Studies on the nutrition and metabolism of turbot (Scophthalmus maximus L) with reference to fish farming

This thesis provides the first detailed study of maximal oxygen consumption of turbot on a fish farm over a range of fish sizes and temperatures. Also provided is a study of the diets used in turbot farming and the development of a diet that contains no fresh fish. A detailed study of previous research on flatfish nutrition, identified fresh fish, sprat in particular, as the optimum diet for turbot farming. A series of experiments was undertaken that confirmed this and also identified one possible explanation for the optimum performance of sprat, as a function of high non-protein energy ratios in sprat. This factor was exploited in the production of a diet containing no fresh fish and which produced superior results to diets containing fresh fish; the optimum level of lipid in the diet was determined as 18%. The study of oxygen consumption was on fully-fed fish so that maximum demand could be quantified. Continuous monitoring of tank water oxygen levels enabled the calculation of the Specific Dynamic Action (SDA) effect in turbot and the relation of it to dietary energy. Variation of SDA with the dietary energy profile was identified as a contributing factor to differential fish growth on various diets. Finally, the implications of this work to fish farming were considered. Economic appraisal and comparison of the diets routinely used in turbot farming identified that the diet developed as a result of this work, ie the diet containing no fresh fish protein, was more cost effective on the basis of the production of one tonne of turbot. The study of oxygen consumption enables water supply to be calculated for any fish size between 1g and 1000g between the temperatures of 7® C and 16® C. The quantification of SDA enables correct adjustment of oxygen flows according to the feeding status of the fish.

Mechanism of action of the tetraflex accommodative intraocular lens

PURPOSE:To investigate the mechanism of action of the Tetraflex (Lenstec Kellen KH-3500) accommodative intraocular lens (IOL). METHODS:Thirteen eyes of eight patients implanted with the Tetraflex accommodating IOL for at least 2 years underwent assessment of their objective amplitude-of-accommodation by autorefraction, anterior chamber depth and pupil size with optical coherence tomography, and IOL flexure with aberrometry, each viewing a target at 0.0 to 4.00 diopters of accommodative demand. RESULTS:Pupil size decreased by 0.62+/-0.41 mm on increasing accommodative demand, but the Tetraflex IOL was relatively fixed in position within the eye. The ocular aberrations of the eye changed with increased accommodative demand, but not in a consistent manner among individuals. Those aberrations that appeared to be most affected were defocus, vertical primary and secondary astigmatism, vertical coma, horizontal and vertical primary and secondary trefoil, and spherical aberration. CONCLUSIONS:Some of the reported near vision benefits of the Tetraflex accommodating IOL appear to be due to changes in the optical aberrations because of the flexure of the IOL on accommodative effort rather than forward movement within the capsular bag.

Mechanism of action of a tumour derived lipid mobilising factor

Cancer cachexia comprises unintentional and debilitating weight loss associated with certain tumour types. Fat loss in cachexia is mediated by a 43kDa Lipid Mobilising Factor (LMF) sharing homology with endogenous Zinc-α2-Glycoprotein (ZAG). LMF and ZAG induced significant lipolysis in isolated epidydimal adipose tissue. This is attenuated by co-incubation with 10μM of antagonist SR59230A and partially attenuated by 25μM PD098059 (indicating β3-AR and MAPK involvement respectively). LMF/ZAG induced in vitro lipid depletion in differentiated 3T3-L1 adipocytes that seen to comprise a significant increase in lipolysis (p<0.01), with only a modest decrease in lipid synthesis (p=0.09). ZAG significantly increased in vitro protein synthesis (p<0.01) in C2C12 myotubes (without an effect on protein degradation). This increase was activated at transcription and attenuated by co-incubation with 10μM SR59230A. Proteolytic digestion of ZAG and LMF followed by sephadex G50 chromatography yielded active fragments of 6-15kDa, indication the entire molecule was not required for bioactivity. Cachexigenic MAC16 cells demonstrated significant in vitro ZAG expression over non-cachexigenic MAC13 cells (p<0.001). WAT and BAT excised from MAC16 mice of varying weight loss demonstrated increased ZAG expression compared to controls. Dosing of NMRI mice with s/c ZAG failed to reproduce this up-regulation, thus another cachectic factor is responsible. 0.58nM LMF conferred significant protection against hydrogen peroxide, paraquat and bleomycin-induced oxidative stress in the non-cachexigenic MAC13 cell line. This protection was attenuated by 10μM SR59230A indicating a β3-AR mediated effect. In addition, 0.58nM LMF significantly up regulated UCP2 expression (p<0.001), (a mitochondrial protein implicated in the detoxification of ROS) implying this to be the mechanism by which survival was achieved. In vitro, LMF caused significant up-regulation of UCP1 in BAT and UCP2 and 3 in C2C12 myotubes. This increase in uncoupling protein expression further potentiates the negative energy balance and wasting observed in cachexia.

