A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes

A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology

Crustal structure of the Niuafo’ou Microplate and Fonualei Rift and Spreading Center in the northeastern Lau Basin, Southwestern Pacific

Key points: First insights into the crustal structure of the northeastern Lau Basin, along a 290 km transect at 17°20’S. Crust in southern Fonualei Rift and Spreading Center was created by extension of arc crust and variable amount of magmatism. Magmatic underplating is present in some parts of the southern Niuafo’ou Microplate The northeastern Lau Basin is one of the fastest opening and magmatically most active back‐arc regions on Earth. Although the current pattern of plate boundaries and motions in this complex mosaic of microplates is reasonably understood, the internal structure and evolution of the back‐arc crust are not. We present new geophysical data from a 290 km long east‐west oriented transect crossing the Niuafo’ou Microplate (back‐arc), the Fonualei Rift and Spreading Centre (FRSC) and the Tofua Volcanic Arc at 17°20’S. Our P‐wave tomography model and density modelling suggests that past crustal accretion inside the southern FRSC was accommodated by a combination of arc crustal extension and magmatic activity. The absence of magnetic reversals inside the FRSC supports this and suggests that focused seafloor spreading has until now not contributed to crustal accretion. The back‐arc crust constituting the southern Niuafo’ou Microplate reveals a heterogeneous structure comprising several crustal blocks. Some regions of the back‐arc show a crustal structure similar to typical oceanic crust, suggesting they originate from seafloor spreading. Other crustal blocks resemble a structure that is similar to volcanic arc crust or a ‘hydrous’ type of oceanic crust that has been created at a spreading center influenced by slab‐derived water at distances < 50 km to the arc. Throughout the back‐arc region we observe a high‐velocity (Vp 7.2‐7.5 km s‐1) lower crust, which is an indication for magmatic underplating, which is likely sustained by elevated upper mantle temperatures in this region

Indirect protein quantification of drug-transforming enzymes using peptide group-specific immunoaffinity enrichment and mass spectrometry

Immunoaffinity enrichment of proteotypic peptides, coupled with selected reaction monitoring, enables indirect protein quantification. However the lack of suitable antibodies limits its widespread application. We developed a method in which multi-specific antibodies are used to enrich groups of peptides, thus facilitating multiplexed quantitative protein assays. We tested this strategy in a pharmacokinetic experiment by targeting a group of homologous drug transforming proteins in human hepatocytes. Our results indicate the generic applicability of this method to any biological system

Indirect protein quantification of drug-transforming enzymes using peptide group-specific immunoaffinity enrichment and mass spectrometry

Immunoaffinity enrichment of proteotypic peptides, coupled with selected reaction monitoring, enables indirect protein quantification. However the lack of suitable antibodies limits its widespread application. We developed a method in which multi-specific antibodies are used to enrich groups of peptides, thus facilitating multiplexed quantitative protein assays. We tested this strategy in a pharmacokinetic experiment by targeting a group of homologous drug transforming proteins in human hepatocytes. Our results indicate the generic applicability of this method to any biological system

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways