Stereochemical and steric control of enzymatic glucuronidation : A rational approach for the design of novel Inhibitors for the human UDP-glucuronosyltransferase 2B7

The UDP-glucuronosyltransferases (UGTs) are enzymes of the phase II metabolic system. These enzymes catalyze the transfer of α-D-glucuronic acid from UDP-glucuronic acid to aglycones bearing nucleophilic groups affording exclusively their corresponding β-D-glucuronides to render lipophilic endobiotics and xenobiotics more water soluble. This detoxification pathway aids in the urinary and biliary excretion of lipophilic compounds thus preventing their accumulation to harmful levels. The aim of this study was to investigate the effect of stereochemical and steric features of substrates on the glucuronidation catalyzed by UGTs 2B7 and 2B17. Furthermore, this study relates to the design and synthesis of novel, selective inhibitors that display high affinity for the key enzyme involved in drug glucuronidation, UGT2B7. The starting point for the development of inhibitors was to assess the influence of the stereochemistry of substrates on the UGT-catalyzed glucuronidation reaction. A set of 28 enantiomerically pure alcohols was subjected to glucuronidation assays employing the human UGT isoforms 2B7 and 2B17. Both UGT enzymes displayed high stereoselectivity, favoring the glucuronidation of the (R)-enantiomers over their respective mirror-image compounds. The spatial arrangement of the hydroxy group of the substrate determined the rate of the UGT-catalyzed reaction. However, the affinity of the enantiomeric substrates to the enzymes was not significantly influenced by the spatial orientation of the nucleophilic hydroxy group. Based on these results, a rational approach for the design of inhibitors was developed by addressing the stereochemical features of substrate molecules. Further studies showed that the rate of the enzymatic glucuronidation of substrates was also highly dependent on the steric demand in vicinity of the nucleophilic hydroxy group. These findings provided a rational approach to turn high-affinity substrates into true UGT inhibitors by addressing stereochemical and steric features of substrate molecules. The tricyclic sesquiterpenols longifolol and isolongifolol were identified as high-affinity substrates which displayed high selectivity for the UGT isoform 2B7. These compounds served therefore as lead structures for the design of potent and selective inhibitors for UGT2B7. Selective and potent inhibitors were prepared by synthetically modifying the lead compounds longifolol and isolongifolol taking stereochemical and steric features into account. The best inhibitor of UGT2B7, β-phenyllongifolol, displayed an inhibition constant of 0.91 nM.

Leibniz on Rational Decision-Making

In this study I discuss G. W. Leibniz's (1646-1716) views on rational decision-making from the standpoint of both God and man. The Divine decision takes place within creation, as God freely chooses the best from an infinite number of possible worlds. While God's choice is based on absolutely certain knowledge, human decisions on practical matters are mostly based on uncertain knowledge. However, in many respects they could be regarded as analogous in more complicated situations. In addition to giving an overview of the divine decision-making and discussing critically the criteria God favours in his choice, I provide an account of Leibniz's views on human deliberation, which includes some new ideas. One of these concerns is the importance of estimating probabilities in making decisions one estimates both the goodness of the act itself and its consequences as far as the desired good is concerned. Another idea is related to the plurality of goods in complicated decisions and the competition this may provoke. Thirdly, heuristic models are used to sketch situations under deliberation in order to help in making the decision. Combining the views of Marcelo Dascal, Jaakko Hintikka and Simo Knuuttila, I argue that Leibniz applied two kinds of models of rational decision-making to practical controversies, often without explicating the details. The more simple, traditional pair of scales model is best suited to cases in which one has to decide for or against some option, or to distribute goods among parties and strive for a compromise. What may be of more help in more complicated deliberations is the novel vectorial model, which is an instance of the general mathematical doctrine of the calculus of variations. To illustrate this distinction, I discuss some cases in which he apparently applied these models in different kinds of situation. These examples support the view that the models had a systematic value in his theory of practical rationality.

On Random Planar Curves and Their Scaling Limits

Planar curves arise naturally as interfaces between two regions of the plane. An important part of statistical physics is the study of lattice models. This thesis is about the interfaces of 2D lattice models. The scaling limit is an infinite system limit which is taken by letting the lattice mesh decrease to zero. At criticality, the scaling limit of an interface is one of the SLE curves (Schramm-Loewner evolution), introduced by Oded Schramm. This family of random curves is parametrized by a real variable, which determines the universality class of the model. The first and the second paper of this thesis study properties of SLEs. They contain two different methods to study the whole SLE curve, which is, in fact, the most interesting object from the statistical physics point of view. These methods are applied to study two symmetries of SLE: reversibility and duality. The first paper uses an algebraic method and a representation of the Virasoro algebra to find common martingales to different processes, and that way, to confirm the symmetries for polynomial expected values of natural SLE data. In the second paper, a recursion is obtained for the same kind of expected values. The recursion is based on stationarity of the law of the whole SLE curve under a SLE induced flow. The third paper deals with one of the most central questions of the field and provides a framework of estimates for describing 2D scaling limits by SLE curves. In particular, it is shown that a weak estimate on the probability of an annulus crossing implies that a random curve arising from a statistical physics model will have scaling limits and those will be well-described by Loewner evolutions with random driving forces.

Do Households Have Rational Expectations on Future Consumption? Evidence from the Finnish Consumer Survey

Ever since its initial introduction some fifty years ago, the rational expectations paradigm has dominated the way economic theory handles uncertainty. The main assertion made by John F. Muth (1961), seen by many as the father of the paradigm, is that expectations of rational economic agents should essentially be equal to the predictions of relevant economic theory, since rational agents should use information available to them in an optimal way. This assumption often has important consequences on the results and interpretations of the models where it is applied. Although the rational expectations assumption can be applied to virtually any economic theory, the focus in this thesis is on macroeconomic theories of consumption, especially the Rational Expectations–Permanent Income Hypothesis proposed by Robert E. Hall in 1978. The much-debated theory suggests that, assuming that agents have rational expectations on their future income, consumption decisions should follow a random walk, and the best forecast of future consumption level is the current consumption level. Then, changes in consumption are unforecastable. This thesis constructs an empirical test for the Rational Expectations–Permanent Income Hypothesis using Finnish Consumer Survey data as well as various Finnish macroeconomic data. The data sample covers the years 1995–2010. Consumer survey data may be interpreted to directly represent household expectations, which makes it an interesting tool for this particular test. The variable to be predicted is the growth of total household consumption expenditure. The main empirical result is that the Consumer Confidence Index (CCI), a balance figure computed from the most important consumer survey responses, does have statistically significant predictive power over the change in total consumption expenditure. The history of consumption expenditure growth itself, however, fails to predict its own future values. This indicates that the CCI contains some information that the history of consumption decisions does not, and that the consumption decisions are not optimal in the theoretical context. However, when conditioned on various macroeconomic variables, the CCI loses its predictive ability. This finding suggests that the index is merely a (partial) summary of macroeconomic information, and does not contain any significant private information on consumption intentions of households not directly deductible from the objective economic variables. In conclusion, the Rational Expectations–Permanent Income Hypothesis is strongly rejected by the empirical results in this thesis. This result is in accordance with most earlier studies conducted on the topic.