Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01

Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. However, it can occur in the absence of this allele with identical clinical manifestations. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell-reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01(+) and HLA-B*58:01(-) donors and assessed their reactivity. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the "pharmacological interaction with immune receptors" (p-i) concept. This direct activation occurred regardless of HLA-B*58:01 status. Although most OXP-specific T cells from HLA-B*58:01(+) donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vβ repertoires. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.

The Plasmodium Class XIV Myosin, MyoB, Has a Distinct Subcellular Location in Invasive and Motile Stages of the Malaria Parasite and an Unusual Light Chain

Myosin B (MyoB) is one of the two short class XIV myosins encoded in the Plasmodium genome. Class XIV myosins are characterized by a catalytic "head," a modified "neck," and the absence of a "tail" region. Myosin A (MyoA), the other class XIV myosin in Plasmodium, has been established as a component of the glideosome complex important in motility and cell invasion, but MyoB is not well characterized. We analyzed the properties of MyoB using three parasite species as follows: Plasmodium falciparum, Plasmodium berghei, and Plasmodium knowlesi. MyoB is expressed in all invasive stages (merozoites, ookinetes, and sporozoites) of the life cycle, and the protein is found in a discrete apical location in these polarized cells. In P. falciparum, MyoB is synthesized very late in schizogony/merogony, and its location in merozoites is distinct from, and anterior to, that of a range of known proteins present in the rhoptries, rhoptry neck or micronemes. Unlike MyoA, MyoB is not associated with glideosome complex proteins, including the MyoA light chain, myosin A tail domain-interacting protein (MTIP). A unique MyoB light chain (MLC-B) was identified that contains a calmodulin-like domain at the C terminus and an extended N-terminal region. MLC-B localizes to the same extreme apical pole in the cell as MyoB, and the two proteins form a complex. We propose that MLC-B is a MyoB-specific light chain, and for the short class XIV myosins that lack a tail region, the atypical myosin light chains may fulfill that role.

Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

OBJECTIVE Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. DESIGN HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. RESULTS HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10-4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10-3), and B*35:01 (OR=1.46 [1.13-1.89] P = 3.64*10-3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10-5) and HLA-C-Ser11 (OR=1.34 [1.15-1.57] P = 2.43*10-4). CONCLUSIONS Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons.

Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti-MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL-2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.

Expression and biological activities of bovine interleukin 4: effects of recombinant bovine interleukin 4 on T cell proliferation and B cell differentiation and proliferation in vitro

Interleukin 4 (IL-4) is a pleotropic cytokine affecting a wide range of cell types in both the mouse and the human. These activities include regulation of the growth and differentiation of both T and B lymphocytes. The activities of IL-4 in nonprimate, nonmurine systems are not well established. Herein, we demonstrate in the bovine system that IL-4 upregulates production of IgM, IgG1, and IgE in the presence of a variety of costimulators including anti-IgM, Staphylococcus aureus cowan strain I, and pokeweed mitogen. IgE responses are potentiated by the addition of IL-2 to IL-4. Culture of bovine B lymphocytes with IL-4 in the absence of additional costimulators resulted in the increased surface expression of CD23 (low-affinity Fc epsilon RII), IgM, IL-2R, and MHC class II in a dose-dependent manner. IL-4 alone increased basal levels of proliferation of bulk peripheral blood mononuclear cells but in the presence of Con A inhibited proliferation. In contrast to the activities of IL-4 in the murine system, proliferation of TH1- and TH2-like clones was inhibited in a dose-dependent manner as assessed by antigen-or IL-2-driven in vitro proliferative responses. These observations are consistent with the role of IL-4 as a key player in regulation of both T and B cell responses.

