Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease

We have previously shown that complement factor 5a(C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(D-Cha) WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(D-Cha) WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(D-Cha) WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(D-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03 - 10 mg/kg/ day p.o.) in the 8-day rat TNBS- colitis model, against the comparator drug AcF-[OP(D-Cha) WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(D-Cha) WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP( D-Cha) WR], equiactive in vitro to AcF-[OP(D-Cha) WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(D-Cha) WR]. However, in the rat TNBS- colitis model, HC-[OP(D-Cha) WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30- fold lower oral doses than AcF-[OP( D-Cha) WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(D-Cha) WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(D-Cha) WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

Rice morphogenesis and plant architecture: Measurement, specification and the reconstruction of structural development by 3D architectural modelling

Background and Aims The morphogenesis and architecture of a rice plant, Oryza sativa, are critical factors in the yield equation, but they are not well studied because of the lack of appropriate tools for 3D measurement. The architecture of rice plants is characterized by a large number of tillers and leaves. The aims of this study were to specify rice plant architecture and to find appropriate functions to represent the 3D growth across all growth stages. Methods A japonica type rice, 'Namaga', was grown in pots under outdoor conditions. A 3D digitizer was used to measure the rice plant structure at intervals from the young seedling stage to maturity. The L-system formalism was applied to create '3D virtual rice' plants, incorporating models of phenological development and leaf emergence period as a function of temperature and photoperiod, which were used to determine the timing of tiller emergence. Key Results The relationships between the nodal positions and leaf lengths, leaf angles and tiller angles were analysed and used to determine growth functions for the models. The '3D virtual rice' reproduces the structural development of isolated plants and provides a good estimation of the fillering process, and of the accumulation of leaves. Conclusions The results indicated that the '3D virtual rice' has a possibility to demonstrate the differences in the structure and development between cultivars and under different environmental conditions. Future work, necessary to reflect both cultivar and environmental effects on the model performance, and to link with physiological models, is proposed in the discussion.

Effects of tourism development on the local poor people - Case study in Taibai Region China

In China, protected areas are one of the main destinations attracting tourists and homeland for many poor people living in and around them. Based on a case study, the paper focuses on correlation between tourism and poverty alleviation by tracing the cash flows to the local poor. It also reviews the social and environmental effects of tourism on local area. The case study is conducted in a group of protected areas in Qinling Mountain Region in Shaanxi, a western province in China. Qinling Mountain is one of the most important distribution zones for Giant Panda and some other endangered wildlife such as Golden Takin and Golden Monkey. The tourism development in the region is happening. Research indicates that there is 29.33%, of tourist expenditure is going to local households, directly or indirectly. Tourist spends US$7.11 (13.67%) in food and beverage, and US$6.39 (12.23%) in accommodation service, which are the greatest contributors to local households in terms of tourism benefits. Local households can get US$8.15 from food/beverage and accommodation sectors, taking 56.64% of total income from tourism. Generally, tourism development benefits all stakeholders. However, poor people get less benefit. The paper analyses the barriers for the poor to be involved in tourism development, and discusses the government roles, major issues in implementation of Sustainable Tourism-Eliminating Poverty (ST-EP) model. [ABSTRACT FROM AUTHOR]

The DVD animal model of schizophrenia: Effects of low maternal vitamin D on brain dopamine

Background: We have previously shown that the offspring of vitamin D3 depleted rats have enlarged ventricles and altered neurotrophin profiles (reduced NGF and GDNF). These findings enhance the biological plausibility that low prenatal vitamin D may be a risk factor for schizophrenia. Our recent behavioural studies have found that adult rats with developmental vitamin D deficiency (DVD) have a subtle increase in baseline locomotor activity and a heightened response to dopamine (DA) antagonists. The aim of this study was to investigate brain DA neurochemistry in the DVD model. Methods: We examined cerebrums and striatal tissue from neonates and a variety of brain tissues from the remaining littermates at adulthood. DA, DOPAC, HVA, serotonin and 5HIAA were analysed by HPLC. Single point comparisons for DA1, DA2 and NMDA receptors were also assessed in these tissues. Results: Significant increases in DA and HVA were found in brains from DVD deplete neonates (P=0.01). However, DA and its metabolites were not increased in either the neonate or adult striatum, however there was a trend towards increased DA and its metabolites in the accumbens (P=0.1). Receptor densities were unaffected by prenatal vitamin D levels. Conclusions: Although the effect of maternal diet appears to increase DA production and turnover in neonatal brain, this does not persist into adulthood. Thus other factors must underlie the increased locomotor activity noted in these animals. Future experiments will concentrate on monitoring accumbens and striatal DA release and turnover using microdialysis in pharmacologically challenged behavioural paradigms. References: Eyles D, Brown J; Mackay-Sim A, McGrath J, Feron F. (2003) Vitamin D3 and brain development. Neuroscience 118 (3) 641–653. Burne T, McGrath J, Eyles D, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. (2005) Behavioural Brain Res: 157 299–308.

