Decompositions of the stress and the rate of deformation tensors for materials undergoing phase transformations

An extension of the “Duhamel-Neumann hypothesis” for materials undergoing phase transformations and for arbitrary magnitudes of strains and rotations is provided

Regulation Of Immune Responses To Self And Nonself

B cells are regulated early upon exposure to antigen by negative Fc signals generated by the crosslinking of antigen receptors with Fc receptors which is mediated by antigen-IgG-antibody complexes. This negative end-product feedback can be overcome by T helper cells, but in their absence, agents which bind to the Fc portion of IgG can replace the need for T cell help. Rheumatoid factor (RF) is a naturally occurring antibody with specificity for IgG-Fc and was investigated for its ability to block negative Fc signals. Monoclonal murine RF was shown to reconstitute, in an antigen-specific and dose-dependent fashion, both the primary and secondary T-dependent antibody response of T cell-depleted murine spleen cell cultures. In order to see this effect, cultures had to be antigen stimulated and T cell depleted. Reconstitution by RF could be abrogated by the addition of non-specific, intact, murine IgG and not by F(ab\u27){dollar}\sb2{dollar} or IgM.;The dysregulation of autoimmune responses was also investigated. It was demonstrated that normal, nonautoimmune-prone mice generated spontaneous anti-ssDNA antibodies in vitro of higher avidity than autoimmune-prone mice as determined by plaque inhibition assay using free ssDNA. Addition of RF to spleen cell cultures of normal mice resulted in a decrease of the IgM-anti-ssDNA antibody avidity as measured by both plaque inhibition and competitive inhibition ELISA assays. These results and the presence, in vivo, of low levels of autoantibody from high avidity antibody-producing cells in normals and high levels from low avidity antibody-producing cells in autoimmune-prone mice indicate that negative Fc signalling plays a role in the resulting spectrum of antibody avidities and possibly of class by being a key control element in the IgM to IgG switch.;This thesis offers a novel role for RF as an Fc signal blocking agent, but more importantly, implicates end-product feedback by endogenously produced IgG as a key immunoregulatory mechanism during critical stages of B cell activation. Furthermore, inefficient negative Fc signal transmission may be the prime deregulating element leading to conditions conducive for the emergence of clinical autoimmunity

Missense mutations in the perforin (PRF1) gene as a cause of hereditary cancer predisposition

Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with a fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), in infants. More recently, it has also been recognized that partial loss of perforin function can cause disease in later life, including delayed onset FHL2 and haematological malignancies. Herein we report a family in which a wide range of systemic inflammatory and neoplastic manifestations have occurred across three generations. We found that disease was linked to two missense perforin gene mutations (encoding A91V, R410W) that cause protein misfolding and partial loss of activity. These cases link the partial loss of perforin function with some solid tumours that are known to be controlled by the immune system, as well as haematological cancers. Our findings also demonstrate that perforin gene mutations can contribute to hereditary cancer predisposition

On the quasi-yield surface concept in plasticity theory

In this paper we provide deeper insights into the concept of the quasi-yield surface in plasticity theory. More specifically, in this work, unlike the traditional treatments of plasticity where special emphasis is placed on an unambiguous definition of a yield criterion and the corresponding loading-unloading conditions, we place emphasis on the study of a general rate equation which is able to enforce elastic-plastic behavior. By means of this equation we discuss the fundamental concepts of the elastic range and the elastic domain. The particular case in which the elastic domain degenerates into its boundary leads to the quasi-yield surface concept. We exploit this concept further by discussing several theoretical issues related to it and by introducing a simple material model. The ability of the model in predicting several patterns of the real behavior of metals is assessed by representative numerical examples

A quantitative three-dimensional image analysis tool for maximal acquisition of spatial heterogeneity data

Three-dimensional (3D) imaging techniques provide spatial insight into environmental and cellular interactions and are implemented in various fields, including tissue engineering, but have been restricted by limited quantification tools that misrepresent or underutilize the cellular phenomena captured. This study develops image postprocessing algorithms pairing complex Euclidean metrics with Monte Carlo simulations to quantitatively assess cell and microenvironment spatial distributions while utilizing, for the first time, the entire 3D image captured. Although current methods only analyze a central fraction of presented confocal microscopy images, the proposed algorithms can utilize 210% more cells to calculate 3D spatial distributions that can span a 23-fold longer distance. These algorithms seek to leverage the high sample cost of 3D tissue imaging techniques by extracting maximal quantitative data throughout the captured image

An energy-based modelling tool for culture medium design and biomanufacturing optimization

Demand for high-value biologics, a rapidly growing pipeline, and pressure from competition, time-to-market and regulators, necessitate novel biomanufacturing approaches, including Quality by Design (QbD) principles and Process Analytical Technologies (PAT), to facilitate accelerated, efficient and effective process development platforms that ensure consistent product quality and reduced lot-to-lot variability. Herein, QbD and PAT principles were incorporated within an innovative in vitro-in silico integrated framework for upstream process development (UPD). The central component of the UPD framework is a mathematical model that predicts dynamic nutrient uptake and average intracellular ATP content, based on biochemical reaction networks, to quantify and characterize energy metabolism and its adaptive response, metabolic shifts, to maintain ATP homeostasis. The accuracy and flexibility of the model depends on critical cell type/product/clone-specific parameters, which are experimentally estimated. The integrated in vitro-in silico platform and the model’s predictive capacity reduced burden, time and expense of experimentation resulting in optimal medium design compared to commercially available culture media (80% amino acid reduction) and a fed-batch feeding strategy that increased productivity by 129%. The framework represents a flexible and efficient tool that transforms, improves and accelerates conventional process development in biomanufacturing with wide applications, including stem cell-based therapies

Key environmental stress biomarker candidates for the optimisation of chemotherapy treatment of leukaemia

The impact of fluctuations of environmental parameters such as oxygen and starvation on the evolution of leukaemia is analysed in the current review. These fluctuations may occur within a specific patient (in different organs) or across patients (individual cases of hypoglycaemia and hyperglycaemia). They can be experienced as stress stimuli by the cancerous population, leading to an alteration of cellular growth kinetics, metabolism and further resistance to chemotherapy. Therefore, it is of high importance to elucidate key mechanisms that affect the evolution of leukaemia under stress. Potential stress response mechanisms are discussed in this review. Moreover, appropriate cell biomarker candidates related to the environmental stress response and/or further resistance to chemotherapy are proposed. Quantification of these biomarkers can enable the combination of macroscopic kinetics with microscopic information, which is specific to individual patients and leads to the construction of detailed mathematical models for the optimisation of chemotherapy. Due to their nature, these models will be more accurate and precise (in comparison to available macroscopic/black box models) in the prediction of responses of individual patients to treatment, as they will incorporate microscopic genetic and/or metabolic information which is patient-specific.peer-reviewe

Thermomechanical couplings in shape memory alloy materials

In this work we address several theoretical and computational issues which are related to the thermomechanical modeling of shape memory alloy materials. More specifically, in this paper we revisit a non-isothermal version of the theory of large deformation generalized plasticity which is suitable for describing the multiple and complex mechanisms occurring in these materials during phase transformations. We also discuss the computational implementation of a generalized plasticity based constitutive model and we demonstrate the ability of the theory in simulating the basic patterns of the experimentally observed behavior by a set of representative numerical examples