Determination of Rapid-Equilibrium Kinetic Parameters of Ordered and Random Enzyme-Catalyzed Reaction A + B = P + Q

This article deals with the rapid-equilibrium kinetics of the forward and reverse reactions together for the ordered and random enzyme-catalyzed A + B = P + Q and emphasizes the importance of reporting the values of the full set of equilibrium constants. Equilibrium constants that are not in the rate equation can be calculated for random mechanisms using thermodynamic cycles. This treatment is based on the use of a computer to derive rate equations for three mechanisms and to estimate the kinetic parameters with the minimum number of velocity measurements. The most general of these three programs is the one to use first when the mechanism for A + B = P + Q is studied for the first time. This article shows the effects of experimental errors in velocity measurements on the values of the kinetic parameters and on the apparent equilibrium constant calculated using the Haldane relation

Transcranial direct current stimulation of right dorsolateral prefrontal cortex does not affect model-based or model-free reinforcement learning in humans

There is broad consensus that the prefrontal cortex supports goal-directed, model-based decision-making. Consistent with this, we have recently shown that model-based control can be impaired through transcranial magnetic stimulation of right dorsolateral prefrontal cortex in humans. We hypothesized that an enhancement of model-based control might be achieved by anodal transcranial direct current stimulation of the same region. We tested 22 healthy adult human participants in a within-subject, double-blind design in which participants were given Active or Sham stimulation over two sessions. We show Active stimulation had no effect on model-based control or on model-free ('habitual') control compared to Sham stimulation. These null effects are substantiated by a power analysis, which suggests that our study had at least 60% power to detect a true effect, and by a Bayesian model comparison, which favors a model of the data that assumes stimulation had no effect over models that assume stimulation had an effect on behavioral control. Although we cannot entirely exclude more trivial explanations for our null effect, for example related to (faults in) our experimental setup, these data suggest that anodal transcranial direct current stimulation over right dorsolateral prefrontal cortex does not improve model-based control, despite existing evidence that transcranial magnetic stimulation can disrupt such control in the same brain region

Unpredictability of metabolism—the key role of metabolomics science in combination with next-generation genome sequencing

Next-generation sequencing provides technologies which sequence whole prokaryotic and eukaryotic genomes in days, perform genome-wide association studies, chromatin immunoprecipitation followed by sequencing and RNA sequencing for transcriptome studies. An exponentially growing volume of sequence data can be anticipated, yet functional interpretation does not keep pace with the amount of data produced. In principle, these data contain all the secrets of living systems, the genotype–phenotype relationship. Firstly, it is possible to derive the structure and connectivity of the metabolic network from the genotype of an organism in the form of the stoichiometric matrix N. This is, however, static information. Strategies for genome-scale measurement, modelling and predicting of dynamic metabolic networks need to be applied. Consequently, metabolomics science—the quantitative measurement of metabolism in conjunction with metabolic modelling—is a key discipline for the functional interpretation of whole genomes and especially for testing the numerical predictions of metabolism based on genome-scale metabolic network models. In this context, a systematic equation is derived based on metabolomics covariance data and the genome-scale stoichiometric matrix which describes the genotype–phenotype relationship

Management of urinary tract infection by early-career general practitioners in Australia

Rationale, aims, and objectives: Urinary tract infection (UTI) is a common presentation to general practitioners (GPs). There is increasing antimicrobial resistance in urinary pathogens in many healthcare systems. Adherence to principles of antimicrobial stewardship is important to combat this problem. Our aim was to describe the prevalence of presentations of clinically diagnosed new UTI to early-career GPs, to describe management choices made, and to identify associations of prescribing antibiotics at the index consultation for UTI. Method: This is a cross-sectional analysis of the Registrar Clinical Encounters in Training cohort study. Early-career GPs from five Australian states (urban to very remote practices) collected data on 60 consecutive patient encounters during each of three 6-month training terms. Proportions of problems being new UTIs, antibiotics prescribed, urine microscopy and culture ordered were calculated. Univariate and multivariable logistic regressions established associations of patient, registrar, and practice factors with prescribing antibiotics for a new UTI. Results: One thousand three hundred thirty-three early-career GPs diagnosed 2850 new UTIs from 189 736 consultations (1.5%; 95% CI, 1.4-1.6). Antibiotics were prescribed at 86% (95% CI, 84.7-87.2) of these index consultations. Antibiotic choice followed Australian therapeutic guideline recommendations. Urine microscopy and culture were requested at the index consultation less than recommended by guidelines in men, 69.2% (95% CI, 62.6-75.1), and children, 80.8% (95% CI, 76.4-84.6). Adults were significantly more likely to be treated with antibiotics at the index consultation than children under 16. Conclusions: A new UTI is a common presentation to Australian early-career GPs. There is general adherence to guidelines for antibiotic choice in UTIs. Further research is needed, however, to understand some decisions made when managing UTI in children and men. This may reflect diagnostic uncertainty with consequent attention to antibiotic stewardship by deferring antibiotic prescription