Computer aided form roll design

Cold roll forming is an extremely important but little studied sheet metal forming process. In this thesis, the process of cold roll forming is introduced and it is seen that form roll design is central to the cold roll forming process. The conventional design and manufacture of form rolls is discussed and it is observed that surrounding the design process are a number of activities which although peripheral are time consuming and a possible source of error. A CAD/CAM system is described which alleviates many of the problems traditional to form roll design. New techniques for the calculation of strip length and controlling the means of forming bends are detailed. The CAD/CAM system's advantages and limitations are discussed and, whilst the system has numerous significant advantages, its principal limitation can be said to be the need to manufacture form rolls and test them on a mill before a design can be stated satisfactory. A survey of the previous theoretical and experimental analysis of cold roll forming is presented and is found to be limited. By considering the previous work, a method of numerical analysis of the cold roll forming process is proposed based on a minimum energy approach. Parallel to the numerical analysis, a comprehensive range of software has been developed to enhance the designer's visualisation of the effects of his form roll design. A complementary approach to the analysis of form roll design is the generation of form roll design, a method for the partial generation of designs is described. It is suggested that the two approaches should continue in parallel and that the limitation of each approach is knowledge of the cold roll forming process. Hence, an initial experimental investigation of the rolling of channel sections is described. Finally, areas of potential future work are discussed.

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.

Computer-aided design, synthesis and screening of potential anti-microbial compounds

The work presented in this thesis falls into three main categories: The design and synthesis of potential anti-tuberculosis drugs targeting a mycobacterial esterase and the enzyme dUTPase; synthesis and anti-microbial SAR studies on a set of carboxamidrazones; synthesis and anti-microbial SAR studies on a set of thiosem icarbazones.

The Use of Situation Representation when Searching for Solutions in Computer Aided Design Systems

Projects solutions reuse methodology is offered for software development. The main idea consists in connection of the system objective with the situation using the entities which describe the condition of the system in the process of the objective statement. Every situation is associated with one or several design solutions, which can be used at the development. Based on this connection the situation representing language has been created, it lets to express a problem situation using a natural language describe. The similarity measure has been built to compare situations, it is based on the similarity coefficients with adding the absent part weight.

Accuracy of computer-aided design/computer-assisted manufacture (CAD/CAM) fabricated dental restorations: a comparative study

Introduction: Computer-Aided-Design (CAD) and Computer-Aided-Manufacture (CAM) has been developed to fabricate fixed dental restorations accurately, faster and improve cost effectiveness of manufacture when compared to the conventional method. Two main methods exist in dental CAD/CAM technology: the subtractive and additive methods. While fitting accuracy of both methods has been explored, no study yet has compared the fabricated restoration (CAM output) to its CAD in terms of accuracy. The aim of this present study was to compare the output of various dental CAM routes to a sole initial CAD and establish the accuracy of fabrication. The internal fit of the various CAM routes were also investigated. The null hypotheses tested were: 1) no significant differences observed between the CAM output to the CAD and 2) no significant differences observed between the various CAM routes. Methods: An aluminium master model of a standard premolar preparation was scanned with a contact dental scanner (Incise, Renishaw, UK). A single CAD was created on the scanned master model (InciseCAD software, V2.5.0.140, UK). Twenty copings were then fabricated by sending the single CAD to a multitude of CAM routes. The copings were grouped (n=5) as: Laser sintered CoCrMo (LS), 5-axis milled CoCrMo (MCoCrMo), 3-axis milled zirconia (ZAx3) and 4-axis milled zirconia (ZAx4). All copings were micro-CT scanned (Phoenix X-Ray, Nanotom-S, Germany, power: 155kV, current: 60µA, 3600 projections) to produce 3-Dimensional (3D) models. A novel methodology was created to superimpose the micro-CT scans with the CAD (GOM Inspect software, V7.5SR2, Germany) to indicate inaccuracies in manufacturing. The accuracy in terms of coping volume was explored. The distances from the surfaces of the micro-CT 3D models to the surfaces of the CAD model (CAD Deviation) were investigated after creating surface colour deviation maps. Localised digital sections of the deviations (Occlusal, Axial and Cervical) and selected focussed areas were then quantitatively measured using software (GOM Inspect software, Germany). A novel methodology was also explored to digitally align (Rhino software, V5, USA) the micro-CT scans with the master model to investigate internal fit. Fifty digital cross sections of the aligned scans were created. Point-to-point distances were measured at 5 levels at each cross section. The five levels were: Vertical Marginal Fit (VF), Absolute Marginal Fit (AM), Axio-margin Fit (AMF), Axial Fit (AF) and Occlusal Fit (OF). Results: The results of the volume measurement were summarised as: VM-CoCrMo (62.8mm3 ) > VZax3 (59.4mm3 ) > VCAD (57mm3 ) > VZax4 (56.1mm3 ) > VLS (52.5mm3 ) and were all significantly different (p presented as areas with different colour. No significant differences were observed at the internal aspect of the cervical aspect between all groups of copings. Significant differences (p< M-CoCrMo Internal Occlusal, Internal Axial and External Axial 2 ZAx3 > ZAx4 External Occlusal, External Cervical 3 ZAx3 < ZAx4 Internal Occlusal 4 M-CoCrMo > ZAx4 Internal Occlusal and Internal Axial The mean values of AMF and AF were significantly (p M-CoCrMo and CAD > ZAx4. Only VF of M-CoCrMo was comparable with the CAD Internal Fit. All VF and AM values were within the clinically acceptable fit (120µm). Conclusion: The investigated CAM methods reproduced the CAD accurately at the internal cervical aspect of the copings. However, localised deviations at axial and occlusal aspects of the copings may suggest the need for modifications in these areas prior to fitting and veneering with porcelain. The CAM groups evaluated also showed different levels of Internal Fit thus rejecting the null hypotheses. The novel non-destructive methodologies for CAD/CAM accuracy and internal fit testing presented in this thesis may be a useful evaluation tool for similar applications.

