The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

Cholecystokinin (CCK) is a peptide hormone, present in the alimentary and the CNS. It is the most abundant peptide in the brain. CCK has been implicated in a number of disorders. The link between CCK and anxiety was the basis for this research. A comprehensive discussion on the many types of CCK receptor antagonists is included. For the drug discovery process, a number of synthetic approaches have been investigated and alternative chemical approaches developed. 1,4-Benzodiazepine analogues were prepared, with substitutents In the 1,2 & 3- position of the benzodiazepine scaffold varied, and substituted 3-anilino benzodiazepines exhibited the greatest in vitro activity towards the CCKA receptor subtype. Through extensive screening, pyrazolinone-ureido derivatives were identified, optimised, SAR studied and re-screened. A comprehensive in vivo study on the most active analogue is included, which has a number of common structural features with L-36S, 260 including activity. Pyrazolinone-amide derivatives, bearing the tryptophan moiety were equally active. A number of existing and novel furan- 2(SH)-one building blocks were prepared, from which a selected mini-library of 4- amino-substituted furan-2(SH)-ones were prepared and evaluated. All synthesised compounds were evaluated in a CCK radiolabelled binding assay (CCKA & CCKB), with compounds demonstrating receptor selectivity and lead structures being discovered. The work in this thesis has identified a number of highly active prime structures, from which further investigations are essential in providing more in vitro & in vivo data and the need to prepare more analogues.

The development and operation of the effective interpersonal relationship skills relevant to career development problems from staff assessment at an industrial research laboratory

This study concerns the application of a model of effective interpersonal relationships to problems arising from staff assessment at I.C.I. Ltd. Corporate Laboratory between 1972 and 1974. In collaboration with academic and industrial supervision, the study commenced with a survey of management and supervisor opinions about the effectiveness of current staff (work) relationships, with particular reference to the problem of recognising and developing creative potential. This survey emphasised a need to improve the relationships between staff in the staff assessment context. A survey of research into creativity emphasised the importance of the interpersonal environment for obtaining creative behaviour in an organisation context. A further survey of theories of how inter­personal behaviour related to personal creativity (therapeutic psychology) provided a model of effective interpersonal behaviour (Carkhuff, 1969) that could be applied to the organisation context of staff assessment. The objective of the project was redefined as a need to improve the conditions of interpersonal behaviour in relation to certain (career development) problems arising from staff assessment practices. In order to demonstrate the application of the model of effective interpersonal behaviour, the research student recorded interviews between himself and members of staff designed to develop and operate the dimensions of the model. Different samples of staff were used to develop the 'facilitative' and the 'action oriented' dimensions of bahaviour, and then for the operation of a helping programme (based on vocational guidance tests). These interactions have been analysed, according to the scales of measurement in the model ana the results are presented in case study form in this thesis. At each stage of the project, results and conclusions were presented to the sponsoring organisation (e.g. industrial supervisor) in order to assess their (subjective) opinion of relevance to the organ­ isation. Finally, recommendations on further actions towards general improvement of the work relationships in the laboratory were presented in a brief report to the sponsor.

Team effectiveness: a test of in-put process-output

This research addressed the question: "Which factors predict the effectiveness of healthcare teams?" It was addressed by assessing the psychometric properties of a new measure of team functioning with the use of data collected from 797 team members in 61 healthcare teams. This new measure is the Aston Team Performance Inventory (ATPI) developed by West, Markiewicz and Dawson (2005) and based on the IPO model. The ATPI was pilot tested in order to examine the reliability of this measure in the Jordanian cultural context. A sample of five teams comprising 3-6 members each was randomly selected from the Jordan Red Crescent health centers in Amman. Factors that predict team effectiveness were explored in a Jordanian sample (comprising 1622 members in 277 teams with 255 leaders from healthcare teams in hospitals in Amman) using self-report and Leader Ratings measures adapted from work by West, Borrill et al (2000) to determine team effectiveness and innovation from the leaders' point of view. The results demonstrate the validity and reliability of the measures for use in healthcare settings. Team effort and skills and leader managing had the strongest association with team processes in terms of team objectives, reflexivity, participation, task focus, creativity and innovation. Team inputs in terms of task design, team effort and skills, and organizational support were associated with team effectiveness and innovation whereas team resources were associated only with team innovation. Team objectives had the strongest mediated and direct association with team effectiveness whereas task focus had the strongest mediated and direct association with team innovation. Finally, among leadership variables, leader managing had the strongest association with team effectiveness and innovation. The theoretical and practical implications of this thesis are that: team effectiveness and innovation are influenced by multiple factors that must all be taken into account. The key factors managers need to ensure are in place for effective teams are team effort and skills, organizational support and team objectives. To conclude, the application of these findings to healthcare teams in Jordan will help improve their team effectiveness, and thus the healthcare services that they provide.

Illusions of team working in health care

Purpose: The ubiquity and value of teams in healthcare are well acknowledged. However, in practice, healthcare teams vary dramatically in their structures and effectiveness in ways that can damage team processes and patient outcomes. The aim of this paper is to highlight these characteristics and to extrapolate several important aspects of teamwork that have a powerful impact on team effectiveness across healthcare contexts. Design/methodology/approach: The paper draws upon the literature from health services management and organisational behaviour to provide an overview of the current science of healthcare teams. Findings: Underpinned by the input-process-output framework of team effectiveness, team composition, team task, and organisational support are viewed as critical inputs that influence key team processes including team objectives, leadership and reflexivity, which in turn impact staff and patient outcomes. Team training interventions and care pathways can facilitate more effective interdisciplinary teamwork. Originality/value: The paper argues that the prevalence of the term "team" in healthcare makes the synthesis and advancement of the scientific understanding of healthcare teams a challenge. Future research therefore needs to better define the fundamental characteristics of teams in studies in order to ensure that findings based on real teams, rather than pseudo-like groups, are accumulated. © Emerald Group Publishing Limited.

Chapter 1 : nucleobases with designed patterns of hydrogen bonding

The chemistry used in key bond-forming steps to prepare nucleobases with designed patterns of hydrogen bonding is surveyed. Incorporation of the nucleobases into DNA and RNA oligomers is achieved either chemically using building blocks such as nucleoside phosphoramidites or enzymatically using nucleotide triphosphates. By varying the hydrogen bonding pattern within nucleobases, and by incorporating additional substituents, new structures have been designed that "reach over" so that contacts with both strands in targeted duplex DNA can be made in antigene strategies to control gene expression. Various new base-pairing systems have been evaluated that expand the genetic alphabet beyond Watson-Crick base pairs A.T and G.C. For example, benzo-homologated analogs of the natural DNA bases represent a new genetic set of orthogonal, size-expanded derivatives that have been shown to encode amino acids of a protein in a living organism.

Investigating polymer-peptide conjugates and electrospinning for the production of advanced materials

This thesis describes the production of advanced materials comprising a wide array of polymer-based building blocks. These materials include bio-hybrid polymer-peptide conjugates, based on phenylalanine and poly(ethylene oxide), and polymers with intrinsic microporosity (PIMs). Polymer-peptides conjugates were previously synthesised using click chemistry. Due to the inherent disadvantages of the reported synthesis, a new, simpler, inexpensive protocol was sought. Three synthetic methods based on amidation chemistry were investigated for both oligopeptide and polymerpeptide coupling. The resulting conjugates produced were then assessed by various analytical techniques, and the new synthesis was compared with the established protocol. An investigation was also carried out focussing on polymer-peptide coupling via ester chemistry, involving deprotection of the carboxyl terminus of the peptide. Polymer-peptide conjugates were also assessed for their propensity to self-assemble into thixotropic gels in an array of solvent mixtures. Determination of the rules governing this particular self-assembly (gelation) was required. Initial work suggested that at least four phenylalanine peptide units were necessary for self-assembly, due to favourable hydrogen bond interactions. Quantitative analysis was carried out using three analytical techniques (namely rheology, FTIR, and confocal microscopy) to probe the microstructure of the material and provided further information on the conditions for self-assembly. Several polymers were electrospun in order to produce nanofibres. These included novel materials such as PIMs and the aforementioned bio-hybrid conjugates. An investigation of the parameters governing successful fibre production was carried out for PIMs, polymer-peptide conjugates, and for nanoparticle cages coupled to a polymer scaffold. SEM analysis was carried out on all material produced during these electrospinning experiments.

Do stressful times call for team-based working? A study of psychiatric nurses in UK mental healthcase

