Determinants of biological activity of nanomaterials in innate immunity cells: the role of aspect ratio, environmental contaminants and protein corona

As defined by the European Union, “ ’Nanomaterial’ (NM) means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or agglomerate, where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm ” (2011/696/UE). Given their peculiar physico-chemical features, nanostructured materials are largely used in many industrial fields (e.g. cosmetics, electronics, agriculture, biomedical) and their applications have astonishingly increased in the last fifteen years. Nanostructured materials are endowed with very large specific surface area that, besides making them very useful in many industrial processes, renders them very reactive towards the biological systems and, hence, potentially endowed with significant hazard for human health. For these reasons, in recent years, many studies have been focused on the identification of toxic properties of nanostructured materials, investigating, in particular, the mechanisms behind their toxic effects as well as their determinants of toxicity. This thesis investigates two types of nanostructured TiO2 materials, TiO2 nanoparticles (NP), which are yearly produced in tonnage quantities, and TiO2 nanofibres (NF), a relatively novel nanomaterial. Moreover, several preparations of MultiWalled Carbon Nanotubes (MWCNT), another nanomaterial widely present in many products, are also investigated.- Although many in vitro and in vivo studies have characterized the toxic properties of these materials, the identification of their determinants of toxicity is still incomplete. The aim of this thesis is to identify the structural determinants of toxicity, using several in vitro models. Specific fields of investigation have been a) the role of shape and the aspect ratio in the determination of biological effects of TiO2 nanofibres of different length; b) the synergistic effect of LPS and TiO2 NP on the expression of inflammatory markers and the role played therein by TLR-4; c) the role of functionalization and agglomeration in the biological effects of MWCNT. As far as biological effects elicited by TiO2 NF are concerned, the first part of the thesis demonstrates that long TiO2 nanofibres caused frustrated phagocytosis, cytotoxicity, hemolysis, oxidative stress and epithelial barrier perturbation. All these effects were mitigated by fibre shortening through ball-milling. However, short TiO2 NF exhibited enhanced ability to activate acute pro-inflammatory effects in macrophages, an effect dependent on phagocytosis. Therefore, aspect ratio reduction mitigated toxic effects, while enhanced macrophage activation, likely rendering the NF more prone to phagocytosis. These results suggest that, under in vivo conditions, short NF will be associated with acute inflammatory reaction, but will undergo a relatively rapid clearance, while long NF, although associated with a relatively smaller acute activation of innate immunity cells, are not expected to be removed efficiently and, therefore, may be associated to chronic inflammatory responses. As far as the relationship between the effects of TiO2 NP and LPS, investigated in the second part of the thesis, are concerned, TiO2 NP markedly enhanced macrophage activation by LPS through a TLR-4-dependent intracellular pathway. The adsorption of LPS onto the surface of TiO2 NP led to the formation of a specific bio-corona, suggesting that, when bound to TiO2 NP, LPS exerts a much more powerful pro-inflammatory effect. These data suggest that the inflammatory changes observed upon exposure to TiO2 NP may be due, at least in part, to their capability to bind LPS and, possibly, other TLR agonists, thus enhancing their biological activities. Finally, the last part of the thesis demonstrates that surface functionalization of MWCNT with amino or carboxylic groups mitigates the toxic effects of MWCNT in terms of macrophage activation and capability to perturb epithelial barriers. Interestingly, surface chemistry (in particular surface charge) influenced the protein adsorption onto the MWCNT surface, allowing to the formation of different protein coronae and the tendency to form agglomerates of different size. In particular functionalization a) changed the amount and the type of proteins adsorbed to MWCNT and b) enhanced the tendency of MWCNT to form large agglomerates. These data suggest that the different biological behavior of functionalized and pristine MWCNT may be due, at least in part, to the different tendency to form large agglomerates, which is significantly influenced by their different capability to interact with proteins contained in biological fluids. All together, these data demonstrate that the interaction between physico-chemical properties of nanostructured materials and the environment (cells + biological fluids) in which these materials are present is of pivotal importance for the understanding of the biological effects of NM. In particular, bio-persistence and the capability to elicit an effective inflammatory response are attributable to the interaction between NM and macrophages. However, the interaction NM-cells is heavily influenced by the formation at the nano-bio interface of specific bio-coronae that confer a novel biological identity to the nanostructured materials, setting the basis for their specific biological activities.

