Development of a co-culture model of the human lungs for toxicity testing and identification of biomarkers of inhalation toxicity

The airway epithelium is the first point of contact in the lung for inhaled material, including infectious pathogens and particulate matter, and protects against toxicity from these substances by trapping and clearance via the mucociliary escalator, presence of a protective barrier with tight junctions and initiation of a local inflammatory response. The inflammatory response involves recruitment of phagocytic cells to neutralise and remove and invading materials and is oftern modelled using rodents. However, development of valid in vitro airway epithelial models is of great importance due to the restrictions on animal studies for cosmetic compound testing implicit in the 7th amendment to the European Union Cosmetics Directive. Further, rodent innate immune responses have fundamental differences to human. Pulmonary endothelial cells and leukocytes are also involved in the innate response initiated during pulmonary inflammation. Co-culture models of the airways, in particular where epithelial cells are cultured at air liquid interface with the presence of tight junctions and differentiated mucociliary cells, offer a solution to this problem. Ideally validated models will allow for detection of early biomarkers of response to exposure and investigation into inflammatory response during exposure. This thesis describes the approaches taken towards developing an in vitro epithelial/endothelial cell model of the human airways and identification biomarkers of response to exposure to xenobiotics. The model comprised normal human primary microvascular endothelial cells and the bronchial epithelial cell line BEAS-2B or normal human bronchial epithelial cells. BEAS-2B were chosen as their characterisation at air liquid interface is limited but they are robust in culture, thereby predicted to provide a more reliable test system. Proteomics analysis was undertaken on challenged cells to investigate biomarkers of exposure. BEAS-2B morphology was characterised at air liquid interface compared with normal human bronchial epithelial cells. The results indicate that BEAS-2B cells at an air liquid interface form tight junctions as shown by expression of the tight junction protein zonula occludens-1. To this author’s knowledge this is the first time this result has been reported. The inflammatory response of BEAS-2B (measured as secretion of the inflammatory mediators interleukin-8 and -6) air liquid interface mono-cultures to Escherichia coli lipopolysaccharide or particulate matter (fine and ultrafine titanium dioxide) was comparable to published data for epithelial cells. Cells were also exposed to polymers of “commercial interest” which were in the nanoparticle range (and referred to particles hereafter). BEAS-2B mono-cultures showed an increased secretion of inflammatory mediators after challenge. Inclusion of microvascular endothelial cells resulted in protection against LPS- and particle- induced epithelial toxicity, measured as cell viability and inflammatory response, indicating the importance of co-cultures for investigations into toxicity. Two-dimensional proteomic analysis of lysates from particle-challenged cells failed to identify biomarkers of toxicity due to assay interference and experimental variability. Separately, decreased plasma concentrations of serine protease inhibitors, and the negative acute phase proteins transthyretin, histidine-rich glycoprotein and alpha2-HS glycoprotein were identified as potential biomarkers of methyl methacrylate/ethyl methacrylate/butylacrylate treatment in rats.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

A multi-level investigation of psychological contract breach and organizational identification through the lens of perceived organizational membership:testing a moderated-mediated model

Drawing on the perceived organizational membership theoretical framework and the social identity view of dissonance theory, I examined in this study the dynamics of the relationship between psychological contract breach and organizational identification. I included group-level transformational and transactional leadership as well as procedural justice in the hypothesized model as key antecedents for organizational membership processes. I further explored the mediating role of psychological contract breach in the relationship between leadership, procedural justice climate, and organizational identification and proposed separateness–connectedness self-schema as an important moderator of the above mediated relationship. Hierarchical linear modeling results from a sample of 864 employees from 162 work units in 10 Greek organizations indicated that employees' perception of psychological contract breach negatively affected their organizational identification. I also found psychological contract breach to mediate the impact of transformational and transactional leadership on organizational identification. Results further provided support for moderated mediation and showed that the indirect effects of transformational and transactional leadership on identification through psychological contract breach were stronger for employees with a low connectedness self-schema.

Data envelopment analysis model for the appraisal and relative performance evaluation of nurses at an intensive care unit

The appraisal and relative performance evaluation of nurses are very important and beneficial for both nurses and employers in an era of clinical governance, increased accountability and high standards of health care services. They enhance and consolidate the knowledge and practical skills of nurses by identification of training and career development plans as well as improvement in health care quality services, increase in job satisfaction and use of cost-effective resources. In this paper, a data envelopment analysis (DEA) model is proposed for the appraisal and relative performance evaluation of nurses. The model is validated on thirty-two nurses working at an Intensive Care Unit (ICU) at one of the most recognized hospitals in Lebanon. The DEA was able to classify nurses into efficient and inefficient ones. The set of efficient nurses was used to establish an internal best practice benchmark to project career development plans for improving the performance of other inefficient nurses. The DEA result confirmed the ranking of some nurses and highlighted injustice in other cases that were produced by the currently practiced appraisal system. Further, the DEA model is shown to be an effective talent management and motivational tool as it can provide clear managerial plans related to promoting, training and development activities from the perspective of nurses, hence increasing their satisfaction, motivation and acceptance of appraisal results. Due to such features, the model is currently being considered for implementation at ICU. Finally, the ratio of the number DEA units to the number of input/output measures is revisited with new suggested values on its upper and lower limits depending on the type of DEA models and the desired number of efficient units from a managerial perspective.

The development of a computer simulation model of the interaction between the supply and usage of major components in car assembly you use in stock control

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Managing enterprises and ERP systems:a contingency model for the enterprization of operations

Purpose: The purpose of this paper is to investigate enterprise resource planning (ERP) systems development and emerging practices in the management of enterprises (i.e. parts of companies working with parts of other companies to deliver a complex product and/or service) and identify any apparent correlations. Suitable a priori contingency frameworks are then used and extended to explain apparent correlations. Discussion is given to provide guidance for researchers and practitioners to deliver better strategic, structural and operational competitive advantage through this approach; coined here as the "enterprization of operations". Design/methodology/approach: Theoretical induction uses a new empirical longitudinal case study from Zoomlion (a Chinese manufacturing company) built using an adapted form of template analysis to produce a new contingency framework. Findings: Three main types of enterprises and the three main types of ERP systems are defined and correlations between them are explained. Two relevant a priori frameworks are used to induct a new contingency model to support the enterprization of operations; known as the dynamic enterprise reference grid for ERP (DERG-ERP). Research limitations/implications: The findings are based on one longitudinal case study. Further case studies are currently being conducted in the UK and China. Practical implications: The new contingency model, the DERG-ERP, serves as a guide for ERP vendors, information systems management and operations managers hoping to grow and sustain their competitive advantage with respect to effective enterprise strategy, enterprise structure and ERP systems. Originality/value: This research explains how ERP systems and the effective management of enterprises should develop in order to sustain competitive advantage with respect to enterprise strategy, enterprise structure and ERP systems use. © Emerald Group Publishing Limited.

Effect of processing variables and bulk composition on the surface composition of spray dried powders of a model food system

Abstract The surface compositions of food powders created from spray drying solutions containing various ratios of sodium caseinate, maltodextrin and soya oil have been analysed by Electron Spectroscopy for Chemical Analysis. The results show significant enrichment of oil at the surface of particles compared to the bulk phase and, when the non-oil components only are considered, a significant surface enrichment of sodium caseinate also. The degree of surface enrichment of both oil and sodium caseinate was found to increase with decreasing bulk levels of the respective components. Surface enrichment of oil was also affected by processing conditions (emulsion drop size and drying temperature), but surface enrichment of sodium caseinate was relatively insensitive to these. The presence of "pock marks" on the particle surfaces strongly suggests that the surface oil was caused by rupturing of emulsion droplets at the surface as the surrounding matrix contracts and hardens. © 2013 Elsevier Ltd. All rights reserved.

Formative variables and unreal variables:why the formative MIMIC model is invalid

In this rejoinder, we provide a response to the three commentaries written by Diamantopoulos, Howell, and Rigdon (all this issue) on our paper The MIMIC Model and Formative Variables: Problems and Solutions (also this issue). We contrast the approach taken in the latter paper (where we focus on clarifying the assumptions required to reject the formative MIMIC model) by spending time discussing what assumptions would be necessary to accept the use of the formative MIMIC model as a viable approach. Importantly, we clarify the implications of entity realism and show how it is entirely logical that some theoretical constructs can be considered to have real existence independent of their indicators, and some cannot. We show how the formative model only logically holds when considering these ‘unreal’ entities. In doing so, we provide important counter-arguments for much of the criticisms made in Diamantopoulos’ commentary, and the distinction also helps clarify a number of issues in the commentaries of Howell and Rigdon (both of which in general agree with our original paper). We draw together these various threads to provide a set of conceptual tools researchers can use when thinking about the entities in their theoretical models.

Effect of Cu and Sn promotion on the catalytic deoxygenation of model and algal lipids to fuel-like hydrocarbons over supported Ni catalysts

The ability of Cu and Sn to promote the performance of a 20% Ni/Al2O3 catalyst in the deoxygenation of lipids to fuel-like hydrocarbons was investigated using model triglyceride and fatty acid feeds, as well as algal lipids. In the semi-batch deoxygenation of tristearin at 260 °C a pronounced promotional effect was observed, a 20% Ni-5% Cu/Al2O3 catalyst affording both higher conversion (97%) and selectivity to C10-C17 alkanes (99%) in comparison with unpromoted 20% Ni/Al2O3 (27% conversion and 87% selectivity to C10-C17). In the same reaction at 350 °C, a 20% Ni-1% Sn/Al2O3 catalyst afforded the best results, giving yields of C10-C17 and C17 of 97% and 55%, respectively, which contrasts with the corresponding values of 87 and 21% obtained over 20% Ni/Al2O3. Equally encouraging results were obtained in the semi-batch deoxygenation of stearic acid at 300 °C, in which the 20% Ni-5% Cu/Al2O3 catalyst afforded the highest yields of C10-C17 and C17. Experiments were also conducted at 260 °C in a fixed bed reactor using triolein − a model unsaturated triglyceride − as the feed. While both 20% Ni/Al2O3 and 20% Ni-5% Cu/Al2O3 achieved quantitative yields of diesel-like hydrocarbons at all reaction times sampled, the Cu-promoted catalyst exhibited higher selectivity to longer chain hydrocarbons, a phenomenon which was also observed in experiments involving algal lipids as the feed. Characterization of fresh and spent catalysts indicates that Cu enhances the reducibility of Ni and suppresses both cracking reactions and coke-induced deactivation.

The MG Rover closure and policy response: an evaluation of the Task Force model in the UK

In recent years there have been a number of high-profile plant closures in the UK. In several cases, the policy response has included setting up a task force to deal with the impacts of the closure. It can be hypothesised that task force involving multi-level working across territorial boundaries and tiers of government is crucial to devising a policy response tailored to people's needs and to ensuring success in dealing with the immediate impacts of a closure. This suggests that leadership, and vision, partnership working and community engagement, and delivery of high quality services are important. This paper looks at the case of the MG Rover closure in 2005, to examine the extent to which the policy response to the closure at the national, regional and local levels dealt effectively with the immediate impacts of the closure, and the lessons that can be learned from the experience. Such lessons are of particular relevance given the closure of the LDV van plant in Birmingham in 2009 and more broadly – such as in the case of the downsizing of the Opel operation in Europe following its takeover by Magna.

Az egyensúlyi ráták unicitása és a bérráta pozitivitása a Neumann-modell általánosításaiban (Uniqueness of equilibrium rates and the positive value of the wage rate in generalizations from the Neumann model)

Cikkünk arról a paradox jelenségről szól, hogy a fogyasztást explicit módon megjelenítő Neumann-modell egyensúlyi megoldásaiban a munkabért meghatározó létszükségleti termékek ára esetenként nulla lehet, és emiatt a reálbér egyensúlyi értéke is nulla lesz. Ez a jelenség mindig bekövetkezik az olyan dekomponálható gazdaságok esetén, amelyekben eltérő növekedési és profitrátájú, alternatív egyensúlyi megoldások léteznek. A jelenség sokkal áttekinthetőbb formában tárgyalható a modell Leontief-eljárásra épülő egyszerűbb változatában is, amit ki is használunk. Megmutatjuk, hogy a legnagyobbnál alacsonyabb szintű növekedési tényezőjű megoldások közgazdasági szempontból értelmetlenek, és így érdektelenek. Ezzel voltaképpen egyrészt azt mutatjuk meg, hogy Neumann kiváló intuíciója jól működött, amikor ragaszkodott modellje egyértelmű megoldásához, másrészt pedig azt is, hogy ehhez nincs szükség a gazdaság dekomponálhatóságának feltételezésére. A vizsgált téma szorosan kapcsolódik az általános profitráta meghatározásának - Sraffa által modern formába öntött - Ricardo-féle elemzéséhez, illetve a neoklasszikus növekedéselmélet nevezetes bér-profit, illetve felhalmozás-fogyasztás átváltási határgörbéihez, ami jelzi a téma elméleti és elmélettörténeti érdekességét is. / === / In the Marx-Neumann version of the Neumann model introduced by Morishima, the use of commodities is split between production and consumption, and wages are determined as the cost of necessary consumption. In such a version it may occur that the equilibrium prices of all goods necessary for consumption are zero, so that the equilibrium wage rate becomes zero too. In fact such a paradoxical case will always arise when the economy is decomposable and the equilibrium not unique in terms of growth and interest rate. It can be shown that a zero equilibrium wage rate will appear in all equilibrium solutions where growth and interest rate are less than maximal. This is another proof of Neumann's genius and intuition, for he arrived at the uniqueness of equilibrium via an assumption that implied that the economy was indecomposable, a condition relaxed later by Kemeny, Morgenstern and Thompson. This situation occurs also in similar models based on Leontief technology and such versions of the Marx-Neumann model make the roots of the problem more apparent. Analysis of them also yields an interesting corollary to Ricardo's corn rate of profit: the real cause of the awkwardness is bad specification of the model: luxury commodities are introduced without there being a final demand for them, and production of them becomes a waste of resources. Bad model specification shows up as a consumption coefficient incompatible with the given technology in the more general model with joint production and technological choice. For the paradoxical situation implies the level of consumption could be raised and/or the intensity of labour diminished without lowering the equilibrium rate of the growth and interest. This entails wasteful use of resources and indicates again that the equilibrium conditions are improperly specified. It is shown that the conditions for equilibrium can and should be redefined for the Marx-Neumann model without assuming an indecomposable economy, in a way that ensures the existence of an equilibrium unique in terms of the growth and interest rate coupled with a positive value for the wage rate, so confirming Neumann's intuition. The proposed solution relates closely to findings of Bromek in a paper correcting Morishima's generalization of wage/profit and consumption/investment frontiers.