Studies on the mechanism of action on antitumour imidazotetrazinones

The imidazotetrazinones are clinically active antitumour agents, temozolomide currently proving successful in the treatment of melanomas and gliomas. The exact nature of the biological processes underlying response are as yet unclear.This thesis attempts to identify the cellular targets important to the cytotoxicity of imidazotetrazinones, to elucidate the pathways by which this damage leads to cell death, and to identify mechanisms by which tumour cells may circumvent this action. The levels of the DNA repair enzymes O6-alkylguanine-DNA-alkyltransferase (O6-AGAT) and 3-methyladenine-DNA-glycosylase (3MAG) have been examined in a range of murine and human cell lines with differential sensitivity to temozolomide. All the cell lines were proficient in 3MAG despite there being 40-fold difference in sensitivity to temozolomide. This suggests that while 3-methyladenine is a major product of temozolomide alkylation of DNA it is unlikely to be a cytotoxic lesion. In contrast, there was a 20-fold variation in O6-AGAT levels and the concentration of this repair enzyme correlated with variations in cytotoxicity. Furthermore, depletion of this enzyme in a resistant, O6-AGAT proficient cell line (Raji), by pre-treatment with the free base O6-methylguanine resulted in 54% sensitisation to the effects of temozolomide. These observations have been extended to 3 glioma cell lines; results that support the view that the cytotoxicity of temozolomide is related to alkylation at the O6-position of guanine and that resistance to this drug is determined by efficient repair of this lesion. It is clear, however, the other factors may influence tumour response since temozolomide showed little differential activity towards 3 established solid murine tumours in vivo, despite different tumour O6-AGAT levels. Unlike mitozolomide, temozolomide is incapable of cross-linking DNA and a mechanism by which O6-methylguanine may exert lethality is unclear. The cytotoxicity of the methyl group may be due to its disruption of DNA-protein interactions, or alternatively cell death may not be a direct result of the alkyl group itself, but manifested by DNA single-strand breaks. Enhanced alkaline elution rates were found for the DNA of Raji cells treated with temozolomide following alkyltransferase depletion, suggesting a relationship between O6-methylguanine and the induction single-strand breaks. Such breaks can activate poly(ADP-ribose) synthetase (ADPRT) an enzyme capable of rapid and lethal depletion of cellular NAD levels. However, at concentrations of temozolomlde relevant in vivo little change in adenine nucleotides was detected in cell lines, although this enzyme would appear important in modulating DNA repair since inhibition of ADPRT potentiated temozolomide cytotoxicity in Raji cells but not O6-AGAT deficient GM892A cells. Cell lines have been reported that are O6-AGAT deficient yet resistant to methylating agents. Thus, resistance to temozolomide may arise not only by removal of the methyl group from the O6-position of guanine, but also from another mechanism involving caffeine-sensitive post-replication repair or mismatch repair activity. A modification of the standard Maxam Gilbert sequencing technique was used to determine the sequence specificity of guanine-N7 alkylation. Temozolomide preferentially alkylated runs of guanines with the intensity of reaction increasing with the number of adjacent guanines in the DNA sequence. Comparable results were obtained with a polymerase-stop assay, although neither technique elucidates the sequence specificity of O6-guanine alkylation. The importance of such specificity to cytotoxicity is uncertain, although guanine-rich sequences are common to the promoter regions of oncogenes. Expression of a plasmid reporter gene under the control of the Ha-ras proto~oncogene promoter was inhibited by alkylation with temozolomide when transfected into cancer cell lines, However, this inhibition did not appear to be related to O6~guanine alkylation and therefore would seem unimportant to the chemotherapeutic activity of temozolomide.