The roles of exercise-induced immune system disturbances in the pathology of heat stroke - The dual pathway model of heat stroke

Heat stroke is a life-threatening condition that can be fatal if not appropriately managed. Although heat stroke has been recognised as a medical condition for centuries, a universally accepted definition of heat stroke is lacking and the pathology of heat stroke is not fully understood. Information derived from autopsy reports and the clinical presentation of patients with heat stroke indicates that hyperthermia, septicaemia, central nervous system impairment and cardiovascular failure play important roles in the pathology of heat stroke. The current models of heat stroke advocate that heat stroke is triggered by hyperthermia but is driven by endotoxaemia. Endotoxaemia triggers the systemic inflammatory response, which can lead to systemic coagulation and haemorrhage, necrosis, cell death and multi-organ failure. However, the current heat stroke models cannot fully explain the discrepancies in high core temperature (Tc) as a trigger of heat stroke within and between individuals. Research on the concept of critical Tc: as a limitation to endurance exercise implies that a high Tc may function as a signal to trigger the protective mechanisms against heat stroke. Athletes undergoing a period of intense training are subjected to a variety of immune and gastrointestinal (GI) disturbances. The immune disturbances include the suppression of immune cells and their functions, suppression of cell-mediated immunity, translocation of lipopolysaccharide (LPS), suppression of anti-LPS antibodies, increased macrophage activity due to muscle tissue damage, and increased concentration of circulating inflammatory and pyrogenic cytokines. Common symptoms of exercise-induced GI disturbances include diarrhoea, vomiting, gastrointestinal bleeding, and cramps, which may increase gut-related LPS translocation. This article discusses the current evidence that supports the argument that these exercise-induced immune and GI disturbances may contribute to the development of endotoxaemia and heat stroke. When endotoxaemia can be tolerated or prevented, continuing exercise and heat exposure will elevate Tc to a higher level (> 42 degrees C), where heat stroke may occur through the direct thermal effects of heat on organ tissues and cells. We also discuss the evidence suggesting that heat stroke may occur through endotoxaemia (heat sepsis), the primary pathway of heat stroke, or hyperthermia, the secondary pathway of heat stroke. The existence of these two pathways of heat stroke and the contribution of exercise-induced immune and GI disturbances in the primary pathway of heat stroke are illustrated in the dual pathway model of heat stroke. This model of heat stroke suggests that prolonged intense exercise suppresses anti-LPS mechanisms, and promotes inflammatory and pyrogenic activities in the pathway of heat stroke.

Understanding the multidimensionality of group development

This article presents a three-dimensional definition space of the group development literature that differentiates group development models on three dimensions: content, population, and path dependency. The multidimensional conceptualization structures and integrates the vast group development literature, enabling direct comparison of competing theories. The utility of this definition space is demonstrated by using the relative positioning of two seemingly competing group development models-the punctuated equilibrium model and the integrative model-to demonstrate their complementarity. The authors also show how organizational researchers and practitioners can use the three-dimensional definition space to select an appropriate theoretical model for the group or group process with which they are working.

Extending a model of shift-work tolerance

The present study contributes to theory and practice through the development of a model of shift-work tolerance with the potential to indicate interventions that reduce nurses' intention toward turnover and increase job satisfaction in hospital-based settings. Survey data from 1257 nurses were used to conduct structural equation modeling that examine the direct and indirect effects of supervisor and colleague support, team identity, team climate, and control over working environment on time-based work/life conflict, psychological well-being, physical symptoms, job satisfaction, and turnover intention. The analysis of the proposed model revealed a good fit The chi-square difference test was non-significant (χ2(26)=338.56), the fit indices were high (CFI=.923, NFI=.918, and NNFI=.868), the distribution of residuals was symmetric and approached zero, the average standardized residual was low (AASR=.04), and the standardized RMR was .072. In terms of the predictor variable, the final model explained 48% of the variance in turnover intention. The data revealed considerable evidence of both direct effects on adjustment and complex indirect links between levels of adjustment and work-related social support, team identity, team climate, and control. Nurses with high supervisor and coworker support experienced more positive team climates, identified more strongly with their team, and increased their perceptions of control over their work environment. This in turn lowered their appraisals of their time-based work/life conflict, which consequently increased their psychological well-being and job satisfaction and reduced their physical health symptoms and turnover intention. The type of shift schedule worked by the nurses influenced levels of turnover intention, control over work environment, time-based work/life conflict, and physical symptoms.

