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

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

Synthesis and characterization of nanohybrid materials based on block copolymers and clays

Η ανάμειξη ανόργανων υλικών με πολυμερή οδηγεί στην παρασκευή σύνθετων υλικών τα οποία παρουσιάζουν βελτιωμένες ιδιότητες σε σχέση με τα αρχικά συστατικά. Μια σημαντική κατηγορία τέτοιων σύνθετων υλικών αποτελούν τα νανοσύνθετα υλικά στα οποία το ανόργανο πρόσθετο έχει τουλάχιστον μια διάσταση της τάξης του νανομέτρου. Σε αυτήν την κατηγορία ανήκουν τα υβρίδια που προκύπτουν από την ανάμειξη πολυμερών με πολυστρωματικούς πυριτιούχους πηλούς. Τα υλικά αυτά εμφανίζουν ανάλογα με τη δομή του σύνθετου υλικού υψηλότερη θερμική αντοχή και καλύτερες μηχανικές ιδιότητες ενώ συγχρόνως διατηρούν πλεονεκτήματα των αρχικών πολυμερών, όπως η διαφάνεια ή η ευκολία στην κατεργασία . Αντικείμενο της παρούσας εργασίας είναι η σύνθεση και η μελέτη των αλληλεπιδράσεων και των ιδιοτήτων νανοσύνθετων υλικών που αποτελούνται από πολυστρωματικούς πυριτιούχους πηλούς και δισυσταδικά συμπολυμερή πολυαιθυλενοξειδίου-πολυστυρενίου (PEO-b-PS). Ο πηλός που χρησιμοποιήθηκε ήταν ο φυσικός υδρόφιλος μοντμοριλλονίτης νατρίου (Na+) ενώ τα συμπολυμερή συντέθηκαν στο εργαστήριο με τη χρήση ελεγχόμενου ριζικού πολυμερισμού. Από την βιβλιογραφία είναι γνωστό ότι το ομοπολυμερές του PEO έχει την δυνατότητα παρεμβολής ανάμεσα στα στρώματα του μοντμοριλλονίτη Νa+καθώς είναι υδρόφιλο μόριο και επομένως οι αλληλεπιδράσεις του με την επιφάνεια του πηλού είναι ευνοϊκές. Αντίθετα το ομοπολυμερές του PS είναι υδρόφοβο με αποτέλεσμα οι αλληλεπιδράσεις του με τον πηλό να είναι μη ευνοϊκές και επομένως δεν δίνει δομές παρεμβολής αλλά φασικά διαχωρισμένες δομές. Σκοπός της εργασίας αυτής είναι να μελετήσει τι συμβαίνει στην περίπτωση των αμφίφιλων συμπολυμερών PEO-b-PS. Ποιες είναι οι συνολικές αλληλεπιδράσεις των συμπολυμερών με τον φυσικό υδρόφιλο μοντμοριλλονίτη και ποια η δομή των νανοσύνθετων υλικών που προκύπτουν. Ειδικότερα εξετάστηκε η επίδραση του μοριακού βάρους και της σύστασης των συμπολυμερών στην τελική δομή των νανοσύνθετων υλικών. Για τον σκοπό αυτό αρχικά συντέθηκαν επτά συμπολυμερή PEO-b-PS με ελεγχόμενο ριζικό πολυμερισμό μεταφοράς ατόμου (Atom Transfer Radical Polymerization, ATRP) και στην συνέχεια τα πολυμερή χαρακτηρίσθηκαν ως προς το μοριακό βάρος, την κατανομή μοριακών βαρών και την σύστασή τους. Μελετήθηκαν επίσης οι θερμικές ιδιότητες των πολυμερών και η θερμοδυναμική τους κατάσταση. Για την παρασκευή των νανοσύνθετων υλικών χρησιμοποιήθηκε η μέθοδος παρεμβολής τήγματος πολυμερούς. Στην συνέχεια χρησιμοποιήθηκε περίθλαση ακτίνων Χ για την μελέτη της δομής τους και για την εύρεση της διαστρωματικής τους απόστασης. Βρέθηκε ότι η δομή που εμφανίζουν τα νανοϋβρίδια είναι δομή παρεμβολής με διαστρωματικές αποστάσεις που μοιάζουν με αυτές που εμφανίζει το ομοπολυμερές PEO όταν αναμειγνύεται με το ίδιο ανόργανο υλικό και φαίνεται ότι ο λόγος που καθορίζει την τελική δομή σε όλες τις περιπτώσεις είναι η σύσταση PEO ως προς Na+. Για να ερευνηθεί ο ρόλος που παίζει η συστάδα του PS σε όλη την διαδικασία μελετήθηκαν οι αλληλεπιδράσεις που αναπτύσσονται ανάμεσα στις συστάδες του συμπολυμερούς και της ανόργανης επιφάνειας με την βοήθεια φασματοσκοπίας υπερύθρου. Τέλος, μελετήθηκε ο φθορισμός της συστάδας του πολυστυρενίου και η επίδραση που έχει σε αυτόν η θέση του πολυστυρενίου στο σύστημα. Η τεχνική που χρησιμοποιήθηκε για τον σκοπό αυτό είναι η φθορισμομετρία η οποία έδειξε ότι ο εγγενής φθορισμός του πολυστυρενίου χάνεται όταν αυτό βρίσκεται περιορισμένο μεταξύ των στρωμάτων του ανόργανου υλικού. Στην περίπτωση των νανοσύνθετων υλικών Na+/PEO-b-PS ο φθορισμός του PS είναι μετρήσιμος, γεγονός που αποδεικνύει ότι η συστάδα του