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Twist1 encodes a basic helix-loop-helix transcription factor (TF), which forms homodimer or heterodimer with other TFs, like E2A, to regulate target genes’ expression. Mutations in TWIST1 are associated with Saethre-Chotzen syndrome (SCS), a rare congenital disorder characterized with osteogenesis abnormalities. However, how dysfunction of TWIST1 leads to SCS is still largely unknown. Here, using an unbiased ENU-induced mutagenesis screening, we identified a novel Twist1 mutation and the mutant mouse phenocopies some features of SCS in a dominant manner. Physically, our mutation p.F191S lies at the edge of a predicted α-helix in Twist1 transactivation (TA) domain. Adjacent to F191, a consecutive three-residue (AFS) has been hit by 3 human and 2 mouse disease-associated mutations, including ours. Unlike previously reported mouse null and p.S192P alleles that lead to hindlimb polydactyly with incomplete penetrance but a severe craniofacial malformation, our p.F191S causes the polydactyly (84.2% bilateral and 15.8% unilateral) with complete penetrance but a mild craniofacial malformation. Consistent with the higher penetrance, p.F191S has stronger impairment on E2A-dependent transcription than p.S192P. Although human p.A186T and mouse p.S192P disease mutations are adjacent to ours, these three mutations function differently to impair the E2A-dependent transcription. Unlike p.A186T and p.S192S that disturb local protein conformation and unstabilize the mutant proteins, p.F191S keeps the mutant protein stable and its interaction with E2A entire. Therefore, we argue that p.F191S we identified acts in a dominant-negative manner to impair E2A-dependent transcription and to cause the biological consequences. In addition, the mutant mouse we provided here could be an additional and valuable model for better understanding the disease mechanisms underlying SCS caused by TWIST1 dysfunction.

Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPIArg189Gln/TPIGlu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.

Presented in this paper is an algorithm to compute the intersections of a parametric regular surface with a set of parallel planes. Rather than using an ordinary surface-plane intersection algorithm repeatedly, we pre-process a surface to identify points, called topology transition points (TTP's), on the surface where the topologies of intersection curves change. It turns out that such points can be computed efficiently, exactly and robustly employing a normal surface, and they are categorized into seven distinct groups. Analyzing the properties of such characteristic points on the surface, the starting points to trace intersection curves can be found rather efficiently and robustly. Such intersection contours can be used in various applications including rapid prototyping, solid freeform fabrication, process planning, NC tool path generation for surfaces, etc.

Flat and filleted endmills are less frequently used than ball-end cutters in 3-axis sculptured surface machining. However, they improve cutting efficiency to a great degree in some applications, such as machining smooth part surfaces or rough cutting. Presented in this paper is a method to generate cutter paths to make effective use of these cutter types. A part surface is first approximated into a triangular polyhedron. Cutter paths are then generated from the tessellated surface model. The robust method makes it possible to machine any compound sculptured surfaces regardless of their complexity. An efficient algorithm is used for calculating cutterlocation data.

In this paper, application of convex hull is proposed to solve the problem of global tool interference avoidance in 5-axis sculptured surface machining. Two different methods for interference checking have been developed. Quick Feasibility Checking is used to find a conservative feasible tool orientation by using the control mesh of a sculptured surface. Detailed Feasibility Checking uses exact surface to detect tool interference. A correction method for removing tool interference has also been developed. In this paper both the algorithms and the implementation are presented.

A fuzzy set multiple criteria decision making approach is proposed to help selecting the most suitable tool steel materials for a specific manufacturing application such as die design, jig and fixture design. The important weights of different criteria and the material suitability ratings of various alternatives under different criteria are given in linguistic terms. Subsequently, they are represented in fuzzy linguistic values and fuzzy numbers. Through aggregation and ranking of fuzzy numbers, the most suitable tool steel material is determined. A hypothetical example is illustrated. Further, by computerizing the proposed method, and incorporating appropriate interface design together with a data base of tool steel materials assessment information from the handbook, a decision support system can be constructed.

