Common structural basis for central nervous system drug design

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

Spectral element model updating for damage identification using clonal selection algorithm

A spectral element model updating procedure is presented to identify damage in a structure using Guided wave propagation results. Two damage spectral elements (DSE1 and DSE2) are developed to model the local (cracks in reinforcement bar) and global (debonding between reinforcement bar and concrete) damage in one-dimensional homogeneous and composite waveguide, respectively. Transfer matrix method is adopted to assemble the stiffness matrix of multiple spectral elements. In order to solve the inverse problem, clonal selection algorithm is used for the optimization calculations. Two displacement-based functions and two frequency-based functions are used as objective functions in this study. Numerical simulations of wave propagation in a bare steel bar and in a reinforcement bar without and with various assumed damage scenarios are carried out. Numerically simulated data are then used to identify local and global damage of the steel rebar and the concrete-steel interface using the proposed method. Results show that local damage is easy to be identified by using any considered objective function with the proposed method while only using the wavelet energy-based objective function gives reliable identification of global damage. The method is then extended to identify multiple damages in a structure. To further verify the proposed method, experiments of wave propagation in a rectangular steel bar before and after damage are conducted. The proposed method is used to update the structural model for damage identification. The results demonstrate the capability of the proposed method in identifying cracks in steel bars based on measured wave propagation data.

The influence of job, team and organizational level resources on employee well-being, engagement, commitment and extra-role performance : test of a model

Purpose – Worker well-being continues to be fundamental to the study of work and a primary consideration for how organizations can achieve competitive advantage and sustainable and ethical work practices (Cartwright and Holmes; Harter, Schmidt and Keyes; Wright and Cropanzano). The science and practice of employee engagement, a key indicator of employee well-being, continues to evolve with ongoing incremental refinements to existing models and measures. This study aims to elaborate the Job Demands-Resources model of work engagement (Bakker and Demerouti) by examining how organizational, team and job level factors interrelate to influence engagement and well-being and downstream outcome variables such as affective commitment and extra-role behaviour.

Design/methodology/approach – Structural equations modelling of survey data obtained from 3,437 employees of a large multi-national mining company was used to test the important direct and indirect influence of organizational focused resources (a culture of fairness and support), team focused resources (team climate) and job level resources (career development, autonomy, supervisor support, and role clarity) on employee well-being, engagement, extra-role behaviour and organizational commitment.

Findings – The fit of the proposed measurement and structural models met criterion levels and the structural model accounted for sizable proportions of the variance in engagement/wellbeing (66 percent), extra-role-behaviour (52 percent) and commitment (69 percent).

Research limitations/implications – Study limitations (e.g. cross-sectional research design) and future opportunities are outlined.

Originality/value – The study demonstrates important extensions to the Job Demands-Resources model and provides researchers and practitioners with a simple but powerful motivational framework, a suite of measures, and a map of their inter-relationships which can be used to help understand, develop and manage employee well-being and engagement and their outcomes.

Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part I: main content

Dynamic treatment regimes are set rules for sequential decision making based on patient covariate history. Observational studies are well suited for the investigation of the effects of dynamic treatment regimes because of the variability in treatment decisions found in them. This variability exists because different physicians make different decisions in the face of similar patient histories. In this article we describe an approach to estimate the optimal dynamic treatment regime among a set of enforceable regimes. This set is comprised by regimes defined by simple rules based on a subset of past information. The regimes in the set are indexed by a Euclidean vector. The optimal regime is the one that maximizes the expected counterfactual utility over all regimes in the set. We discuss assumptions under which it is possible to identify the optimal regime from observational longitudinal data. Murphy et al. (2001) developed efficient augmented inverse probability weighted estimators of the expected utility of one fixed regime. Our methods are based on an extension of the marginal structural mean model of Robins (1998, 1999) which incorporate the estimation ideas of Murphy et al. (2001). Our models, which we call dynamic regime marginal structural mean models, are specially suitable for estimating the optimal treatment regime in a moderately small class of enforceable regimes of interest. We consider both parametric and semiparametric dynamic regime marginal structural models. We discuss locally efficient, double-robust estimation of the model parameters and of the index of the optimal treatment regime in the set. In a companion paper in this issue of the journal we provide proofs of the main results.

Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part II: proofs of results

In this companion article to "Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part I: Main Content" [Orellana, Rotnitzky and Robins (2010), IJB, Vol. 6, Iss. 2, Art. 7] we present (i) proofs of the claims in that paper, (ii) a proposal for the computation of a confidence set for the optimal index when this lies in a finite set, and (iii) an example to aid the interpretation of the positivity assumption.

