Interindividual variability in TPMT enzyme activity: 10 years of experience with thiopurine pharmacogenetics and therapeutic drug monitoring.

Background & Aims: TPMT activity and metabolite determination (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) remain controversial during thiopurine management. This study assessed associations between patient characteristics and TPMT activity, and their impact on metabolite levels.

Patients & Methods: A retrospective review of the laboratory database from a French university hospital identified 7360 patients referred for TPMT phenotype/genotype determination, and/or for 6-TGN/6-MMPN monitoring.

RNA sequencing and proteogenomics reveal the importance of leaderless mRNAs in the radiation-tolerant bacterium Deinococcus deserti.

Deinococcus deserti is a desiccation- and radiation-tolerant desert bacterium. Differential RNA sequencing (RNA-seq) was performed to explore the specificities of its transcriptome. Strikingly, for 1,174 (60%) mRNAs, the transcription start site was found exactly at (916 cases, 47%) or very close to the translation initiation codon AUG or GUG.

Assessing the quality of modelled 3D protein structures using the ModFOLD server.

Model quality assessment programs (MQAPs) aim to assess the quality of modelled 3D protein structures. The provision of quality scores, describing both global and local (per-residue) accuracy are extremely important, as without quality scores we are unable to determine the usefulness of a 3D model for further computational and experimental wet lab studies.Here, we briefly discuss protein tertiary structure prediction, along with the biennial Critical Assessment of Techniques for Protein Structure Prediction (CASP) competition and their key role in driving the field of protein model quality assessment methods (MQAPs).

Predictors of smoking lapse in a human laboratory paradigm.

Rationale: During a smoking quit attempt, a single smoking lapse is highly predictive of future relapse. While several risk factors for a smoking lapse have been identified during clinical trials, a laboratory model of lapse was until recently unavailable and, therefore, it is unclear whether these characteristics also convey risk for lapse in a laboratory environment.

Objectives: The primary study goal was to examine whether real-world risk factors of lapse are also predictive of smoking behavior in a laboratory model of smoking lapse.

Probing atomic scale transformation of fossil dental enamel using Fourier transform infrared and nuclear magnetic resonance spectroscopy: a case study from the Tugen Hills (Rift Gregory, Kenya).

A series of fossil tooth enamel samples was investigated by Fourier transform infrared (FTIR) spectroscopy, (13)C and (19)F magic-angle spinning nuclear magnetic resonance (MAS NMR) and scanning electron microscopy (SEM). Tooth remains were collected in Mio-Pliocene deposits of the Tugen Hills in Kenya. Significant transformations were observed in fossil enamel as a function of increasing fluorine content (up to 2.

Phenome-wide association studies on a quantitative trait: application to TPMT enzyme activity and thiopurine therapy in pharmacogenomics.

Phenome-Wide Association Studies (PheWAS) investigate whether genetic polymorphisms associated with a phenotype are also associated with other diagnoses. In this study, we have developed new methods to perform a PheWAS based on ICD-10 codes and biological test results, and to use a quantitative trait as the selection criterion. We tested our approach on thiopurine S-methyltransferase (TPMT) activity in patients treated by thiopurine drugs.

Pax3 and Zic1 trigger the early neural crest gene regulatory network by the direct activation of multiple key neural crest specifiers.

Neural crest development is orchestrated by a complex and still poorly understood gene regulatory network. Premigratory neural crest is induced at the lateral border of the neural plate by the combined action of signaling molecules and transcription factors such as AP2, Gbx2, Pax3 and Zic1. Among them, Pax3 and Zic1 are both necessary and sufficient to trigger a complete neural crest developmental program.

The metabolic sensors FXRα, PGC-1α, and SIRT1 cooperatively regulate hepatitis B virus transcription.

Hepatitis B virus (HBV) genome transcription is highly dependent on liver-enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor α (FXRα) enhances HBV core promoter activity and pregenomic RNA synthesis. Interestingly, two food-withdrawal-induced FXRα modulators, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and deacetylase SIRT1, have been found to be associated with HBV genomes ex vivo.

Exploration of ICD-9-CM coding of chronic disease within the Elixhauser Comorbidity Measure in patients with chronic heart failure.

Introduction: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes capture comorbidities that can be used to risk adjust nonrandom patient groups. We explored the accuracy of capturing comorbidities associated with one risk adjustment method, the Elixhauser Comorbidity Measure (ECM), in patients with chronic heart failure (CHF) at one Veterans Affairs (VA) medical center. We explored potential reasons for the differences found between the original codes assigned and conditions found through retrospective review.

Mathematical modeling of G protein-coupled receptor function: what can we learn from empirical and mechanistic models?

Empirical and mechanistic models differ in their approaches to the analysis of pharmacological effect. Whereas the parameters of the former are not physical constants those of the latter embody the nature, often complex, of biology. Empirical models are exclusively used for curve fitting, merely to characterize the shape of the E/[A] curves.

Localised intraspecific variation in the swimming phenotype of a coral reef fish across different wave exposures.

