Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia

A prominent feature of several type of cancer is cachexia. This syndrome causes a marked loss of lean body mass and muscle wasting, and appears to be mediated by cytokines and tumour products. There are several proteases and proteolytic pathways that could be responsible for the protein breakdown. In the present study, we investigated whether caspases are involved in the proteolytic process of skeletal muscle catabolism observed in a murine model of cancer cachexia (MAC16), in comparison with a related tumour (MAC13), which does not induce cachexia. Using specific peptide substrates, there was an increase of 54% in the proteolytic activity of caspase-1, 84% of caspase-8, 98% of caspase-3 151% to caspase-6 and 177% of caspase-9, in the gastrocnemius muscle of animals bearing the MAC16 tumour (up to 25% weight loss), in relation to muscle from animals bearing the MAC13 tumour (1-5% weight loss). The dual pattern of 89 kDa and 25 kDa fragmentation of poly (ADP-ribose) polymerase (PARP) occurred in the muscle samples from animals bearing the MAC16 tumour and with a high amount of caspase-like activity. Cytochrome c was present in the cytosolic fractions of gastrocnemius muscles from both groups of animals, suggesting that cytochrome c release from mitochondria may be involved in caspase activation. There was no evidence for DNA fragmentation into a nucleosomal ladder typical of apoptosis in the muscles of either group of mice. This data supports a role for caspases in the catabolic events in muscle involved in the cancer cachexia syndrome. © 2001 Cancer Research Campaign.

Computer aided design and analysis of cold formed sections

The work reported in this thesis is concerned with the improvement and expansion of the assistance given to the designer by the computer in the design of cold formed sections. The main contributions have been in four areas, which have consequently led to the fifth, the development of a methodology to optimise designs. This methodology can be considered an `Expert Design System' for cold formed sections. A different method of determining section properties of profiles was introduced, using the properties of line and circular elements. Graphics were introduced to show the outline of the profile on screen. The analysis of beam loading has been expanded to beam loading conditions where the number of supports, point loads, and uniform distributive loads can be specified by the designer. The profile can then be checked for suitability for the specified type of loading. Artificial Intelligence concepts have been introduced to give the designer decision support from the computer, in combination with the computer aided design facilities. The more complex decision support was adopted through the use of production rules. All the support was based on the British standards. A method has been introduced, by which the appropriate use of stiffeners can be determined and consequently designed by the designer. Finally, the methodology by which the designer is given assistance from the computer, without constraining the designer, was developed. This methodology gives advice to the designer on possible methods of improving the design, but allows the designer to reject that option, and analyse the profile accordingly. The methodology enables optimisation to be achieved by the designer, designing variety of profiles for a particular loading, and determining which one is best suited.

Exploration of steroselective cleavage of 4, 5-epoycholestane-3, 6-diols and stero controlled epoxidation of cholest-4-en-3 β, 6β-diol-6-acetate

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Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABAA receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity. © 2006 IBRO.

Computer-aided categorisation and quantification of connectives in English and Arabic (based on newspaper text corpora).

This study presents a detailed contrastive description of the textual functioning of connectives in English and Arabic. Particular emphasis is placed on the organisational force of connectives and their role in sustaining cohesion. The description is intended as a contribution for a better understanding of the variations in the dominant tendencies for text organisation in each language. The findings are expected to be utilised for pedagogical purposes, particularly in improving EFL teaching of writing at the undergraduate level. The study is based on an empirical investigation of the phenomenon of connectivity and, for optimal efficiency, employs computer-aided procedures, particularly those adopted in corpus linguistics, for investigatory purposes. One important methodological requirement is the establishment of two comparable and statistically adequate corpora, also the design of software and the use of existing packages and to achieve the basic analysis. Each corpus comprises ca 250,000 words of newspaper material sampled in accordance to a specific set of criteria and assembled in machine readable form prior to the computer-assisted analysis. A suite of programmes have been written in SPITBOL to accomplish a variety of analytical tasks, and in particular to perform a battery of measurements intended to quantify the textual functioning of connectives in each corpus. Concordances and some word lists are produced by using OCP. Results of these researches confirm the existence of fundamental differences in text organisation in Arabic in comparison to English. This manifests itself in the way textual operations of grouping and sequencing are performed and in the intensity of the textual role of connectives in imposing linearity and continuity and in maintaining overall stability. Furthermore, computation of connective functionality and range of operationality has identified fundamental differences in the way favourable choices for text organisation are made and implemented.

Computer aided design and manufacture for three dimensional milling

Advances in both computer technology and the necessary mathematical models capable of capturing the geometry of arbitarily shaped objects has led to the development in this thesis of a surface generation package called 'IBSCURF' aimed at providing a more economically viable solution to free-form surface manufacture. A suit of computer programs written in FORTRAN 77 has been developed to provide computer aids for every aspect of work in designing and machining free-form surfaces. A vector-valued parametric method was used for shape description and a lofting technique employed for the construction of the surface. The development of the package 'IBSCURF' consists of two phases. The first deals with CAD. The design process commences in defining the cross-sections which are represented by uniform B-spline curves as approximations to give polygons. The order of the curve and the position and number of the polygon vertices can be used as parameters for the modification to achieve the required curves. When the definitions of the sectional curves is complete, the surface is interpolated over them by cubic cardinal splines. To use the CAD function of the package to design a mould for a plastic handle, a mathematical model was developed. To facilitate the integration of design and machining using the mathematical representation of the surface, the second phase of the package is concerned with CAM which enables the generation of tool offset positions for ball-nosed cutters and a general post-processor has been developed which automatically generates NC tape programs for any CNC milling machine. The two phases of these programs have been successfully implemented, as a CAD/CAM package for free-form surfaces on the VAX 11/750 super-minicomputer with graphics facilities for displaying drawings interactively on the terminal screen. The development of this package has been beneficial in all aspects of design and machining of free form surfaces.