The selectivity and structural determinants of peptide antagonists at the CGRP receptor of rat, L6 myocytes

1. Potency orders were determined for a series of agonists and antagonists on the calcitonin gene-related peptide (CGRP) receptor of rat L6 myocytes. The agents tested were all shown to have been active against CGRP, amylin or adrenomedullin receptors. 2. AC187 had a PIC50 Of 6.8 ± 0.10, making it 14 fold less potent as an antagonist than CGRP8-37 (PIC50, 7.95 ± 0.14). Amyline8-37 was equipotent to AC187 (PIC50, 6.6 ± 0.16) and CGRP19-37 was a fold less potent than either (pIC50 6.1 ± 0.24). 3. [Ala11]-CGRP8-37 was 6 fold less potent than CGRP8-37, (pIC50 7.13 ± 0.14), whereas [Ala18] CGRP8-37 was approximately equipotent to CGRP8-37 (pIC50, 7.52 ± 0.15). However, [Ala11,Ala18]- CGRP8-37 was over 300 fold less potent than CGRP8-37 (pIC50, 5.30 ± 0.04). 4. [Tyr0]-CGRP28-37, amylin19-37 and adrenomedullin22-52 were inactive as antagonists at concentrations of up to 1 μM. 5. Biotinyl-human α-CGRP was 150 fold less potent than human α-CGRP itself (EC50 values of 48 ± 17 nM and 0.31 ± 0.13 nM, respectively). At 1 μM, [Cys(acetomethoxy)(2'7)]-CGRP was inactive as an agonist. 6. These results confirm a role for Arg11 in maintaining the high affinity binding of CGRP8-37. Arg18 is of less direct significance for high affinity binding, but it may be important in maintaining the amphipathic nature of CGRP and its analogues.

Sales manager and sales team determinants of salesperson ethical behaviour

Purpose – The purpose of this paper is to develop and test a model of the role managers and peers play in shaping salespeople's ethical behaviour. The model specifies that sales manager personal moral philosophies, whether sales managers themselves are rewarded according to the outcomes or behaviours of their salespeople, sales team job security, intra-team cooperation, and sales team tactical performance all influence sales team ethical standards. In turn, ethical standards influence the probability that sales team members will behave (un)ethically when faced with ethical dilemmas. Design/methodology/approach – The model is tested on a sample of 154 Finnish sales managers. Data were collected via mail survey. Analysis was undertaken using structural equation modelling. Findings – Ethical standards appear to be shaped by several factors; behaviour-based management controls increase ethical standards, relativist managers tend to manage less ethically-minded sales teams, job insecurity impedes the development of ethical standards, and sales teams' cooperation activity increases ethical standards. Sales teams are less likely to engage in unethical behaviour when the teams have strong ethical standards. Research limitations/implications – Cross-sectional data limits generalisability; single country data may limit the ability to generalise to different sales environments; additional measure development is needed; identification of additional antecedent factors would be beneficial. Practical implications – Sales managers should consciously develop high ethical standards in sales teams if they wish to reduce unethical behaviour. Ethical standards can be improved if sales managers change their own outward behaviour (exhibit a less relativistic ethical philosophy), foster cooperation amongst salespeople, and develop perceptions of job security. How sales managers are rewarded may shape how they approach the management of ethical behaviour in their sales teams. Originality/value – This paper appears to be the first to simultaneously examine both sales manager-specific and sales team-specific antecedents to sales team ethical standards and behaviours. As such, it provides an important base for research in this critical area.

The determinants of export performance:evidence for manufacturing plants in Ireland and Northern Ireland

The dramatic GDP and export growth of Ireland over the last decade forms a marked contrast with that of its nearest neighbour Northern Ireland. In Ireland, export volume growth averaged 15.5% p.a. from 1991 to 1999 compared with 6.3% from Northern Ireland. Using data on individual manufacturing plants this paper considers the determinants of export performance in the two areas. Larger, externally owned plants with higher skill levels are found to have the highest export propensities in both areas. Other influences (plant age, R&D, etc.) prove more strongly conditional on location, plant size, and ownership. Structural factors (e.g. ownership, industry) explain almost all of the difference in export propensity between larger plants in Northern Ireland and Ireland but only around one-third of that between smaller plants. Significant differences are also evident between plants in terms of their sources of new technology. For indigenously owned plants, inhouse R&D is important. For externally owned plants, R&D conducted elsewhere in the group - typically outside Ireland and Northern Ireland - proves more significant. This external dependency and lower than expected export propensity on the part of small plants in Northern Ireland represent significant policy challenges for the future.© 2006 Scottish Economic Society. Published by Blackwell Publishing Ltd.

