Evolution of JAK-STAT pathway components : mechanisms and role in immune system development

BackgroundLying downstream of a myriad of cytokine receptors, the Janus kinase (JAK) &ndash; Signal transducer and activator of transcription (STAT) pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP), Protein inhibitors against Stats (PIAS), and Suppressor of cytokine signaling (SOCS) proteins across a diverse range of organisms.ResultsOur analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components.ConclusionDiversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.<br /

Standard Model Higgs inflation: CMB, Higgs mass and quantum cosmology

We consider the inflation model generated by the Standard Model (SM) Higgs boson having a strong non-minimal curvature coupling. This model suggests the range of the Higgs mass $135.6\; {\rm GeV} \lesssim M_H\lesssim 184.5\;{\rm GeV}$ entirely determined by the lower WMAP bound on the CMB spectral index. This result is based on the renormalization group analysis of quantum effects which make the SM phenomenology sensitive to the current cosmological data and thus suggest CMB measurements as a SM test complementary to the LHC program. We show naturalness of the gradient and curvature expansion in this model in a conventional perturbation theory range of SM. The origin of initial conditions for inflation within the quantum cosmology concept of the tunneling state of the Universe is also considered. In this way a complete cosmological scenario is obtained, which embraces the formation of initial conditions for the inflationary background in the form of a sharp probability peak in the distribution of the inflaton field and the ongoing generation of the CMB spectrum on this background.Comment: 19 pages, 5 figures, talk given at the Yukawa Institute for Theoretical Physics Symposium "Cosmology-the Next Generation", Kyoto, 2010, to appear in Prog. Theor. Phy

The atomistic level structure for the activated human κ-opioid receptor bound to the full Gi protein and the MP1104 agonist

The kappa opioid receptor (κOR) is an important target for pain therapeutics to reduce depression and other harmful side effects of existing medications. The analgesic activity is mediated by κOR signaling through the adenylyl cyclase-inhibitory family of Gi protein. Here, we report the three-dimensional (3D) structure for the active state of human κOR complexed with both heterotrimeric Gi protein and MP1104 agonist. This structure resulted from long molecular dynamics (MD) and metadynamics (metaMD) simulations starting from the 3.1-Å X-ray structure of κOR–MP1104 after replacing the nanobody with the activated Gi protein and from the 3.5-Å cryo-EM structure of μOR–Gi complex after replacing the 168 missing residues. Using MD and metaMD we discovered interactions to the Gi protein with strong anchors to two intracellular loops and transmembrane helix 6 of the κOR. These anchors strengthen the binding, contributing to a contraction in the binding pocket but an expansion in the cytoplasmic region of κOR to accommodate G protein. These remarkable changes in κOR structure reveal that the anchors are essential for activation

CD28 between tolerance and autoimmunity: The side effects of animal models [version 1; referees: 2 approved]

Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans

From Strangeness Enhancement to Quark-Gluon Plasma Discovery

This is a short survey of signatures and characteristics of the quark-gluon plasma in the light of experimental results that have been obtained over the past three decades. In particular, we present an in-depth discussion of the strangeness observable, including a chronology of the experimental effort to detect QGP at CERN-SPS, BNL-RHIC, and CERN-LHC.Comment: 30 pages, about 20 figures; Dedicated to our mentor Walter Greiner; to be published in the memorial volume edited by Peter O. Hes

Tunneling cosmological state revisited: Origin of inflation with a non-minimally coupled Standard Model Higgs inflaton

We suggest a path integral formulation for the tunneling cosmological state, which admits a consistent renormalization and renormalization group (RG) improvement in particle physics applications of quantum cosmology. We apply this formulation to the inflationary cosmology driven by the Standard Model (SM) Higgs boson playing the role of an inflaton with a strong non-minimal coupling to gravity. In this way a complete cosmological scenario is obtained, which embraces the formation of initial conditions for the inflationary background in the form of a sharp probability peak in the distribution of the inflaton field and the ongoing generation of the Cosmic Microwave Background (CMB) spectrum on this background. Formation of this probability peak is based on the same RG mechanism which underlies the generation of the CMB spectrum which was recently shown to be compatible with the WMAP data in the Higgs mass range $135.6 {\rm GeV} \lesssim M_H\lesssim 184.5 {\rm GeV}$. This brings to life a convincing unification of quantum cosmology with the particle phenomenology of the SM, inflation theory, and CMB observations.Comment: 18 pages, 3 figures, LaTe

The bootstrap -A review

The bootstrap, extensively studied during the last decade, has become a powerful tool in different areas of Statistical Inference. In this work, we present the main ideas of bootstrap methodology in several contexts, citing the most relevant contributions and illustrating with examples and simulation studies some interesting aspects

Metazoans evolved by taking domains from soluble proteins to expand intercellular communication network.

A central question in animal evolution is how multicellular animals evolved from unicellular ancestors. We hypothesize that membrane proteins must be key players in the development of multicellularity because they are well positioned to form the cell-cell contacts and to provide the intercellular communication required for the creation of complex organisms. Here we find that a major mechanism for the necessary increase in membrane protein complexity in the transition from non-metazoan to metazoan life was the new incorporation of domains from soluble proteins. The membrane proteins that have incorporated soluble domains in metazoans are enriched in many of the functions unique to multicellular organisms such as cell-cell adhesion, signaling, immune defense and developmental processes. They also show enhanced protein-protein interaction (PPI) network complexity and centrality, suggesting an important role in the cellular diversification found in complex organisms. Our results expose an evolutionary mechanism that contributed to the development of higher life forms