To machine a part from the CAD data, machining information has to be extracted from the design model. In the planning stage, the machining information such as the cutting area, removal volume, estimated machining time, etc., is important for the generation of a “good” process plan. This machining information is typically not readily available from the design. This paper discusses a methodology of applying computational geometry techniques to extract machining information of geometric constraints from a given complex surface design to support the process planning activity. The machining process is determined by part surface classification based on surface geometry interrogation. An application of convex hulls is also presented to improve the machining productivity by preprocessing the object geometry for machining. The proposed methodology can be applied in the automation of planning and manufacturing of complex surface parts. Some practical examples and testing results are presented to show the application in solving manufacturing problems.

Sculptured surfaces are frequently encountered in modern engineering designs. Sculptured surface machining is a time-consuming and error-prone process. It is critical that proper tools are selected and cutter paths generated. In this paper, a method called the virtual boundary approach is proposed to integrate a protrusion free-form surface feature with conventional polyhedron features in a feature-based design and manufacturing system. Using the proposed virtual boundary approach, a protrusion free-form feature can be converted into a virtual pocket with islands. The machining of a protrusion sculptured surface feature is transformed into a series of virtual pocketing processes. The proposed methodology transforms the union operation of a protrusion free-form feature into a difference operation of removal volumes. Techniques of automatic cutter selection and cutter path generation are presented. A complete operation plan and cutter path can be generated for machining using the proposed virtual boundary method. Practical examples and automatic cutter path generation for machining are also presented.

A generic kanban system that is designed for non-repetitive manufacturing environments is described. The purpose of this paper is to determine the number of kanbans and lot sizes needed to achieve the best system performance. System objectives include minimizing the cycle time, minimizing operation cost, and minimizing capital loss. A multiattribute utility function is constructed and a modified simulated annealing algorithm is proposed to search the maximal utility value. To show this algorithm at work, we compared the results with those from the traditional algorithm. The utility values found by both algorithms are insignificantly different; however, the computational time required by the modified algorithm is much less. The modified algorithm is feasible to solve our problem. Finally, a heuristic for generating good initial seed is developed to further improve the efficiency of the modified algorithm and an example is given to illustrate its benefits.

Kanbans have shown successful results in lowering inventory and shortening lead time in repetitive production systems. Unfortunately, such systems are not applicable to production environments with dynamic characteristics. Here a modified kanban system, the generic kanban system, is proposed for such dynamic environments. The generic kanban system behaves similarly to the push system except that it is more flexible with respect to system performance and more robust as to the location of the bottleneck. The simulation results that the generic kanban system is dominant over the dedicated kanban system and the CONWIP system. The adaptability of such a system to dynamic environments is justified.

In a feature-based design system, a designer should be able to design with both protrusion and depression features. Since depression features loosely correspond to machining processes, they are easy to handle during process planning and NC cutter-path generation. However, the same cannot be said for protrusion features. Not only do the removal volumes surrounding the feature need to be extracted into depression features, but the original workpiece needs to increase in size so that there is enough material for the protruding features. A backward-growing methodology for handling protrusion features for process planning is discussed. Its implementation in an integrated design/ manufacturing system called QTC II is described.

3D MAPS, an acronym for 3-Dimensional Mechanical Assembly Planning System, is an automated system that generates detailed assembly plans for three-dimensional mechanical products. It has three major modules: description of mechanical assembly design, analysis of assembly models, and generation of assembly plans. Both geometric models and nongeometric properties are considered in describing a 3-D assembly design, and the following information is inferred from the system: mating parts, mating faces, mating directions, collision constraints, and nongeometric sequence constraints. The inferred information is then used in the subsequent planning stage for generating detailed assembly instructions. The planning scheme contains two parts: initial assembly planning that considers solely geometric constraints, and plan modification that further considers nongeometric constraints. In this paper, the algorithms developed to implement the above three modules are discussed. Examples of mechanical assemblies are used to illustrate the information flow of the entire planning system, from the assembly design input through the execution of the developed algorithms to the final assembly plan output. Analysis of the results is also included.