Background: Team-based working is now an inherent part of effective health care delivery. Previous research has identified that team working is associated with positive mental health and well-being outcomes for individuals operating in an effective team environment. This is a particularly important topic in the health services context, although little empirical attention has been paid to mental-health services. Psychiatric nurses work on a day-to-day basis with a particularly stressful and demanding client group in an environment which is characterised by high demands, uncertainty, and limited resources. This paper specifically focuses on psychiatric nurses working in National Health Service (NHS) and casts some light on the ways in which effective team-based working can help to alleviate a number of occupational stressors and strains. Method: A questionnaire method (2005 NHS Staff Survey) was employed to collect data from 6655 psychiatric nurses from 64 different NHS Trusts. The hypotheses were concerned with four overall measures from the survey; effective team working, occupational stress, work pressure and social support. Hypothesis 1 stated that effective team working will have a significant negative relationship with occupational stress and work pressure. Further, Hypothesis 2 stated that social support from supervisors and co-workers will moderate this relationship. Findings: Data was treated with a series of regression analyses. For Hypothesis 1, working in a real team did have main effects on work pressure and accounted for 1.6 per cent of the variance. Using the Nagelkerke R square value, working in a real team also had main effects on occupational stress an accounted for approximately 2.8 per cent of the variance. Further, the Exp (B) value of 0.662 suggests that the odds of suffering from occupational stress are cut by 33.8 per cent when a psychiatric nurse works in a real team. Results failed to provide support for Hypothesis 2. The analysis then went on to adopt a unique approach for assessing the extent of real team-based working, distinguishing between real teams, and a number of pseudo team typologies, as well as the absence of teamwork all together. As was hypothesised, results demonstrated that psychiatric nurses working in real teams (ones with clear objectives, where-by team members work closely with one another to achieve team objectives and meet regularly to discuss team effectiveness and how it can be improved) experienced the lowest levels of stress and work pressure of the sample. However, contrary to prediction, results indicated that psychiatric nurses working in any type of pseudo team actually experienced significantly higher levels of stress and work pressure than those who did not report as working in a team at all. Discussion: These findings have serious implications for NHS Mental Health Trusts, which may not be implementing, structuring and managing their nursing teams adequately. Indeed, results suggest that poorly-structured team work may actually facilitate stress and pressure in the workplace. Conversely, well-structured real teams serve to reduce stress and work pressure, which in turn not only enhances the working lives and well-being of psychiatric nurses, but also greatly improves the service that the NHS provides to its users.

Structure of glassy GeO2

The full set of partial structure factors for glassy germania, or GeO2, were accurately measured by using the method of isotopic substitution in neutron diffraction in order to elucidate the nature of the pair correlations for this archetypal strong glass former. The results show that the basic tetrahedral Ge(O-1/2)(4) building blocks share corners with a mean inter-tetrahedral Ge-O-Ge bond angle of 132(2)degrees. The topological and chemical ordering in the resultant network displays two characteristic length scales at distances greater than the nearest neighbour. One of these describes the intermediate range order, and manifests itself by the appearance of a first sharp diffraction peak in the measured diffraction patterns at a scattering vector k(FSDP) approximate to 1.53 angstrom(-1), while the other describes so-called extended range order, and is associated with the principal peak at k(PP) = 2.66( 1) angstrom(-1). We find that there is an interplay between the relative importance of the ordering on these length scales for tetrahedral network forming glasses that is dominated by the extended range ordering with increasing glass fragility. The measured partial structure factors for glassy GeO2 are used to reproduce the total structure factor measured by using high energy x-ray diffraction and the experimental results are also compared to those obtained by using classical and first principles molecular dynamics simulations.

Novel anti-bacterials against MRSA:Synthesis of focussed combinatorial libraries of tri-substituted 2(5H)-furanones

Mucobromic and mucochloric acid were used as building blocks for the construction of a chemical combinatorial library of 3,4,5-trisubstituted 2(5H)-furanones. With these 2 butenolide building blocks, and eight alcohols a sublibrary of 16 dihalogenated 5-alkoxy-2(5H)-furanones was prepared. This sublibrary of 5-alkoxylated furanones was reacted with 16 amines generating a full size focussed combinatorial library of 256 individual compounds. This three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones was prepared around the benzimidazolyl furanone lead structure by applying a solution phase combinatorial chemistry concept. Typical representatives of the library were purified and fully characterized and one x-ray structures was recorded, additionally. The 3-bromo-4-benzimizazolyl-5-methoxy-2(5H)furanone, Br-A-l, showed an MIC of 8 μg/ml against the multiresistant Staphylococcus aureus ( MRSA). © 2006 Bentham Science Publishers Ltd.

Who wants to be the leader? The discursive construction of emerging leadership in differently gendered teams

Increasingly, scholars are contesting the value of grand theories of leadership in favour of a social constructionist approach that posits the centrality of language for ‘doing’ leadership. This article investigates the extent to which the linguistic enactment of leadership is often gendered, which may have consequences for the career progression of women business leaders. Drawing on a UK-based study of three teams with different gender compositions (men-only; women-only and mixed gender), I use an Interactional Sociolinguistic framework to compare what leadership ‘looks and sounds like’ during the course of a competitive, leadership task. My findings show that the linguistic construction of leadership varies considerably within each team although not always in conventionally gendered ways. The study potentially provides linguistic insights on the business issue of why so few women progress from middle management to senior leadership roles.

