A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man

An increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. However, individuals vary largely in their response to cholesterol lowering drugs and 40% of them, do not reach their cholesterol-lowering target. Development of novel therapies, for example combinations of existing drugs, can be accelerated by more mechanistic understanding of cholesterol metabolism. This understanding can be improved using computational models. This thesis describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. For this purpose, first a PBK model for the mouse was set up, calibrated and validated, using ensemble modeling. Then the mouse model was converted to a model for humans. It describes the 21 most influential physiological reactions affecting cholesterol concentrations in 8 pools, including liver, HDL, and non-HDL. The model was parameterized using literature data and validated using clinical data for human mutations and drug interventions, taken from literature. The model was applied to find properties that determine the individual response to drugs. The processes: hepatic cholesterol synthesis, peripheral cholesterol synthesis, and hepatic cholesterol esterification were major determinants of the non-HDL-C response to the cholesterol-lowering drug pravastatin. We conclude that plasma cholesterol concentrations and effects of genetic polymorphisms and drugs thereupon can be predicted in silico and thatPBK modeling can provide novel mechanistic insights. </p

Manganese carbonyl-mediated reactions of azabutadienes with phenylacetylene, methyl acrylate and other unsaturated molecules

Reaction of PhCH₂Mn(CO)₅ with l,4-di-aryl-1-aza-1,3-butadienes gave substituted pyrrolinonyl rings which were η⁴-coordinated to a Mn(CO)₃ group. These are formed by intramolecular CO insertion into a (non-isolated) cyclomanganated intermediate, followed by cyclisation. Other unsaturated reagents (PhC≡CH, CH2=CHCOOMe, PhNCO) gave products arising from insertion of these, including a structurally characterised tri-aryl-η⁵-azacyclohexadienyl-Mn(CO)₃ complex from the reaction with the alkyne. PhCH₂Mn(CO)₅ reacts with l,4-di-aryl-1-aza-1,3-butadienes in the presence of unsaturated substrates to give products based on a cyclomanganated intermediate

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics are discussed including their promising future value for dairy cow fertility