Structural studies on antifolate drugs

Single crystal X-ray structure determinations are reported for eleven compounds all of which are either biologically active or potentially biologically important. The compounds fall into two distinct classes:- 1. Substituted diaminopyrimidines 2. Substituted aminopyrimidinones The first class of compounds were all selected on the basis of their common diaminopyrimidine nucleus which has been demonstrated to be a vital requirement for antifolate activity. They may all be described as non-classical or small molecule lipophilic dihydrofolate reductase (DHFR) inhibitors, as opposed to the classical folate analogues, having the ability to cross the blood-brain barrier, enter cells via a rapid passive diffusion process, and achieve high intracellular concentrations. Thus they are an excellent choice in the search for crystallography in the solid state, providing geometrical and distance data not available from any other analytical techniques to date; supporting and enhancing data obtained in the lower resolution studies of protein crystallography. The biological importance of these compounds is discussed and an attempt is made to relate/predict their pharmacological activity to observed structural features in the crystalline environment. Special attention is focussed on hydrogen bonding, confirmational flexibility and hydrophobicity of substituents; each of which appear to make contributions to tight binding in the enzyme active site. Chapter 9 describes the use of data from the literature and the solid state modelling of an observed enzyme-substrate interaction in an attempt to define it more accurately in terms of its geometric flexibility. Of the second class, one compound (ABPP) is reported; studies in two different crystal forms. In demonstrating both antiviral and high interferon inducing activity it is possible that this compound could be useful against cancer and also viral infections.

Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

Receptor activity-modifying proteins (RAMPs) are single pass membrane proteins initially identified by their ability to determine the pharmacology of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR). It is now known that RAMPs can interact with a much wider range of GPCRs. This review considers recent developments on the structure of the complexes formed between the extracellular domains (ECDs) of CLR and RAMP1 or RAMP2 as these provide insights as to how the RAMPs direct ligand binding. The range of RAMP interactions is also considered; RAMPs can interact with numerous family B GPCRs as well as examples of family A and family C GPCRs. They influence receptor expression at the cell surface, trafficking, ligand binding and G protein coupling. The GPCR-RAMP interface offers opportunities for drug targeting, illustrated by examples of drugs developed for migraine.

Ecosystem structure, nutrient dynamics, and hydrologic relationships in tree islands of the southern Everglades, Florida, USA

Tree islands are an important structural component of many graminoid-dominated wetlands because they increase ecological complexity in the landscape. Tree island area has been drastically reduced with hydrologic modifications within the Everglades ecosystem, yet still little is known about the ecosystem ecology of Everglades tree islands. As part of an ongoing study to investigate the effects of hydrologic restoration on short hydroperiod marshes of the southern Everglades, we report an ecosystem characterization of seasonally flooded tree islands relative to locations described by variation in freshwater flow (i.e. locally enhanced freshwater flow by levee removal). We quantified: (1) forest structure, litterfall production, nutrient utilization, soil dynamics, and hydrologic properties of six tree islands and (2) soil and surface water physico-chemical properties of adjacent marshes. Tree islands efficiently utilized both phosphorus and nitrogen, but indices of nutrient-use efficiency indicated stronger P than N limitation. Tree islands were distinct in structure and biogeochemical properties from the surrounding marsh, maintaining higher organically bound P and N, but lower inorganic N. Annual variation resulting in increased hydroperiod and lower wet season water levels not only increased nitrogen use by tree species and decreased N:P values of the dominant plant species (Chrysobalanus icaco), but also increased soil pH and decreased soil temperature. When compared with other forested wetlands, these Everglades tree islands were among the most nutrient efficient, likely a function of nutrient immobilization in soils and the calcium carbonate bedrock. Tree islands of our study area are defined by: (1) unique biogeochemical properties when compared with adjacent short hydroperiod marshes and other forested wetlands and (2) an intricate relationship with marsh hydrology. As such, they may play an important and disproportionate role in nutrient and carbon cycling in Everglades wetlands. With the loss of tree islands that has occurred with the degradation of the Everglades system, these landscape processes may have been altered. With this baseline dataset, we have established a long-term ecosystem-scale experiment to follow the ecosystem trajectory of seasonally flooded tree islands in response to hydrologic restoration of the southern Everglades.