One interesting application of mechanical assembly systems is the synthesis of fixture assemblies in automatic process planners. Fixture assembly deals with the design of a configuration of selected fixture elements and a workpiece so as to locate, support and clamp die latter. Complete automation of this function promises various advantages. Firstly, it will lead to a systematization of the fixture configuration process, hitherto a skill developed by experience by tool engineers on the shop floor. Secondly, it will reduce significantly the design time. Finally, it will aid the complete automation of process planning. The capability of modem machining centers to handle a wide variety of part geometries directly implies the necessity of versatile fixturing hardware. One approach to this end is the use of modular fixturing element sets. La this research, a generalized representation scheme is developed to model a large variety of fixturing elements, capturing detailed geometric as well as functional information. Since the design of fixture configurations requires reasoning over mechanical assemblies, a representational scheme is also developed to model assemblies of parts. Methods involving screw theory are used to represent the total degrees of freedom of any rigid body subject to constraints imposed by contacts with other bodies in the assembly. Procedures are also developed to integrate die effect of multiple mating joints, and to infer from that information the requirements of further restraints on the bod/ to achieve form closure. These methods are used by a knowledge based planner to assemble fixtures around a workpiece defined by its current geometry and the machining requirements for the current setup. The outcome of the planner wiH be in the form of visual graphic displays that can then be used by the machine tool operator to assemble die actual fixture.

This paper describes a system, agips (Automatic Generator for Insertion and Placement Sequences), which can immediately evaluate the manufacturability of printed wiring boards (PWB) at the design stage by examining potential collisions and then generate collision-free insertion sequences within reasonable computation time. The input files come from three different sources: PWB CAD database, machines and set-up specifications, and process planning. The sequences generated by agips can be translated into NC codes to drive the NC assembly machine. In agips , the PWB assembly sequence problem is considered at three hierarchical levels: machine sequence, machine head sequence, and component sequence. During collision checking, three directed arcs representing the precedence relationships among assembly machines, machine heads and components are generated to avoid a collision if any occurs. The developed agips can automatically generate collision-free sequences and provide immediate feedback to the PWB designer the producibility of a design. An example is given to illustrate agips's abilities.

A systematic procedure that automatically generates machining processes for sculptured surface cavity machining is presented. The work proposed here includes the evaluation of machining information, decision for machining process strategy, automatic cutter selection, and cutter path generation. Machining information is first evaluated by considering the cavity geometric shape, removal volume, and constraints of machining. A decision on the process strategy is determined based on the machining information evaluated. Then the procedures of machining the cavity are decided. The cutter selection is automatically determined by considering geometric constraints, the maximum material removal rate in the roughing process and the minimum cutter movement with the required accuracy in the finishing process. The roughing process is approached by some arbitrary-shape pocketing procedures combined with islands on the cutting planes. Cutter movements and cutter selection are optimized by considering the global information of machining conditions on adjacent cutting planes. A system called cascam has been developed to prove the feasibility of the proposed concept.

The aim of this paper is to present a practical method to reduce setups for PCB assembly machines by improving the assembly sequence. First, we introduce an integer programming (IP) formulation that gives the optimal sequences. However, this IP formulation demands too much computation. Next, we take a three-step approach. Grouping PCBs is the first step and we apply a new heuristic grouping method. Second step is ordering the groups and we treat this problem as a traveling salesman problem. Third step is the component assignment to the machine and a new algorithmic method is presented. This approach is shown to be efficient for large-size very industrial problems.

SUMMARY In this paper important issues in the automatic generation of process plans are addressed. Since the conventional method of electronic assembly planning is subjective and depends greatly on the skills, memory, knowledge, and experience of the planners, inconsistencies in the plan arise, which in turn create problems in the manufacturing environment. An automatic electronic assembly planning system that would offer advantages over manual systems has been implemented. Due to frequent advances in technology, the electronic industry is a very dynamic one. This affects the effectiveness of the current process plans and the applicability of the system that generates them. The framework of a system which takes into account the dynamic nature of the environment is presented as an example. A network representation of plans that allows for flexibility and modularity in the planning system is being used. A hybrid architecture consisting of production rules, procedural algorithms and a hierarchical database h...

The conventional method of electronic assembly planning is subjective and depends greatly on the skills, memory, knowledge and experience of the planners. This gives rise to inconsistencies which in turn create problems in the manufacturing environment. Since the computer logics are systematic and consistent, it is conceivable that an automatic electronic assembly planning system would have advances over manual systems. Due to the frequent advances in technology the electronic industry is a very dynamic one. This affects the effectiveness of the current process plans and the applicability of the system that generates them. In this paper important issues which address the automatic generation of process plans will be presented. The framework of a system which takes into account the dynamic nature of the environment will be introduced as an example.

