Quality Control in the Secretory Pathway: The Role of Calreticulin, Calnexin and BiP in the Retention of Glycoproteins with C-Terminal Truncations

Unlike properly folded and assembled proteins, most misfolded and incompletely assembled proteins are retained in the endoplasmic reticulum of mammalian cells and degraded without transport to the Golgi complex. To analyze the mechanisms underlying this unique sorting process and its fidelity, the fate of C-terminally truncated fragments of influenza hemagglutinin was determined. An assortment of different fragments was generated by adding puromycin at low concentrations to influenza virus-infected tissue culture cells. Of the fragments generated, <2% was secreted, indicating that the system for detecting defects in newly synthesized proteins is quite stringent. The majority of secreted species corresponded to folding domains within the viral spike glycoprotein. The retained fragments acquired a partially folded structure with intrachain disulfide bonds and conformation-dependent antigenic epitopes. They associated with two lectin-like endoplasmic reticulum chaperones (calnexin and calreticulin) but not BiP/GRP78. Inhibition of the association with calnexin and calreticulin by the addition of castanospermine significantly increased fragment secretion. However, it also caused association with BiP/GRP78. These results indicated that the association with calnexin and calreticulin was involved in retaining the fragments. They also suggested that BiP/GRP78 could serve as a backup for calnexin and calreticulin in retaining the fragments. In summary, the results showed that the quality control system in the secretory pathway was efficient and sensitive to folding defects, and that it involved multiple interactions with endoplasmic reticulum chaperones.

Mitigação de falhas críticas em sistemas produtivos.

O cenário competitivo e globalizado em que as empresas estão inseridas, sobretudo a partir do século XXI, associados a ciclos de vida cada vez menores dos produtos, rigorosos requisitos de qualidade, além de políticas de preservação do meio ambiente, com redução de consumo energético e de recursos hídricos, somadas às exigências legais de melhores condições de trabalho, resultaram em uma quebra de paradigma nos processos produtivos até então concebidos. Como solução a este novo cenário produtivo pode-se citar o extenso uso da automação industrial, fato que resultou em sistemas cada vez mais complexos, tanto do ponto de vista estrutural, em função do elevado número de componentes, quanto da complexidade dos sistemas de controle. A previsibilidade de todos os estados possíveis do sistema torna-se praticamente impossível. Dentre os estados possíveis pode-se citar os estados de falha que, dependendo da severidade do efeito associado à sua ocorrência, podem resultar em sérios danos para o homem, o meio ambiente e às próprias instalações, caso não sejam corretamente diagnosticados e tratados. Fatos recentes de catástrofes relacionadas à sistemas produtivos revelam a necessidade de se implementar medidas para prevenir e para mitigar os efeitos da ocorrência de falhas, com o objetivo de se evitar a ocorrência de catástrofes. De acordo com especialistas, os Sistemas Instrumentados de Segurança SIS, referenciados em normas como a IEC 61508 e IEC 61511, são uma solução para este tipo de problema. Trabalhos publicados tratam de métodos para a implementação de camadas SIS de prevenção, porém com escassez de trabalhos para camadas SIS de mitigação. Em função do desconhecimento da dinâmica do sistema em estado de falha, técnicas tradicionais de modelagem tornam-se inviáveis. Neste caso, o uso de inteligência artificial, como por exemplo a lógica fuzzy, pode se tornar uma solução para o desenvolvimento do algoritmo de controle, associadas a ferramentas de edição, modelagem e geração dos códigos de controle. A proposta deste trabalho é apresentar uma sistemática para a implementação de um sistema de controle para a mitigação de falhas críticas em sistemas produtivos, com referência às normas IEC 61508/61511, com ação antecipativa à ocorrência de catástrofes.

Dynamic Visual Servoing With Chaos Control for Redundant Robots

This paper presents a new dynamic visual control system for redundant robots with chaos compensation. In order to implement the visual servoing system, a new architecture is proposed that improves the system maintainability and traceability. Furthermore, high performance is obtained as a result of parallel execution of the different tasks that compose the architecture. The control component of the architecture implements a new visual servoing technique for resolving the redundancy at the acceleration level in order to guarantee the correct motion of both end-effector and joints. The controller generates the required torques for the tracking of image trajectories. However, in order to guarantee the applicability of this technique, a repetitive path tracked by the robot-end must produce a periodic joint motion. A chaos controller is integrated in the visual servoing system and the correct performance is observed in low and high velocities. Furthermore, a method to adjust the chaos controller is proposed and validated using a real three-link robot.

Robust multivariable control of complex biological processes

This paper addresses advanced control of a biological nutrient removal (BNR) activated sludge process. Based on a previously validated distributed parameter model of the BNR activated sludge process, we present robust multivariable controller designs for the process, involving loop shaping of plant model, robust stability and performance analyses. Results from three design case studies showed that a multivariable controller with stability margins of 0.163, 0.492 and 1.062 measured by the normalised coprime factor, multiplicative and additive uncertainties respectively give the best results for meeting performance robustness specifications. The controller robustly stabilises effluent nutrients in the presence of uncertainties with the behaviour of phosphorus accumulating organisms as well as to effectively attenuate major disturbances introduced as step changes. This study also shows that, performance of the multivariable robust controller is superior to multi-loops SISO PI controllers for regulating the BNR activated sludge process in terms of robust stability and performance and controlling the process using inlet feed flowrate is infeasible. (C) 2003 Elsevier Ltd. All rights reserved.

Genetic algorithm-based spinning reserve dispatching in a competitive electricity market

Power systems rely greatly on ancillary services in maintaining operation security. As one of the most important ancillary services, spinning reserve must be provided effectively in the deregulated market environment. This paper focuses on the design of an integrated market for both electricity and spinning reserve service with particular emphasis on coordinated dispatch of bulk power and spinning reserve services. A new market dispatching mechanism has been developed to minimize the ISO's total payment while ensuring system security. Genetic algorithms are used in the finding of the global optimal solutions for this dispatching problem. Case studies and corresponding analyses haw been carried out to demonstrate and discuss the efficiency and usefulness of the proposed market.

Multivariate monitoring of a biological wastewater treatment process: a case study at Melbourne Water's Western Treatment Plant

Biological wastewater treatment is a complex, multivariate process, in which a number of physical and biological processes occur simultaneously. In this study, principal component analysis (PCA) and parallel factor analysis (PARAFAC) were used to profile and characterise Lagoon 115E, a multistage biological lagoon treatment system at Melbourne Water's Western Treatment Plant (WTP) in Melbourne, Australia. In this study, the objective was to increase our understanding of the multivariate processes taking place in the lagoon. The data used in the study span a 7-year period during which samples were collected as often as weekly from the ponds of Lagoon 115E and subjected to analysis. The resulting database, involving 19 chemical and physical variables, was studied using the multivariate data analysis methods PCA and PARAFAC. With these methods, alterations in the state of the wastewater due to intrinsic and extrinsic factors could be discerned. The methods were effective in illustrating and visually representing the complex purification stages and cyclic changes occurring along the lagoon system. The two methods proved complementary, with each having its own beneficial features. (C) 2003 Elsevier B.V. All rights reserved.

On stability in nonsequential MIMO QFT designs

This paper reexamines the stability of uncertain closed-loop systems resulting from the nonsequential (NS) MIMO QFT design methodology. By combining the effect of satisfying both the robust stability and robust performance specifications in a NS MIMO QFT design, a proof for the stability of the uncertain closed-loop system is derived. The stability theorem proves that, subject to the satisfaction of a critical necessary and sufficient condition, the original NS MIMO QFT design methodology will provide a robustly stable closed-loop system. This necessary and sufficient condition provides a useful existence test for a successful NS MIMO QFT design. The results expose the salient features of the NS MIMO QFT design methodology. Two 2 x 2 MIMO design examples are presented to illustrate the key features of the stability, theorem.

Identification of MIMO Hammerstein systems using cardinal spline functions

A new approach to identify multivariable Hammerstein systems is proposed in this paper. By using cardinal cubic spline functions to model the static nonlinearities, the proposed method is effective in modelling processes with hard and/or coupled nonlinearities. With an appropriate transformation, the nonlinear models are parameterized such that the nonlinear identification problem is converted into a linear one. The persistently exciting condition for the transformed input is derived to ensure the estimates are consistent with the true system. A simulation study is performed to demonstrate the effectiveness of the proposed method compared with the existing approaches based on polynomials. (C) 2006 Elsevier Ltd. All rights reserved.

Fitness assessment of document model

Document classification is a supervised machine learning process, where predefined category labels are assigned to documents based on the hypothesis derived from training set of labelled documents. Documents cannot be directly interpreted by a computer system unless they have been modelled as a collection of computable features. Rogati and Yang [M. Rogati and Y. Yang, Resource selection for domain-specific cross-lingual IR, in SIGIR 2004: Proceedings of the 27th annual international conference on Research and Development in Information Retrieval, ACM Press, Sheffied: United Kingdom, pp. 154-161.] pointed out that the effectiveness of document classification system may vary in different domains. This implies that the quality of document model contributes to the effectiveness of document classification. Conventionally, model evaluation is accomplished by comparing the effectiveness scores of classifiers on model candidates. However, this kind of evaluation methods may encounter either under-fitting or over-fitting problems, because the effectiveness scores are restricted by the learning capacities of classifiers. We propose a model fitness evaluation method to determine whether a model is sufficient to distinguish positive and negative instances while still competent to provide satisfactory effectiveness with a small feature subset. Our experiments demonstrated how the fitness of models are assessed. The results of our work contribute to the researches of feature selection, dimensionality reduction and document classification.

Functional analysis of a real-time protocol for networked control systems

Traditional real-time control systems are tightly integrated into the industrial processes they govern. Now, however, there is increasing interest in networked control systems. These provide greater flexibility and cost savings by allowing real-time controllers to interact with industrial processes over existing communications networks. New data packet queuing protocols are currently being developed to enable precise real-time control over a network with variable propagation delays. We show how one such protocol was formally modelled using timed automata, and how model checking was used to reveal subtle aspects of the control system's dynamic behaviour.

Anisotropy-based robust performance analysis of finite horizon linear discrete time varying systems

We consider a problem of robust performance analysis of linear discrete time varying systems on a bounded time interval. The system is represented in the state-space form. It is driven by a random input disturbance with imprecisely known probability distribution; this distributional uncertainty is described in terms of entropy. The worst-case performance of the system is quantified by its a-anisotropic norm. Computing the anisotropic norm is reduced to solving a set of difference Riccati and Lyapunov equations and a special form equation.

Multi-robot control in highly dynamic, competitive environments

The control and coordination of multiple mobile robots is a challenging task; particularly in environments with multiple, rapidly moving obstacles and agents. This paper describes a robust approach to multi-robot control, where robustness is gained from competency at every layer of robot control. The layers are: (i) a central coordination system (MAPS), (ii) an action system (AES), (iii) a navigation module, and (iv) a low level dynamic motion control system. The multi-robot coordination system assigns each robot a role and a sub-goal. Each robot’s action execution system then assumes the assigned role and attempts to achieve the specified sub-goal. The robot’s navigation system directs the robot to specific goal locations while ensuring that the robot avoids any obstacles. The motion system maps the heading and speed information from the navigation system to force-constrained motion. This multi-robot system has been extensively tested and applied in the robot soccer domain using both centralized and distributed coordination.

Modelling and control of a hybrid stepping motor

The integration of a microprocessor and a medium power stepper motor in one control system brings together two quite different disciplines. Various methods of interfacing are examined and the problems involved in both hardware and software manipulation are investigated. Microprocessor open-loop control of the stepper motor is considered. The possible advantages of microprocessor closed-loop control are examined and the development of a system is detailed. The system uses position feedback to initiate each motor step. Results of the dynamic response of the system are presented and its performance discussed. Applications of the static torque characteristic of the stepper motor are considered followed by a review of methods of predicting the characteristic. This shows that accurate results are possible only when the effects of magnetic saturation are avoided or when the machine is available for magnetic circuit tests to be carried out. A new method of predicting the static torque characteristic is explained in detail. The method described uses the machine geometry and the magnetic characteristics of the iron types used in the machine. From this information the permeance of each iron component of the machine is calculated and by using the equivalent magnetic circuit of the machine, the total torque produced is predicted. It is shown how this new method is implemented on a digital computer and how the model may be used to investigate further aspects of the stepper motor in addition to the static torque.

A structural method for the design of fault tolerant distributed control systems

Distributed digital control systems provide alternatives to conventional, centralised digital control systems. Typically, a modern distributed control system will comprise a multi-processor or network of processors, a communications network, an associated set of sensors and actuators, and the systems and applications software. This thesis addresses the problem of how to design robust decentralised control systems, such as those used to control event-driven, real-time processes in time-critical environments. Emphasis is placed on studying the dynamical behaviour of a system and identifying ways of partitioning the system so that it may be controlled in a distributed manner. A structural partitioning technique is adopted which makes use of natural physical sub-processes in the system, which are then mapped into the software processes to control the system. However, communications are required between the processes because of the disjoint nature of the distributed (i.e. partitioned) state of the physical system. The structural partitioning technique, and recent developments in the theory of potential controllability and observability of a system, are the basis for the design of controllers. In particular, the method is used to derive a decentralised estimate of the state vector for a continuous-time system. The work is also extended to derive a distributed estimate for a discrete-time system. Emphasis is also given to the role of communications in the distributed control of processes and to the partitioning technique necessary to design distributed and decentralised systems with resilient structures. A method is presented for the systematic identification of necessary communications for distributed control. It is also shwon that the structural partitions can be used directly in the design of software fault tolerant concurrent controllers. In particular, the structural partition can be used to identify the boundary of the conversation which can be used to protect a specific part of the system. In addition, for certain classes of system, the partitions can be used to identify processes which may be dynamically reconfigured in the event of a fault. These methods should be of use in the design of robust distributed systems.

Mathematical modelling and control of agitated extraction columns

Liquid-liquid extraction has long been known as a unit operation that plays an important role in industry. This process is well known for its complexity and sensitivity to operation conditions. This thesis presents an attempt to explore the dynamics and control of this process using a systematic approach and state of the art control system design techniques. The process was studied first experimentally under carefully selected. operation conditions, which resembles the ranges employed practically under stable and efficient conditions. Data were collected at steady state conditions using adequate sampling techniques for the dispersed and continuous phases as well as during the transients of the column with the aid of a computer-based online data logging system and online concentration analysis. A stagewise single stage backflow model was improved to mimic the dynamic operation of the column. The developed model accounts for the variation in hydrodynamics, mass transfer, and physical properties throughout the length of the column. End effects were treated by addition of stages at the column entrances. Two parameters were incorporated in the model namely; mass transfer weight factor to correct for the assumption of no mass transfer in the. settling zones at each stage and the backmixing coefficients to handle the axial dispersion phenomena encountered in the course of column operation. The parameters were estimated by minimizing the differences between the experimental and the model predicted concentration profiles at steady state conditions using non-linear optimisation technique. The estimated values were then correlated as functions of operating parameters and were incorporated in·the model equations. The model equations comprise a stiff differential~algebraic system. This system was solved using the GEAR ODE solver. The calculated concentration profiles were compared to those experimentally measured. A very good agreement of the two profiles was achieved within a percent relative error of ±2.S%. The developed rigorous dynamic model of the extraction column was used to derive linear time-invariant reduced-order models that relate the input variables (agitator speed, solvent feed flowrate and concentration, feed concentration and flowrate) to the output variables (raffinate concentration and extract concentration) using the asymptotic method of system identification. The reduced-order models were shown to be accurate in capturing the dynamic behaviour of the process with a maximum modelling prediction error of I %. The simplicity and accuracy of the derived reduced-order models allow for control system design and analysis of such complicated processes. The extraction column is a typical multivariable process with agitator speed and solvent feed flowrate considered as manipulative variables; raffinate concentration and extract concentration as controlled variables and the feeds concentration and feed flowrate as disturbance variables. The control system design of the extraction process was tackled as multi-loop decentralised SISO (Single Input Single Output) as well as centralised MIMO (Multi-Input Multi-Output) system using both conventional and model-based control techniques such as IMC (Internal Model Control) and MPC (Model Predictive Control). Control performance of each control scheme was. studied in terms of stability, speed of response, sensitivity to modelling errors (robustness), setpoint tracking capabilities and load rejection. For decentralised control, multiple loops were assigned to pair.each manipulated variable with each controlled variable according to the interaction analysis and other pairing criteria such as relative gain array (RGA), singular value analysis (SVD). Loops namely Rotor speed-Raffinate concentration and Solvent flowrate Extract concentration showed weak interaction. Multivariable MPC has shown more effective performance compared to other conventional techniques since it accounts for loops interaction, time delays, and input-output variables constraints.