Development, validation and uncertainty analysis of quantitative structure and activity relationship models for Log P of disinfection by -products

Hydrophobicity as measured by Log P is an important molecular property related to toxicity and carcinogenicity. With increasing public health concerns for the effects of Disinfection By-Products (DBPs), there are considerable benefits in developing Quantitative Structure and Activity Relationship (QSAR) models capable of accurately predicting Log P. In this research, Log P values of 173 DBP compounds in 6 functional classes were used to develop QSAR models, by applying 3 molecular descriptors, namely, Energy of the Lowest Unoccupied Molecular Orbital (ELUMO), Number of Chlorine (NCl) and Number of Carbon (NC) by Multiple Linear Regression (MLR) analysis. The QSAR models developed were validated based on the Organization for Economic Co-operation and Development (OECD) principles. The model Applicability Domain (AD) and mechanistic interpretation were explored. Considering the very complex nature of DBPs, the established QSAR models performed very well with respect to goodness-of-fit, robustness and predictability. The predicted values of Log P of DBPs by the QSAR models were found to be significant with a correlation coefficient R2 from 81% to 98%. The Leverage Approach by Williams Plot was applied to detect and remove outliers, consequently increasing R 2 by approximately 2% to 13% for different DBP classes. The developed QSAR models were statistically validated for their predictive power by the Leave-One-Out (LOO) and Leave-Many-Out (LMO) cross validation methods. Finally, Monte Carlo simulation was used to assess the variations and inherent uncertainties in the QSAR models of Log P and determine the most influential parameters in connection with Log P prediction. The developed QSAR models in this dissertation will have a broad applicability domain because the research data set covered six out of eight common DBP classes, including halogenated alkane, halogenated alkene, halogenated aromatic, halogenated aldehyde, halogenated ketone, and halogenated carboxylic acid, which have been brought to the attention of regulatory agencies in recent years. Furthermore, the QSAR models are suitable to be used for prediction of similar DBP compounds within the same applicability domain. The selection and integration of various methodologies developed in this research may also benefit future research in similar fields.

Patterns of Behaviour, Group Structure and Reproductive Status Predict Levels of Glucocorticoid Metabolites in Zoo-Housed Ring-Tailed Lemurs, Lemur catta

In ring-tailed lemurs, Lemur catta, the factors modulating hypothalamic-pituitaryadrenal (HPA) activity differ between wild and semi-free-ranging populations. Here we assess factors modulating HPA activity in ring-tailed lemurs housed in a third environment: the zoo. First we validate an enzyme immunoassay to quantify levels of glucocorticoid (GC) metabolites in the faeces of L. catta . We determine the nature of the femalefemale dominance hierarchies within each group by computing David's scores and examining these in relation to faecal GC (fGC). Relationships between female age and fGC are assessed to evaluate potential age-related confounds. The associations between fGC, numbers of males in a group and reproductive status are explored. Finally, we investigate the value of 7 behaviours in predicting levels of fGC. The study revealed stable linear dominance hierarchies in females within each group. The number of males in a social group together with reproductive status, but not age, influenced fGC. The 7 behavioural variables accounted for 68% of the variance in fGC. The amounts of time an animal spent locomoting and in the inside enclosure were both negative predictors of fGC. The study highlights the flexibility and adaptability of the HPA system in ring-tailed lemurs.

Quality Physical Activity Participation for Military Veterans with a Physical Disability

Minimal research has explored what comprises a quality physical activity (PA) participation experience, particularly among military Veterans with a physical disability for whom evidence of the benefits of PA is growing. To address this research gap, this dissertation examines quality PA participation among military Veterans with a physical disability. Manuscript 1 explores the views of Veterans with a physical disability regarding what elements constitute a quality PA experience, and how these elements may be fostered. Eighteen Veterans with various physical disabilities and PA experiences participated in interviews. Four quality elements were identified via thematic analysis: group cohesion, challenge, having a role, and independence and choice. A further three factors (the physical and social environments, and program structure) were identified as precursors for a quality experience. Manuscript 2 explores how PA programs for Veterans with a physical disability are delivered, and how these delivery strategies link conceptually to quality participation. Interviews were conducted with program staff from three PA programs for Veterans, and program documentation collected, to develop an understanding of program delivery strategies. Four strategies with potential links to quality participation were identified through thematic analysis: foster social connections, challenge participants, tailor programs and outcomes to match participant needs, and include knowledgeable coaches and instructors. Manuscript 3 evaluates the participation of Veterans with functional impairments in PA events, and examines the relationships among quality precursors, quality elements, and participation outcomes. Results indicate that program participation did not promote long-term increases in PA indicators. However, an indicator of the quality element belongingness mediated the relationship at particular time-points between coach interpersonal skills and three participation outcomes: family integration, PA intentions, and PA planning. These findings suggest that a quality participation experience created by coaches may positively impact the transition to civilian life, and promote efforts to engage in ongoing PA. Overall, this dissertation contributes towards a greater depth in understanding of the experiences of Veterans with a physical disability in PA programs. The findings begin to provide a foundation for researchers and practitioners aiming to create, deliver, and promote quality PA interventions and programming for Veterans with a physical disability.