Jury decision making and the Story Model: How do deliberation style and evidence order influence the story that juries create?

This study investigated the utility of the Story Model for decision making at the jury level by examining the influence of evidence order and deliberation style on story consistency and guilt. Participants were shown a video-taped trial stimulus and then provided case perceptions including a guilt judgment and a narrative about what occurred during the incident. Participants then deliberated for approximately thirty minutes using either an evidence-driven or verdict-driven deliberation style before again providing case perceptions, including a guilt determination, a narrative about what happened during the incident, and an evidence recognition test. Multi-level regression analyses revealed that evidence order, deliberation style and sample interacted to influence both story consistency measures and guilt. Among students, participants in the verdict-driven deliberation condition formed more consistent pro-prosecution stories when the prosecution presented their case in story-order, while participants in the evidence-driven deliberation condition formed more consistent pro-prosecution stories when the defense's case was presented in story-order. Findings were the opposite among community members, with participants in the verdict-driven deliberation condition forming more consistent pro-prosecution stories when the defense's case was presented in story-order, and participants in the evidence-driven deliberation condition forming more consistent pro-prosecution stories when the prosecution's case was presented in story-order. Additionally several story consistency measures influenced guilt decisions. Thus there is some support for the hypothesis that story consistency mediates the influence of evidence order and deliberation style on guilt decisions.

The role of overseas Chinese investment in the emerging countries of Southeast and East Asia: A Confucian model of the foreign direct investment decision-making process using factors unconsidered in the West

The purpose of this study was to gain a better understanding of the foreign direct investment location decision making process through the examination of non-Western investors and their investment strategies in non-traditional markets. This was accomplished through in-depth personal interviews with 50 Overseas Chinese business owners and executives in several different industries from Hong Kong, Singapore, Taiwan, Malaysia, and Thailand about 97 separate investment projects in Southeast and East Asia, including The Philippines, Malaysia, Hong Kong, Singapore, Vietnam, India, Pakistan, South Korea, Australia, Indonesia, Cambodia, Thailand, Burma, Taiwan, and Mainland China.^ Traditional factors utilized in Western models of the foreign direct investment decision making process are reviewed, as well as literature on Asian management systems and the current state of business practices in emerging countries of Southeast and East Asia. Because of the lack of institutionalization in these markets and the strong influences of Confucian and patriarchal value systems on the Overseas Chinese, it was suspected that while some aspects of Western rational economic models of foreign direct investment are utilized, these models are insufficient in this context, and thus are not fully generalizable to the unique conditions of the Overseas Chinese business network in the region without further modification.^ Thus, other factors based on a Confucian value system need to be integrated into these models. Results from the analysis of structured interviews suggest Overseas Chinese businesses rely more heavily on their network and traditional Confucian values than rational economic factors when making their foreign direct investment location decisions in emerging countries in Asia. This effect is moderated by the firm's industry and the age of the firm's owners. ^

A model of the hydrothermal system at Casa Diablo in Long Valley, California, based on resistivity profiles and soil mercury analyses

A description and model of the near-surface hydrothermal system at Casa Diablo, with its implications for the larger-scale hydrothermal system of Long Valley, California, is presented. The data include resistivity profiles with penetrations to three different depth ranges, and analyses of inorganic mercury concentrations in 144 soil samples taken over a 1.3 by 1.7 km area. Analyses of the data together with the mapping of active surface hydrothermal features (fumaroles, mudpots, etc.), has revealed that the relationship between the hydrothermal system, surface hydrothermal activity, and mercury anomalies is strongly controlled by faults and topography. There are, however, more subtle factors responsible for the location of many active and anomalous zones such as fractures, zones of high permeability, and interactions between hydrothermal and cooler groundwater. In addition, the near-surface location of the upwelling from the deep hydrothermal reservoir, which supplies the geothermal power plants at Casa Diablo and the numerous hot pools in the caldera with hydrothermal water, has been detected. The data indicate that after upwelling the hydrothermal water flows eastward at shallow depth for at least 2 km and probably continues another 10 km to the east, all the way to Lake Crowley.