A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies

Transcriptomics approaches in the early Arabidopsis embryo

Early plant embryogenesis condenses the fundamental processes underlying plant development into a short sequence of predictable steps. The main tissues, as well as stem cells for their post-embryonic maintenance, are specified through genetic control networks. A key question is how cell fates are instructed by unique cellular transcriptomes, and important insights have recently been gained through cell type-specific transcriptomics during post-embryonic development. However, the poor accessibility and small size of Arabidopsis (Arabidopsis thaliana) embryos have obstructed similar progress during embryogenesis. Here, we review the current situation in plant embryo transcriptomics, and discuss how the recent development of novel cell-specific analysis technologies will enable the identification of cellular transcriptomes in the early Arabidopsis embryo

Regulation of proteorhodopsin phototrophy in the flavobacterium Dokdonia sp. MED134

17th Ocean Sciences Meeting, 23-28 February 2014, Honolulu, Hawaii USARecent advances reveal the benefit of proteorhodopsin (PR) phototrophy for promoting growth and survival in marine bacteria. Still, the metabolic pathways actually mediating these light responses remain unknown. We therefore investigated metabolic activities and gene expression patterns in Dokdonia sp. MED134 growing in seawater with low concentrations of complex (yeast extract and peptone) or simple (alanine) dissolved organic carbon (DOC). Remarkably, anaplerotic CO2 fixation supplied 30% of the carbon demand in these carbon-limited cultures, with much stronger light responses in alanine. Expression analysis of 11 key genes in bicarbonate uptake, anaplerotic CO2 fixation and TCA cycle pathways showed the PR gene was up-regulated 40-fold in the light, independently of DOC source. Strikingly, the two genes in the glyoxylate shunt (icl and ms) were up-regulated 40- to 100-fold in the light – but only in seawater with alanine. This implies the glyoxylate shunt, which is widespread in marine bacteria, efficiently allows house holding with carbon when PR phototrophy provides ATP. Thus, regulatory interactions between DOC quality and central metabolic pathways critically determine the fitness of surface ocean bacteria engaging in PR phototrophyPeer Reviewe

Response of rare, common and abundant bacterioplankton to anthropogenic perturbations in a Mediterranean coastal site

12 pages, 4 figures, 3 tables, supplementary data http://femsec.oxfordjournals.org/content/suppl/2015/05/31/fiv058.DC1Bacterioplankton communities are made up of a small set of abundant taxa and a large number of low-abundant organisms (i.e. 'rare biosphere'). Despite the critical role played by bacteria in marine ecosystems, it remains unknown how this large diversity of organisms are affected by human-induced perturbations, or what controls the responsiveness of rare compared to abundant bacteria. We studied the response of a Mediterranean bacterioplankton community to two anthropogenic perturbations (i.e. nutrient enrichment and/or acidification) in two mesocosm experiments (in winter and summer). Nutrient enrichment increased the relative abundance of some operational taxonomic units (OTUs), e.g. Polaribacter, Tenacibaculum, Rhodobacteraceae and caused a relative decrease in others (e.g. Croceibacter). Interestingly, a synergistic effect of acidification and nutrient enrichment was observed on specific OTUs (e.g. SAR86). We analyzed the OTUs that became abundant at the end of the experiments and whether they belonged to the rare (1% relative abundance) fractions. Most of the abundant OTUs at the end of the experiments were abundant, or at least common, in the original community of both experiments, suggesting that ecosystem alterations do not necessarily call for rare members to growThe experiments were funded by projects ACDC (CTM2009-08849, to EC and CP), STORM (CTM2009-09352/MAR, to CM and JMG) and ECOBAF (CTM2010-10462-E/MAR, to JMG). FB was supported by an University of Otago Research Grant (UORG). The diversity work was supported by projects from the European Science Foundation (EuroEEFG project MOCA) and the Swedish Research Council to JPPeer Reviewe

Will ocean acidification or eutrophication impact bacterioplankton diversity and carbon processing in the coastal Mediterranean Sea?

IMBIZO III The future of marine biogeochemistry, ecosystems and societies - Multi-dimensional approaches to the challenges of global change in continental margins and open ocean systems. Workshop 2 The impact of anthropogenic perturbations on open ocean carbon sequestration via the dissolved and particulate phases of the biological carbon pump, 28-31 January 2013, Goa, IndiaPeer Reviewe

Response of rare versus abundant bacterioplankton to disturbances in a Mediterranean coastal site

SAME13 - 13th Symposium on Aquatic microbial Ecology, 8-13 September 2013, Stresa, ItalyPeer Reviewe

Linguistic Validation of Genomic Nursing Concept Inventory to Finnish Applying Mandysova's Decision Tree Algorithm.

BACKGROUND AND PURPOSE: Currently, there is no available Finnish version of the Genomic Nursing Concept Inventory tool (GNCI). This study tested the validity, reliability, and clinical usability of a Finnish translation. METHODS: A decision tree algorithm was used to guide the translation, as per International Society for Pharmacoeconomics and Outcomes Research guidelines. Item-Content Validity Index (I-CVI), modified kappa (k*) statistics, and Cronbach's alpha were calculated. RESULTS: The I-CVI and k* values were "good" to "excellent" (I-CVI = 0.63-1.00, k* = 0.52-1.00), and Cronbach's alpha value was "good" (α = 0.816; 95% confidence interval: 0.567-0.956). CONCLUSION: The Mandysova's decision tree algorithm provided clear and rigorous direction for the translation and validity of the Finnish GNCI