Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor \u3b3. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents

Abstinence-only-until-marriage : An Updated review of U.S. policies and programs and their impact

Adolescence is marked by the emergence of human sexuality, sexual identity and the initiation of intimate relations; within this context, abstinence from sexual intercourse can be a healthy choice. However, programs that promote abstinence-only-until-marriage (AOUM) or sexual risk avoidance (SRA), are scientifically and ethically problematic and—as such—have been widely rejected by medical and public health professionals. Although abstinence is theoretically effective, in actual practice, intentions to abstain from sexual activity often fail. Given a rising age at first marriage around the world, a rapidly declining percentage of young people remain abstinent until marriage. Promotion of AOUM policies by the United States (U.S.) government has undermined sexuality education in the U.S. and in U.S. foreign aid programs; funding for AOUM continues in the U.S. The weight of scientific evidence finds that AOUM programs are not effective in delaying initiation of sexual intercourse or changing other sexual risk behaviors. AOUM programs, as defined by U.S. federal funding requirements, inherently withhold information about human sexuality and may provide medically inaccurate and stigmatizing information. Thus, AOUM programs threaten fundamental human rights to health, information, and life. Young people need access to accurate and comprehensive sexual health information to protect their health and lives

Vergleichende Lebenszykluskostenanalyse für Fußgängerbrücken aus unterschiedlichen Werkstoffen

Bei Infrastrukturobjekten können im Laufe der Nutzungsdauer erhebliche Kosten für Instandhaltungsmaßnahmen anfallen. Die Wahl der baulichen Variante sollte deshalb nicht nur anhand des Anschaffungspreises sondern unter Berücksichtigung der entstehenden Folgekosten erfolgen. Vor diesem Hintergrund wurde in einer Studie mit der Deutschen Bahn AG und der Peter Maier Leichtbau GmbH untersucht, welcher Werkstoff für Fußgängerbrücken die beste Gesamtwirtschaftlichkeit verspricht. Dabei wurde die Gesamtwirtschaftlichkeit anhand einer Lebenszykluskosten-Analyse beurteilt. Untersucht wurden Fußgängerbrücken als sog. Personenüberführungen aus den konventionellen Brückenbaustoffen Holz, Stahl und Stahlbeton sowie aus dem Werkstoff Aluminium. Als Vergleichswert für die Lebenszykluskosten wurde die Annuität herangezogen. Unsicherheiten bei der Kostenprognose wurden mit Hilfe von Sensitivitätsanalysen eingegrenzt. Für das im Rahmen der Untersuchung betrachtete System stellte sich die Aluminiumbrücke als die wirtschaftlichste Variante heraus

Energy transition pathways to a low-carbon Europe in 2050: the degree of cooperation and the level of decentralization

In the framework of the Paris Agreement, the European Union (EU) will have to firmly set decarbonization targets to 2050. However, the viability on these targets is an ongoing discussion. The European Commission has made several propositions for energy and climate "roadmaps". In this regard, this paper contributes by analyzing alternative pathways derived in a unique modelling process. As part of the SET-Nav project, we defined four pathways to a clean, secure and efficient energy system - taking different routes. Two key uncertainties shape the SET-Nav pathways: the level of cooperation (i.e. cooperation versus entrenchment) and the level of decentralization (i.e. decentralization versus path dependency). All four pathways achieve an 85-95% emissions reduction by 2050. We include a broad portfolio of options under distinct framework conditions by comprehensively analyzing all energy-consuming and energy-providing sectors as well as the general economic conditions. We do this by applying a unique suite of linked models developed in the SET-Nav project. By linking more than ten models, we overcome the traditional limitation of models that cover one single sector while at the same time having access to detail sectoral data and expertise. In this paper, we focus on the implications for the energy demand sectors (buildings, transport, and industry) and the electricity supply mix in Europe and compare our insights of the electricity sector to the scenarios of the recent European Commission (2018a) report "A clean Planet for all"

Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from Zafirlukast

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti‐asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver‐related metabolic diseases

Parent and adolescent attitudes towards preventive care and confidentiality

Objective Little is known about whether parents and adolescents agree in their attitudes towards preventive care, private time and confidentiality for adolescent care. Methods We surveyed a nationally representative sample of 1,209 13¬-18 year-old U.S. adolescents and their parents. Parent and adolescents attitudes towards preventive services, private time and confidentiality were compared. Parent-youth dyad agreement was measured using Cohen's kappa and Spearman coefficients and modeled for association with demographic variables. Results Parents are more likely than adolescents to think preventive services are important (71% vs 48%; p<0.001). Parent-youth attitudes were weakly to moderately correlated (Cohen's kappa coefficient = 0.22; p<0.001). Parents and adolescents report similar ages for when teens should start having private time (median 16 years for both) and many think this age should be at 18, the legal age of adulthood). Fewer than half believe confidentiality should be provided for 10 services, ranging from routine care to abortion care (parents range: 12.8-52.3%; adolescents: 24.0%-58.8%). While most adolescents agreed with their parents, teens were more likely to report wanting confidential access than parents. Older age, Hispanic ethnicity, having divorced parents and higher family income were associated with both adolescent/parent and adolescent endorsement of confidentiality. Conclusion Adolescents and parents generally agree about the importance of preventive services, private time, confidentiality, and what should and should not be confidential. On average, parents value clinical preventive services more than youth, and youth value confidentiality more than parents. Both believe private time should start at ages older than those recommended in clinical guidelines

Controlling intramolecular interactions in the design of selective, high-affinity, ligands for the CREBBP Bromodomain

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise ten domains through which they interact with >400 proteins, making them important transcriptional coactivators, and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable binding of acetylated lysine residues from histones, and a number of other important proteins, including p53, p73, E2F and GATA1. Here we report work to develop a high affinity, small molecule, ligand for the CREBBP and EP300 bromodomains [(−)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc, and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2), inhibition of the CREBBP/EP300 bromodomain results in enhanced stabilization of HIF-1α

Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor γ. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents