A concurrent development tool for flexible assembly systems

Global competition and the rapid pace of technological change now require the almost continual introduction of product upgrades by any manufacturer. Thus, such a manufacturer is likely to market older and newer versions of a product simultaneously, not to mention niche-specific editions of any product upgrade. An increasingly successful response to this product proliferation is the implementation of flexible assembly systems. In the context of a flexible assembly system (FAS), the ability to estimate the impact of various product and process options on the maximal level of system output becomes crucial to managing the ever-changing product mix. This paper presents a tool for such impact estimation that can facilitate concurrent development and engineering. Experience with an actual FAS is the basis for the reported results. The tool is a specialized combination of discreteevent computer simulation, experimental design, and regression analysis. Application of the tool assumes FAS use with a cellular manufacturing philosophy. Thus, uncluttered process flow for a family of products in the sense of group technology places the focus on potential bottlenecks. The new tool here models the impact of process and product options on bottleneck and, hence, FAS behavior.     

Evaluating the design of flexible manufacturing systems

Evaluating the design of flexible manufacturing systems is complex. Developing a measure of performance useful for evaluating alternate designs continues to be interesting. Here, total productivity of the system is proposed as an appropriate measure. Specification of parameters based upon strategic considerations for this measure are discussed. Finally, the usefulness of the measure is demonstrated through an example.     

A framework for capacity planning and machine configuration in flexible assembly systems

We consider the problem of simultaneously determining the number of machines (and/or workers), the assignment of tasks (and related tools and components) to these machines, and the number of jobs circulating in a flexible assembly system (FAS), to satisfy steady-state throughput requirements for a family of similar products at minimum cost. We focus on situations where there are precedence relations among the various tasks, as is common in assembly systems. We present a framework for solving this problem based on a heuristic decomposition approach which involves the solution of only a few types of sub-problems. We demonstrate the efficiency and effectiveness of the overall procedure using a number of example problems.     

A case study in genome-level fragment assembly

MOTIVATION: We use the fact of two teams independently sequencing the one megabase genome of Borrelia burgdorferi as an opportunity to study the accuracy of genome-level assembly. RESULTS: We compare the results of three different assembly programs (PHRAP, TIGR Assembler, and STROLL) on the DNA fragments used in both the Brookhaven and TIGR sequencing projects. We also describe the algorithms and data structures used in our assembly program STROLL, which was used in the Brookhaven Borrelia project.     

Analytical performance models for closed-loop flexible assembly systems

Flexible Assembly Systems (FASs), which form an important subset of modern manufacturing systems, are finding increasing use in today's industry. In the planning and design phase of these systems, it is useful to have tools that predict system performance for various operating conditions. In this article, we present such a performance analysis tool based on queueing approximation for a class of FASs, namely, closed-loop flexible assembly systems (CL-FASs). For CL-FASs, we describe iterative algorithms for computing steady-state performance measures, including production rate and station utilizations. These algorithms are computationally simple and have a fast convergence rate. We derive a new approximation to correct the mean delay at each queue. This improves the accuracy of performance prediction, especially in the case of small CL-FASs. Comparisons with simulation results indicate that the approximation technique is reasonably accurate for a broad range of parameter values and system sizes. This makes possible efficient (fast and computationally inexpensive) analysis of CL-FASs under various conditions.     

A loop layout design problem for flexible manufacturing systems

The interconnection pattern of the processing modules of a computerized manufacturing system affects its performance. In this article, we discuss a set of requirements that the interconnection network should satisfy. Subsequently, we concentrate on a simple and popular architecture, the loop network. The problem we address is to design the layout of the system so that the number of machines that the part types cross in their manufacturing process is minimized. We formulate the problem mathematically and solve it by a heuristic that obtains consistently better results than an earlier popular method.     

Performance comparison of assembly systems with fixed and flexible cycle times

The traditional assembly system consists of a series of balanced workstations operating at the same rate with fixed cycle times. Recent advances in technology allow more flexible assembly systems, in which workstations operate independently and cycle times vary from job to job. This article develops an analytical model for comparing the throughputs (jobs per hour) of assembly systems with fixed and variable cycle times. The throughputs are compared on a common basis by requiring that both systems allow sufficient processing time to ensure product quality and that they have the same total times in system per job. Results indicate that an assembly system with variable cycle times can operate at a significantly higher throughput than one with fixed cycle times, provided there is sufficient buffer storage space between workstations to accommodate queueing. This benefit must be weighed against possible increased capital investment and practical considerations associated with system control.     

BglBricks: A flexible standard for biological part assembly

Background  

Standard biological parts, such as BioBricks™ parts, provide the foundation for a new engineering discipline that enables the design and construction of synthetic biological systems with a variety of applications in bioenergy, new materials, therapeutics, and environmental remediation. Although the original BioBricks™ assembly standard has found widespread use, it has several shortcomings that limit its range of potential applications. In particular, the system is not suitable for the construction of protein fusions due to an unfavorable scar sequence that encodes an in-frame stop codon.     

A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors

A new crystal structure of activin in complex with the extracellular domain of its type II receptor (ActRIIb-ECD) shows that the ligand exhibits an unexpected flexibility. The motion in the activin dimer disrupts its type I receptor interface, which may account for the disparity in its affinity for type I versus type II receptors. We have measured the affinities of activin and its antagonist inhibin for ActRIIb-ECD and found that the affinity of the 2-fold symmetric homodimer activin for ActRIIb-ECD depends on the availability of two spatially coupled ActRIIb-ECD molecules, whereas the affinity of the heterodimer inhibin does not. Our results indicate that activin's affinity for its two receptor types is greatly influenced by their membrane-restricted setting. We propose that activin affinity is modulated by the ligand flexibility and that cooperativity is achieved by binding to two ActRII chains that immobilize activin in a type I binding-competent orientation.     

A quantitative systems view of the spindle assembly checkpoint

The idle assembly checkpoint acts to delay chromosome segregation until all duplicated sister chromatids are captured by the mitotic spindle. This pathway ensures that each daughter cell receives a complete copy of the genome. The high fidelity and robustness of this process have made it a subject of intense study in both the experimental and computational realms. A significant number of checkpoint proteins have been identified but how they orchestrate the communication between local spindle attachment and global cytoplasmic signalling to delay segregation is not yet understood. Here, we propose a systems view of the spindle assembly checkpoint to focus attention on the key regulators of the dynamics of this pathway. These regulators in turn have been the subject of detailed cellular measurements and computational modelling to connect molecular function to the dynamics of spindle assembly checkpoint signalling. A review of these efforts reveals the insights provided by such approaches and underscores the need for further interdisciplinary studies to reveal in full the quantitative underpinnings of this cellular control pathway.     

Computational protein design using flexible backbone remodeling and resurfacing: case studies in structure-based antigen design

Computational protein design has promise for vaccine design and other applications. We previously transplanted the HIV 4E10 epitope onto non-HIV protein scaffolds for structural stabilization and immune presentation. Here, we developed two methods to optimize the structure of an antigen, flexible backbone remodeling and resurfacing, and we applied these methods to a 4E10 scaffold. In flexible-backbone remodeling, an existing backbone segment is replaced by a de novo designed segment of prespecified length and secondary structure. With remodeling, we replaced a potentially immunodominant domain on the scaffold with a helix-loop segment that made intimate contact to the protein core. All three domain trim designs tested experimentally had improved thermal stability and similar binding affinity for the 4E10 antibody compared to the parent scaffold. A crystal structure of one design had a 0.8 Å backbone RMSD to the computational model in the rebuilt region. Comparison of parent and trimmed scaffold reactivity to anti-parent sera confirmed the deletion of an immunodominant domain. In resurfacing, the surface of an antigen outside a target epitope is redesigned to obtain variants that maintain only the target epitope. Resurfaced variants of two scaffolds were designed in which 50 positions amounting to 40% of the protein sequences were mutated. Surface-patch analyses indicated that most potential antibody footprints outside the 4E10 epitope were altered. The resurfaced variants maintained thermal stability and binding affinity. These results indicate that flexible-backbone remodeling and resurfacing are useful tools for antigen optimization and protein engineering generally.     

A decision-making approach to the operation of flexible manufacturing systems

This paper introduces a generic decision-making framework for assigning resources of a manufacturing system to production tasks. Resources are broadly defined production units, such as machines, human operators, or material handling vehicles; and tasks are activities performed by resources. In the specific context of FMS, resources correspond to individual machines; tasks correspond to operations to be performed on parts. The framework assumes a hierarchical structure of the system and calls for the execution of four consecutive steps to make a decision for the assignment of a resource to a task. These steps are 1) establishment of decision-making criteria, 2) formation of alternative assignments, 3) estimation of the consequences of the assignments, and 4) selection of the best alternative assignment. This framework has been applied to an existing FMS as an operational policy that decides what task will be executed on which resource of this FMS. Simulation runs provide some initial results of the application of this policy. It is shown that the policy provides flexibility in terms of system performance and computational effort.     

A heuristic algorithm for the loading problem in flexible manufacturing systems

The paper considers the loading problem in flexible manufacturing systems (FMSs). This problem involves the assignment to the machine tools of all operations and associated cutting tools required for part types that have been selected to be produced simultaneously. The loading problem is first formulated as a linear mixed 0–1 program with the objective to minimize the greatest workload assigned to each machine. A heuristic procedure is presented in which an assignment of operations to machine tools is obtained by solving a parameterized generalized assignment problem with an objective function that approximates the use of tool slots required by the operations assigned to the machines. The algorithm is coded in FORTRAN and tested on an IBM-compatible personal computer. Computational results are presented for different test problems to demonstrate the efficiency and effectiveness of the suggested procedure.     

A flexible brace maintains the assembly of a hexameric replicative helicase during DNA unwinding

The mechanism of DNA translocation by papillomavirus E1 and polyomavirus LTag hexameric helicases involves consecutive remodelling of subunit-subunit interactions around the hexameric ring. Our biochemical analysis of E1 helicase demonstrates that a 26-residue C-terminal segment is critical for maintaining the hexameric assembly. As this segment was not resolved in previous crystallographic analysis of E1 and LTag hexameric helicases, we determined the solution structure of the intact hexameric E1 helicase by Small Angle X-ray Scattering. We find that the C-terminal segment is flexible and occupies a cleft between adjacent subunits in the ring. Electrostatic potential calculations indicate that the negatively charged C-terminus can bridge the positive electrostatic potentials of adjacent subunits. Our observations support a model in which the C-terminal peptide serves as a flexible 'brace' maintaining the oligomeric state during conformational changes associated with ATP hydrolysis. We argue that these interactions impart processivity to DNA unwinding. Sequence and disorder analysis suggest that this mechanism of hexamer stabilization would be conserved among papillomavirus E1 and polyomavirus LTag hexameric helicases.     

A model for the minimum cost configuration problem in flexible manufacturing systems

This paper presents a mathematical programming model to help select equipment for a flexible manufacturing system, i.e., the selection of the types and numbers of CNC machines, washing stations, load/unload stations, transportation vehicles, and pallets. The objective is to minimize equipment costs and work-in-process inventory cost, while fulfilling production requirements for an average period. Queueing aspects and part flow interactions are considered with the help of a Jacksonian-type closed queueing network model in order to evaluate the system's performance. Since the related decision problem of our model can be shown to be NP-complete, the proposed solution procedure is based on implicit enumeration. Four bounds are provided, two lower and two upper bounds. A tight lower bound is obtained by linearizing the model through the application of asymptotic bound analysis. Furthermore, asymptotic bound analysis allows the calculation of a lower bound for the number of pallets in the system. The first upper bound is given by the best feasible solution and the second is based on the anti-starshaped form of the throughput function.     

Performance management in flexible manufacturing systems

This article treats several performance management decision problems in flexible manufacturing systems (FMSs). This work differs from a number of other studies in that we allow the processing rates at the machines to be varied, and the system has to meet a given throughput goal per unit time. The managerial decision options modeled here include part routing and allocation of tasks to machines, work-in-progress (WIP) levels, capacity expansions, tool-type selection, the setting of throughput goals, and multiperiod production planning. We discuss and explain the insights and implications, partly nonintuitive, gained from our investigations. Finally, extensive numerical evaluations are included to illustrate the economic and performance impact of the various performance management alternatives. These results demonstrate that substantial economic benefits can be achieved by careful tuning of the FMS operational parameters.     

The case for decoupling assembly and submission standards to maintain a more flexible registry of biological parts

The Registry of Standard Biological Parts only accepts genetic parts compatible with the RFC 10 BioBrick format. This combined assembly and submission standard requires that four unique restriction enzyme sites must not occur in the DNA sequence encoding a part. We present evidence that this requirement places a nontrivial burden on iGEM teams developing large and novel parts. We further argue that the emergence of inexpensive DNA synthesis and versatile assembly methods reduces the utility of coupling submission and assembly standards and propose a submission standard that is compatible with current quality control strategies while nearly eliminating sequence constraints on submitted parts.     

A recursion model for cellular production/assembly systems

This article presents an efficient algorithm for applying the recursion modeling approach to describe the transient operation of cellular production/assembly systems that incorporate features such as finite buffers, job-shop routing, lot sequencing, and material handling. Tests evaluate the approximation method relative to number of machines at a station, capacity of input/output buffers, degree of balance among station processing times, and sequencing rule. Furthermore, the method is demonstrated in application to a hypothetical industrial setting that involves the assembly of electronic circuit cards in a facility composed of several cells. All tests indicate that the method gives accurate estimates of transient performance within reasonable runtime. In comparison with earlier recursion models, this research incorporates a number of new features (see list above), improves the accuracy of approximation, and facilitates implementation with a new, more efficient algorithm.     

Optimal input design: case study of the metabolic process

An optimal input of nutrients into the metabolic process of the individual subject so as to effect desired therapeutic results is particularly important for the critically ill. A patient-related, individualized nutrients optimization procedure is proposed here. The procedure is applicable to any time-invariant and deterministic metabolic model that is bound by one or more quantitative limiting criteria. As a case in hand, the procedure is used to optimize the individual metabolic needs of critically ill patients. The results indicate that, given a proper metabolic model, the patient may be treated on an individual appropriateness basis rather than on the traditional statistical intuitive approach.     

A regulatory view on adaptive/flexible clinical trial design

Recently there is growing interest in use of adaptive or flexible designs for development of pharmaceutical products. Statistical methodology has been greatly advanced in the literature. However, there are still some important issues with the methodology and application. In addition, there are many other challenges with these designs, including efficiency of these designs in the entire development program, trial conduct and logistics, the infrastructure of an adaptive trial, the regulatory evaluation of trial results and trial conduct, etc. Up till now, regulatory experience in these designs is very limited. We share some of the challenges.