Etapas de cambio comportamental frente al consumo de drogas ilegales, tabaco y alcohol en escolares de 9 a 17 años de Bogotá – Colombia

Objetivo: El propósito del estudio fue describir estadísticamente las etapas de cambio comportamental frente al consumo de sustancias psicoactivas –SPA– (alcohol, tabaco y drogas ilegales) en escolares entre 9 y 17 años de Bogotá- Colombia, pertenecientes al estudio FUPRECOL. Método: Se trata de un estudio descriptivo y transversal en 6.965 niños y adolescentes entre 9 y 17 años, pertenecientes a 24 instituciones educativas oficiales de Bogotá - Colombia. La medición de los procesos de cambio propuestos por el Modelo Transteórico (MTT), aplicados al consumo de drogas, tabaco y alcohol se aplicaron de manera auto-diligenciada mediante un cuestionario estructurado. Resultados: De la muestra evaluada, el 58,4% fueron mujeres con un promedio de edad 12,74 ± 2.38 años. En la población en general, frente al consumo de drogas, el 6% de los escolares se encontraban en etapa de pre-contemplación, 44 % en contemplación; 30% en preparación/acción, 20% en mantenimiento. Con relación al consumo de alcohol, el 5% de los niños y adolescentes se encontraban en etapa de pre-contemplación, 36 % en contemplación; 12% en preparación/acción, 46% en mantenimiento. Frente al tabaco, el 4% de los niños y adolescentes se encontraban en etapa de pre-contemplación, 33 % en contemplación; 12% en preparación/acción, 51% en mantenimiento. Conclusiones: En los escolares evaluados, un importante porcentaje se ubica en la etapa de mantenimiento frente a la intención de consumo de tabaco y alcohol. Frente al consumo de drogas ilegales los niños y adolescentes están en la etapa de contemplación. Se requieren esfuerzos mayores para fomentar programas preventivos que enseñen sobre el riesgo del abuso/dependencia de este tipo de sustancias psicoactiva sobre la salud; dándole prioridad en las agendas y políticas públicas dentro del ámbito escolar.

Market Structures in Air Conditioning Maintenance Activity

It is questionable whether activities like construction, including maintenance and repair, can be considered a single entity or industry - on the basis that different sectors of construction/maintenance use fundamentally distinct resource and skill bases. This creates a number of issues including the development of competition and reform policy. de Valance deployed the Structure-Conduct-Performance model (SCP) to delineate sectors of new/installation construction activity and, in doing so, proposes that there exists multiple market structures in a given project. The purpose of this paper is to apply the SCP model to a different sector of construction activity, that is air conditioning maintenance and test de Valance's proposition concerning the existence of multiple market structures in a supply chain but this time to a built facility. The research method combines secondary data concerning the "Structure" component of the SCP model and primary data with regard to the "Conduct" and "Performance" parts of the SCP model. The results provide further support (beyond de Valance's analysis of new/installation activity) that a sector system approach using the SCP model is a more effective way to analyse market structures in construction activity. This paper also supports de Valance's proposition concerning the existence of multiple market structures in a supply chain to a project/facility.

Sustainable Australia : containing travel in master planned estates

Low density suburban development and excessive use of automobiles are associated with serious urban and environmental problems. These problems include traffic congestion, longer commuting times, high automobile dependency, air and water pollution, and increased depletion of natural resources. Master planned development suggests itself as a possible palliative for the ills of low density and high travel. The following study examines the patterns and dynamics of movement in a selection of master planned estates in Australia. The study develops new approaches for assessing the containment of travel within planned development. Its key aim is to clarify and map the relationships between trip generation and urban form and structure. The initial conceptual framework of the paper is developed in a review of literature related to urban form and travel behaviour. These concepts are tested empirically in a pilot study of suburban travel activity in master planned estates. A geographical information systems methodology is used to determine regional journey-to-work patterns and travel containment rates. Factors that influence selfcontainment patterns are estimated with a regression model. This research is a useful preliminary examination of travel self-containment in Australian master planned estates.