Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists.

In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.

Synthesis and evaluation of novel HCV replication inhibitors.

Direct acting antiviral agents to cure hepatitis C virus (HCV) infection has emerged as the gold standard therapy. Along with protease inhibitors, nucleoside polymerase inhibitors and non-nucleoside polymerase inhibitors, the inhibition of NS5a has proved to be an effective way to treat HCV patients. Here we report on novel HCV NS5a inhibitors which were synthesized and evaluated in the HCV replicon assay. A series of inhibitors were formed by a cycloaddition reaction in parallel to establish new leads and explore the effects of unsymmetrical cap substitution. This led to the identification of several triazoles with picomolar potency in vitro against hepatitis C virus.

GIS-based quantification of future nutrient loads into Lake Peipsi/Chudskoe using qualitative regional development scenarios.

This study aims at the quantification of possible future nutrient loads into Lake Peipsi/Chudskoe under different economic development scenarios. This drainage basin is on the borders of Russia, Estonia and Latvia. The sudden disintegration of the Soviet Union in 1991 caused a collapse of agricultural economy, and consequently, a substantial decrease of diffuse and point-source nutrient emissions. For the future, uncertainties about economic development and the priorities that will be set for this region make it difficult to assess the consequences for river water quality and nutrient loads into the lake. We applied five integrated scenarios of future development of this transboundary region for the next twelve to fifteen years. Each scenario consists of a qualitative story line, which was translated into quantitative changes in the input variables for a geographical information system based nutrient transport model. This model calculates nutrient emissions, as well as transport and retention and the resulting nutrient loads into the lake. The model results show that the effects of the different development scenarios on nutrient loads are relatively limited over a time span of about 15 years. In general, a further reduction of nutrient loads is expected, except for a fast economic development scenario.

Modelling nutrient fluxes from diffuse and point emissions to river loads: the Estonian part of the transboundary Lake Peipsi/Chudskoe drainage basin (Russia/Estonia/Latvia).

First results are presented of a large-scale GIS-based nutrient transport modelling for the 1985-1999 period in the Estonian part of the transboundary drainage basin of Lake Peipsi (Estonian)/Chudskoe (Russian), one of the largest lakes in Europe, shared by Russia and Estonia. Although the lake is relatively undisturbed by human pollution, it is vulnerable for eutrophication by increased river loads, as shown in the past, when the north-eastern part of the former Soviet Union suffered from intensive agriculture. The collapse of the Soviet Union caused a dramatic decline in fertilizer application rates and widespread abandonment of agricultural land. Although concentration measurements and modelling results indicate a general decrease in nutrient loads, modelling is complicated by the transfer of nutrients from diffuse emissions, which is strongly governed by retention and assumed periodic release from storages within the river basin, like the root zone, tile drains, ditches, channels, bed sediments, floodplains and lakes. Modelling diffuse emission contribution to river loads can be improved by better knowledge about the spatial and temporal distribution of this retention and release within the drainage basin.

Abolition of Wolff-Parkinson-White pattern during episodes of angina.

A 70-year-old woman presented with unstable angina following a myocardial infarction. At cardiac catheterisation she had inferoapical dyskinesia, blocked right and circumflex arteries and an 80% stenosis of the left anterior descending artery. When free of angina, the ECG showed a Wolff-Parkinson-White (WPW) pattern consistent with a posterior free wall accessory pathway. However, during some episodes of angina at rest, she reverted to normal conduction and back again to the WPW pattern after the angina subsided with sublingual nitrate. The disappearance of the WPW pattern during angina can be explained by transient ischaemia blocking conduction in the accessory pathway.