The design and Evaluation of 'CAP Tools' - A computer aided parallelisation tool-kit

Abstract not available

Computer Aided Design Algorithmic Technique for Very Large Scale Integrated Circuit Design and Smart Home Embedded System Design

To tackle the challenges at circuit level and system level VLSI and embedded system design, this dissertation proposes various novel algorithms to explore the efficient solutions. At the circuit level, a new reliability-driven minimum cost Steiner routing and layer assignment scheme is proposed, and the first transceiver insertion algorithmic framework for the optical interconnect is proposed. At the system level, a reliability-driven task scheduling scheme for multiprocessor real-time embedded systems, which optimizes system energy consumption under stochastic fault occurrences, is proposed. The embedded system design is also widely used in the smart home area for improving health, wellbeing and quality of life. The proposed scheduling scheme for multiprocessor embedded systems is hence extended to handle the energy consumption scheduling issues for smart homes. The extended scheme can arrange the household appliances for operation to minimize monetary expense of a customer based on the time-varying pricing model.

Rational design of serine protease inhibitors

Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.

ICADA: Intelligent computer aided defect analysis for castings

An intelligent computer aided defect analysis (ICADA) system, based on artificial intelligence techniques, has been developed to identify design, process or material parameters which could be responsible for the occurrence of defective castings in a manufacturing campaign. The data on defective castings for a particular time frame, which is an input to the ICADA system, has been analysed. It was observed that a large proportion, i.e. 50-80% of all the defective castings produced in a foundry, have two, three or four types of defects occurring above a threshold proportion, say 10%. Also, a large number of defect types are either not found at all or found in a very small proportion, with a threshold value below 2%. An important feature of the ICADA system is the recognition of this pattern in the analysis. Thirty casting defect types and a large number of causes numbering between 50 and 70 for each, as identified in the AFS analysis of casting defects-the standard reference source for a casting process-constituted the foundation for building the knowledge base. Scientific rationale underlying the formation of a defect during the casting process was identified and 38 metacauses were coded. Process, material and design parameters which contribute to the metacauses were systematically examined and 112 were identified as rootcauses. The interconnections between defects, metacauses and rootcauses were represented as a three tier structured graph and the handling of uncertainty in the occurrence of events such as defects, metacauses and rootcauses was achieved by Bayesian analysis. The hill climbing search technique, associated with forward reasoning, was employed to recognize one or several root causes.

Use of Vertex Index in Structure-Activity Analysis and Design of Molecules

The last few decades have witnessed application of graph theory and topological indices derived from molecular graph in structure-activity analysis. Such applications are based on regression and various multivariate analyses. Most of the topological indices are computed for the whole molecule and used as descriptors for explaining properties/activities of chemical compounds. However, some substructural descriptors in the form of topological distance based vertex indices have been found to be useful in identifying activity related substructures and in predicting pharmacological and toxicological activities of bioactive compounds. Another important aspect of drug discovery e. g. designing novel pharmaceutical candidates could also be done from the distance distribution associated with such vertex indices. In this article, we will review the development and applications of this approach both in activity prediction as well as in designing novel compounds.

Conformational dynamics of HIV-1 protease: a comparative molecular dynamics simulation study with multiple amber force fields

Flap dynamics of HIV-1 protease (HIV-pr) controls the entry of inhibitors and substrates to the active site. Dynamical models from previous simulations are not all consistent with each other and not all are supported by the NMR results. In the present work, the er effect of force field on the dynamics of HIV-pr is investigated by MD simulations using three AMBER force fields ff99, ff99SB, and ff03. The generalized order parameters for amide backbone are calculated from the three force fields and compared with the NMR S2 values. We found that the ff99SB and ff03 force field calculated order parameters agree reasonably well with the NMR S2 values, whereas ff99 calculated values deviate most from the NMR order parameters. Stereochemical geometry of protein models from each force field also agrees well with the remarks from NMR S2 values. However, between ff99SB and ff03, there are several differences, most notably in the loop regions. It is found that these loops are, in general, more flexible in the ff03 force field. This results in a larger active site cavity in the simulation with the ff03 force field. The effect of this difference in computer-aided drug design against flexible receptors is discussed.