A novel and rational approach towards designing aluminium chelators

Aluminium (Al) is known to be neurotoxic and has been associated with the aetiology of Alzheimer's Disease. To date, only desferrioxamine (DFO), a trihydroxamic acid siderophore has been used in the clinical environment for the removal of Al from the body. However, this drug is expensive, orally inactive and is associated with many side effects. These studies employed a theoretical approach, with the use of quantum mechanics (QM) via semi-empirical molecular orbital (MO) calculations, and a practical approach using U87-MG glioblastoma cells as a model for evaluating the influence of potential chelators on the passage of aluminium into cells. Preliminary studies involving the Cambridge Structural Database (CSD) identified that Al prefers binding to bidentate ligands in a 3:1 manner, whereby oxygen was the exclusive donating atom. Statistically significant differences in M-O bond lengths when compared to other trivalent metal ions such as Fe3+ were established and used as an acceptance criterion for subsequent MO calculations. Of the semi-empirical methods parameterised for Al, the PM3 Hamiltonian was found to give the most reliable final optimised geometries of simple 3:1 Al complexes. Consequently the PM3 Hamiltonian was used for evaluating the Hf of 3:1 complexes with more complicated ligands. No correlation exists between published stability constants and individual parameters calculated via PM3 optimisations, although investigation of the dicarboxylates reveals a correlation of 0.961 showing promise for affinity prediction of closely related ligands. A simple and inexpensive morin spectrofluorescence assay has been developed and optimised producing results comparable to atomic absorption spectroscopy methods for the quantitative analysis of Al. This assay was used in subsequent in vitro models, initially on E. coli, which indicated that Al inhibits the antimicrobial action of ciprofloxacin, a potent quinolone antibiotic. Ensuing studies using the second model, U87-MG cells, investigated the influence of chelators on the transmembrane transport of Al, identifying 1,2-diethylhydroxypyridin-4-one as a ligand showing greatest potential for chelating Al in the clinical situation. In conclusion, these studies have explored semi-empirical MO Hamiltonians and an in-vitro U87-MG cell line, both as possible methods for predicting effective chelators of Al.

Non-classical inhibitors of dihydrofolate reductase

This thesis comprises two main objectives. The first objective involved the stereochemical studies of chiral 4,6-diamino-1-aryl-1,2-dihydro-s-triazines and an investigation on how the different conformations of these stereoisomers may affect their binding affinity to the enzyme dihydrofolate reductase (DHFR). The ortho-substituted 1-aryl-1,2-dihydro-s-triazines were synthesised by the three component method. An ortho-substitution at the C6' position was observed when meta-azidocycloguanil was decomposed in acid. The ortho-substituent restricts free rotation and this gives rise to atropisomerism. Ortho-substituted 4,6-diamino-1-aryl-2-ethyl-1,2-dihydro-2-methyl-s-triazine contains two elements of chirality and therefore exists as four stereoisomers: (S,aR), (R,aS), (R,aR) and (S,aS). The energy barriers to rotation of these compounds were calculated by a semi-empirical molecular orbital program called MOPAC and they were found to be in excess of 23 kcal/mol. The diastereoisomers were resolved and enriched by C18 reversed phase h.p.l.c. Nuclear overhauser effect experiments revealed that (S,aR) and (R,aS) were the more stable pair of stereoisomers and therefore existed as the major component. The minor diastereoisomers showed greater binding affinity for the rat liver DHFR in in vitro assay. The second objective entailed the investigation into the possibility of retaining DHFR inhibitory activity by replacing the classical diamino heterocyclic moiety with an amidinyl group. 4-Benzylamino-3-nitro-N,N-dimethyl-phenylamidine was synthesised in two steps. One of the two phenylamidines indicated weak inhibition against the rat liver DHFR. This weak activity may be due to the failure of the inhibitor molecule to form strong hydrogen bonds with residue Glu-30 at the active site of the enzyme.

Lexical database enrichment through semi-automated morphological analysis

Derivational morphology proposes meaningful connections between words and is largely unrepresented in lexical databases. This thesis presents a project to enrich a lexical database with morphological links and to evaluate their contribution to disambiguation. A lexical database with sense distinctions was required. WordNet was chosen because of its free availability and widespread use. Its suitability was assessed through critical evaluation with respect to specifications and criticisms, using a transparent, extensible model. The identification of serious shortcomings suggested a portable enrichment methodology, applicable to alternative resources. Although 40% of the most frequent words are prepositions, they have been largely ignored by computational linguists, so addition of prepositions was also required. The preferred approach to morphological enrichment was to infer relations from phenomena discovered algorithmically. Both existing databases and existing algorithms can capture regular morphological relations, but cannot capture exceptions correctly; neither of them provide any semantic information. Some morphological analysis algorithms are subject to the fallacy that morphological analysis can be performed simply by segmentation. Morphological rules, grounded in observation and etymology, govern associations between and attachment of suffixes and contribute to defining the meaning of morphological relationships. Specifying character substitutions circumvents the segmentation fallacy. Morphological rules are prone to undergeneration, minimised through a variable lexical validity requirement, and overgeneration, minimised by rule reformulation and restricting monosyllabic output. Rules take into account the morphology of ancestor languages through co-occurrences of morphological patterns. Multiple rules applicable to an input suffix need their precedence established. The resistance of prefixations to segmentation has been addressed by identifying linking vowel exceptions and irregular prefixes. The automatic affix discovery algorithm applies heuristics to identify meaningful affixes and is combined with morphological rules into a hybrid model, fed only with empirical data, collected without supervision. Further algorithms apply the rules optimally to automatically pre-identified suffixes and break words into their component morphemes. To handle exceptions, stoplists were created in response to initial errors and fed back into the model through iterative development, leading to 100% precision, contestable only on lexicographic criteria. Stoplist length is minimised by special treatment of monosyllables and reformulation of rules. 96% of words and phrases are analysed. 218,802 directed derivational links have been encoded in the lexicon rather than the wordnet component of the model because the lexicon provides the optimal clustering of word senses. Both links and analyser are portable to an alternative lexicon. The evaluation uses the extended gloss overlaps disambiguation algorithm. The enriched model outperformed WordNet in terms of recall without loss of precision. Failure of all experiments to outperform disambiguation by frequency reflects on WordNet sense distinctions.

An empirical investigation of the effect of rights issue announcements on share returns and the determinants of abnormal returns on the Kuala Lumpur Stock Exchange

This thesis examines the effect of rights issue announcements on stock prices by companies listed on the Kuala Lumpur Stock Exchange (KLSE) between 1987 to 1996. The emphasis is to report whether the KLSE is semi strongly efficient with respect to the announcement of rights issues and to check whether the implications of corporate finance theories on the effect of an event can be supported in the context of an emerging market. Once the effect is established, potential determinants of abnormal returns identified by previous empirical work and corporate financial theory are analysed. By examining 70 companies making clean rights issue announcements, this thesis will hopefully shed light on some important issues in long term corporate financing. Event study analysis is used to check on the efficiency of the Malaysian stock market; while cross-sectional regression analysis is executed to identify possible explanators of the rights issue announcements' effect. To ensure the results presented are not contaminated, econometric and statistical issues raised in both analyses have been taken into account. Given the small amount of empirical research conducted in this part of the world, the results of this study will hopefully be of use to investors, security analysts, corporate financial managements, regulators and policy makers as well as those who are interested in capital market based research of an emerging market. It is found that the Malaysian stock market is not semi strongly efficient since there exists a persistent non-zero abnormal return. This finding is not consistent with the hypothesis that security returns adjust rapidly to reflect new information. It may be possible that the result is influenced by the sample, consisting mainly of below average size companies which tend to be thinly traded. Nevertheless, these issues have been addressed. Another important issue which has emerged from the study is that there is some evidence to suggest that insider trading activity existed in this market. In addition to these findings, when the rights issue announcements' effect is compared to the implications of corporate finance theories in predicting the sign of abnormal returns, the signalling model, asymmetric information model, perfect substitution hypothesis and Scholes' information hypothesis cannot be supported.

