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.

Heavy haul sleeper design: A rational cost-saving method

Heavy haul railway lines are important and expensive items of infrastructure operating in an environment which is increasingly focussed on risk-based management and constrained profit margins. It is vital that costs are minimised but also that infrastructure satisfies failure criteria and standards of reliability which account for the random nature of wheel-rail forces and of the properties of the materials in the track. In Australia and the USA, concrete railway sleepers/ties are still designed using methods which the rest of the civil engineering world discarded decades ago in favour of the more rational, more economical and probabilistically based, limit states design (LSD) concept. This paper describes a LSD method for concrete sleepers which is based on (a) billions of measurements over many years of the real, random wheel-rail forces on heavy haul lines, and (b) the true capacity of sleepers. The essential principles on which the new method is based are similar to current, widely used LSD-based standards for concrete structures. The paper proposes and describes four limit states which a sleeper must satisfy, namely: strength; operations; serviceability; and fatigue. The method has been applied commercially to two new major heavy haul lines in Australia, where it has saved clients millions of dollars in capital expenditure.

The Effect of Framing on Layoff Decisions: Are More-Experienced Managers More Rational? Does Computerized Data Make Any Difference?

[Excerpt] The effects of framing on decisions has been widely studied, producing research that suggests individuals respond to framing in predictable and fairly consistent ways (Bazerman, 1984, 1990; Tversky & Kahneman, 1986; Thaler, 1980). The essential finding from this body of research is that "individuals treat risks concerning perceived gains (for example, saving jobs and plants) differently from risks concerning perceived losses (losing jobs and plants)" (Bazerman, 1990, pp. 49-50). Specifically, individuals tend to avoid risks concerning gains, and seek risks concerning losses.

Tipping points: Teachers' reported reasons for referring primary school children for excessive anxiety

The current study explored the reasons that primary school teachers reported were tipping points for them in deciding whether or not and when to refer a child to the school student support team for excessive anxiety. Twenty teachers in two Queensland primary schools were interviewed. Content analysis of interview transcripts revealed six themes reflecting teachers' perceived reasons for deciding to refer anxious children: 1)impact on learning; 2)atypical child behavior; 3)repeated difficulties that do not improve over time; 4)poor response to strategies; 5)teachers' need for support; and 6)information from parents/carers. Teachers considered different combinations of reasons, and had many different tipping points for making a referral. Both teacher-and system-level influences impacted referral decisions. Implications and future research are discussed.

Continuation of limit cycles near saddle homoclinic points using splines in phase space

We present a new algorithm for continuation of limit cycles of autonomous systems as a system parameter is varied. The algorithm works in phase space with an ordered set of points on the limit cycle, along with spline interpolation. Currently popular algorithms in bifurcation analysis packages compute time-domain approximations of limit cycles using either shooting or collocation. The present approach seems useful for continuation near saddle homoclinic points, where it encounters a corner while time-domain methods essentially encounter a discontinuity (a relatively short period of rapid variation). Other phase space-based algorithms use rescaled arclength in place of time, but subsequently resemble the time-domain methods. Compared to these, we introduce additional freedom through a variable stretching of arclength based on local curvature, through the use of an auxiliary index-based variable. Several numerical examples are presented. Comparisons with results from the popular package, MATCONT, are favorable close to saddle homoclinic points.

Sustaining productivity of tropical red snappers using new monitoring and reference points

OBJECTIVES: 1. Analyse current monitoring and logbook data sets, as well as survey and other information,to establish whether these data provide sufficient power to develop critical indicators of fishery performance. 2. Provide a risk analysis that examines the use of age structure and catch rate information for development of critical indicators, and response rules for those criteria, in the absence of other fishery information. 3. Develop a monitoring program that uses commercial vessels from the fishery to provide independent data.