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.

An exploration of the determinants of innovation:the top management team, organisational climate and organisational learning

Some researchers argue that the top team, rather than the CEO, is a better predictor of an organisation’s fate (Finkelstein & Hambrick, 1996; Knight et al., 1999). However, others suggest that the importance of the top management team (TMT) composition literature is exaggerated (West & Schwenk, 1996). This has stimulated a need for further research on TMTs. While the importance of TMT is well documented in the innovation literature, the organisational environment also plays a key role in determining organisational outcomes. Therefore, the inclusion of both TMT characteristics and organisational variables (climate and organisational learning) in this study provides a more holistic picture of innovation. The research methodologies employed includes (i) interviews with TMT members in 35 Irish software companies (ii) a survey completed by managerial respondents and core workers in these companies (iii) in-depth interviews with TMT members from five companies. Data were gathered in two phases, time 1 (1998-2000) and time 2 (2003). The TMT played an important part in fostering innovation. However, it was a group process, rather than team demography, that was most strongly associated with innovation. Task reflexivity was an important predictor of innovation time 1, time 2). Only one measure of TMT diversity was associated with innovation - tenure diversity -in time 2 only. Organisational context played an important role in determining innovation. This was positively associated with innovation - but with one dimension of organisational learning only. The ability to share information (access to information) was not associated with innovation but the motivation to share information was (perceiving the sharing of information to be valuable). Innovative climate was also associated with innovation. This study suggests that this will lead to innovative outcomes if employees perceive the organisation to support risk, experimentation and other innovative behaviours.

Determinants of sales performance in insurance industry:a cross-cultural comparison between the UK and Malaysia

This thesis is concerned with an empirical investigation of the factors that predict a successful salesperson, using a cross-cultural comparison of two countries: the UK and Malaysia. Besides collecting quantitative data, qualitative data on organisational, environmental and cultural factors were also collected through interviews, personal and case observations. The quantitative data consist of sixteen independent factors and three dependent factors. The independent variables include self-efficacy, self-esteem, locus of control, self-monitoring, extrinsic motivation, intrinsic motivation, experience, training perception, role ambiguity, role conflict, role inaccuracy, gender, age, education, race and religion. The dependent variables are performance target achieved, performance earnings and performance ratings. Questionnaires were distributed to about 500 salespersons in each country, from three insurance companies in the UK and two insurance companies in Malaysia. Response rates were 75 and 50 percent from the UK and Malaysia respectively. The survey results indicated that a salesperson's performance in the UK is predicted by self-efficacy, internal locus of control, self-esteem, extrinsic motivation, experience, training perceptions, role conflict and gender. In Malaysia, a salesperson's performance is predicted by self-efficacy, self-monitoring, experience, role conflict, role ambiguity, education, gender, race and religion. Self-efficacy, experience, role conflict and gender are common predictors of salespersons' performance in both cultures. The likely explanation for these results is culture differences, i.e. UK has a homogeneous culture, while Malaysia has a heterogeneous one. Results from the case observations, such as organisational and environmental factors, give supporting evidence in explaining the empirical results. Implications from the findings are discussed from two aspects: (1) theoretical implications for divergence/convergence theory, Hofstede's model, Churchill's model, and (2) managerial implications for selection, training, motivation and appraisal.

Determinants of employment growth at MNEs:evidence from Egypt, India, South Africa and Vietnam

Many foreign investment operations into emerging markets are small, and are likely to have only a limited impact on the local economy. However, host governments often expect transfer of advanced technology from multinational enterprises (MNEs) operating in these markets to local firms by way of inter-firm mobility of skilled labourers. The extent of such transfers would be limited, among other factors, by the size of the pool of skilled labourers that can potentially be mobile between MNEs and local firms. This, in turn, is determined by employment growth at the MNEs. We develop an empirical specification that models this employment growth, by drawing on both the economics and international business literature. This model is then estimated using firm-level data from four emerging markets. We find that wholly owned foreign direct investment operations have higher employment growth, while local industry and institutional characteristics moderate the growth effect. This suggests that policies encouraging foreign investors to set up in form of joint ventures may not actually raise the benefits for the host economy.