PS βρίσκεται έξω από τις γαλαρίες.Mixing polymers with inorganic materials leads to the synthesis of composites, which have improved properties with respect to the original materials. An important category among them, are the nanohybrids in which the inorganic component has at least one dimension at the nanometer scale. This category includes hybrids that are formed by mixing polymers with layered silicate clays. Such materials exhibit (depending on their structure) high thermal resistance and improved mechanical properties, whereas they retain the advantages of the initial polymers, such as the transparency or the easy processability. The purpose of the present project is the synthesis and the study of the interactions and the properties of nanocomposite materials which consist of layered silicate clays and poly(ethylene oxide)-b-poly(styrene) (PEO-b-PS) diblock copolymers. The clay used is a natural hydrophilic sodium montmorillonite (Na+) whereas the copolymers were synthesized in the lab, in the framework of this work, utilizing controlled radical polymerization. It is well known from the literature that the PEO homopolymer has the ability to intercalate between the layers of the clay, as it is hydrophilic molecule, therefore has favorable interactions with the surface of the clay. On the other hand, the PS homopolymer is hydrophobic molecule and has unfavorable interactions with the clay, leading to phase separated structures. This study is focalized in the case of PEO-b-PS amphiphilic copolymers. The total interactions of the copolymers with the natural montmorillonite as well as the structure of the resulted nanocomposite materials are investigated. Especially, the influence of the molecular weight and the concentration of the copolymers to the final structure of the nanocomposite materials is examined in detail. Seven PEO-b-PS copolymers with varying molecular weight and composition were synthesized utilizing controlled Atom Transfer Radical Polymerization (ATRP). Their molecular weight and their polydispersity were evaluated with Size Exclusion Chromatography (SEC) whereas their composition was measured with 1H Nuclear Magnetic Resonance (1H NMR). The thermal properties and the thermodynamic condition of the polymers were also studied with Differential Scanning Calorimetry (DSC) and Small Angle X-ray Scattering (SAXS) respectively. For the preparation of the nanocomposite materials, the polymer melt intercalation method was used and hybrids with composition that varied from pure polymer to pure clay were synthesized. Following the synthesis, X-ray diffraction (XRD) was utilized to study the structure and to determine the interlayer distance. It was found that all nanohybrids have intercalated structure with interlayer distances that are similar to the ones that correspond to the respective of PEO homopolymer when it is mixed with the same inorganic material. There is, thus, a strong indication that in every case the final structure is determined by just the Na+/PEO ratio in the copolymer hybrids. In order to investigate the role of the PS block in the system, the interactions between the blocks of the copolymer and the inorganic surface were studied by infrared spectroscopy (FTIR). Finally, the fluorescence of the PS block as well as the way it is affected by whether the polystyrene is intercalated or not was studied. It was proved that the intrinsic fluorescence of PS is vanished when it is intercalated between the inorganic layers. In the case of the Na+/PEO-b-PS nanocomposites the PS fluorescence is measurable, evidencing that the PS block is outside of the inorganic galleries and only the PEO block of the copolymer intercalates

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