A Hybrid Boundary Element Method for Elliptic Problems with Singularities

The singularities that arise in elliptic boundary value problems are treated locally by a singular function boundary integral method. This method extracts the leading singular coefficients from a series expansion that describes the local behavior of the singularity. The method is fitted into the framework of the widely used boundary element method (BEM), forming a hybrid technique, with the BEM computing the solution away from the singularity. Results of the hybrid technique are reported for the Motz problem and compared with the results of the standalone BEM and Galerkin/finite element method (GFEM). The comparison is made in terms of the total flux (i.e. the capacitance in the case of electrostatic problems) on the Dirichlet boundary adjacent to the singularity, which is essentially the integral of the normal derivative of the solution. The hybrid method manages to reduce the error in the computed capacitance by a factor of 10, with respect to the BEM and GFEM

Advanced computational tools to enhance continuous monoclonal antibody production

Leading pharmaceutical companies invest high percentage of their revenue in the improvement of existing technologies used for the production of monoclonal antibodies (mAbs). Recently, there has been a paradigm shift towards the development of continuous/quasi-continuous purification operations, aiming to reduce capital and operational costs [1]. At the moment, however, there are no standardized methods and/or tools that can be used for global control and monitoring of integrated processes. Mathematical models and advanced computational tools can be the key for the development of robust, integrated processes, as they can provide valuable insight in the process dynamics and ensure optimal operation [2]. However, such processes are usually characterized by complex mathematical models and periodic operation profiles that result into computationally expensive solutions and challenge the development of global control methods and tools. In this work, we are presenting a novel approach for the development of advanced controllers towards the intensification of mAb production, considering the fed-batch culturing of GS-NS0 cells and the semi-continuous Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) process [3]. The controller development is realized via the application of a generic framework for the development of advanced control strategies (PAROC) [4] that involves: (i) development of a high-fidelity process model, (ii) approximation of the complex, process model, (iii) design of the multi-parametric controller, (iv) ‘closed-loop’, in-silico validation of the controller against the process model. The development of the control policies is based on multi-parametric Model Predictive Control (mp-MPC) policies that reduce the online, computational force of the controller by deriving the control inputs as a set of explicit functions of the system states and can be implemented on embedded devices [5]. One of the main advantages of the proposed framework is the ability to test the controllers ‘in-silico’, against the high-fidelity process model and evaluate their performance before operating them online. The results from this study indicate that optimal operation, under maximum purity and productivity yield can be ensured with the development of advanced computational tools. The control policies are applied both in the upstream and the downstream processing; yielding therefore a fertile ground towards the development of a global control strategy that can ensure continuous operation

Patients with early rheumatoid arthritis exhibit elevated autoantibody titers against mildly oxidized low-density lipoprotein and exhibit decreased activity of the lipoprotein-associated phospholipase A(2)

Rheumatoid arthritis is a chronic inflammatory disease, associated with an excess of cardiovascular morbidity and mortality due to accelerated atherosclerosis. Oxidized low-density lipoprotein (oxLDL), the antibodies against oxLDL and the lipoprotein-associated phospholipase A(2 )(Lp-PLA(2)) may play important roles in inflammation and atherosclerosis. We investigated the plasma levels of oxLDL and Lp-PLA(2 )activity as well as the autoantibody titers against mildly oxLDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined. Fifty-eight ERA patients who met the American College of Rheumatology criteria were included in the study. Patients were treated with methotrexate and prednisone. Sixty-three apparently healthy volunteers also participated in the study and served as controls. Three different types of mildly oxLDL were prepared at the end of the lag, propagation and decomposition phases of oxidation. The serum autoantibody titers of the IgG type against all types of oxLDL were determined by an ELISA method. The plasma levels of oxLDL and the Lp-PLA(2 )activity were determined by an ELISA method and by the trichloroacetic acid precipitation procedure, respectively. At baseline, ERA patients exhibited elevated autoantibody titers against all types of mildly oxLDL as well as low activity of the total plasma Lp-PLA(2 )and the Lp-PLA(2 )associated with the high-density lipoprotein, compared with controls. Multivariate regression analysis showed that the elevated autoantibody titers towards oxLDL at the end of the decomposition phase of oxidation and the low plasma Lp-PLA(2 )activity are independently associated with ERA. After immunointervention autoantibody titers against all types of oxLDL were decreased in parallel to the increase in high-density lipoprotein-cholesterol and high-density lipoprotein-Lp-PLA(2 )activity. We conclude that elevated autoantibody titers against oxLDL at the end of the decomposition phase of oxidation and low plasma Lp-PLA(2 )activity are feature characteristics of patients with ERA, suggesting an important role of these parameters in the pathophysiology of ERA as well as in the accelerated atherosclerosis observed in these patients