Computer aided design and manufacture of form-rolls

Cold roll forming of thin-walled sections is a very useful process in the sheet metal industry. However, the conventional method for the design and manufacture of form-rolls, the special tooling used in the cold roll forming process, is a very time consuming and skill demanding exercise. This thesis describes the establishment of a stand-alone minicomputer based CAD/CAM system for assisting the design and manufacture of form-rolls. The work was undertaken in collaboration with a leading manufacturer of thin-walled sections. A package of computer programs have been developed to provide computer aids for every aspect of work in form-roll design and manufacture. The programs have been successfully implemented, as an integrated CAD/CAM software system, on the ICL PERQ minicomputer with graphics facilities. Thus, the developed CAD/CAM system is a single-user workstation, with software facilities to help the user to perform the conventional roll design activities including the design of the finished section, the flower pattern, and the form-rolls. A roll editor program can then be used to modify, if required, the computer generated roll profiles. As far as manufacturing is concerned, a special-purpose roll machining program and postprocessor can be used in conjunction to generate the NC control part-programs for the production of form-rolls by NC turning. Graphics facilities have been incorporated into the CAD/CAM software programs to display drawings interactively on the computer screen throughout all stages of execution of the CAD/CAM software. It has been found that computerisation can shorten the lead time in all activities dealing with the design and manufacture of form-rolls, and small or medium size manufacturing companies can gain benefits from the CAD/CM! technology by developing, according to its own specification, a tailor-made CAD/CAM software system on a low cost minicomputer.

Man, I feel like a woman:when and how gender-role motivation helps mind-reading

Two experiments were undertaken with 3 goals: (a) to determine whether manipulating the desirability of including empathy as part of one's gender-role identity motivates accurate mind-reading, (b) to ascertain whether target readability moderates the strength of this effect, and (c) to test whether these effects are mediated by the complexity of perceivers' inferential strategies. Participants viewed videotapes of 2 couples discussing relationship problems and attempted to infer each partner's thoughts and feelings. Both experiments demonstrated that motivation improved accuracy when male and female perceivers valued the empathy-relevant aspects of the traditional female gender role. However, as predicted, high levels of motivation facilitated the accurate reading of easy targets but not of difficult targets. Several mediational models were tested, the results of which showed that the complexity of perceivers' attributions mediated the link between motivation and mind-reading accuracy.

Pyrolysis of polyamide 6 under catalytic conditions and its application to reutilization of carpets

ε-caprolactam is a monomer of high value. Therefore, the chemical reutilization of polyamide 6 containing carpets for ε-caprolactam recovery offers some economic benefit and is performed on a technical scale with the help of the Zimmer-process. By this process polyamide 6 is depolymerized with steam and phosphoric acid. An alternative to this process is the thermal depolymerization - catalyzed or non-catalyzed. To investigate this alternative in more detail, the formal kinetic parameters of (i) the thermal depolymerization of polyamide 6, (ii) the thermal depolymerization in presence of sodium/potassium hydoxide, and (iii) the thermal depolymerization in presence of phosphoric acid are determined in this work. Based on the kinetics of the catalyzed or non-catalyzed depolymerization a stepwise pyrolysis procedure is designed by which the formation of ε-caprolactam from polyamide 6 can be separated from the formation of other pyrolysis products. © 2001 Elsevier Science B.V.

The design of contact lens based ocular drug delivery systems for single-day use:part (I) structural factors, surrogate ophthalmic dyes and passive diffusion studies

The poor retention and efficacy of instilled drops as a means of delivering drugs to the ophthalmic environment is well-recognised. The potential value of contact lenses as a means of ophthalmic drug delivery, and consequent improvement of pre-corneal retention is one obvious route to the development of a more effective ocular delivery system. Furthermore, the increasing availability and clinical use of daily disposable contact lenses provides the platform for the development of viable single-day use drug delivery devices based on existing materials and lenses. In order to provide a basis for the effective design of such devices, a systematic understanding of the factors affecting the interaction of individual drugs with the lens matrix is required. Because a large number of potential structural variables are involved, it is necessary to achieve some rationalisation of the parameters and physicochemical properties (such as molecular weight, charge, partition coefficients) that influence drug interactions. Ophthalmic dyes and structurally related compounds based on the same core structure were used to investigate these various factors and the way in which they can be used in concert to design effective release systems for structurally different drugs. Initial studies of passive diffusional release form a necessary precursor to the investigation of the features of the ocular environment that over-ride this simple behaviour. Commercially available contact lenses of differing structural classifications were used to study factors affecting the uptake of the surrogate actives and their release under 'passive' conditions. The interaction between active and lens material shows considerable and complex structure dependence, which is not simply related to equilibrium water content. The structure of the polymer matrix itself was found to have the dominant controlling influence on active uptake; hydrophobic interaction with the ophthalmic dye playing a major role. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.