Principles and guidelines for managing cattle grazing in the grazing lands of northern Australia: stocking rates, pasture resting, prescribed fire, paddock size and water points - a review

Beef cattle grazing is the dominant land use in the extensive tropical and sub-tropical rangelands of northern Australia. Despite the considerable knowledge on land and herd management gained from both research and practical experience, the adoption of improved management is limited by an inability to predict how changes in practices and combinations of practices will affect cattle production, economic returns and resource condition. To address these issues, past Australian and international research relating to four management factors that affect productivity and resource condition was reviewed in order to identify key management principles. The four management factors considered were stocking rates, pasture resting, prescribed fire, and fencing and water point development for managing grazing distribution. Four management principles for sound grazing management in northern Australia were formulated as follows: (1) manage stocking rates to meet goals for livestock production and land condition; (2) rest pastures to maintain them in good condition or to restore them from poor condition to increase pasture productivity; (3) devise and apply fire regimes that enhance the condition of grazing land and livestock productivity while minimising undesirable impacts; and (4) use fencing and water points to manipulate grazing distribution. Each principle is supported by several more specific guidelines. These principles and guidelines, and the supporting research on which they are based, are presented.

A rational approach to the synthesis of one-dimensional acoustic filters

The velocity ratio algorithm developed from a heuristic study of transfer matrix multiplication has been employed to bring out the relative effects of the elements constituting a linear, one-dimensional acoustic filter, the overall dimensions of which are fixed, and synthesize a suitable straight-through configuration for a low-pass, wide-band, non-dissipative acoustic filter. The potential of the foregoing approach in applications to the rational design of practical acoustic filters such as automotive mufflers is indicated.

A rational synthesis of vibration isolators

The paper deals with a rational approach to the development of general design criteria for non-dissipative vibration isolation systems. The study covers straight-through springmass systems as well as branched ones with dynamic absorbers. Various design options, such as the addition of another spring-mass pair, replacement of an existing system by one with more spring-mass pairs for the same space and material requirements, provision of one or more dynamic absorbers for the desired frequency range, etc., are investigated quantitatively by means of an algebraic algorithm which enables one to write down straightaway the velocity ratio and hence transmissibility of a linear dynamical system in terms of the constituent parameters.

Rational design of 3D dendritic TiO2 nanostructures with favorable architectures

Controlling the morphology and size of titanium dioxide (TiO2) nanostructures is crucial to obtain superior photocatalytic, photovoltaic, and electrochemical properties. However, the synthetic techniques for preparing such structures, especially those with complex configurations, still remain a challenge because of the rapid hydrolysis of Ti-containing polymer precursors in aqueous solution. Herein, we report a completely novel approach-three- dimensional (3D) TiO2 nanostructures with favorable dendritic architectures-through a simple hydrothermal synthesis. The size of the 3D TiO2 dendrites and the morphology of the constituent nano-units, in the form of nanorods, nanoribbons, and nanowires, are controlled by adjusting the precursor hydrolysis rate and the surfactant aggregation. These novel configurations of TiO2 nanostructures possess higher surface area and superior electrochemical properties compared to nanoparticles with smooth surfaces. Our findings provide an effective solution for the synthesis of complex TiO2 nano-architectures, which can pave the way to further improve the energy storage and energy conversion efficiency of TiO 2-based devices.

New rational interpolation functions for finite element analysis of rotating beams

A rotating beam finite element in which the interpolating shape functions are obtained by satisfying the governing static homogenous differential equation of Euler–Bernoulli rotating beams is developed in this work. The shape functions turn out to be rational functions which also depend on rotation speed and element position along the beam and account for the centrifugal stiffening effect. These rational functions yield the Hermite cubic when rotation speed becomes zero. The new element is applied for static and dynamic analysis of rotating beams. In the static case, a cantilever beam having a tip load is considered, with a radially varying axial force. It is found that this new element gives a very good approximation of the tip deflection to the analytical series solution value, as compared to the classical finite element given by the Hermite cubic shape functions. In the dynamic analysis, the new element is applied for uniform, and tapered rotating beams with cantilever and hinged boundary conditions to determine the natural frequencies, and the results compare very well with the published results given in the literature.

Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria

We have recently implicated heat shock protein 90 from Plasmodium falciparum (PfHsp90) as a potential drug target against malaria. Using inhibitors specific to the nucleotide binding domain of Hsp90, we have shown potent growth inhibitory effects on development of malarial parasite in human erythrocytes. To gain better understanding of the vital role played by PfHsp90 in parasite growth, we have modeled its three dimensional structure using recently described full length structure of yeast Hsp90. Sequence similarity found between PfHsp90 and yeast Hsp90 allowed us to model the core structure with high confidence. The superimposition of the predicted structure with that of the template yeast Hsp90 structure reveals an RMSD of 3.31 angstrom. The N-terminal and middle domains showed the least RMSD (1.76 angstrom) while the more divergent C-terminus showed a greater RMSD (2.84 angstrom) with respect to the template. The structure shows overall conservation of domains involved in nucleotide binding, ATPase activity, co-chaperone binding as well as inter-subunit interactions. Important co-chaperones known to modulate Hsp90 function in other eukaryotes are conserved in malarial parasite as well. An acidic stretch of amino acids found in the linker region, which is uniquely extended in PfHsp90 could not be modeled in this structure suggesting a flexible conformation. Our results provide a basis to compare the overall structure and functional pathways dependent on PfHsp90 in malarial parasite. Further analysis of differences found between human and parasite Hsp90 may make it possible to design inhibitors targeted specifically against malaria.

Stereochemical analysis of the antigenic tip of the V3 loop peptide of HIV-1 gp120

A novel multiple turn conformation has been observed for a segment GPGRAFY in the crystal structure of a complex of HIV-1 gp120 V3 loop peptide with the Fab fragment of a neutralizing antibody [Ghiara ct al. (1994) Science 264, 82-85]. A structural motif has been defined for the peptide segment, employing idealized backbone conformations characterized by ranges of virtual C-alpha torsion angles and bond angles. A search of 122 high-resolution protein crystal structures has permitted identification of 24 examples of similar structural motifs. Two major conformational families have been identified, which differ primarily in the conformation at residue 3. The observed conformation at residue 3 in family 1 is left-handed helical (alpha(L)) and that in family 2 is right-handed helical (alpha(R)). Of the 10 examples in family 1, 9 examples have Gly residues at position 3. Of the 12 examples in family 2, 7 examples have Asn/Asp at position 3. Computer modeling of the V3 loop tip sequence using the two backbone conformational families as starting points leads to minimum-energy conformations in which antigenically important side-chains occupy similar spatial arrangements. This stereochemical analysis of the V3 loop tip sequence suggests a rational basis for the design of synthetic analog peptides for use as viral antagonists or synthetic antigens. (C) Munksgaard 1995.

Doing marriage and parenthood: The division of household labour across two life course events

The current study is a longitudinal investigation into changes in the division of household labour across transitions to marriage and parenthood in the UK. Previous research has noted a more traditional division of household labour, with women performing the majority of housework, amongst spouses and couples with children. However, the bulk of this work has been cross-sectional in nature. The few longitudinal studies that have been carried out have been rather ambiguous about the effect of marriage and parenthood on the division of housework. Theoretically, this study draws on gender construction theory. The key premise of this theory is that gender is something that is performed and created in interaction, and, as a result, something fluid and flexible rather than fixed and stable. The idea that couples ‘do gender’ through housework has been a major theoretical breakthrough. Gender-neutral explanations of the division of household labour, positing rational acting individuals, have failed to explicate why women continue to perform an unequal share of housework, regardless of socio-economic status. Contrastingly, gender construction theory situates gender as the key process in dividing household labour. By performing and avoiding certain housework chores, couples fulfill social norms of what it means to be a man and a woman although, given the emphasis on human agency in producing and contesting gender, couples are able to negotiate alternative gender roles which, in turn, feed back into the structure of social norms in an ever-changing societal landscape. This study adds extra depth to the doing gender approach by testing whether or not couples negotiate specific conjugal and parent roles in terms of the division of household labour. Both transitions hypothesise a more traditional division of household labour. Data comes from the British Household Panel Survey, a large, nationally representative quantitative survey that has been carried out annually since 1991. Here, data tracks the same 776 couples at two separate time points – 1996 and 2005. OLS regression is used to test whether or not transitions to marriage and parenthood have a significant impact on the division of household labour whilst controlling for host of relevant socio-economic factors. Results indicate that marriage has no significant effect on how couples partition housework. Those couples making the transition from cohabitation to marriage do not show significant changes in housework arrangements from those couples who remain cohabiting in both waves. On the other hand, becoming parents does lead to a more traditional division of household labour whilst controlling for socio-economic factors which accompany the move to parenthood. There is then some evidence that couples use the site of household labour to ‘do parenthood’ and generate identities which both use and inform socially prescribed notions of what it means to be a mother and a father. Support for socio-economic explanations of the division of household labour was mixed although it remains clear that they, alone, cannot explain how households divide housework.