STUDIES ON THE CLASS I GLYCOPROTEINS OF THE MURINE MAJOR HISTOCOMPATIBILITY COMPLEX (TRANSPLANTATION ANTIGEN, LYMPHOCYTE, CELL SURFACE MOLECULE)

A series of studies were undertaken to analyze and compare various aspects of murine class I glycoproteins. An initial area of investigation characterized the Qa-1 alloantigens using two-dimensional gel electrophoresis. Analysis of the products of the Qa-1('b), Qa-1('c) and Qa-1('d) alleles indicated that these were distinct molecules as determined by their lack of comigration upon comparative two-dimensional gel analysis. The importance of asparagine-linked glycosylation in the cell surface expression of class I molecules was also examined. These studies employed tunicamycin, an inhibitor of N-linked glycosylation. Tunicamycin treatment of activated T lymphocytes diminished the surface expression of Qa-1 to undetectable levels; the levels of other class I molecules exhibited little or no decrease. These results indicated that N-linked glycosylation has a differential importance in the cell surface expression of various class I molecules. The molecular weight diversity of class I molecules was also investigated. Molecular weight determination of both the fully glycosylated and unglycosylated forms of H-2 and Qa/Tla region encoded molecules established that there is a significant variation in the sizes of these forms of various class I molecules. The most significant difference ((TURN)9,000 daltons) exists between the unglycosylated forms of H-2K('b) and Qa-2, suggesting that the structural organization of these two molecules may be very different. A comparative two-dimensional gel analysis of various class I glycoproteins isolated from resting and activated T and B lymphocytes indicated that class I molecules expressed on activated T cells exhibited an isoelectrophoretic pattern that was distinct from the isoelectrophoretic pattern of class I molecules expessed on the other cell populations. This difference was attributed to a lower sialic acid content of the molecules expressed on activated T cells. Analysis of cell homogenates determined that activated T cells contained a higher level of endogenous neuraminidase activity than was detected in the other populations, suggesting that this may be the basis of the lower sialic acid content. The relationship of the Qa-4 and Qa-2 alloantigens was also examined. It was established that upon mitogen activation, the expression of Qa-4 was greatly decreased, whereas Qa-2 expression was not decreased. However, an anti-Qa-2 monoclonal antibody blocked the binding of an anti-Qa-4 monoclonal antibody to resting cells. These studies established that Qa-4 is a determinant restricted to resting cells, which is closely associated on the surface with the Qa-2 molecule. ^

Na 1 Nachlass Max Horkheimer, 639 - "On the Sociology of Class Relations" und "The Psychology of Nazidom" (p. IX 16.1-2-IX 17.1-2)

"On the Sociology of Class Relations" (GS 12, S.75-104); 1. 1943 Aufsatz. a) Typoskript mit handschriftlichen Korrekturen, 34 Blatt b) Typoskript mit eigenhändigen Korrekturen, 31 Blatt c) Typoskript, 31 Blatt und eigenhändigen Ergänzungen, 1 Blatt d) Typoskript mit eigenhändigen Korrekturen, 26 Blatt; 2. Franz Neumann: 1 eigenhändiger Brief mit Unterschrift an Max Horkheimer mit Anmerkungen zum Aufsatz, ohne Ort, 30.09.1943, 11 Blatt; "The Psychology of Nazidom" (GS 5, S. 354-359); 1. Buchbesprechung von "Is Germany Inucable?" von Richard M. Brickner; veröffentlicht in: "The New Leader", 14.08.1943. a)Typoskript, 7 Blatt b) Typoskript mit eigenhändigen und handschriftlichen Korrekturen, 7 Blatt c) Zeitungsdruck, 3 Exemplare; 2. "What Shall We Do With Germany? A Panel Discussion of 'Is Germany Incurable?'". Zeitungsausschnitte aus : "The Saturday Review of Literature", 29.05.1343, 6 Blatt;

Identification and analysis of novel mitotic inhibitors of the Caenorhabditis elegans Aurora B kinase