Developing a scalable model of recombinant protein yield from Pichia pastoris:the influence of culture conditions, biomass and induction regime

Background The optimisation and scale-up of process conditions leading to high yields of recombinant proteins is an enduring bottleneck in the post-genomic sciences. Typical experiments rely on varying selected parameters through repeated rounds of trial-and-error optimisation. To rationalise this, several groups have recently adopted the 'design of experiments' (DoE) approach frequently used in industry. Studies have focused on parameters such as medium composition, nutrient feed rates and induction of expression in shake flasks or bioreactors, as well as oxygen transfer rates in micro-well plates. In this study we wanted to generate a predictive model that described small-scale screens and to test its scalability to bioreactors. Results Here we demonstrate how the use of a DoE approach in a multi-well mini-bioreactor permitted the rapid establishment of high yielding production phase conditions that could be transferred to a 7 L bioreactor. Using green fluorescent protein secreted from Pichia pastoris, we derived a predictive model of protein yield as a function of the three most commonly-varied process parameters: temperature, pH and the percentage of dissolved oxygen in the culture medium. Importantly, when yield was normalised to culture volume and density, the model was scalable from mL to L working volumes. By increasing pre-induction biomass accumulation, model-predicted yields were further improved. Yield improvement was most significant, however, on varying the fed-batch induction regime to minimise methanol accumulation so that the productivity of the culture increased throughout the whole induction period. These findings suggest the importance of matching the rate of protein production with the host metabolism. Conclusion We demonstrate how a rational, stepwise approach to recombinant protein production screens can reduce process development time.

Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia

Prostate cancer (CaP) patients with disseminated disease often suffer from severe cachexia, which contributes to mortality in advanced cancer. Human cachexia-associated protein (HCAP) was recently identified from a breast cancer library based on the available 20-amino acid sequence of proteolysis-inducing factor (PIF), which is a highly active cachectic factor isolated from mouse colon adenocarcinoma MAC16. Herein, we investigated the expression of HCAP in CaP and its potential involvement in CaP-associated cachexia. HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases. In situ hybridization showed HCAP mRNA to be localized only in the epithelial cells in CaP tissues, in the metastatic foci in bone, liver and lymph node, but not in the stromal cells or in normal prostate tissues. HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors. Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients. HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models. Our results demonstrated that human CaP cells express HCAP and the expression of HCAP is associated with the progression of CaP and the development of CaP cachexia. © 2003 Wiley-Liss, Inc.

An Investigation into the adoption and implementation of computer aided production management systems:using the Rogers model of adoption and implementation and a social constuctionist account of technology

The research investigates the processes of adoption and implementation, by organisations, of computer aided production management systems (CAPM). It is organised around two different theoretical perspectives. The first part is informed by the Rogers model of the diffusion, adoption and implementation of innovations, and the second part by a social constructionist approach to technology. Rogers' work is critically evaluated and a model of adoption and implementation is distilled from it and applied to a set of empirical case studies. In the light of the case study data, strengths and weaknesses of the model are identified. It is argued that the model is too rational and linear to provide an adequate explanation of adoption processes. It is useful for understanding processes of implementation but requires further development. The model is not able to adequately encompass complex computer based technologies. However, the idea of 'reinvention' is identified as Roger's key concept but it needs to be conceptually extended. Both Roger's model and definition of CAPM found in the literature from production engineering tend to treat CAPM in objectivist terms. The problems with this view are addressed through a review of the literature on the sociology of technology, and it is argued that a social constructionist approach offers a more useful framework for understanding CAPM, its nature, adoption, implementation, and use. CAPM it is argued, must be understood on terms of the ways in which it is constituted in discourse, as part of a 'struggle for meaning' on the part of academics, professional engineers, suppliers, and users.

By writers for writers: developing a writer-centred model of the writing process

This thesis, set within an Action Research framework, details the development and validation of a writer-centred model of the writing process. The model was synthesised within the boundaries of a writers’ group for MA students. The initial data collected, and analysed using the principles of grounded theory, were retrospective descriptions of group members’ writing processes. After initial analysis, additional data, from group members’ writing, and from audio recordings, were used for further analysis, and to form a model of the writing process. To ascertain whether the model had value outside the specific context in which it was made, it was validated from three different perspectives. Firstly, the retrospective descriptions of other writers were collected and analysed, using the model as a framework. Secondly, the model was presented at academic conferences; comments about the model, made by members of the audience, were collected and analysed. Finally, the model was used in writing courses for PhD students. Comments from these students, along with questionnaire responses, were collected and the content analysed. Upon examination of all data sources, the model was updated to reflect additional insights arising from the analysis. Analysis of the data also indicated that the model is useable outside its original context. Potential uses for the model are 1) raising awareness of the process of writing, 2) putting writers at ease, 3) serving as a starting point for individuals or groups to design their own models of the writing process, and 4) as a tool to help writers take control of their writing processes.

A formal model of the Semantic Web Service Ontology (WSMO)

Semantic Web Service, one of the most significant research areas within the Semantic Web vision, has attracted increasing attention from both the research community and industry. The Web Service Modelling Ontology (WSMO) has been proposed as an enabling framework for the total/partial automation of the tasks (e.g., discovery, selection, composition, mediation, execution, monitoring, etc.) involved in both intra- and inter-enterprise integration of Web services. To support the standardisation and tool support of WSMO, a formal model of the language is highly desirable. As several variants of WSMO have been proposed by the WSMO community, which are still under development, the syntax and semantics of WSMO should be formally defined to facilitate easy reuse and future development. In this paper, we present a formal Object-Z formal model of WSMO, where different aspects of the language have been precisely defined within one unified framework. This model not only provides a formal unambiguous model which can be used to develop tools and facilitate future development, but as demonstrated in this paper, can be used to identify and eliminate errors present in existing documentation.