Modeling the effects of pharmaceutical marketing

Successful innovation of prescription drugs requires a substantial amount of marketing support. There is, however, much concern about the effects of marketing expenditures on the demand of pharmaceutical products (Manchanda et al., Market Lett 16(3/4):293–308, 2005). For example, excessive marketing could stimulate demand for products in the absence of a fundamental need. It also has been suggested that increased marketing expenditures may reduce the price elasticity of demand and allow firms to charge higher prices (Windmeijer et al., Health Econ 15(1):5–18, 2005). In this paper, we present the outcomes of an empirical study in which we determine the effects of pharmaceutical marketing expenditures using a number of frequently used “standardized” models. We determine which models perform best in terms of predictive validity and adequate descriptions of reality. We demonstrate, among others, that the effects of promotional efforts are brand specific and that most standardized models do not provide adequate descriptions of reality. We find that marketing expenditures have no or moderate effects on demand for pharmaceutical products in The Netherlands.

Dynamic causal modeling of load-dependent modulation of effective connectivity within the verbal working memory network

Neuroimaging studies have consistently shown that working memory (WM) tasks engage a distributed neural network that primarily includes the dorsolateral prefrontal cortex, the parietal cortex, and the anterior cingulate cortex. The current challenge is to provide a mechanistic account of the changes observed in regional activity. To achieve this, we characterized neuroplastic responses in effective connectivity between these regions at increasing WM loads using dynamic causal modeling of functional magnetic resonance imaging data obtained from healthy individuals during a verbal n-back task. Our data demonstrate that increasing memory load was associated with (a) right-hemisphere dominance, (b) increasing forward (i.e., posterior to anterior) effective connectivity within the WM network, and (c) reduction in individual variability in WM network architecture resulting in the right-hemisphere forward model reaching an exceedance probability of 99% in the most demanding condition. Our results provide direct empirical support that task difficulty, in our case WM load, is a significant moderator of short-term plasticity, complementing existing theories of task-related reduction in variability in neural networks. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.

Quality management (QM) implementation in the Kuwaiti Oil Industry:An empirical study and a proposed generic framework

In an Arab oil producing country in the Middle East such as Kuwait, Oil industry is considered as the main and most important industry of the country. This industry’s importance emerged from the significant role it plays in both country’s national economy and also global economy. Moreover, Oil industry’s criticality comes from its interconnectivity with national security and power in the Middle East region. Hence, conducting this research in this crucial industry had certainly added values to companies in this industry as it investigated thoroughly the main components of the TQM implementation process and identified which components affects significantly TQM’s implementation and its gained business results. In addition, as the Oil sector is a large sector that is known for its richness of employees with different national cultures and backgrounds. Thus, this culture-heterogeneous industry seems to be the most appropriate environment to address and satisfy a need in the literature to investigate the national culture values’ effects on TQM implementation process. Furthermore, this research has developed a new conceptual model of TQM implementation process in the Kuwaiti Oil industry that applies in general to operations and productions organizations at the Kuwaiti business environment and in specific to organizations in the Oil industry, as well it serves as a good theoretical model for improving operations and production level of the oil industry in other developing and developed countries. Thus, such research findings minimized the literature’s gap found the limited amount of empirical research of TQM implementation in well-developed industries existing in an Arab, developing countries and specifically in Kuwait, where there was no coherent national model for a universal TQM implementation in the Kuwaiti Oil industry in specific and Kuwaiti business environment in general. Finally, this newly developed research framework, which emerged from the literature search, was validated by rigorous quantitative analysis tools including SPSS and Structural Equation Modeling. The quantitative findings of questionnaires collected were supported by the qualitative findings of interviews conducted.

