LYSOLECITHIN AND SPHINGOSINEPHOSPHORYL-CHOLINE IN THE METABOLISM OF BRAIN PHOSPHOLIPIDS OF THE RHESUS MONKEY (MACAC A MULATTA): EFFECTS OF DEVELOPMENT

The rates of incorporation of palmitate from palmitoyl CoA into lecithin or sphingomyelin by homogenates of neural tissue of rhesus monkeys were greatly increased by the addition of lysolecithin or sphingosinephosphorylcholine (SPC). Labelled lysolecithin and SPC were also incorporated into lecithin and sphingomyelin. There was a low level of nonenzymic sphingomyelin formation from SPC and palmitoyl CoA. Choline from CDP-choline was rapidly incorporated into lecithin and slowly into SPC and sphingomyelin by homogenates of pons. The activity of lysolecithin acyl hydrolase (EC 3.1.1.5) was high throughout life in homogenates of pons and cerebral cortex. The rate of utilization of palmitoyl CoA and lysolecithin for phospholipid synthesis was higher in neural tissue from fetal and neonatal monkeys than from adults. Lysolecithin was acylated most rapidly with palmitoleic, linoleic and arachidonic acids. All phospholipid metabolic activities were higher in the cerebral cortex than in the pons.     

Distinguishing driver and passenger mutations in an evolutionary history categorized by interference

In many biological scenarios, from the development of drug resistance in pathogens to the progression of healthy cells toward cancer, quantifying the selection acting on observed mutations is a central question. One difficulty in answering this question is the complexity of the background upon which mutations can arise, with multiple potential interactions between genetic loci. We here present a method for discerning selection from a population history that accounts for interference between mutations. Given sequences sampled from multiple time points in the history of a population, we infer selection at each locus by maximizing a likelihood function derived from a multilocus evolution model. We apply the method to the question of distinguishing between loci where new mutations are under positive selection (drivers) and loci that emit neutral mutations (passengers) in a Wright-Fisher model of evolution. Relative to an otherwise equivalent method in which the genetic background of mutations was ignored, our method inferred selection coefficients more accurately for both driver mutations evolving under clonal interference and passenger mutations reaching fixation in the population through genetic drift or hitchhiking. In a population history recorded by 750 sets of sequences of 100 individuals taken at intervals of 100 generations, a set of 50 loci were divided into drivers and passengers with a mean accuracy of >0.95 across a range of numbers of driver loci. The potential application of our model, either in full or in part, to a range of biological systems, is discussed.     

Effects of fish oil on VLDL triglyceride kinetics in humans

Dietary n-3 fatty acids (FAs) found in fish oils markedly lower plasma triglyceride (TG) and very low density lipoprotein (VLDL) levels in both normal and hypertriglyceridemic subjects. The present study examined the mechanism of this effect. Ten subjects with widely different plasma triglyceride levels (82 to 1002 mg/dl) were fed metabolically controlled diets containing 20% fat. The control diet contained a blend of cocoa butter and peanut oil (P/S = 0.8). The test diet contained fish oil (P/S = 1.1) and provided 10-17 g of n-3 FAs per day (depending on calorie intake). After 3 to 5 weeks of each diet, the kinetics of VLDL-TG were determined over a 48-h period after the injection of [3H]glycerol. The fish oil diet reduced the VLDL-TG synthetic rate from 23 +/- 14.3 (mean +/- SD) to 12.6 +/- 7.5 mg/h per kg ideal weight (P less than 0.005) and increased the fractional catabolic rate (FCR) for VLDL-TG from 0.23 +/- 0.12 to 0.38 +/- 0.16 h -1 (P less than 0.005). At the same time, there was a 66% reduction of plasma triglyceride levels, resulting largely from a 78% decrease in VLDL-TG levels (398 +/- 317 to 87 +/- 77 mg/dl; P less than 0.005). There was a strong correlation (r = 0.83; P less than 0.01) between the change in synthetic rates and pool sizes, but there was no correlation (r = 0.24; NS) between changes in FCRs and pool sizes. The VLDL cholesterol: triglyceride ratio increased during the n-3 diet suggesting that smaller VLDL particles were present. These particles would be expected to leave the VLDL fraction more rapidly than larger particles producing a higher FCR. We conclude that the hypotriglyceridemic effect of fish oil appears to be caused primarily by an inhibition of very low density lipoprotein-triglyceride synthesis, but an additional, independent effect upon VLDL catabolism cannot be ruled out.     

Bayer revisited

Bayer accuses me of wrongly claiming that he holds a negative thesis about the role that the liberal emphasis on privacy rights has had on AIDS public health policy. In his reply to my review essay, he denies holding such a thesis and, moreover, makes the stronger claim that his position is sympathetic to liberalism, or at least to some versions of it. Although I appreciate Bayer's efforts to clarify his views about liberalism and a "culture of restraint and responsibility", it is clear to me that our differences are related not to a misunderstanding on my part, but to a fundamental disagreement concerning what liberalism as a political philosophy is, and what public policy implications it entails in the case of AIDS....