Object-oriented graphical modeling of FMSs

Presented in the article is a method for constructing a graphical model of an FMS by using a new modeling tool called JR-net (Job Resource relation-net). JR-net is an object-oriented graphical tool for modeling automated manufacturing systems (AMSs), such as FMSs, FASs, and AS/RSs. As with the object-oriented modeling paradigm of Rumbaugh et al. (1991), the JR-net modeling framework supports the three stages of models: static layout model (object model); job flow model (functional model); and supervisory control model (dynamic model). In this article, the existing JR-net structure (Park 1992, Han et al., 1995) is extended further to make it a graphical tool for FMS modeling. Using the extended JR-net, a step-by-step procedure for constructing a graphical model of FMSs is presented. Also addressed are issues of classifying FMSs in terms of their generic functions and of utilizing the JR-net model of FMSs.     

Dynamic load control policies for a flexible manufacturing system with stochastic processing rates

Real-time scheduling and load controls of FMSs are complex processes in which the control logic must consider a broad spectrum of instantaneous state variables while taking into account the probabilistic future impact of each decision at each time epoch. These processes are particularly important in the management of modern FMS environment, since they are known to have a significant impact on the FMS productive capacity and economic viability. In this article we outline the approach developed for dynamic load controls within an FMS producing a variety of glass lenses. Two revenue-influencing objective functions are evaluated for this capital-intensive facility. It is shown that by using Semi-Markovian modeling concepts, the FMS states need to be observed only at certain decision epochs. The mean holding time in each state is then obtained using the probability distribution function of the conditional state occupancy times. Several key performance measures are then derived by means of the value equations. In addition, the structure of the optimal policies are exemplified for a variety of operational parameters. It is shown that the optimal policies tend to generate higher buffer stocks of parts in those work centers having the highest revenue-generation rates. These buffer stocks get smaller and smaller as the relative processing capacity of the centers increases. Similar observations lead us to the introduction of several promising heuristics that capture the structural properties of the optimal policies with a significantly smaller computational effort. Results of the empirical evaluation of these heuristics are also analyzed here.     

ELISA: Structure-Function Inferences based on statistically significant and evolutionarily inspired observations

The problem of functional annotation based on homology modeling is primary to current bioinformatics research. Researchers have noted regularities in sequence, structure and even chromosome organization that allow valid functional cross-annotation. However, these methods provide a lot of false negatives due to limited specificity inherent in the system. We want to create an evolutionarily inspired organization of data that would approach the issue of structure-function correlation from a new, probabilistic perspective. Such organization has possible applications in phylogeny, modeling of functional evolution and structural determination. ELISA (Evolutionary Lineage Inferred from Structural Analysis, http://romi.bu.edu/elisa) is an online database that combines functional annotation with structure and sequence homology modeling to place proteins into sequence-structure-function "neighborhoods". The atomic unit of the database is a set of sequences and structural templates that those sequences encode. A graph that is built from the structural comparison of these templates is called PDUG (protein domain universe graph). We introduce a method of functional inference through a probabilistic calculation done on an arbitrary set of PDUG nodes. Further, all PDUG structures are mapped onto all fully sequenced proteomes allowing an easy interface for evolutionary analysis and research into comparative proteomics. ELISA is the first database with applicability to evolutionary structural genomics explicitly in mind.Availability: The database is available at http://romi.bu.edu/elisa.     

An Assessment Framework for Optimal FMS Effectiveness

Equipment failures in an FMS are significant to performance and can lead to costly, incorrect decisions. Fortunately, effectiveness measurement techniques can be mapped to clever modeling frameworks to help predict, track, and then improve upon the FMS performability or mission effectiveness, and improve maintenance. This article provides sources and guidelines for efficient and effective FMS modeling, a framework for applying the modeling to predict the impact on customers from their point of view, and a method for tying it all together for improving the FMS effectiveness. It is not enough to simply examine the working and failed states of an FMS or even to calculate common reliability metrics. It is necessary to consider the FMS as a whole, and that system includes the needs of the customer and the business. It is also necessary to be purposeful about the measures of performance selected and to support the measures of effectiveness. In this article, we present: a framework for considering customer needs in the measures of effectiveness for FMS; modeling approaches for solving for effectiveness measures; and an example to show how to apply it to an FMS, to improve it or plan for meeting specific customer needs.     

Efficiency, selectivity, and robustness of nucleocytoplasmic transport

All materials enter or exit the cell nucleus through nuclear pore complexes (NPCs), efficient transport devices that combine high selectivity and throughput. NPC-associated proteins containing phenylalanine–glycine repeats (FG nups) have large, flexible, unstructured proteinaceous regions, and line the NPC. A central feature of NPC-mediated transport is the binding of cargo-carrying soluble transport factors to the unstructured regions of FG nups. Here, we model the dynamics of nucleocytoplasmic transport as diffusion in an effective potential resulting from the interaction of the transport factors with the flexible FG nups, using a minimal number of assumptions consistent with the most well-established structural and functional properties of NPC transport. We discuss how specific binding of transport factors to the FG nups facilitates transport, and how this binding and competition between transport factors and other macromolecules for binding sites and space inside the NPC accounts for the high selectivity of transport. We also account for why transport is relatively insensitive to changes in the number and distribution of FG nups in the NPC, providing an explanation for recent experiments where up to half the total mass of the FG nups has been deleted without abolishing transport. Our results suggest strategies for the creation of artificial nanomolecular sorting devices.     

TSAR,a new graph–theoretical approach to computational modeling of protein side‐chain flexibility: Modeling of ionization properties of proteins

A new graph–theoretical approach called thermodynamic sampling of amino acid residues (TSAR) has been elaborated to explicitly account for the protein side chain flexibility in modeling conformation‐dependent protein properties. In TSAR, a protein is viewed as a graph whose nodes correspond to structurally independent groups and whose edges connect the interacting groups. Each node has its set of states describing conformation and ionization of the group, and each edge is assigned an array of pairwise interaction potentials between the adjacent groups. By treating the obtained graph as a belief‐network—a well‐established mathematical abstraction—the partition function of each node is found. In the current work we used TSAR to calculate partition functions of the ionized forms of protein residues. A simplified version of a semi‐empirical molecular mechanical scoring function, borrowed from our Lead Finder docking software, was used for energy calculations. The accuracy of the resulting model was validated on a set of 486 experimentally determined pK_a values of protein residues. The average correlation coefficient (R) between calculated and experimental pK_a values was 0.80, ranging from 0.95 (for Tyr) to 0.61 (for Lys). It appeared that the hydrogen bond interactions and the exhaustiveness of side chain sampling made the most significant contribution to the accuracy of pK_a calculations. Proteins 2011; © 2011 Wiley‐Liss, Inc.     

Functional impacts of non-synonymous single nucleotide polymorphisms: selective constraint and structural environments

In this work, we studied the correlations between selective constraint, structural environments and functional impacts of non-synonymous single nucleotide polymorphisms (nsSNPs). We found that the relation between solvent accessibility and functional impacts of nsSNPs is not as simple as generally thought. Finer structural classifications need to be taken into account to reveal the complex relations between the characteristics of a structure environment and its influence on the functional impacts of nsSNPs. We introduced two parameters for each structural environment, consensus residue percentage and residue distribution distance, to characterize the selective constraint imposed by the environment. Both parameters significantly correlate with the functional bias of nsSNPs across the structural environments. This result shows that selective constraint underlies the bias of a structural environment towards a certain type of nsSNPs (disease-associated or benign).     

Comparative homology modeling of pyruvate dehydrogenase kinase isozymes from Xenopus tropicalis reveals structural basis for their subfunctionalization

Structural-functional divergence is responsible for the preservation of highly homologous genes. Protein functions affected by mutagenesis in divergent sequences require investigation on an individual basis. In the present study, comparative homology modeling and predictive bioinformatics analysis were used to reveal for the first time the subfunctionalization of two pyruvate dehydrogenase kinase (PDK) isozymes in the western clawed frog Xenopus tropicalis. Three-dimensional structures of the two proteins were built by homology modeling based on the crystal structures of mammalian PDKs. A detailed comparison of them revealed important structural differences that modify the accessibility of the nucleotide binding site in the two isozymes. Based on the generated models and bioinformatics data analysis, the differences between the two proteins in terms of kinetic parameters, metabolic regulation, and tissue distribution are predicted. The results obtained are consistent with the idea that one of the xtPDKs is the major isozyme responsible for metabolic control of PDC activity in X. tropicalis, whereas the other one has more specialized functions. Hence, this study provides a rationale for the existence of two closely related PDK isozymes in X. tropicalis, thereby enhancing our understanding of the functional evolution of PDK family genes.     

