Phosphatidylinositol 3-kinase (PI 3-kinase) is a lipid kinase that is likely to play an important role in lymphocyte biology and immune function. PI 3-kinase is activated by the T cell antigen ...receptor (TCR) and the interleukin-2 (IL-2) receptor which govern T cell activation and growth, respectively. Moreover, accessory receptors such as CD28 and CTLA-4 or other cytokine receptors regulate PI 3-kinase activity in T cells. One aim of this thesis was to examine mechanism by which the TCR couples to PI 3-kinase. It was shown that the adaptor molecule Grb2 via its SH3 domains can bind to the p85 subunit of PI 3-kinase and provides a potential link between the TCR and PI 3-kinase. Importantly, these studies led to the first identification of a novel haematopoietic-lineage specific 75 kDa protein that associates with Grb2 SH3 domains. p75 is tyrosine phosphorylated in response to TCR engagement. In parallel studies by other investigators, a 76 kDa Grb2 associated protein was cloned, termed SLP-76. I show that p75 and SLP-76 are identical. p75/SLP-76 is involved in TCR signal transduction pathways leading to IL-2 gene transcription. In order to analyse the cellular functions of PI 3-kinase I generated a constitutively active form of the enzyme. The strategy I employed was to membrane localise its p110 catalytic subunit. P110 was fused to a truncated rat CD2 cell surface receptor giving rise to rCD2p110. Expression of the rCD2p110 chimera elevates the cellular levels of D-3 phosphorylated inositol lipids. Using rCD2p110 it was demonstrated that PI 3-kinase signals are sufficient to stimulate p70S6k but not the MAP kinases Erk or Sapk/Jnk in fibroblasts or T cells. However, in T cells, PI 3-kinase signals can contribute to Erk activation. Importantly, it was established that the protooncogene PKB/Akt is activated by IL-2 in a PI 3-kinase-dependent fashion. Active PI 3-kinase can substitute for IL-2 in stimulating PKB and an active form of PKB can substitute for rCD2p110 or IL-2 in activating p70S6k. Rac/Rho-dependent effector pathways play a role in cytoskeletal changes and regulation of gene transcription. PI 3-kinase is a putative upstream regulator of Rac and hence Rho. Here, I show that PI 3-kinase only regulates a subset of Rac/Rho-mediated cellular responses. PI 3-kinase signals are sufficient to induce Rac/Rho-controlled actin rearrangements but fail to trigger Rac/Rho-mediated effector pathways for activation of transcription factors. I propose that specific subcellular compartmentalisation mechanisms exist that localise different exchange factor/GTPase complexes to divergent downstream effector pathways. Finally, I describe a previously unrecognised function for PI 3-kinase during T cell activation. PI 3-kinase can act as a selective negative regulator of TCR-mediated induction of the transcription factor NF-AT. This involves a novel uncharacterised effector of PI 3-kinase. The significance of these findings for immune homeostasis will be discussed.
Six mutant xylanases were obtained by in vitro mutagenesis of a xylanase gene from the extremely thermophilic bacterium Caldocellum saccharolyticum. The temperature stability of all enzymes was ...affected by mutation to various degrees and one of the xylanases had an altered temperature optimum. The mutations had no effect on the pH optimum. The C. saccharolyticum xylanase showed strong homology to several thermophilic and mesophilic xylanases, and comparison of primary sequences allowed the localization of probable active sites and residues involved in thermostability.
The delivery of signals that control the growth of T cells is a key event for effective co-ordination of T-cell-dependent immune responses. It is now recognized that guanine nucleotide binding ...proteins play an important role in signal transduction by the T-cell receptor (TCR) and cytokine receptors. Here, Manolo Izquierdo Pastor, Karin Reif and Doreen Cantrell review the numerous recent advances in understanding how the p21
ras guanine nucleotide binding protein couples the TCR to the T-cell signalling cascade.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The delivery of signals that control the growth of T cells is a key event for effective co-ordination of T-cell-dependent immune responses. It is now recognized that guanine nucleotide binding ...proteins play an important role in signal transduction by the T-cell receptor (TCR) and cytokine receptors. Here, Manolo Izquierdo Pastor, Karin Reif and Doreen Cantrell review the numerous recent advances in understanding how the p21ras guanine nucleotide binding protein couples the TCR to the T-cell signalling cascade.
Full text
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Chemical reaction networks (CRNs) provide a powerful abstraction to formally represent complex biochemical processes. DNA provides a promising substrate to implement the abstract representation (or ...programming language) of CRNs due to its programmable nature. Prior works that used DNA to implement CRNs either used DNA-only systems or multienzyme DNA circuits. Architectures with DNA-only components had the rationale of being biologically simple systems. Multienzyme systems, on the other hand, aimed at using natural enzymes to improve circuit performance, although, at the cost of increased complexity. In this work, we explore an alternative architecture that lies along the spectrum in between DNA-only systems and multienzyme DNA systems. Our architecture relies on only a strand displacing polymerase enzyme and DNA hybridization reactions for implementing CRNs. First, we briefly introduce the theory and DNA design of simple CRNs and then explore the fundamental properties of polymerase-based strand displacement systems. Finally, we engineer a catalytic amplifier in vitro as a use-case of our framework since such amplifiers require the intricate design of DNA sequences and reaction conditions.
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IJS, KILJ, NUK, PNG, UL, UM
Consistent failure over the past few decades to reduce the high prevalence of stress-related disorders has motivated a search for alternative research strategies. Resilience refers to the phenomenon ...of many people maintaining mental health despite exposure to psychological or physical adversity. Instead of aiming to understand the pathophysiology of stress-related disorders, resilience research focuses on protective mechanisms that shield people against the development of such disorders and tries to exploit its insights to improve treatment and, in particular, disease prevention. To fully harness the potential of resilience research, a critical appraisal of the current state of the art — in terms of basic concepts and key methods — is needed. We highlight challenges to resilience research and make concrete conceptual and methodological proposals to improve resilience research. Most importantly, we propose to focus research on the dynamic processes of successful adaptation to stressors in prospective longitudinal studies.
Fußball könnte eine Arena für queere Vielfalt werden, welche die errungene gesellschaftliche Akzeptanz von LSBTIQ* widerspiegelt. Sein öffentlicher Stellenwert prädestiniert ihn dafür. Der ...vorliegende Sammelband möchte dazu beitragen, die Akzeptanz für sexuelle und geschlechtliche Diversität zu verbessern. Die wissenschaftlichen Beiträge diskutieren aus unterschiedlichen Perspektiven Schritte zu ihrer nachhaltigen Verwirklichung.
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