Novel regulators of hepatic energy metabolism

Metabolic syndrome is a rapidly increasing global epidemic with a prevalence of 20 to 25% in the adult population. The metabolic syndrome strongly increases the risk of developing cardiovascular disease, which remains the leading cause of death worldwide. The hepatic manifestation of the metabolic syndrome is non-alcoholic fatty liver disease (NAFLD), which covers a spectrum of disease stages ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Despite great advances in understanding the pathophysiology of these diseases, there are currently no Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved drugs for the treatment of NAFLD. Currently, many drugs are developed and in the pipeline. One promising group of hormone-based drugs is based on several members of the fibroblast growth factor (FGF) family with strong metabolic effects, including amelioration of hepatic steatosis. In our research into the mechanisms underlying the hepatic lipid lowering effects of FGF1, we have recently identified several interesting downstream targets. This thesis investigates the individual role of these FGF targets in hepatic lipid metabolism and their potential in treating NAFLD. We have studied the biological function and molecular mechanisms of these regulators and their involvement in hepatic energy metabolism and hepatic function. Using experimental approaches, including mouse models and in vitro systems, we uncovered new functions and angles to guide future research efforts to understand hepatic energy metabolism and combat NAFLD

Testing Modeling Assumptions in the West Africa Ebola Outbreak

The Ebola virus in West Africa has infected almost 30,000 and killed over 11,000 people. Recent models of Ebola Virus Disease (EVD) have often made assumptions about how the disease spreads, such as uniform transmissibility and homogeneous mixing within a population. In this paper, we test whether these assumptions are necessarily correct, and offer simple solutions that may improve disease model accuracy. First, we use data and models of West African migration to show that EVD does not homogeneously mix, but spreads in a predictable manner. Next, we estimate the initial growth rate of EVD within country administrative divisions and find that it significantly decreases with population density. Finally, we test whether EVD strains have uniform transmissibility through a novel statistical test, and find that certain strains appear more often than expected by chance.Comment: 16 pages, 14 figure

Interference enhanced thermoelectricity in quinoid type structures

Quantum interference (QI) effects in molecular junctions may be used to obtain large thermoelectric responses. We study the electrical conductance G and the thermoelec- tric response of a series of molecules featuring a quinoid core using density functional theory (DFT), as well as a semi-empirical interacting model Hamiltonian describing the {\pi}-system of the molecule which we treat in the GW approximation. Molecules with a quinoid type structure are shown to have two distinct destructive QI features close to the frontier orbital energies. These manifest themselves as two dips in the transmission, that remain separated, even when either electron donating or withdraw- ing side groups are added. We find that the position of the dips in the transmission and the frontier molecular levels can be chemically controlled by varying the electron donating or withdrawing character of the side groups as well as the conjugation length inside the molecule. This feature results in a very high thermoelectric power factor S^2G and figure of merit ZT, where S is the Seebeck coefficient, making quinoid type molecules potential candidates for efficient thermoelectric devices.Comment: 22 pages, 11 figure

Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology

Our aim was to correlate the activity of matrix metalloproteinases (MMPs) with denaturation and the turnover of collagen in normal and pathological human tendons. MMPs were extracted from ruptured supraspinatus tendons (n=10), macroscopically normal (‘control’) supraspinatus tendons (n=29) and normal short head of biceps brachii tendons (n=24). Enzyme activity was measured using fluorogenic substrates selective for MMP-1, MMP-3 and enzymes with gelatinolytic activity (MMP-2, MMP-9 and MMP-13). Collagen denaturation was determined by a-chymotrypsin digestion. Protein turnover was determined by measuring the percentage of d-aspartic acid (% d-Asp). Zymography was conducted to identity specific gelatinases. MMP-1 activity was higher in ruptured supraspinatus compared to control supraspinatus and normal biceps brachii tendons (70.9, 26.4 and 11.5 fmol/mg tendon, respectively;