Left anterior descending coronary artery blood flow was controlled by a extracorporeal perfusion circuit, and flow was decreased by 40% for 80 min to induce myocardial hibernation (n = 8). An intracoronary infusion of [U-(13)C(3)]lactate and [U-(13)C(3)]pyruvate was given to measure the entry of pyruvate into the CAC through pyruvate carboxylation from the (13)C-labeled isotopomers of CAC intermediates. Compared with normal coronary flow, myocardial hibernation resulted in parallel decreases of 65% and 79% in pyruvate carboxylation and net citrate release by the myocardium, respectively, and maintenance of the CAC intermediate content. Elevation of the arterial pyruvate concentration by 1 mM had no effect. Thus a 40% decrease in coronary blood flow resulted in a concomitant decrease in pyruvate carboxylation and citrate release as well as maintenance of the CAC intermediates.