Molecular architecture of Aβ fibrils grown in cerebrospinal fluid solution and in a cell culture model of Aβ plaque formation

OBJECTIVES: The detailed structure of brain-derived Aβ amyloid fibrils is unknown. To approach this issue, we investigate the molecular architecture of Aβ(1-40) fibrils grown in either human cerebrospinal fluid solution, in chemically simple phosphate buffer in vitro or extracted from a cell culture model of Aβ amyloid plaque formation. METHODS: We have used hydrogen-deuterium exchange (HX) combined with nuclear magnetic resonance, transmission electron microscopy, seeding experiments both in vitro and in cell culture as well as several other spectroscopic measurements to compare the morphology and residue-specific conformation of these different Aβ fibrils. RESULTS AND CONCLUSIONS: Our data reveal that, despite considerable variations in morphology, the spectroscopic properties and the pattern of slowly exchanging backbone amides are closely similar in the fibrils investigated. This finding implies that a fundamentally conserved molecular architecture of Aβ peptide fold is common to Aβ fibrils.

Self-determination theory and needs satisfaction in marketing education : are we meeting the needs of students in large marketing classes?

The aim of this study is to assess whether universities are meeting the needs of students in large marketing classes. In so doing the study investigates the application of self determination theory and psychological needs satisfaction. The basic needs scale, comprising of three constructs; Control, Competence and Caring was adapted and used to evaluate students’ perception of an introductory marketing subject. The study used a multi-method approach consisting of a literature review, a qualitative phase involving in-depth interviews with marketing teaching staff and focus groups with marketing students and a survey of students about introductory level marketing. An adapted version of the basic psychological needs scale was included in a questionnaire that was administered to a convenience sample of 366 students. MANOVA, ANOVA and descriptive statistics were used to analyse the data. The results show that the psychological needs satisfaction of many students are not being fully realised. It was also found that marketing degree students enjoyed the challenges and were more stimulated by the subject. The higher achieving students enjoyed the challenge of the subject more than the lower achieving students. As a result of this study, there are three suggestions for further research. Firstly, further study should compare subjects, with relatively small enrolments, to those with large enrolments to corroborate the value of this method of assessing student satisfaction. Secondly, the use of a larger sample across other universities would confirm whether these findings hold for other institutions. Finally, it is suggested that a structural model should be developed to extend this investigation of student satisfaction and the constructs used in the study.

Relationship-based determinants of building project performance in China

The aim of this paper is to investigate the relationship-based factors that affect performance of general building projects in China. Eight performance metrics that may be used to measure the success level of construction projects are defined and categorized into two groups namely 'hard' and 'soft' performance. Eight indicators of risks inherent in relationships and seven indicators of tools expected to facilitate relationship building that may affect project success are identified. Data of different projects were collected in China via a self-administered postal survey. By using structural equation modelling techniques, a structural model is developed to help explain the relationship among different variables. It has been found that relational risk has negative influence on project performance. It is recommended that firms in the Chinese construction industry manage the relationship-based factors that are significant in the model so as to achieve project success.

Microphase separation through competitive hydrogen bonding in double crystalline diblock copolymer/homopolymer blends

Microphase separation induced by competitive hydrogen bonding interactions in double crystalline diblock copolymer/homopolymer blends was studied for the first time. Poly(ethylene oxide)- block-poly(e-caprolactone) (PEO-b-PCL)/poly(4-vinylphenol) (PVPh) blends were prepared in tetrahydrofuran. The diblock copolymer PEO-b-PCL consists of two immiscible crystallizable blocks wherein bothPEO and PCL blocks can form hydrogen bonds with PVPh. In these A-b-B/C diblock copolymer homopolymer blends, microphase separation takes place due to the disparity in intermolecular interactions; specifically, PVPh and PEO block interact strongly whereas PVPh and PCL block interact weakly. The TEM and SAXS results show that the cubic PEO-b-PCL diblock copolymer changes into ordered hexagonal cylindrical morphology upon addition of 20 wt % PVPh followed by disordered bicontinuous phase in the blend with 40 wt % PVPh and then to homogeneous phase at 60 wt % PVPh and above blends. Up to 40 wt % PVPh there is only weak interaction between PVPh and PCL due to the selective hydrogen bonding between PVPh and PEO. However, with higher PVPh concentration, the blends become homogeneous since a sufficient amount of PVPh is available to form hydrogen bonds with both PEO and PCL. A structural model was proposed to explain the self-assembly and microphase morphology of these blends based on the experimental results obtained. The formation of nanostructures and changes in morphologies depend on the relative strength of hydrogen bonding interaction between each block of the block copolymer and the homopolymer.

Microphase separation in double crystalline poly (ethylene oxide)-block-poly (caprolactone)/poly (4-vinyl phenol) blends

We report microphase separation induced by competitive hydrogen bonding interactions in double crystalline diblock copolymer/homopolymer blends of poly(ethylene oxide)-block-poly(ɛ-caprolactone) (PEO-b-PCL) and poly(4-vinyl phenol) (PVPh). The diblock copolymer PEO-b-PCL consists of two immiscible crystallizable blocks wherein both PEO and PCL blocks can form hydrogen bonds with PVPh. In these A-b-B/C diblock copolymer/homopolymer blends, microphase separation takes place due to the disparity in intermolecular interactions; specifically PVPh and PEO block interact strongly whereas PVPh and PCL block interact weakly. The TEM and SAXS results show that the cubic PEO-b-PCL diblock copolymer changes into ordered hexagonal cylindrical morphology upon addition of 20 wt % PVPh followed by disordered bicontinuous phase in the blend with 40 wt % PVPh and then to homogenous phase at 60 wt% PVPh and above. Up to 40 wt % PVPh there is only weak interaction between PVPh and PCL due to the selective hydrogen bonding between PVPh and PEO. However, with higher PVPh concentration, the blends become homogeneous since a sufficient amount of PVPh is available to form hydrogen bonds with both PEO and PCL. A structural model was proposed to explain the self-assembly and morphology of these blends based on the experimental results obtained. The formation of nanostructures and changes in morphologies depend on the relative strength of hydrogen bonding interaction between each block of the block copolymer and the homopolymer (1-3).

Self-assembly and competitive hydrogen bonding interactions of double crystalline diblock copolymer/homopolymer blends

In the present work, nanostructured blends were prepared from double crystalline diblock copolymer poly(ɛ-caprolactone)-block-poly(ethylene oxide) and homopolymer poly(4-vinyl phenol) (PVPh). The diblock copolymer PEO-b-PCL consists of two immiscible crystallizable blocks wherein both PEO and PCL blocks can form hydrogen bonds with PVPh. In these A-b-B/C diblock copolymer/homopolymer blends, microphase separation takes place due to the disparity in intermolecular interactions; specifically, PVPh and PEO block interact strongly whereas PVPh and PCL block interact weakly. The TEM and SAXS results show that the cubic PEO-b-PCL diblock copolymer changes into ordered hexagonal cylindrical morphology upon addition of 20 wt % PVPh followed by disordered bicontinuous phase in the blend with 40 wt % PVPh and then to homogeneous phase at 60 wt % PVPh and above blends. Up to 40 wt % PVPh there is only weak interaction between PVPh and PCL due to the selective hydrogen bonding between PVPh and PEO. However, with higher PVPh concentration, the blends become homogeneous since a sufficient amount of PVPh is available to form hydrogen bonds with both PEO and PCL. A structural model was proposed to explain the self-assembly and microphase morphology of these blends based on the experimental results obtained. The formation of nanostructures and changes in morphologies depend on the relative strength of hydrogen bonding interaction between each block of the block copolymer and the homopolymer.

Institutional environment, managerial attitudes and environmental sustainability orientation of small firms

This study examines the direct impact of three dimensions of the institutional environment on managerial attitudes toward the natural environment and the direct influence of the latter on the environmental sustainability orientation (ESO) of small firms. We contend that when the institutional environment is perceived by owner–managers as supportive of sound natural environment management practices, they are more likely to develop a positive attitude toward natural environment issues and concerns. Such owner–manager attitudes are likely to lead to a positive and proactive orientation of their firms toward environmental sustainability. The study uses survey data from 166 small manufacturing firms located in three Philippine cities. First, the study develops and tests the measurement models to examine the validity of the constructs representing the firm’s institutional environment, managerial attitudes toward the natural environment and the ESO of firms. Second, the study develops and tests the structural models examining the institutional environment–managerial attitudes–ESO linkages. Multi-sample invariance structural model analysis shows the mediating role of managerial attitudes in the institutional environment–ESO nexus. The findings show that ESO is a construct comprising three dimensions: knowledge of environmental issues, sustainable practices and commitment toward environmental sustainability. The cognitive, regulatory and normative elements of the institutional environment are strongly linked to positive managerial attitudes toward environmental sustainability, which in turn, positively influences the firm’s overall ESO. Managerial attitudes play a mediating role in the institutional environment–ESO linkages. The managerial, practical, research and policy implications of the research findings are discussed.