Dynamic learning as entrepreneurial action in the context of open innovation:an instrumental case from a communities-of-practice perspective

Recent scholarly discussion on open innovation put forward the notion that an organisation's ability to internalise external knowledge and learn from various sources in undertaking new product development is crucial to its competitive performance. Nevertheless, little attention has been paid to how growth-oriented small firms identify and exploit entrepreneurial opportunities (i.e. take entrepreneurial action) related to such development, in an open innovation context, from a social learning perspective. This chapter, based on an instrumental case-firm, demonstrates analytically how learning as entrepreneurial action takes place, drawing on situated learning theory. It is argued that such learning is dynamic in nature and is founded on specific organising principles that foster both inter- and intracommunal learning. © 2012, IGI Global.

Studies of the mechanism of action of anitumour compounds

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The synthesis and mechanism of action of organic accelerators of the sulphur vilcanisation of rubber

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Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genomewide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.

The impact of supply chain performance measurement systems on dynamic behaviour in supply chains

The amplification of demand variation up a supply chain widely termed ‘the Bullwhip Effect’ is disruptive, costly and something that supply chain management generally seeks to minimise. Originally attributed to poor system design; deficiencies in policies, organisation structure and delays in material and information flow all lead to sub-optimal reorder point calculation. It has since been attributed to exogenous random factors such as: uncertainties in demand, supply and distribution lead time but these causes are not exclusive as academic and operational studies since have shown that orders and/or inventories can exhibit significant variability even if customer demand and lead time are deterministic. This increase in the range of possible causes of dynamic behaviour indicates that our understanding of the phenomenon is far from complete. One possible, yet previously unexplored, factor that may influence dynamic behaviour in supply chains is the application and operation of supply chain performance measures. Organisations monitoring and responding to their adopted key performance metrics will make operational changes and this action may influence the level of dynamics within the supply chain, possibly degrading the performance of the very system they were intended to measure. In order to explore this a plausible abstraction of the operational responses to the Supply Chain Council’s SCOR® (Supply Chain Operations Reference) model was incorporated into a classic Beer Game distribution representation, using the dynamic discrete event simulation software Simul8. During the simulation the five SCOR Supply Chain Performance Attributes: Reliability, Responsiveness, Flexibility, Cost and Utilisation were continuously monitored and compared to established targets. Operational adjustments to the; reorder point, transportation modes and production capacity (where appropriate) for three independent supply chain roles were made and the degree of dynamic behaviour in the Supply Chain measured, using the ratio of the standard deviation of upstream demand relative to the standard deviation of the downstream demand. Factors employed to build the detailed model include: variable retail demand, order transmission, transportation delays, production delays, capacity constraints demand multipliers and demand averaging periods. Five dimensions of supply chain performance were monitored independently in three autonomous supply chain roles and operational settings adjusted accordingly. Uniqueness of this research stems from the application of the five SCOR performance attributes with modelled operational responses in a dynamic discrete event simulation model. This project makes its primary contribution to knowledge by measuring the impact, on supply chain dynamics, of applying a representative performance measurement system.

Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate

The leucine metabolite β-hydroxy-β-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied in vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 μmol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome α- and β-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 μmol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor κBα and nuclear accumulation of nuclear factor κB. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.

A multi-agent system using iterative bidding mechanism to enhance manufacturing agility

The global market has become increasingly dynamic, unpredictable and customer-driven. This has led to rising rates of new product introduction and turbulent demand patterns across product mixes. As a result, manufacturing enterprises were facing mounting challenges to be agile and responsive to cope with market changes, so as to achieve the competitiveness of producing and delivering products to the market timely and cost-effectively. This paper introduces a currency-based iterative agent bidding mechanism to effectively and cost-efficiently integrate the activities associated with production planning and control, so as to achieve an optimised process plan and schedule. The aim is to enhance the agility of manufacturing systems to accommodate dynamic changes in the market and production. The iterative bidding mechanism is executed based on currency-like metrics; each operation to be performed is assigned with a virtual currency value and agents bid for the operation if they make a virtual profit based on this value. These currency values are optimised iteratively and so does the bidding process based on new sets of values. This is aimed at obtaining better and better production plans, leading to near-optimality. A genetic algorithm is proposed to optimise the currency values at each iteration. In this paper, the implementation of the mechanism and the test case simulation results are also discussed. © 2012 Elsevier Ltd. All rights reserved.