The spatial distribution of self-employment in India:evidence from semi-parametric geoadditive models

The spatial distribution of self-employment in India: evidence from semiparametric geoadditive models, Regional Studies. The entrepreneurship literature has rarely considered spatial location as a micro-determinant of occupational choice. It has also ignored self-employment in developing countries. Using Bayesian semiparametric geoadditive techniques, this paper models spatial location as a micro-determinant of self-employment choice in India. The empirical results suggest the presence of spatial occupational neighbourhoods and a clear north–south divide in self-employment when the entire sample is considered; however, spatial variation in the non-agriculture sector disappears to a large extent when individual factors that influence self-employment choice are explicitly controlled. The results further suggest non-linear effects of age, education and wealth on self-employment.

Individual spirit at work and its outcomes:an empirical examination in corporate Thailand

The purpose of the present study was to conduct empirical research in corporate Thailand in order to (1) investigate the relationships between individual spirit at work and three employee work attitudinal variables (organisational identification, job satisfaction and psychological well-being) and three organisational outcomes (in-role performance, organisational citizenship behaviours (OCB), and turnover intentions) (2) further examine causal relations among these organisational behaviour variables with a longitudinal design (3) examine three employee work attitudes as mediator variables between individual spirit at work and three organisational outcomes and (4) explore the potential antecedents of organisational conditions that foster employee experienced individual spirit at work. The 715 completed questionnaires were received from the first wave of data collection during July 2008 and the second wave was conducted again within the same organisations and 501 completed questionnaires were received during April 2009. Data were obtained through 52 organisations which were from three types of organisations within Thailand: public organisations (N=237,185), for-profit organisations (N=244,155), and not-for-profit organisations (N=234,161). Confirmatory factor analysis of all measures used in the study and hypothesized model were tested with structural equation modeling techniques. Results were strongly supportive. In addition, although the model was invariant across rater of performance and OCB, there were differences across self report and supervisor rating. Additionally, the antecedents of organisational conditions that fostered employees experienced individual spirit at work and the implications of these findings for practice and research are discussed.

A modified semi-oriented radial measure for target setting with negative data

Over the last few years Data Envelopment Analysis (DEA) has been gaining increasing popularity as a tool for measuring efficiency and productivity of Decision Making Units (DMUs). Conventional DEA models assume non-negative inputs and outputs. However, in many real applications, some inputs and/or outputs can take negative values. Recently, Emrouznejad et al. [6] introduced a Semi-Oriented Radial Measure (SORM) for modelling DEA with negative data. This paper points out some issues in target setting with SORM models and introduces a modified SORM approach. An empirical study in bank sector demonstrates the applicability of the proposed model. © 2014 Elsevier Ltd. All rights reserved.

Content vs. process in the HRM-performance relationship:an empirical examination

This study investigates the impact of a human resource management (HRM) system, which integrates both content and process of human resource (HR) practices, on organizational performance, through collective employee reactions. The analysis is based on a sample of 1,250 Greek employees working in 133 public- and private-sector organizations, which operate in the present context of severe financial and economic crises. The findings of the structural equation modeling suggest that content and process are two inseparable faces of an HRM system that help to reveal a comprehensive picture of the HRM-organizational performance relationship. Based on the findings that collective employee reactions mediate the HRM content (i.e., organizational performance relationship) and HRM process moderates the HRM content (i.e., employee reactions relationship), the study has several theoretical and practice implications. © 2014 Wiley Periodicals, Inc.

B2B service brand identity and brand performance:an empirical investigation in the UK’s B2B IT services sector

Purpose – This paper aims to apply the business-to-business (B2B) Service Brand Identity (SBI) scale to empirically assess the influence of service brand identity on brand performance for the first time. Design/methodology/approach – Based on data collected from 421 senior marketing executives, this paper applies the B2B SBI and structural equation modeling to fulfill the above purpose. Findings – Brand personality and human resource initiatives have a positive and significant influence on brand performance. Corporate visual identity, in addition to an employee and client focus, has an insignificant impact on performance. Consistent communications have a negative and significant influence on brand performance. Research limitations/implications – Data were only collected from executives in the UK. This research would benefit from replicative studies. Practical implications – This research empirically establishes the brand management activities that drive brand performance. Originality/value – This is the first empirical study to assess the influence service brand identity has on brand performance.