Transformation kinetics of alloys under non-isothermal conditions

The overall solid-to-solid phase transformation kinetics under non-isothermal conditions has been modeled by means of a differential equation method. The method requires provisions for expressions of the fraction of the transformed phase in equilibrium condition and the relaxation time for transition as functions of temperature. The thermal history is an input to the model. We have used the method to calculate the time/temperature variation of the volume fraction of the favored phase in the alpha-to-beta transition in a zirconium alloy under heating and cooling, in agreement with experimental results. We also present a formulation that accounts for both additive and non-additive phase transformation processes. Moreover, a method based on the concept of path integral, which considers all the possible paths in thermal histories to reach the final state, is suggested.Comment: 16 pages, 7 figures. To appear in Modelling Simul. Mater. Sci. En

T-Cell Artificial Focal Triggering Tools: Linking Surface Interactions with Cell Response

T-cell activation is a key event in the immune system, involving the interaction of several receptor ligand pairs in a complex intercellular contact that forms between T-cell and antigen-presenting cells. Molecular components implicated in contact formation have been identified, but the mechanism of activation and the link between molecular interactions and cell response remain poorly understood due to the complexity and dynamics exhibited by whole cell-cell conjugates. Here we demonstrate that simplified model colloids grafted so as to target appropriate cell receptors can be efficiently used to explore the relationship of receptor engagement to the T-cell response. Using immortalized Jurkat T cells, we monitored both binding and activation events, as seen by changes in the intracellular calcium concentration. Our experimental strategy used flow cytometry analysis to follow the short time scale cell response in populations of thousands of cells. We targeted both T-cell receptor CD3 (TCR/CD3) and leukocyte-function-associated antigen (LFA-1) alone or in combination. We showed that specific engagement of TCR/CD3 with a single particle induced a transient calcium signal, confirming previous results and validating our approach. By decreasing anti-CD3 particle density, we showed that contact nucleation was the most crucial and determining step in the cell-particle interaction under dynamic conditions, due to shear stress produced by hydrodynamic flow. Introduction of LFA-1 adhesion molecule ligands at the surface of the particle overcame this limitation and elucidated the low TCR/CD3 ligand density regime. Despite their simplicity, model colloids induced relevant biological responses which consistently echoed whole cell behavior. We thus concluded that this biophysical approach provides useful tools for investigating initial events in T-cell activation, and should enable the design of intelligent artificial systems for adoptive immunotherapy

Force Generation upon T Cell Receptor Engagement

T cells are major players of adaptive immune response in mammals. Recognition of an antigenic peptide in association with the major histocompatibility complex at the surface of an antigen presenting cell (APC) is a specific and sensitive process whose mechanism is not fully understood. The potential contribution of mechanical forces in the T cell activation process is increasingly debated, although these forces are scarcely defined and hold only limited experimental evidence. In this work, we have implemented a biomembrane force probe (BFP) setup and a model APC to explore the nature and the characteristics of the mechanical forces potentially generated upon engagement of the T cell receptor (TCR) and/or lymphocyte function-associated antigen-1 (LFA-1). We show that upon contact with a model APC coated with antibodies towards TCR-CD3, after a short latency, the T cell developed a timed sequence of pushing and pulling forces against its target. These processes were defined by their initial constant growth velocity and loading rate (force increase per unit of time). LFA-1 engagement together with TCR-CD3 reduced the growing speed during the pushing phase without triggering the same mechanical behavior when engaged alone. Intracellular Ca2+ concentration ([Ca2+]i) was monitored simultaneously to verify the cell commitment in the activation process. [Ca2+]i increased a few tens of seconds after the beginning of the pushing phase although no strong correlation appeared between the two events. The pushing phase was driven by actin polymerization. Tuning the BFP mechanical properties, we could show that the loading rate during the pulling phase increased with the target stiffness. This indicated that a mechanosensing mechanism is implemented in the early steps of the activation process. We provide here the first quantified description of force generation sequence upon local bidimensional engagement of TCR-CD3 and discuss its potential role in a T cell mechanically-regulated activation process

Primary immunodeficiency secondary to ZAP-70 deficiency

The authors present the case of a child with recurrent infections since the age of 4 months, including bilateral pneumonia by Pneumocystis carinii and protracted varicella. Serum immunoglobulin values (when 10 months old), and B cell values were normal. There was persistent lymphocytic leucocytosis, near absence of CD8+ cells, and an increased CD4/CD8 ratio. The percentage of activated T cells and the expression of HLA class I were normal. Proliferation, activation and IL-2 synthesis studies in T cells showed a TCR/CD3-associated signal transduction deficit. ZAP-70 cDNA sequencing showed a mutation, and no ZAP-70 protein was detected in T cells. ZAP-70 deficiency is associated with a rare immune deficiency with absence of CD8+ T cells as well as a functional deficiency in T cells. Seven months after bone marrow transplantation the child is clinically well and immunologically recovere

Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis

Complete interferon-γ receptor 1 (IFNγR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guerin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNγR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-γ was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-α secretion. Whereas cells from healthy children responded to even low IFN-γ concentrations (10 IU/ml), and cells from a child with complete IFNγR1 deficiency did not respond to even high IFN-γ concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-γ concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNγR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNγR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis