Systematic Evaluation of the Descriptive and Predictive Performance of Paediatric Morphine Population Models

Purpose: A framework for the evaluation of paediatric population models is proposed and applied to two different paediatric population pharmacokinetic models for morphine. One covariate model was based on a systematic covariate analysis, the other on fixed allometric scaling principles. Methods: The six evaluation criteria in the framework were 1) number of parameters and condition number, 2) numerical diagnostics, 3) prediction-based diagnostics, 4) η-shrinkage, 5) simulation-based diagnostics, 6) diagnostics of individual and population parameter estimates versus covariates, including measurements of bias and precision of the population values compared to the observed individual values. The framework entails both an internal and external model evaluation procedure. Results: The application of the framework to the two models resulted in the detection of overparameterization and misleading diagnostics based on individual predictions caused by high shrinkage. The diagnostic of individual and population parameter estimates versus covariates proved to be highly informative in assessing obtained covariate relationships. Based on the framework, the systematic covariate model proved to be superior over the fixed allometric model in terms of predictive performance. Conclusions: The proposed framework is suitable for the evaluation of paediatric (covariate) models and should be applied to corroborate the descriptive and predictive properties of these models

Hydrophilicity Matching – A Potential Prerequisite for the Formation of Protein-Protein Complexes in the Cell

A binding event between two proteins typically consists of a diffusional search of binding partners for one another, followed by a specific recognition of the compatible binding sites resulting in the formation of the complex. However, it is unclear how binding partners find each other in the context of the crowded, constantly fluctuating, and interaction-rich cellular environment. Here we examine the non-specific component of protein-protein interactions, which refers to those physicochemical properties of the binding partners that are independent of the exact details of their binding sites, but which can affect their localization or diffusional search for one another. We show that, for a large set of high-resolution experimental 3D structures of binary, transient protein complexes taken from the DOCKGROUND database, the binding partners display a surprising, statistically significant similarity in terms of their total hydration free energies normalized by a size-dependent variable. We hypothesize that colocalization of binding partners, even within individual cellular compartments such as the cytoplasm, may be influenced by their relative hydrophilicity, potentially in response to local hydrophilic gradients

On the thermodynamic origin of metabolic scaling

This work has been funded by projects AYA2013-48623-C2-2, FIS2013-41057-P, CGL2013-46862-C2-1-P and SAF2015-65878-R from the Spanish Ministerio de Economa y Competitividad and PrometeoII/2014/086, PrometeoII/2014/060 and PrometeoII/2014/065 from the Generalitat Valenciana (Spain). BL acknowledges funding from a Salvador de Madariaga fellowship, and L.L. acknowledges funding from EPSRC Early Career fellowship EP/P01660X/1

Gene duplication and phenotypic changes in the evolution of Mammalian metabolic networks

Metabolic networks attempt to describe the complete suite of biochemical reactions available to an organism. One notable feature of these networks in mammals is the large number of distinct proteins that catalyze the same reaction. While the existence of these isoenzymes has long been known, their evolutionary significance is still unclear. Using a phylogenetically-aware comparative genomics approach, we infer enzyme orthology networks for sixteen mammals as well as for their common ancestors. We find that the pattern of isoenzymes copy-number alterations (CNAs) in these networks is suggestive of natural selection acting on the retention of certain gene duplications. When further analyzing these data with a machine-learning approach, we found that that the pattern of CNAs is also predictive of several important phenotypic traits, including milk composition and geographic range. Integrating tools from network analyses, phylogenetics and comparative genomics both allows the prediction of phenotypes from genetic data and represents a means of unifying distinct biological disciplines

Matrin 3 is a co-factor for HIV-1 Rev in regulating post-transcriptional viral gene expression

Post-transcriptional regulation of HIV-1 gene expression is mediated by interactions between viral transcripts and viral/cellular proteins. For HIV-1, post-transcriptional nuclear control allows for the export of intron-containing RNAs which are normally retained in the nucleus. Specific signals on the viral RNAs, such as instability sequences (INS) and Rev responsive element (RRE), are binding sites for viral and cellular factors that serve to regulate RNA-export. The HIV-1 encoded viral Rev protein binds to the RRE found on unspliced and incompletely spliced viral RNAs. Binding by Rev directs the export of these RNAs from the nucleus to the cytoplasm. Previously, Rev co-factors have been found to include cellular factors such as CRM1, DDX3, PIMT and others. In this work, the nuclear matrix protein Matrin 3 is shown to bind Rev/RRE-containing viral RNA. This binding interaction stabilizes unspliced and partially spliced HIV-1 transcripts leading to increased cytoplasmic expression of these viral RNAs

The self-organizing fractal theory as a universal discovery method: the phenomenon of life

A universal discovery method potentially applicable to all disciplines studying organizational phenomena has been developed. This method takes advantage of a new form of global symmetry, namely, scale-invariance of self-organizational dynamics of energy/matter at all levels of organizational hierarchy, from elementary particles through cells and organisms to the Universe as a whole. The method is based on an alternative conceptualization of physical reality postulating that the energy/matter comprising the Universe is far from equilibrium, that it exists as a flow, and that it develops via self-organization in accordance with the empirical laws of nonequilibrium thermodynamics. It is postulated that the energy/matter flowing through and comprising the Universe evolves as a multiscale, self-similar structure-process, i.e., as a self-organizing fractal. This means that certain organizational structures and processes are scale-invariant and are reproduced at all levels of the organizational hierarchy. Being a form of symmetry, scale-invariance naturally lends itself to a new discovery method that allows for the deduction of missing information by comparing scale-invariant organizational patterns across different levels of the organizational hierarchy

Estimating the biological half-life for radionuclides in homoeothermic vertebrates: a simplified allometric approach

The application of allometric, or mass-dependent, relationships within radioecology has increased with the evolution of models to predict the exposure of organisms other than man. Allometry presents a method of addressing the lack of empirical data on radionuclide transfer and metabolism for the many radionuclide–species combinations which may need to be considered. However, sufficient data across a range of species with different masses are required to establish allometric relationships and this is not always available. Here, an alternative allometric approach to predict the biological half-life of radionuclides in homoeothermic vertebrates which does not require such data is derived. Biological half-life values are predicted for four radionuclides and compared to available data for a range of species. All predictions were within a factor of five of the observed values when the model was parameterised appropriate to the feeding strategy of each species. This is an encouraging level of agreement given that the allometric models are intended to provide broad approximations rather than exact values. However, reasons why some radionuclides deviate from what would be anticipated from Kleiber’s law need to be determined to allow a more complete exploitation of the potential of allometric extrapolation within radioecological models

Postconditioning Hormesis Put in Perspective: An Overview of Experimental and Clinical Studies

A beneficial effect of applying mild stress to cells or organisms, that were initially exposed to a high dose of stress, has been referred to as ‘postconditioning hormesis’. The initial high dose of stress activates intrinsic self-recovery mechanisms. Modulation of these endogenous adaptation strategies by administration of a subsequent low dose of stress can confer effects that are beneficial to the biological system. Owing to its potentially therapeutic applications, postconditioning hormesis is subject to research in various scientific disciplines. This paper presents an overview of the dynamics of postconditioning hormesis and illustrates this phenomenon with a number of examples in experimental and clinical research