Knowledge management culture, strategy and process in Malaysian firms

Malaysia is one of the leading countries in Asia that are at the forefront in the development of a knowledge-based economy (KBE). The Malaysian government has been making substantial investments in both physical and technological infrastructure to facilitate knowledge-intensive economic activities. Foreign and local firms in Malaysia are encouraged to take advantage of the opportunities brought by the emerging KBE. However, little is known as to how firms in Malaysia respond to this new trajectory of economic development. In particular, there is paucity in the literature as to how Malaysian firms manage knowledge in their organizations as they strive to achieve sustainable competitive performance. Little is known as to how and why firms in Malaysia develop and manage their intangible and knowledge-based resources as they operate and respond to the modern knowledge-based competitive economic arena. This paper examines a type of organizational culture that supports and promotes knowledge management (KM) within firms in Malaysia. The paper argues that KM-oriented culture shapes the overall KM strategy of firms, which consequently shapes the organizational process required to manage the firm's knowledge-based resources. The study uses survey data from a sample of 153 firms from Malaysia. Structural equation modelling was used to develop and test the measurement model of KM-oriented culture, KM strategy and KM process of the sample firms, as well as the structural model of their hypothesized relationships. The results show that firms with high level of KM-oriented culture demonstrated well-defined KM strategies. Firms that implemented well-defined KM strategies also reported that they have better KM processes in place. Building a KM-oriented culture within the organization is a pre-requisite to the implementation of any KM systems in Malaysian firms. Successful implementation of KM strategies, processes and the supporting technological infrastructure depends on whether organizational members consider KM as a norm within the firm. The study's focus on the linkages between KM-oriented culture, strategy and process in the context of Malaysian firms contributes to a more nuanced understanding of KM among firms in the Asian context in general, and in the Malaysian context in particular.

Benzene adsorption at the aqueous (011) α-quartz interface : is surface flexibility important?

Atomistic simulations of molecular adsorption onto inorganic substrates under aqueous conditions can be used to guide the rational design of new materials, fabricated using biomimetic methods. The success of such work depends critically on the model used. Here, we investigate the impact of using a rigid structural model of the (0 1 1) ?-quartz surface, over a fully flexible model, on the calculated free energy change in the adsorption of a single molecule of benzene (a simple analogue of the amino acid phenylalanine) from liquid water. Subtle differences in the mobility of the adsorbate close to the surface result in the free energy of adsorption being overestimated by the rigid model, relative to the fully flexible case. Moreover, we find that the distribution of bound configurations of the adsorbate at their respective free energy minima is different between the two models.

Microphase separation induced by competitive hydrogen bonding interactions in semicrystalline triblock copolymer/homopolymer complexes

Microphase separation through competitive hydrogen bonding interactions in ABC/D triblock copolymer/ homopolymer complexes is studied for the first time. This study investigated self-assembled nanostructures that are obtained in the bulk, by the complexation of a semicrystalline polystyrene-block-poly(4-vinylpyridine)-block-poly(ethylene oxide) (SVPEO) triblock copolymer with a poly(4-vinyl phenol) (PVPh) homopolymer in tetrahydrofuran (THF). In these complexes, microphase separation takes place due to the disparity in intermolecular interactions among PVPh/P4VP and PVPh/PEO pairs. At low PVPh concentrations, PEO interacts relatively weakly with PVPh, whereas in the complexes containing more than 30 wt% PVPh, the PEO block interacts considerably with PVPh, leading to the formation of composition-dependent nanostructures. SAXS and TEM results indicate that the cylindrical morphology of a neat SVPEO triblock copolymer changes into lamellae structures at 20 wt% of PVPh then to disordered lamellae with 40 wt% PVPh. Wormlike structures are obtained in the complex with 50 wt%PVPh, followed by disordered spherical microdomains with size in the order of 40–50 nm in the complexes with 60–80 wt% PVPh. Moreover, when the content of PVPh increases to 80 wt%, the complexes show a completely homogenous phase of PVPh/P4VP and PVPh/PEO with phase separated spherical PS domains. The fractional crystallization behavior in SVPEO and complexes at lower PVPh content was also examined. A structural model was proposed to explain the microphase separation and self-assembled morphologies of these complexes based on the experimental results obtained. The formation of nanostructures and changes in morphologies depend on the relative strength of hydrogen bonding interactions between each component block of the copolymer and the homopolymer.