Immunoglobulin 1 (IgG1) Fc-glycosylation profiling of anti-citrullinated peptide antibodies from human serum

In several autoimmune disorders, including rheumatoid arthritis (RA), autoantibodies are thought to be the driving force of pathogenicity. Glycosylation of the Fc-part of human Igs is known to modulate biological activity. Hitherto, glycosylation of human IgG-Fc has been analyzed predominantly at the level of total serum IgG, revealing reduced galactosylation in RA. Given the pathogenic relevance of autoantibodies in RA, we wished, in the present study, to address the question whether distinct Fc-glycosylation features are observable at the level of antigen-specific IgG subpopulations. For this purpose, we have developed a method for the microscale purification and Fc-glycosylation analysis of anti-citrullinated peptide antibodies (ACPA). ACPA represent a group of autoantibodies that occur with unique specificity in RA patients. Their presence is associated with increased inflammatory disease activity and rapid joint destruction. Results indicate that ACPA of the IgG1 subclass vary considerably from total serum IgG1 with respect to Fc-galactosylation, with galactosylation being higher on ACPA than on serum IgG1 for some patients, while other patients show higher galactosylation on serum IgG1 than on ACPA. Using this method, studies can be performed on the biological and clinical relevance of ACPA glycosylation within RA patient cohorts.     

An element-based formulation for ES-FEM and FS-FEM models for implementation in standard solid mechanics finite element codes for 2D and 3D static analysis

Edge-based and face-based smoothed finite element methods (ES-FEM and FS-FEM, respectively) are modified versions of the finite element method allowing to achieve more accurate results and to reduce sensitivity to mesh distortion, at least for linear elements. These properties make the two methods very attractive. However, their implementation in a standard finite element code is nontrivial because it requires heavy and extensive modifications to the code architecture. In this article, we present an element-based formulation of ES-FEM and FS-FEM methods allowing to implement the two methods in a standard finite element code with no modifications to its architecture. Moreover, the element-based formulation permits to easily manage any type of element, especially in 3D models where, to the best of the authors' knowledge, only tetrahedral elements are used in FS-FEM applications found in the literature. Shape functions for non-simplex 3D elements are proposed in order to apply FS-FEM to any standard finite element.     

The levels of memory (CD45RA-, RO+) CD4+ and CD8+ peripheral blood T-lymphocytes correlate with IgM rheumatoid factors in rheumatoid arthritis

We investigated whether, in rheumatoid arthritis (RA), the CD45 isoform expression of peripheral blood T-lymphocytes (T-PBL) is related to auto-immune processes (e.g. IgM rheumatoid factors) and to clinical manifestations. By three-colour flow cytometry, we quantified three subsets of CD4+ or CD8+ T-PBL: "naive" CD45RA+,RO-, "transient" CD45RA+,RO+, and "memory" CD45RA-,RO+ cells, in 102 patients with RA and in 41 age- and sex-matched controls. The serum levels of rheumatoid factors (RF) were determined--besides conventional agglutination tests--by ELISA (IgM-RF). Extensive clinical examination was performed at the time of blood sampling. In RA, age, sex and drug therapy did not constitute major influences on the CD45RA/RO patterns. In "healthy" men, higher age significantly' correlated with fewer naive and more memory CD4+ T-PBL (P < 0.01). In RA, distinct correlations between the T-PBL subsets, autoimmune and clinical manifestations became obvious when patients with low and high levels of RF against human IgG Fc fragments, as determined by ELISA, were analysed separately. RA patients with high IgM-RF had elevated proportions of CD45RO+ T-PBL (P < 0.05), that correlated with clinical parameters of disease activity (tender joint count, Ritchie index, P < 0.05) and outcome (Health Assessment Questionnaire, Larsen radiographic scores, P < 0.05). The proportions of memory CD4+ and CD8+ T-PBL correlated strongly (P < 0.001) with the IgM-RF levels. Within 1 year, only three of 34 patients (disease duration of 5-9 years) showed seroconversion from low to high levels of IgM-RF (and positive agglutination tests); this was paralleled by reductions in naive and increases in transient T-PBL (P < 0.02). Thus, in RA, the proportions of memory CD4+ and CD8+ T-PBL correlate with the level of IgM-RF and, together with transient T-PBL, with clinical parameters of disease activity and outcome.     

Modelling and analysis of the dynamics of a tilting three-wheeled vehicle

To understand the handling behaviour of a three-wheeled tilting vehicle, models of the vehicle with different level of detail, corresponding to specific fields of investigation, have been developed. Then the proposed kinematics of the three-wheeler are assessed and optimized with respect to desired dynamic properties by applying a detailed multibody system model. The partially unstable nature of the motion of the vehicle suggests the application of an analytically derived, simplified model, to allow for focusing on stability aspects and steady-state handling properties. These investigations reveal the necessity of employing a steer-by-wire control system to support the driver by stabilizing the motion of the vehicle. Thus, an additional basic vehicle model is derived for control design, and an energy-efficient control strategy is presented. Numerical simulation results demonstrate the dynamic properties of the optimized kinematics and the control system, approved by successful test runs of a prototype.     

Simulation process of flexible multibody systems with non-modal model order reduction techniques

One important issue for the simulation of flexible multibody systems is the reduction of the flexible body’s degrees of freedom. In this work, nonmodal model reduction techniques for flexible multibody systems within the floating frame of reference framework are considered. While traditionally in the multibody community modal techniques in many different forms are used, here other methods from system dynamics and mathematics are in the focus. For the reduction process, finite element data and user inputs are necessary. Prior to the reduction process, the user first needs to choose boundary conditions fitting the chosen reference frame before defining the appropriate in- and outputs. In this work, four different possibilities of modeling appropriate interface points to reduce the number of inputs and outputs are presented.     

On generic context lemmas for higher-order calculi with sharing

This paper proves several generic variants of context lemmas and thus contributes to improving the tools for observational semantics of deterministic and non-deterministic higher-order calculi that use a small-step reduction semantics. The generic (sharing) context lemmas are provided for may- as well as two variants of must-convergence, which hold in a broad class of extended process- and extended lambda calculi, if the calculi satisfy certain natural conditions. As a guide-line, the proofs of the context lemmas are valid in call-by-need calculi, in call-by-value calculi if substitution is restricted to variable-by-variable and in process calculi like variants of the $\pi$-calculus. For calculi employing beta-reduction using a call-by-name or call-by-value strategy or similar reduction rules, some iu-variants of ciu-theorems are obtained from our context lemmas. Our results reestablish several context lemmas already proved in the literature, and also provide some new context lemmas as well as some new variants of the ciu-theorem. To make the results widely applicable, we use a higher-order abstract syntax that allows untyped calculi as well as certain simple typing schemes. The approach may lead to a unifying view of higher-order calculi, reduction, and observational equality.     

The effect of the microfluidic diodicity on the efficiency of valve-less rectification micropumps using Lattice Boltzmann Method

The efficiency of the valve-less rectification micropump depends primarily on the microfluidic diodicity (the ratio of the backward pressure drop to the forward pressure drop). In this study, different rectifying structures, including the conventional structures (nozzle/diffuser and Tesla structures), were investigated at very low Reynolds numbers (between 0.2 and 60). The rectifying structures were characterized with respect to their design, and a numerical approach was illustrated to calculate the diodicity for the rectifying structures. In this study, the microfluidic diodicity was evaluated numerically for different rectifying structures including half circle, semicircle, heart, triangle, bifurcation, nozzle/diffuser, and Tesla structures. The Lattice Boltzmann Method (LBM) was utilized as a numerical method to simulate the fluid flow in the microscale. The results suggest that at very low Reynolds number flow, rectification and multifunction micropumping may be achievable by using a number of the presented structures. The results for the conventional structures agree with the reported results.