Effectiveness of flexible routing control

Flexibility in part process representation and in highly adaptive routing algorithms are two major sources for improvement in the control of flexible manufacturing systems (FMSs). This article reports the investigation of the impact of these two kinds of flexibilities on the performance of the system. We argue that, when feasible, the choices of operations and sequencing of the part process plans should be deferred until detailed knowledge about the real-time factory state is available. To test our ideas, a flexible routing control simulation system (FRCS) was constructed and a programming language for modeling FMS part process plans, control strategies, and environments of the FMS was designed and implemented. In addition, a scheme for implementing flexible process routing called data flow dispatching rule (DFDR) was derived. The simulation results indicate that flexible processing can reduce mean flow time while increasing system throughput and machine utilization. We observed that this form of flexibility makes automatic load balancing of the machines possible. On the other hand, it also makes the control and scheduling process more complicated and calls for new control algorithms.     

Modeling FMS with decision Petri nets

Decision point extended timed Petri nets or decision Petri nets (DPN) are introduced as an extended modeling framework for FMS performance evaluation. The decision point extension allows the explicit modeling of the control of the flow of tokens in timed Petri nets and hence represents the control of the flow of material, resources, and information in FMS. Further, the concept of a bounded transition is proposed to conveniently model the blocking logic in an FMS with limited buffer capacities. The motivation to present these conventions is to develop a user-friendly graphic model to represent FMS designs for analysis by discrete event simulation. DPN affords concise models that can be conveniently developed and easily transformed into discrete event simulation models. With the help of a simple FMS example, which includes a number of part types, loading rules, dispatching rules, and probabilistic branching (at an inspection station), we illustrate the DPN model development. As an illustration of the ease with which it can be tranformed into a simulation model, we have developed a generalized simulator called ROBSIM and outline here its methodological basis. The proposed concepts should be of interest to users of discrete event simulation in FMS design or elsewhere to tap the potential of basic Petri net concepts for graphic representation and specification purposes. In particular, our work should encourage other researchers to develop extensions relevant to their own areas of interest.     

The Application of Enterprise Modeling for Aerospace Manufacturing System Integration

The objective of enterprise modeling is to develop a repository regarding organizational elements and functions that maps information objectives with business functions. This is accomplished through an exhaustive process that analyzes and models the business to a level of detail sufficient to enable selection of appropriate technologies and the design of specific information systems. In this paper, enterprise modeling is utilized to provide a baseline reference for the successful integration of an FMS in an aerospace electronics manufacturing facility.     

simBio: a Java package for the development of detailed cell models

Quantitative dynamic computer models, which integrate a variety of molecular functions into a cell model, provide a powerful tool to create and test working hypotheses. We have developed a new modeling tool, the simBio package (freely available from http://www.sim-bio.org/), which can be used for constructing cell models, such as cardiac cells (the Kyoto model from Matsuoka et al., 2003, 2004a, b, the LRd model from Faber and Rudy, 2000, and the Noble 98 model from Noble et al., 1998), epithelial cells (Strieter et al., 1990) and pancreatic β cells (Magnus and Keizer, 1998). The simBio package is written in Java, uses XML and can solve ordinary differential equations. In an attempt to mimic biological functional structures, a cell model is, in simBio, composed of independent functional modules called Reactors, such as ion channels and the sarcoplasmic reticulum, and dynamic variables called Nodes, such as ion concentrations. The interactions between Reactors and Nodes are described by the graph theory and the resulting graph represents a blueprint of an intricate cellular system. Reactors are prepared in a hierarchical order, in analogy to the biological classification. Each Reactor can be composed or improved independently, and can easily be reused for different models. This way of building models, through the combination of various modules, is enabled through the use of object-oriented programming concepts. Thus, simBio is a straightforward system for the creation of a variety of cell models on a common database of functional modules.     

