From metabonomics to pharmacometabonomics: Mice, men and microbiota

This talk will highlight new metabonomics findings from a knockout (KO) mouse model of potential importance to the understanding and treatment of obesity, together with new methods of assessing confidence in metabolite structure elucidation. The development of metabonomics to pharmacometabonomics will also be discussed and the potential for its use in personalised medicine

A new paradigm for known metabolite identification in metabonomics/metabolomics: Metabolite identification efficiency

A new paradigm is proposed for assessing confidence in the identification of known metabolites in metabonomics studies using NMR spectroscopy approaches. This new paradigm is based upon the analysis of the amount of metabolite identification information retrieved from NMR spectra relative to the molecular size of the metabolite. Several new indices are proposed: metabolite identification efficiency (MIE) and metabolite identification carbon efficiency (MICE), both of which can be easily calculated. These indices, together with some guidelines, can be used to provide a better indication of known metabolite identification confidence in metabonomics studies than existing methods. Since known metabolite identification in untargeted metabonomics studies is one of the key bottlenecks facing the science currently, it is hoped that these concepts based on molecular spectroscopic informatics, will find utility in the field

Academic drug discovery: Current status and prospects

Introduction. The contraction in pharmaceutical drug discovery operations in the past decade has been counter-balanced by a significant rise in the number of academic drug discovery groups. In addition, pharmaceutical companies that used to operate in completely independent, vertically-integrated operations for drug discovery are now collaborating more with each other, and with academic groups. We are in a new era of drug discovery. Areas Covered. This review provides an overview of the current status of academic drug discovery groups, their achievements and the challenges they face,, together with perspectives on ways to achieve improved outcomes. Expert Opinion. Academic groups have made important contributions to drug discovery, from its earliest days and continue to do so today. However, modern drug discovery and development is exceedingly complex, and has high failure rates, principally because human biology is complex and poorly understood. Academic drug discovery groups need to play to their strengths and not just copy what has gone before. However, there are lessons to be learnt from the experiences of the industrial drug discoverers and four areas are highlighted for attention: (i) increased validation of targets, (ii) elimination of false hits from HTS, (iii) increasing the quality of molecular probes and (iv) investing in a high quality informatics infrastructure

The role of pharmacometabonomics in predicting drug pharmacokinetics

Individual variability in drug response is a key challenge in current clinical practice and in drug discovery and development. Pharmacological response is closely associated with drug concentration at the site of action and therefore knowledge of drug pharmacokinetics is vital to delivering effective therapy. In addition to genetic polymorphisms, environmental factors also play an important role in determining drug efficacy, safety, metabolism and pharmacokinetics. The newly emerging field of pharmacometabonomics uses information from pre-dose metabolite profiles to predict individual drug responses, can be sensitive to both genetic and environmental factors and thus has great promise to help the future delivery of personalized medicine. This article introduces pharmacometabonomics and covers its application to the prediction of pharmacokinetics

Pharmacometabonomics in humans: a new tool for personalized medicine

Pharmacogenomics is now over 50 years old and has had some impact in clinical practice, through its use to select patient subgroups who will enjoy efficacy without side effects when treated with certain drugs. However, pharmacogenomics, has had less impact than initially predicted. One reason for this is that many diseases, and the way in which the patients respond to drug treatments, have both genetic and environmental elements. Pure genomics is almost blind to the environmental elements. A new methodology has emerged, termed pharmacometabonomics that is concerned with the prediction of drug effects through the analysis of predose, biofluid metabolite profiles, which reflect both genetic and environmental influences on human physiology. In this review we will cover what pharmacometabonomics is, how it works, what applications exist and what the future might hold in this exciting new area

Advancing Childhood Food Security through Organizing Strategies

This paper focuses on a project developed in Texas that utilizes community organizing strategies to advance childhood food security. With a dual focus on organizing policymakers and local communities, The Texas Hunger Initiative provides an example of an organizing project with the goal of ending childhood food insecurity in Texas

Assessing the Effectiveness of a Bedtime Behavioral Intervention for Military Children with a Deployed Parent

While there are advantages and disadvantages to the lifestyle of a military family, challenges often include frequent moves, stressful military work environments, and deployments of the active duty member to dangerous war zones. Military children often display an array of internalizing and externalizing problems, with one common problem being disrupted sleep. The purpose of the current study was to evaluate the use of current technology to minimize problematic sleep behaviors affecting young children with a recently deployed parent. The intervention required parents to show their child a previously recorded DVD of the deployed parent reading a children’s book prior to the child’s bedtime. Sleep diary data were collected for two children who had been previously identified as having significant bedtime resistant behavior. A nonconcurrent, multiple-baselines across participants research design was used to evaluate data with two data collection phases for both participants. Analyses revealed considerable reductions in the number of bedtime resistant behaviors post-intervention and large effect sizes were yielded for the intervention phases for both participants. Implications for clinical practice are discussed

Analyzing Math-to-Mastery through Brief Experimental Analysis

The current study evaluated the effectiveness of individualized math-to-mastery (MTM) interventions, selected though brief experimental analysis (BEA), at increasing math fluency skills for 3 elementary-aged females. As MTM has only been investigated as a multicomponent intervention, the present study utilized BEA to identify those specific components which led to math skills gains in the most efficient manner possible. BEA results indicated that for 2 of 3 participants only a partial MTM intervention was necessary to prompt fluency gains, while the entire intervention was the most effective for the third. During extended analysis all 3 participants displayed math skills gains above those seen during repeated baseline assessments. Results are discussed in terms of further refining MTM through BEA procedures so as to individually target math skill deficits by considering both intervention effectiveness and efficiency

Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines.

INTRODUCTION: KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation. OBJECTIVES: To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected. METHODS: Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRAS G13D/+ HCT116 cell line and its isogenic, derivative cell lines KRAS +/- and KRAS G13D/-. RESULTS: Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRASG13D/+ and KRASG13D/- cells have a distinct metabolic profile characterized by dysregulation of TCA cycle, up-regulation of glycolysis and glutathione metabolism pathway as well as increased glutamine uptake and acetate utilization. CONCLUSIONS: Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS

Doubly isogenous genus-2 curves with D₄-action

We study the extent to which curves over finite fields are characterized by their zeta functions and the zeta functions of certain of their covers. Suppose C and C are curves over a finite field K, with K-rational base points P and P , and let D and D be the pullbacks (via the Abel–Jacobi map) of the multiplication-by-2 maps on their Jacobians. We say that (C, P) and (C , P ) are doubly isogenous if Jac(C) and Jac(C ) are isogenous over K and Jac(D) and Jac(D ) are isogenous over K. For curves of genus 2 whose automorphism groups contain the dihedral group of order eight, we show that the number of pairs of doubly isogenous curves is larger than na¨ıve heuristics predict, and we provide an explanation for this phenomenon