Proper execution of mitosis requires the accurate segregation of replicated DNA into each daughter cell. The highly conserved mitotic kinase AIR-2/Aurora B is a dynamic protein that interacts with subsets of cofactors and substrates to coordinate chromosome segregation and cytokinesis in Caenorhabdiris elegans. To identify components of the AIR-2 regulatory pathway, a genome-wide RNAi-based screen for suppressors of air-2 temperature-sensitive mutant lethality was conducted. Here, I present evidence that two classes of suppressors identified in this screen are bona fide regulators of the AIR-2 kinase. The strongest suppressor cdc-48.3, encodes an Afg2/Spaf-related Cdc48-like AAA+ ATPase that regulates AIR-2 kinase activity and stability during C. elegans embryogenesis. Loss of CDC-48.3 suppresses the lethality of air-2 mutant embryos, marked by the restoration of the dynamic behavior of AIR-2 and rescue of chromosome segregation and cytokinesis defects. Loss of CDC-48.3 leads to mitotic delays and abnormal accumulation of AIR-2 during late telophase/mitotic exit. In addition, AIR-2 kinase activity is significantly upregulated from metaphase through mitotic exit in CDC-48.3 depleted embryos. Inhibition of the AIR-2 kinase is dependent on (1) a direct physical interaction between CDC-48.3 and AIR-2, and (2) CDC-48.3 ATPase activity. Importantly, the increase in AIR-2 kinase activity does not correlate with the stabilization of AIR-2 in late mitosis. Hence, CDC-48.3 is a bi-functional inhibitor of AIR-2 that is likely to act via distinct mechanisms. The second class of suppressors consists of psy-2/smk-1 and pph-4.1, which encode two components of the conserved PP4 phosphatase complex that is essential for spindle assembly, chromosome segregation, and overall mitotic progression. AIR-2 and its substrates are likely to be targets of this complex since mitotic AIR-2 kinase activity is significantly increased during mitosis when either PSY-2/SMK-1 or PPH-4.l is depleted. Altogether, this study demonstrates that during the C. elegans embryonic cell cycle, regulators including the CDC-48.3 ATPase and PP4 phosphatase complex interact with and control the kinase activity, targeting behavior and protein stability of the Aurora B kinase to ensure accurate and timely progression of mitosis. ^

Learning an L1-regularized Gaussian Bayesian Network in the Equivalence Class Space

Learning the structure of a graphical model from data is a common task in a wide range of practical applications. In this paper, we focus on Gaussian Bayesian networks, i.e., on continuous data and directed acyclic graphs with a joint probability density of all variables given by a Gaussian. We propose to work in an equivalence class search space, specifically using the k-greedy equivalence search algorithm. This, combined with regularization techniques to guide the structure search, can learn sparse networks close to the one that generated the data. We provide results on some synthetic networks and on modeling the gene network of the two biological pathways regulating the biosynthesis of isoprenoids for the Arabidopsis thaliana plant

Some minor problems with B.E.M.

As it is well known B.E.M. works efficiently in the treatment of a bread class of potential and elasticity problems. In this paper we present the results of several runs established with linear elements in plane potential theory and treating the importance of singularities and the pattern and size of elements used in the boundary discretization.

Multidisciplinary Design Optimization Application to Conceptual Design of University-class Microsatellite Projects

Esta tesis se ha realizado en el contexto del proyecto UPMSat-2, que es un microsatélite diseñado, construido y operado por el Instituto Universitario de Microgravedad "Ignacio Da Riva" (IDR / UPM) de la Universidad Politécnica de Madrid. Aplicación de la metodología Ingeniería Concurrente (Concurrent Engineering: CE) en el marco de la aplicación de diseño multidisciplinar (Multidisciplinary Design Optimization: MDO) es uno de los principales objetivos del presente trabajo. En los últimos años, ha habido un interés continuo en la participación de los grupos de investigación de las universidades en los estudios de la tecnología espacial a través de sus propios microsatélites. La participación en este tipo de proyectos tiene algunos desafíos inherentes, tales como presupuestos y servicios limitados. Además, debido al hecho de que el objetivo principal de estos proyectos es fundamentalmente educativo, por lo general hay incertidumbres en cuanto a su misión en órbita y cargas útiles en las primeras fases del proyecto. Por otro lado, existen limitaciones predeterminadas para sus presupuestos de masa, volumen y energía, debido al hecho de que la mayoría de ellos están considerados como una carga útil auxiliar para el lanzamiento. De este modo, el costo de lanzamiento se reduce considerablemente. En este contexto, el subsistema estructural del satélite es uno de los más afectados por las restricciones que impone el lanzador. Esto puede afectar a diferentes aspectos, incluyendo las dimensiones, la resistencia y los requisitos de frecuencia. En la primera parte de esta tesis, la atención se centra en el desarrollo de una herramienta de diseño del subsistema estructural que evalúa, no sólo las propiedades de la estructura primaria como variables, sino también algunas variables de nivel de sistema del satélite, como la masa de la carga útil y la masa y las dimensiones extremas de satélite. Este enfoque permite que el equipo de diseño obtenga una mejor visión del diseño en un espacio de diseño extendido. La herramienta de diseño estructural se basa en las fórmulas y los supuestos apropiados, incluyendo los modelos estáticos y dinámicos del satélite. Un algoritmo genético (Genetic Algorithm: GA) se aplica al espacio de diseño para optimizaciones de objetivo único y también multiobjetivo. El resultado de la optimización multiobjetivo es un Pareto-optimal basado en dos objetivo, la masa total de satélites mínimo y el máximo presupuesto de masa de carga útil. Por otro lado, la aplicación de los microsatélites en misiones espaciales es de interés por su menor coste y tiempo de desarrollo. La gran necesidad de las aplicaciones de teledetección es un fuerte impulsor de su popularidad en este tipo de misiones espaciales. Las misiones de tele-observación por satélite son esenciales para la investigación de los recursos de la tierra y el medio ambiente. En estas misiones existen interrelaciones estrechas entre diferentes requisitos como la altitud orbital, tiempo de revisita, el ciclo de vida y la resolución. Además, todos estos requisitos puede afectar a toda las características de diseño. Durante los últimos años la aplicación de CE en las misiones espaciales ha demostrado una gran ventaja para llegar al diseño óptimo, teniendo en cuenta tanto el rendimiento y el costo del proyecto. Un ejemplo bien conocido de la aplicación de CE es la CDF (Facilidad Diseño Concurrente) de la ESA (Agencia Espacial Europea). Está claro que para los proyectos de microsatélites universitarios tener o desarrollar una instalación de este tipo parece estar más allá de las capacidades del proyecto. Sin embargo, la práctica de la CE a cualquier escala puede ser beneficiosa para los microsatélites universitarios también. En la segunda parte de esta tesis, la atención se centra en el desarrollo de una estructura de optimización de diseño multidisciplinar (Multidisciplinary Design Optimization: MDO) aplicable a la fase de diseño conceptual de microsatélites de teledetección. Este enfoque permite que el equipo de diseño conozca la interacción entre las diferentes variables de diseño. El esquema MDO presentado no sólo incluye variables de nivel de sistema, tales como la masa total del satélite y la potencia total, sino también los requisitos de la misión como la resolución y tiempo de revisita. El proceso de diseño de microsatélites se divide en tres disciplinas; a) diseño de órbita, b) diseño de carga útil y c) diseño de plataforma. En primer lugar, se calculan diferentes parámetros de misión para un rango práctico de órbitas helio-síncronas (sun-synchronous orbits: SS-Os). Luego, según los parámetros orbitales y los datos de un instrumento como referencia, se calcula la masa y la potencia de la carga útil. El diseño de la plataforma del satélite se estima a partir de los datos de la masa y potencia de los diferentes subsistemas utilizando relaciones empíricas de diseño. El diseño del subsistema de potencia se realiza teniendo en cuenta variables de diseño más detalladas, como el escenario de la misión y diferentes tipos de células solares y baterías. El escenario se selecciona, de modo de obtener una banda de cobertura sobre la superficie terrestre paralelo al Ecuador después de cada intervalo de revisita. Con el objetivo de evaluar las interrelaciones entre las diferentes variables en el espacio de diseño, todas las disciplinas de diseño mencionados se combinan en un código unificado. Por