Rapid evolution exposes the boundaries of domain structure and function in natively unfolded FG nucleoporins

Nucleoporins with phenylalanine-glycine repeats (FG Nups) function at the nuclear pore complex (NPC) to facilitate nucleocytoplasmic transport. In Saccharomyces cerevisiae, each FG Nup contains a large natively unfolded domain that is punctuated by FG repeats. These FG repeats are surrounded by hydrophilic amino acids (AAs) common to disordered protein domains. Here we show that the FG domain of Nups from human, fly, worm, and other yeast species is also enriched in these disorder-associated AAs, indicating that structural disorder is a conserved feature of FG Nups and likely serves an important role in NPC function. Despite the conservation of AA composition, FG Nup sequences from different species show extensive divergence. A comparison of the AA substitution rates of proteins with syntenic orthologs in four Saccharomyces species revealed that FG Nups have evolved at twice the rate of average yeast proteins with most substitutions occurring in sequences between FG repeats. The rapid evolution of FG Nups is poorly explained by parameters known to influence AA substitution rate, such as protein expression level, interactivity, and essentiality; instead their rapid evolution may reflect an intrinsic permissiveness of natively unfolded structures to AA substitutions. The overall lack of AA sequence conservation in FG Nups is sharply contrasted by discrete stretches of conserved sequences. These conserved sequences highlight known karyopherin and nucleoporin binding sites as well as other uncharacterized sites that may have important structural and functional properties.     

Probing mechanisms for enzymatic activity enhancement of organophosphorus hydrolase in functionalized mesoporous silica

We have previously reported that organophosphorus hydrolase (OPH) can be spontaneously entrapped in functionalized mesoporous silica (FMS) with HOOC- as the functional groups and the entrapped OPH in HOOC-FMS showed enhanced enzyme specific activity. This work is to study the mechanisms that why OPH entrapped in FMS displayed the enhanced activity in views of OPH-FMS interactions using spectroscopic methods. The circular dichroism (CD) spectra show that, comparing to the secondary structure of OPH free in solution, OPH in HOOC-FMS displayed increased α-helix/β-strand transition of OPH with increased OPH loading density. The fluorescence emission spectra of Trp residues were used to assess the tertiary structural changes of the enzyme. There was a 42% increase in fluorescence. This is in agreement with the fact that the fluorescence intensity of OPH was increased accompanying with the increased OPH activity when decreasing urea concentrations in solution. The steady-state anisotropy was increased after OPH entrapping in HOOC-FMS comparing to the free OPH in solution, indicating that protein mobility was reduced upon entrapment. The solvent accessibility of Trp residues of OPH was probed by using acrylamide as a collisional quencher. Trp residues of OPH-FMS had less solvent exposure comparing with free OPH in solution due to its electrostatical binding to HOOC-FMS thereby displaying the increased fluorescence intensity. These results suggest the interactions of OPH with HOOC-FMS resulted in the protein immobilization and a favorable conformational change for OPH in the crowded confinement space and accordingly the enhanced activity.     

The FEATURE framework for protein function annotation: modeling new functions,improving performance,and extending to novel applications

Structural genomics efforts contribute new protein structures that often lack significant sequence and fold similarity to known proteins. Traditional sequence and structure-based methods may not be sufficient to annotate the molecular functions of these structures. Techniques that combine structural and functional modeling can be valuable for functional annotation. FEATURE is a flexible framework for modeling and recognition of functional sites in macromolecular structures. Here, we present an overview of the main components of the FEATURE framework, and describe the recent developments in its use. These include automating training sets selection to increase functional coverage, coupling FEATURE to structural diversity generating methods such as molecular dynamics simulations and loop modeling methods to improve performance, and using FEATURE in large-scale modeling and structure determination efforts.     

