Resilience trinity: safeguarding ecosystem functioning and services across three different time horizons and decision contexts

Ensuring ecosystem resilience is an intuitive approach to safeguard the functioning of ecosystems and hence the future provisioning of ecosystem services (ES). However, resilience is a multi‐faceted concept that is difficult to operationalize. Focusing on resilience mechanisms, such as diversity, network architectures or adaptive capacity, has recently been suggested as means to operationalize resilience. Still, the focus on mechanisms is not specific enough. We suggest a conceptual framework, resilience trinity, to facilitate management based on resilience mechanisms in three distinctive decision contexts and time‐horizons: 1) reactive, when there is an imminent threat to ES resilience and a high pressure to act, 2) adjustive, when the threat is known in general but there is still time to adapt management and 3) provident, when time horizons are very long and the nature of the threats is uncertain, leading to a low willingness to act. Resilience has different interpretations and implications at these different time horizons, which also prevail in different disciplines. Social ecology, ecology and engineering are often implicitly focussing on provident, adjustive or reactive resilience, respectively, but these different notions of resilience and their corresponding social, ecological and economic tradeoffs need to be reconciled. Otherwise, we keep risking unintended consequences of reactive actions, or shying away from provident action because of uncertainties that cannot be reduced. The suggested trinity of time horizons and their decision contexts could help ensuring that longer‐term management actions are not missed while urgent threats to ES are given priority

Exploration of Catalytic Properties of CYP2D6 and CYP3A4 Through Metabolic Studies of Levorphanol and Levallorphan □ S

ABSTRACT: CYP2D6 and CYP3A4, two members of the cytochrome P450 superfamily of monooxygenases, mediate the biotransformation of a variety of xenobiotics. The two enzymes differ in substrate specificity and size and characteristics of the active site cavity. The aim of this study was to determine whether the catalytic properties of these isoforms, reflected by the differences observed from crystal structures and homology models, could be confirmed with experimental data. Detailed metabolite identification, reversible inhibition, and time-dependent inhibition were examined for levorphanol and levallorphan with CYP2D6 and CYP3A4. The studies were designed to provide a comparison of the orientations of substrates, the catalytic sites of the two enzymes, and the subsequent outcomes on metabolism and inhibition. The metabolite identification revealed that CYP3A4 catalyzed the formation of a variety of metabolites as a result of presenting different parts of the substrates to the heme. CYP2D6 was a poorer catalyst that led to a more limited number of metabolites that were interpreted in terms to two orientations of the substrates. The inhibition studies showed evidence for strong reversible inhibition of CYP2D6 but not for CYP3A4. Levallorphan acted as a time-dependent inhibitor on CYP3A4, indicating a productive binding mode with this enzyme not observed with CYP2D6 that presumably resulted from close interactions of the N-allyl moiety oriented toward the heme. All the results are in agreement with the large and flexible active site of CYP3A4 and the more restricted active site of CYP2D6

Resilience trinity: safeguarding ecosystem functioning and services across three different time horizons and decision contexts

Ensuring ecosystem resilience is an intuitive approach to safeguard the functioning of ecosystems and hence the future provisioning of ecosystem services (ES). However, resilience is a multi-faceted concept that is difficult to operationalize. Focusing on resilience mechanisms, such as diversity, network architectures or adaptive capacity, has recently been suggested as means to operationalize resilience. Still, the focus on mechanisms is not specific enough. We suggest a conceptual framework, resilience trinity, to facilitate management based on resilience mechanisms in three distinctive decision contexts and time-horizons: i) reactive, when there is an imminent threat to ES resilience and a high pressure to act, ii) adjustive, when the threat is known in general but there is still time to adapt management, and iii) provident, when time horizons are very long and the nature of the threats is uncertain, leading to a low willingness to act. Resilience has different interpretations and implications at these different time horizons, which also prevail in different disciplines. Social ecology, ecology, and engineering are often implicitly focussing on provident, adjustive, or reactive resilience, respectively, but these different notions and of resilience and their corresponding social, ecological, and economic trade-offs need to be reconciled. Otherwise, we keep risking unintended consequences of reactive actions, or shying away from provident action because of uncertainties that cannot be reduced. The suggested trinity of time horizons and their decision contexts could help ensuring that longer-term management actions are not missed while urgent threats to ES are given priority

Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimisation for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 >9) and by careful manipulation of the pKa and lipophilicity we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in-vivo studies where significant target engagement could be demonstrated

Experimental and computational investigation of affinity and selectivity factors in CYP2D6 and CYP3A4 mediated metabolism