This paper presents an algorithm to obtain the intersections of a free-form surface with a series of parallel planes. When sectioning the surface with parallel planes, the change of the topology of the intersection curves is caused by characteristic points of the surface. There are seven types of characteristic points: interior maximum, interior minimum, interior saddle, boundary maximum, boundary minimum, boundary max-saddle, and boundary min-saddle points. The starting points of the intersections are found efficiently and robustly using the characteristic points. The characteristic points as well as the intersection contours can be used to evaluate the machining information for process planning, to generate NC tool path for surfaces, and to generate slices for rapid prototyping.

In this paper, a methodology of applying convex hull property in solving the tool interference problem is presented for 5-axis NC machining of free-form surfaces. Instead of exhausted point-by-point checking for possible tool interference, a quick checking can be done by using the convex hull constructed from the control polygon of free-form surface modeling. Global tool interference in 5-axis NC machining is detected using the convex hull of the free-form surface. A correction method for removing tool interference has also been developed to generate correct tool path for 5-axis NC machining. The inter-surface tool interference can be avoided by using the developed technique.

In modern product design, sculptured surfaces are commonly used for functional and artistic shape design. Design of sculptured surfaces is evolutionary, consisting primarily of incremental changes to existing part surfaces. Manual operation planning for sculptured surface machining is known to be error-prone and inefficient, which requires considerable checking, verification, and rework. Five-axis machining has higher productivity and better machining quality than 3-axis machining. However, the programming for 5-axis machining is more difficult due to the complex simultaneous cutter movements along the machine’s five axes. This paper presents a systematic methodology to generate operation plans for 5-axis sculptured surface machining. A complete operation plan and the error-free cutter path can be automatically generated from the CAD part design. To achieve design for manufacturing of sculptured surface products, the machining unfeasibility information can be fed back to the designer for further design modification. Results of computer implementation and testing examples are also presented.

Sculptured surfaces often appear in mechanical parts of various industrial products as external form or the functional surface and are commonly found in molds and dies. In this study a sculptured surface is defined by a Non-Uniform Rational B-spline (NURB) surface that provides the flexibility and freedom for surface description. The work proposed here includes the evaluation of machining information, decision for machining process sequence selection, automatic cutter selection, and cutter path generation. Machining information is first evaluated by using series of hunting planes, calculating the geometric shape and constraints of the machining cavity. A decision on the process sequence is made based on the evaluated machining information. The cutter size is automatically determined by considering geometric constraints, the maximum material removal rate in roughing process and the minimum cutter movement with the required accuracy in finishing process. The roughing process is done by some pocketing procedures that consider arbitrary shaped pockets with islands on the cutting planes. Cutter movement and cutter selection are optimized by considering machining conditions on adjacent cutting planes. An integrated system called CASCAM has been developed to prove the feasibility of the proposed approach.

This paper discusses the process planning problem with a view to automate its solution methods. The problem is formulated using AI techniques. The basic issues involved in modelling the process planning problem are discussed. A hierarchical planning structure is proposed, in which the highest level is a simplification or abstraction of the plan and the lowest is a detailed plan, sufficient to solve the problem. States in the problem can be modelled using the CAD representation schemes, such as Constructive Solid Geometry and Boundary Representation. The advantages and disadvantages of these schemes are discussed. Operators which correspond physically to material removal are also modelled using the same representation scheme. The design of a control strategy is discussed.

Many educators find that CAD and CAM laboratories and software which are necessary for their programs are prohibitively expensive to install and maintain. With the advent of powerful yet inexpensive microcomputing equipment, educational institutions now have an excellent opportunity to instruct NC, CAD and CAM technologies using personal computers (PCs). In this paper, several PC-based software programs developed for educational use are presented.

In most frame-based reasoning systems, the information being manipulated is represetned using frames, but the problem-solving knowledge that manipulates the frames is represented as production rules. One problem with this approach is that rules are not always a natrual way to represent knowledge; another is that systems containing lots of rules may suffer from problems with “exponetial blowup” in the amount of computation required. This paper describes a way to address these problems by organizing the problem-solving knowledge not as rules, but in a particular kind of frame hierarchy. the approach described in this paper has been implemented in a problem-solving system called SIPP (Semi-Intelligent Process Planner), which produces plans of action for the manufacture of metal parts. the paper gives an overview of SIPP, compares its knowledge representation and problem solving methods to approaches used in other knowledge-based systems, and describes goals for further research.