Stabilisation of isocyanate cross linked polybutadiene binder

Isocyanate cross-linked hydroxy terminated polybutadiene is used as a binder for solid rocket propellant. Rocket motors containing this propellant require a storage life of at least 20 years. During storage it has been found that the important rubbery properties of the binder can be lost due to oxidative cross-linking of the polybutadiene chains. This could cause catastrophic failure when the rocket motor is required. At present the bis-hindered phenol Calco 2246 is used as a thermal oxidative stabiliser, but it's performance is only adequate. This has led to the search for a more efficient stabiliser system. To hasten the evaluation of new antioxidant systems the use of dynamic thermal analysis was investigated. Results showed that a tentative relationship existed between predictions by thermal analysis and the long term oven ageing for simple single antioxidant systems. But for more complex systems containing either autosynergistic or mixed antioxidants no relationship was observed suggesting that results for such an "accelerated" technique cannot be used for the purpose of extrapolation for long term performance. This was attributed to the short time and more aggressive condition used (hjgher temperature and oxygen rich atmosphere in thermal analysis) altering the mechanism of action of the antioxidants and not allowing time for co-operative effect of the combined antioxidant system to form. One potential problem for the binder system is the use of an diisocyanate as a cross-linking agent. This reacts with the hydroxyl hydrogen on the polymer as well as other active hydrogens such as those contained in a number of antioxidants, affecting both cross-linking and antioxidant effectiveness. Studies in this work showed that only antioxidants containing amine moieties have a significant affect on binder preparation, with the phenolic antioxidants not reacting. This is due to the greater nucleophilicity of the amines. Investigation of a range of antioxidant systems, including potentially homo, hetero and autosynergistic systems, has highlighted a number of systems which show considerably greater effectiveness than the currently used antioxidant Calco 2246. The only single antioxidant which showed improvement was the partially unhindered phenol y-Tocopherol. Of the mixed systems combinations of the sulphur containing antioxidants e.g. DLTP with higher levels of chain-breaking antioxidants, especially Calco 2246, were the most promising. Also the homosynergistic mix of an aromatic amine and a phenol was seen to be very effective but the results were inconsistent. This inconsistency could be explained by the method of sample preparation used. It was shown that the efficiency of a number of antioxidant.s could be dramatically improved by the use of ultrasound during the mixing stage of preparation. The reason for this increase in performance is unclear but in the case of the homosynergistic amine/phenol mix both more efficient mixing and/or the production of a novel mechanism of action are suggested

Dynamic simulation of chemical processes

This thesis describes the design and implementation of an interactive dynamic simulator called DASPRII. The starting point of this research has been an existing dynamic simulation package, DASP. DASPII is written in standard FORTRAN 77 and is implemented on universally available IBM-PC or compatible machines. It provides a means for the analysis and design of chemical processes. Industrial interest in dynamic simulation has increased due to the recent increase in concern over plant operability, resiliency and safety. DASPII is an equation oriented simulation package which allows solution of dynamic and steady state equations. The steady state can be used to initialise the dynamic simulation. A robust non linear algebraic equation solver has been implemented for steady state solution. This has increased the general robustness of DASPII, compared to DASP. A graphical front end is used to generate the process flowsheet topology from a user constructed diagram of the process. A conversational interface is used to interrogate the user with the aid of a database, to complete the topological information. An original modelling strategy implemented in DASPII provides a simple mechanism for parameter switching which creates a more flexible simulation environment. The problem description generated is by a further conversational procedure using a data-base. The model format used allows the same model equations to be used for dynamic and steady state solution. All the useful features of DASPI are retained in DASPII. The program has been demonstrated and verified using a number of example problems, Significant improvements using the new NLAE solver have been shown. Topics requiring further research are described. The benefits of variable switching in models has been demonstrated with a literature problem.