The assessment of ADME properties and metabolic behavior of a drug is central in drug discovery and drug design. The main target for studies of metabolic properties is the Cytochrome P450 (CYP), which is responsible for the metabolism of a majority of drugs on the market and consequently also involved in many drug-drug interactions. Examples of information and tools that could guide drug design towards favorable metabolic properties are structural information of the CYPs, affinity and selectivity towards the CYPs and the site of metabolism (SOM). The present work was initiated to use experimental and computational tools to study the affinity and selectivity for two of the most important isoenzymes, CYP2D6 and CYP3A4, and highlight the benefit of combining different approaches and assays to understand the metabolic properties of a drug. A novel computational approach resulting in an assessment of enzyme-ligand interaction patterns were successfully used for a comparison of different 3D-structures in order to highlight discriminative amino acid residues. This method could also offer an identification of important interactions when understanding affinity and selectivity for an enzyme. In order to explore affinity and selectivity factors in CYP3A4 and CYP2D6 mediated metabolism two compounds were selected for an experimental evaluation of the catalytic properties of the enzyme. Based on the results from different in vitro assays it could be concluded that CYP3A4 was more unselective, producing metabolites as a result of orientations presenting many different parts of the molecules to the heme. CYP2D6 on the other hand showed more restricted binding modes. The combined information from inhibition studies and metabolite identification also gave indications on productive and non-productive binding modes in the two enzymes. With further exploration of CYP2D6, and its pharmacophore, N-dealkylation and the effect of blocking the SOM in CYP2D6 substrates were studied. These results were in agreement with the previously stated pharmacophore and also showed that the SOM for these substrates could be successfully assigned with a ligand-based approach, which could also be used to assign selectivity for CYP2D6. Key information, in designing compounds towards preferable metabolic properties, is obtained from metabolite identification or SOM determinations. I order to enhance metabolite identification a semi-automated software was tested that assigned the metabolite structure from MS raw data with high success rate. This could consequently be beneficial for drug design in that it enables a high throughput of metabolite identification data. During the course of these work important aspects to consider in drug design has been observed, e.g. improving metabolic stability by blocking soft spots tend to result in CYP inhibition. Instead of blocking soft spots the affinity for an enzyme could be diminished and this could be guided by the computational approach used in the first project. In summary, the combined knowledge from in vitro and in silico tools could be beneficial for the understanding of the metabolic behavior of a drug

Die Europapolitik linker Parteien in den post-kommunistischen Beitrittslaendern

Die vorliegende Kurzstudie prueft die Vertraeglichkeit zwischen dem Wesen und den Zielen der EU und den linken Parteien in den postkommunistischen Beitrittslaendern, indem deren Programmatik und Politik untersucht werden. Neben den Primaerquellen stuetzten sich die Autoren auf Quellen, die allgemein die Europapolitik der Beitrittslaender beschreiben. Insbesondere wenn die hier betrachteten linken Parteien an der Regierung beteiligt sind, darf das faktische Regierungshandeln als Ausdruck einer von diesen Parteien geteilten oder zumindest geduldeten Position gelten. Die Autoren beschreiben linke Parteien, ihre Einbettung in das Parteiensystem des jeweiligen Landes und insbesondere ihre Haltung zur Europapolitik. Dabei erfolgt zunaechst ein Ueberblick ueber die Zusammensetzung des Parlamentes, die Regierungsparteien und - sofern moeglich - die Ergebnisse des Referendums ueber einen Beitritt zur EU. In einem zweiten Schritt werden sodann die vorliegenden Stellungnahmen und Programme der einzelnen Parteien ausgewertet. Es wird deutlich, dass im Feld der Parteienkonkurrenz innerhalb der politischen Systeme der Beitrittslaender die Parteien der demokratischen Linken die klarsten Befuerworter der europaeischen Integration sind. (ICD)SIGLEAvailable from Friedrich-Ebert-Stiftung e.V. Abt. Internationale Politikanalyse, Bonn (DE) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Montelukast Disposition: No Indication of Transporter-Mediated Uptake in OATP2B1 and OATP1B1 Expressing HEK293 Cells

Clinical studies with montelukast show variability in effect and polymorphic OATP2B1-dependent absorption has previously been implicated as a possible cause. This claim has been challenged with conflicting data and here we used OATP2B1-transfected HEK293 cells to clarify the mechanisms involved. For montelukast, no significant difference in cell uptake between HEK-OATP2B1 and empty vector cell lines was observed at pH 6.5 or pH 7.4, and no concentration-dependent uptake was detected. Montelukast is a carboxylic acid, a relatively potent inhibitor of OATP1B1, OATP1B3, and OATP2B1, and has previously been postulated to be actively transported into human hepatocytes. Using OATP1B1-transfected HEK293 cells and primary human hepatocytes in the presence of OATP inhibitors we demonstrate for the first time that active OATP-dependent transport is unlikely to play a significant role in the human disposition of montelukast