Wave-driven water flow is a major force structuring marine communities. Species distributions are partly determined by the ability to cope with variation in water flow, such as differences in the assemblage of fish species found in a given water flow environment being linked to swimming ability (based on fin shape and mode of locomotion). It remains unclear, however, whether similar assembly rules apply within a species.

Acute alcohol response phenotype in heavy social drinkers is robust and reproducible.

Background: In 3 previously published works (Brumback et al., 2007, Drug Alcohol Depend 91:10-17; King et al., 2011a, Arch Gen Psychiatry 68:389-399; Roche and King, 2010, Psychopharmacology (Berl) 212:33-44), our group characterized acute alcohol responses in a large group of young, heavy binge drinkers (n = 104) across a variety of subjective, eye-tracking, and psychometric performance measures.

Unsteady flow affects swimming energetics in a labriform fish (Cymatogaster aggregata).

Unsteady water flows are common in nature, yet the swimming performance of fishes is typically evaluated at constant, steady speeds in the laboratory. We examined how cyclic changes in water flow velocity affect the swimming performance and energetics of a labriform swimmer, the shiner surfperch, Cymatogaster aggregata, during station holding. Using intermittent-flow respirometry, we measured critical swimming speed (Ucrit), oxygen consumption rates (O2) and pectoral fin use in steady flow versus unsteady flows with either low- [0.

The FunFOLD2 server for the prediction of protein-ligand interactions.

The FunFOLD2 server is a new independent server that integrates our novel protein-ligand binding site and quality assessment protocols for the prediction of protein function (FN) from sequence via structure. Our guiding principles were, first, to provide a simple unified resource to make our function prediction software easily accessible to all via a simple web interface and, second, to produce integrated output for predictions that can be easily interpreted. The server provides a clean web interface so that results can be viewed on a single page and interpreted by non-experts at a glance.

Silencing of ghrelin receptor expression inhibits endometrial cancer cell growth in vitro and in vivo.

Ghrelin is a 28-amino acid peptide hormone produced predominantly in the stomach but also in a range of normal cell types and tumors, where it has endocrine, paracrine, and autocrine roles. Previously, we have demonstrated that ghrelin has proliferative and antiapoptotic effects in endometrial cancer cell lines, suggesting a potential role in promoting tumor growth. In the present study, we investigated the effect of ghrelin receptor, GHSR, and gene silencing in vitro and in vivo and characterized ghrelin and GHSR1a protein expression in human endometrial tumors.

Hormonal contraceptive use diminishes salivary cortisol response to psychosocial stress and naltrexone in healthy women.

The use of hormonal contraception (HC) may affect salivary cortisol levels at rest and in response to a pharmacological or stress challenge. Therefore, the current study used a secondary data analysis to investigate the effect of HC on salivary cortisol levels in response to the mu-opioid receptor antagonist naltrexone and a psychosocial stressor, and also across the diurnal curve. Two hundred and nine women (n=72 using hormonal contraception; HC+) completed a two-session stress response study that consisted of a stress day, in which they were exposed to public speaking and mental arithmetic, and a rest day, in which unstimulated cortisol levels were measured to assess the diurnal rhythm.

Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models.

Two-state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor-dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two-state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one-by-one correspondence between parameters is found.

The Nocardia cyriacigeorgica GUH-2 genome shows ongoing adaptation of an environmental Actinobacteria to a pathogen's lifestyle.

Background: Nocardia cyriacigeorgica is recognized as one of the most prevalent etiological agents of human nocardiosis. Human exposure to these Actinobacteria stems from direct contact with contaminated environmental matrices. The full genome sequence of N.

The ModFOLD4 server for the quality assessment of 3D protein models.

Once you have generated a 3D model of a protein, how do you know whether it bears any resemblance to the actual structure? To determine the usefulness of 3D models of proteins, they must be assessed in terms of their quality by methods that predict their similarity to the native structure. The ModFOLD4 server is the latest version of our leading independent server for the estimation of both the global and local (per-residue) quality of 3D protein models. The server produces both machine readable and graphical output, providing users with intuitive visual reports on the quality of predicted protein tertiary structures.

Pax3 and Zic1 drive induction and differentiation of multipotent, migratory, and functional neural crest in Xenopus embryos.

Defining which key factors control commitment of an embryonic lineage among a myriad of candidates is a longstanding challenge in developmental biology and an essential prerequisite for developing stem cell-based therapies. Commitment implies that the induced cells not only express early lineage markers but further undergo an autonomous differentiation into the lineage. The embryonic neural crest generates a highly diverse array of derivatives, including melanocytes, neurons, glia, cartilage, mesenchyme, and bone.

Finding the best estimates of metabolic rates in a coral reef fish.

Metabolic rates of aquatic organisms are estimated from measurements of oxygen consumption rates ( ) through swimming and resting respirometry. These distinct approaches are increasingly used in ecophysiology and conservation physiology studies; however, few studies have tested whether they yield comparable results. We examined whether two fundamental measures, standard metabolic rate (SMR) and maximum metabolic rate (MMR), vary based on the method employed.

Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis.

Global spread and limited genetic variation are hallmarks of M. tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa.