Genotype to phenotype mapping still needs under-pinning by research in metabolism and enzymology

The article "Evidence that the metabolite repair enzyme NAD(P)HX epimerase has a moonlighting function" in this issue illustrates a number of the problems that still arise when attempting to translate genotypes to phenotypes, such as for interpreting mutant phenotypes or building genome-scale metabolic models. In this case, the mutation concerned appears to map to an enzyme in one of the little-known but essential metabolite repair pathways that have been discovered in recent years. However, the bioinformatic and experimental evidence presented suggests that the annotated enzyme activity of the mutated gene product, whilst correct, accounts neither for the phenotype nor the chromosomal and transcriptional associations of the gene. The bioinformatic and metabolomic evidence presented points to an additional but important role for the gene product in pyridoxal phosphate homeostasis, thus adding the enzyme to the expanding list of those with a "moonlighting function"

Does influenza vaccination improve pregnancy outcome? Methodological issues and research needs

AbstractEvidence that influenza vaccination during pregnancy is safe and effective at preventing influenza disease in women and their children through the first months of life is increasing. Several reports of reduced risk of adverse outcomes associated with influenza vaccination have generated interest in its potential for improving pregnancy outcome. Gavi, the Vaccine Alliance, estimates maternal influenza immunization programs in low-income countries would have a relatively modest impact on mortality compared to other new or under-utilized vaccines, however the impact would be substantially greater if reported vaccine effects on improved pregnancy outcomes were accurate. Here, we examine the available evidence and methodological issues bearing on the relationship between influenza vaccination and pregnancy outcome, particularly preterm birth and fetal growth restriction, and summarize research needs. Evidence for absence of harm associated with vaccination at a point in time is not symmetric with evidence of benefit, given the scenario in which vaccination reduces risk of influenza disease and, in turn, risk of adverse pregnancy outcome. The empirical evidence for vaccination preventing influenza in pregnant women is strong, but the evidence that influenza itself causes adverse pregnancy outcomes is inconsistent and limited in quality. Studies of vaccination and pregnancy outcome have produced mixed evidence of potential benefit but are limited in terms of influenza disease assessment and control of confounding, and their analytic methods often fail to fully address the longitudinal nature of pregnancy and influenza prevalence. We recommend making full use of results of randomized trials, re-analysis of existing observational studies to account for confounding and time-related factors, and quantitative assessment of the potential benefits of vaccination in improving pregnancy outcome, all of which should be informed by the collective engagement of experts in influenza, vaccines, and perinatal health

Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells

AbstractAlthough epidermal growth factor (EGF) induces transient activation of Ras and the mitogen-activated protein kinase (MAPK) cascade in PC12 cells, whereas nerve growth factor (NGF) stimulates sustained activation, the basis for these contrasting responses is not known. We have developed a computer simulation of EGF-induced MAPK cascade activation, which provides quantitative evidence that feedback inhibition of the MAPK cascade is the most important factor in determining the duration of cascade activation. Hence, we propose that the observed quantitative differences in EGF and NGF signalling can be accounted for by differential feedback regulation of the MAPK cascade

Metabolic control analysis of triacylglycerol accumulation in oilseed rape

The increasing global demand for vegetable oils will only be met if there are significant improvements in the productivity of the major oil crops, such as oilseed rape. Metabolic engineering offers the prospect of further gains in yield beyond that already achieved by breeding and selection but requires guidance as to the changes that need to be made. Metabolic Control Analysis, through measurement and estimation of flux control coefficients, can indicate which enzymes have the most influence on a desired flux. Some experiments have previously reported flux control coefficients for oil accumulation in the seeds of oilseed rape, and others have measured control coefficient distributions for multi-enzyme segments of oil synthesis in seed embryo metabolism measured in vitro. In addition, other reported manipulations of oil accumulation contain results that are exploited further here to calculate previously unknown flux control coefficients. These results are then assembled within a framework that allows an integrated interpretation of the controls on oil accumulation from the assimilation of CO2 to deposition of oil in the seed. The analysis shows that the control is distributed to an extent that the gains from amplifying any single target are necessarily limited, but there are candidates for joint amplification that are likely to act synergistically to produce much more significant gains

Typical and Atypical Antipsychotic Drugs Increase Extracellular Histamine Levels in the Rat Medial Prefrontal Cortex: Contribution of Histamine H1 Receptor Blockade

Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA) efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine, and perphenazine treatment. We found no effect of the selective 5-HT2A antagonist MDL100907, 5-HT2c antagonist SB242084, or the 5-HT6 antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H1 receptor antagonists pyrilamine, diphenhydramine, and triprolidine, the H3 receptor antagonist ciproxifan and the mixed 5-HT2A/H1 receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H1 receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H1 receptor affinity (risperidone, aripiprazole, and haloperidol) were also without effect on HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H1 receptors whereas nine other receptors, including 5-HT2A, were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H1 receptors

The chicken gene nomenclature committee report

Comparative genomics is an essential component of the post-genomic era. The chicken genome is the first avian genome to be sequenced and it will serve as a model for other avian species. Moreover, due to its unique evolutionary niche, the chicken genome can be used to understand evolution of functional elements and gene regulation in mammalian species. However comparative biology both within avian species and within amniotes is hampered due to the difficulty of recognising functional orthologs. This problem is compounded as different databases and sequence repositories proliferate and the names they assign to functional elements proliferate along with them. Currently, genes can be published under more than one name and one name sometimes refers to unrelated genes. Standardized gene nomenclature is necessary to facilitate communication between scientists and genomic resources. Moreover, it is important that this nomenclature be based on existing nomenclature efforts where possible to truly facilitate studies between different species. We report here the formation of the Chicken Gene Nomenclature Committee (CGNC), an international and centralized effort to provide standardized nomenclature for chicken genes. The CGNC works in conjunction with public resources such as NCBI and Ensembl and in consultation with existing nomenclature committees for human and mouse. The CGNC will develop standardized nomenclature in consultation with the research community and relies on the support of the research community to ensure that the nomenclature facilitates comparative and genomic studies