Modular construction of dynamic nucleodendrimers

Isoguanosine-containing dendritic small molecules self-assemble into decameric nucleodendrimers as observed by 1D NMR spectroscopy, 2D DOSY, and mass spectrometry. In particular, apolar building blocks readily form pentameric structures in acetonitrile while the presence of alkali metals promotes the formation of stable decameric assemblies with a preference for cesium ions. Remarkably, co-incubation of guanosine and isoguanosine-containing nucleodendrons results in the formation of decameric structures in absence of added salts. Further analysis of the mixture indicated that guanosine derivatives facilitate the formation, but are not involved in decameric structures; a process reminiscent of molecular crowding. This molecular system provides a powerful canvas for the rapid and modular assembly of polyfunctional dendritic macromolecules. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and characterization of silica-supported L-Lysine-based dendritic branches

Two series of novel modified silicas have been prepared in which individual dendritic branches have been attached to aminopropylsilica using standard peptide coupling methodology. The dendritic branches are composed of enantiomerically pure l-lysine building blocks, and hence, the modified silicas have the potential to act as chiral stationary phases in chromatography. In one series of modified silicas, the surface of the dendritic branch consists of Boc carbamate groups, whereas the other has benzoyl amide surface groups. Different coupling reagents have been investigated in order to maximize the loading onto the solid phase. The new supported dendritic materials have been fully characterized with properties of the bulk material determined by elemental analysis, 13C NMR, and IR spectroscopy, whereas XPS provides important information about the surface of the modified silica exposed to the incident X-rays, the key region in which potential chromatographic performance of these materials will take place. Although the bulk analyses indicate that loading of the dendritic branch onto silica decreases with increasing dendritic generation (and consequently steric bulk), XPS indicates that the optimum surface coverage is actually obtained at the second generation of dendritic growth.

Facile synthesis of polymer-peptide conjugates via direct amino acid coupling chemistry

Polymer-peptide conjugates (also known as biohy-brids) are attracting considerable attention as injectable materials owing to the self-assembling behavior of the peptide and the ability to control the material properties using the polymer component. To this end, a simple method for preparing poly(ethylene oxide)-oligophenylalanine polymer-peptide conjugates (mPEOm-F n-OEt) using isobutylchloroformate as the activating reagent has been identified and developed. The synthetic approach reported employs an industrially viable route to produce conjugates with high yield and purity. Moreover, the approach allows judicious selection of the precursor building blocks to produce libraries of polymer-peptide conjugates with complete control over the molecular composition. Control over the molecular make-up of the conjugates allows fine control of the physicochemical properties, which will be exploited in future studies into the prominent self-assembling behavior of such materials. © 2013 Wiley Periodicals, Inc.

Well-structured teams and the buffering of hospital employees from stress

Membership in well-structured teams, which show clarity in team and individual goals, meet regularly, and recognize diverse skills of their members, is known to reduce stress. This study examined how membership of well-structured teams was associated with lower levels of strain, when testing a work stressors-to-strains relationship model across the three levels of team structure, namely well-structured, poorly structured (do not fulfill all the criteria of well-structured teams) and no team. The work stressors tested, were quantitative overload and hostile environment, whereas strains were measured through job satisfaction and intention to leave job. This investigation was carried out on a random sample of 65,142 respondents in acute/specialist National Health Service hospitals across the UK. Using multivariate analysis of variance, statistically significant differences between means across the three groups of team structure, with mostly moderate effect sizes, were found for the study variables. Those in well-structured teams have the highest levels of job satisfaction and the least intention to leave job. Multigroup structural equation modelling confirmed the model's robustness across the three groups of team structure. Work stressors explained 45%, 50% and 65% of the variance of strains for well-structured, poorly structured and no team membership, respectively. An increase of one standard deviation in work stressors, resulted in an increase in 0.67, 0.70 and 0.81 standard deviations in strains for well-structured, poorly structured and no team membership, respectively. This investigation is an eye-opener for hospitals to work towards achieving well-structured teams, as this study shows weaker stressor-to-strain relationships for members of these teams.

Base-free, one-pot chemocatalytic conversion of glycerol to methyl lactate using supported gold catalysts

We report an efficient one-pot conversion of glycerol (GLY) to methyl lactate (MLACT) in methanol in good yields (73 % at 95 % GLY conversion) by using Au nanoparticles on commercially available ultra-stable zeolite-Y (USY) as the catalyst (160 °C, air, 47 bar pressure, 0.25 M GLY, GLY-to-Au mol ratio of 1407, 10 h). The best results were obtained with zeolite USY-600, a catalyst that has both Lewis and Brønsted sites. This methodology provides a direct chemo-catalytic route for the synthesis of MLACT from GLY. MLACT is stable under the reaction conditions, and the Au/USY catalyst was recycled without a decrease in the activity and selectivity. From glycerol to green building blocks and solvents! An efficient, base-free conversion of glycerol to methyl lactate in methanol is reported, achieving good yields (73 % at 95 % glycerol conversion) using Au/ultra-stable zeolite-Y (USY) as the catalyst and environmentally benign oxygen as the oxidant by combining two separate reaction steps efficiently in a one pot procedure. The Au/USY catalyst can be recycled without a decrease in the activity and selectivity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.