Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.

Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.Leverhulme Trus

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.

A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.This study was supported by the Swiss National Science Foundation (SNSF professorship PP00P2_123536 and PP00P2_146321 to M.L.), the BBSRC (G.L., BB/G01227X/1 and BB/M00015X/1), an MRC Doctoral Training Partnership (I.W. MR/J003964/1), and the EPSRC (A.K., EP/G500045/1).This is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/acs.jmedchem.5b0140

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991-2003: methods and characterization of participants

Summary.: Objectives: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution. Methods: The health assessment at recruitment (1991) and at the first reassessment (2001-3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates. Results: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6528 individuals (70%) agreed to the health examination and 5973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5kg in 11years and 28% of smokers in 1991 had quit by the time of the reassessmen

Evaluation von universellen Toxizitätstests zur Abklärung der „akuten Giftigkeit“ einer unbekannten (ABC)-Verdachtsprobe

Drei biologische Toxizitätstests (vom BAG vorgeschlagen) mit vier verschiedenen Testsubstanzen (Atropin, Dichlorvos, Kaliumdichromat und Ricin) evaluieren um einen Test zu finden, der es erlaubt die Toxizität einer Verdachtsprobe systematisch zu überprüfen

The variability in the carbon sinks as reconstructed for the last 1000 years

The atmospheric CO2 and δ13C records for the last millennium have been analyzed to reconstruct the evolution and the temporal variability in the terrestrial and oceanic carbon sinks and to identify natural variations in the marine carbon cycle. Reconstructed natural variations in sinks are usually less than ± 0.2 Gt C yr−1 on time scales of decades to centuries and thus one order of magnitude smaller than the sink fluxes driven by the anthropogenic perturbation. The natural oceanic carbon cycle was generally close to steady state on a multi-decadal time scale. A large anomalous oceanic carbon sink is found around 1940 that is attributed to a higher than usual El Niño activity. Interannual variations in the oceanic sink as reconstructed for the 1980–1996 period are around ±1 Gt C yr−1 and are significantly correlated with the Southern Oscillation. The relatively low atmospheric CO2 concentrations between 1600 and 1750 were caused by an additional terrestrial storage of 40 Gt C. The land biota acted as a carbon source between 1750 and 1950 and as a sink afterwards. Terrestrial changes can be explained by land use emission up to 1920. Then, additional mechanisms such as CO2 fertilization are responsible for an estimated terrestrial sequestration of 100 Gt C between 1920 and 1996