último, una forma básica de MDO se ajusta a la herramienta de diseño de sistema de satélite. La optimización del diseño se realiza por medio de un GA con el único objetivo de minimizar la masa total de microsatélite. Según los resultados obtenidos de la aplicación del MDO, existen diferentes puntos de diseños óptimos, pero con diferentes variables de misión. Este análisis demuestra la aplicabilidad de MDO para los estudios de ingeniería de sistema en la fase de diseño conceptual en este tipo de proyectos. La principal conclusión de esta tesis, es que el diseño clásico de los satélites que por lo general comienza con la definición de la misión y la carga útil no es necesariamente la mejor metodología para todos los proyectos de satélites. Un microsatélite universitario, es un ejemplo de este tipo de proyectos. Por eso, se han desarrollado un conjunto de herramientas de diseño para encarar los estudios de la fase inicial de diseño. Este conjunto de herramientas incluye diferentes disciplinas de diseño centrados en el subsistema estructural y teniendo en cuenta una carga útil desconocida a priori. Los resultados demuestran que la mínima masa total del satélite y la máxima masa disponible para una carga útil desconocida a priori, son objetivos conflictivos. En este contexto para encontrar un Pareto-optimal se ha aplicado una optimización multiobjetivo. Según los resultados se concluye que la selección de la masa total por satélite en el rango de 40-60 kg puede considerarse como óptima para un proyecto de microsatélites universitario con carga útil desconocida a priori. También la metodología CE se ha aplicado al proceso de diseño conceptual de microsatélites de teledetección. Los resultados de la aplicación del CE proporcionan una clara comprensión de la interacción entre los requisitos de diseño de sistemas de satélites, tales como la masa total del microsatélite y la potencia y los requisitos de la misión como la resolución y el tiempo de revisita. La aplicación de MDO se hace con la minimización de la masa total de microsatélite. Los resultados de la aplicación de MDO aclaran la relación clara entre los diferentes requisitos de diseño del sistema y de misión, así como que permiten seleccionar las líneas de base para el diseño óptimo con el objetivo seleccionado en las primeras fase de diseño. ABSTRACT This thesis is done in the context of UPMSat-2 project, which is a microsatellite under design and manufacturing at the Instituto Universitario de Microgravedad “Ignacio Da Riva” (IDR/UPM) of the Universidad Politécnica de Madrid. Application of Concurrent Engineering (CE) methodology in the framework of Multidisciplinary Design application (MDO) is one of the main objectives of the present work. In recent years, there has been continuing interest in the participation of university research groups in space technology studies by means of their own microsatellites. The involvement in such projects has some inherent challenges, such as limited budget and facilities. Also, due to the fact that the main objective of these projects is for educational purposes, usually there are uncertainties regarding their in orbit mission and scientific payloads at the early phases of the project. On the other hand, there are predetermined limitations for their mass and volume budgets owing to the fact that most of them are launched as an auxiliary payload in which the launch cost is reduced considerably. The satellite structure subsystem is the one which is most affected by the launcher constraints. This can affect different aspects, including dimensions, strength and frequency requirements. In the first part of this thesis, the main focus is on developing a structural design sizing tool containing not only the primary structures properties as variables but also the satellite system level variables such as payload mass budget and satellite total mass and dimensions. This approach enables the design team to obtain better insight into the design in an extended design envelope. The structural design sizing tool is based on the analytical structural design formulas and appropriate assumptions including both static and dynamic models of the satellite. A Genetic Algorithm (GA) is applied to the design space for both single and multiobejective optimizations. The result of the multiobjective optimization is a Pareto-optimal based on two objectives, minimum satellite total mass and maximum payload mass budget. On the other hand, the application of the microsatellites is of interest for their less cost and response time. The high need for the remote sensing applications is a strong driver of their popularity in space missions. The satellite remote sensing missions are essential for long term research around the condition of the earth resources and environment. In remote sensing missions there are tight interrelations between different requirements such as orbital altitude, revisit time, mission cycle life and spatial resolution. Also, all of these requirements can affect the whole design characteristics. During the last years application of the CE in the space missions has demonstrated a great advantage to reach the optimum design base lines considering both the performance and the cost of the project. A well-known example of CE application is ESA (European Space Agency) CDF (Concurrent Design Facility). It is clear that for the university-class microsatellite projects having or developing such a facility seems beyond the project capabilities. Nevertheless practicing CE at any scale can be beneficiary for the university-class microsatellite projects. In the second part of this thesis, the main focus is on developing a MDO framework applicable to the conceptual design phase of the remote sensing microsatellites. This approach enables the design team to evaluate the interaction between the different system design variables. The presented MDO framework contains not only the system level variables such as the satellite total mass and total power, but also the mission requirements like the spatial resolution and the revisit time. The microsatellite sizing process is divided into the three major design disciplines; a) orbit design, b) payload sizing and c) bus sizing. First, different mission parameters for a practical range of sun-synchronous orbits (SS-Os) are calculated. Then, according to the orbital parameters and a reference remote sensing instrument, mass and power of the payload are calculated. Satellite bus sizing is done based on mass and power calculation of the different subsystems using design estimation relationships. In the satellite bus sizing, the power subsystem design is realized by considering more detailed design variables including a mission scenario and different types of solar cells and batteries. The mission scenario is selected in order to obtain a coverage belt on the earth surface parallel to the earth equatorial after each revisit time. In order to evaluate the interrelations between the different variables inside the design space all the mentioned design disciplines are combined in a unified code. The integrated satellite system sizing tool developed in this section is considered as an application of the CE to the conceptual design of the remote sensing microsatellite projects. Finally, in order to apply the MDO methodology to the design problem, a basic MDO framework is adjusted to the developed satellite system design tool. Design optimization is done by means of a GA single objective algorithm with the objective function as minimizing the microsatellite total mass. According to the results of MDO application, there exist different optimum design points all with the minimum satellite total mass but with different mission variables. This output demonstrates the successful applicability of MDO approach for system engineering trade-off studies at the conceptual design phase of the design in such projects. The main conclusion of this thesis is that the classical design approach for the satellite design which usually starts with the mission and payload definition is not necessarily the best approach for all of the satellite projects. The university-class microsatellite is an example for such projects. Due to this fact an integrated satellite sizing tool including different design disciplines focusing on the structural subsystem and considering unknown payload is developed. According to the results the satellite total mass and available mass for the unknown payload are conflictive objectives. In order to find the Pareto-optimal a multiobjective GA optimization is conducted. Based on the optimization results it is concluded that selecting the satellite total mass in the range of 40-60 kg can be considered as an optimum approach for a university-class microsatellite project with unknown payload(s). Also, the CE methodology is applied to the remote sensing microsatellites conceptual design process. The results of CE application provide a clear understanding of the interaction between satellite system design requirements such as satellite total mass and power and the satellite mission variables such as revisit time and spatial resolution. The MDO application is done with the total mass minimization of a remote sensing satellite. The results from the MDO application clarify the unclear relationship between different system and mission design variables as well as the optimum design base lines according to the selected objective during the initial design phases.

Disruption of the CD4–major histocompatibility complex class II interaction blocks the development of CD4+ T cells in vivo

The experiments presented in this report were designed to specifically examine the role of CD4–major histocompatibility complex (MHC) class II interactions during T cell development in vivo. We have generated transgenic mice expressing class II molecules that cannot interact with CD4 but that are otherwise competent to present peptides to the T cell receptor. MHC class II expression was reconstituted in Aβ gene knock-out mice by injection of a transgenic construct encoding either the wild-type I-Aβb protein or a construct encoding a mutation designed to specifically disrupt binding to the CD4 molecule. We demonstrate that the mutation, EA137 and VA142 in the β2 domain of I-Ab, is sufficient to disrupt CD4–MHC class II interactions in vivo. Furthermore, we show that this interaction is critical for the efficient selection of a complete repertoire of mature CD4+ T helper cells as evidenced by drastically reduced numbers of conventional CD4+ T cells in animals expressing the EA137/VA142 mutant I-Ab and by the failure to positively select the transgenic AND T cell receptor on the mutated I-Ab. These results underscore the importance of the CD4–class II interaction in the development of mature peripheral CD4+ T cells.