Structural and Functional Analysis of Multi-Interface Domains

A multi-interface domain is a domain that can shape multiple and distinctive binding sites to contact with many other domains, forming a hub in domain-domain interaction networks. The functions played by the multiple interfaces are usually different, but there is no strict bijection between the functions and interfaces as some subsets of the interfaces play the same function. This work applies graph theory and algorithms to discover fingerprints for the multiple interfaces of a domain and to establish associations between the interfaces and functions, based on a huge set of multi-interface proteins from PDB. We found that about 40% of proteins have the multi-interface property, however the involved multi-interface domains account for only a tiny fraction (1.8%) of the total number of domains. The interfaces of these domains are distinguishable in terms of their fingerprints, indicating the functional specificity of the multiple interfaces in a domain. Furthermore, we observed that both cooperative and distinctive structural patterns, which will be useful for protein engineering, exist in the multiple interfaces of a domain.     

Intramolecular cohesion of coils mediated by phenylalanine--glycine motifs in the natively unfolded domain of a nucleoporin

The nuclear pore complex (NPC) provides the sole aqueous conduit for macromolecular exchange between the nucleus and the cytoplasm of cells. Its diffusion conduit contains a size-selective gate formed by a family of NPC proteins that feature large, natively unfolded domains with phenylalanine-glycine repeats (FG domains). These domains of nucleoporins play key roles in establishing the NPC permeability barrier, but little is known about their dynamic structure. Here we used molecular modeling and biophysical techniques to characterize the dynamic ensemble of structures of a representative FG domain from the yeast nucleoporin Nup116. The results showed that its FG motifs function as intramolecular cohesion elements that impart order to the FG domain and compact its ensemble of structures into native premolten globular configurations. At the NPC, the FG motifs of nucleoporins may exert this cohesive effect intermolecularly as well as intramolecularly to form a malleable yet cohesive quaternary structure composed of highly flexible polypeptide chains. Dynamic shifts in the equilibrium or competition between intra- and intermolecular FG motif interactions could facilitate the rapid and reversible structural transitions at the NPC conduit needed to accommodate passing karyopherin-cargo complexes of various shapes and sizes while simultaneously maintaining a size-selective gate against protein diffusion.     

An Object-Oriented Approach for Flexible Manufacturing Control Systems Analysis and Design Using the Unified Modeling Language

In reacting to global competition and rapidly changing customer demands, industrial business organizations have developed a strong interest in flexible automation. The aim of flexible automation focuses on achieving agility in handling uncertainties from internal or external environments. Modeling complex structures, promoting reuse, and shortening the development time cycle are particularly significant aspects in the analysis and design of CIM systems, where heterogeneous elements have to be integrated in a complex control architecture. The design methodology for FMS control software involves the abstraction of an FMS and the estimation of the system performances. The aim of this activity is to suggest the optimal configuration of an FMS for given specifications, through simulation tools. In the software engineering field, object-oriented (OO) approaches have proven to be a powerful technique with respect to such aspects. The unified modeling language (UML), by using OO design methodologies, can offer reusability, extendibility, and modifiability in software design. Also, it bridges the gap that exists between the OO analysis and design area and the area of OO programming by creating an integrative metamodel of OO concepts. The specific goal of this paper is to formulate a new methodology for developing reusable, extendible, and modifiable control software for an FMS in an object-oriented environment. It is demonstrated that, with few diagrams, UML can be used to model such systems without being associated with other modeling tools.     

Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor

TAP-p15 heterodimers have been implicated in the export of mRNAs through nuclear pore complexes (NPCs). We report a structural analysis of the interaction domains of TAP and p15 in a ternary complex with a Phe-Gly (FG) repeat of an NPC component. The TAP-p15 heterodimer is structurally similar to the homodimeric transport factor NTF2, but unlike NTF2, it is incompatible with either homodimerization or Ran binding. The NTF2-like heterodimer functions as a single structural unit in recognizing an FG repeat at a hydrophobic pocket present only on TAP and not on p15. This FG binding site interacts synergistically with a second site at the C terminus of TAP to mediate mRNA transport through the pore. In general, our findings suggest that FG repeats bind with a similar conformation to different classes of transport factors.