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31.
Misregulated innate immune signaling and cell death form the basis of much human disease pathogenesis. Inhibitor of apoptosis (IAP) protein family members are frequently overexpressed in cancer and contribute to tumor cell survival, chemo-resistance, disease progression, and poor prognosis. Although best known for their ability to regulate caspases, IAPs also influence ubiquitin (Ub)-dependent pathways that modulate innate immune signaling via activation of nuclear factor κB (NF-κB). Recent research into IAP biology has unearthed unexpected roles for this group of proteins. In addition, the advances in our understanding of the molecular mechanisms that IAPs use to regulate cell death and innate immune responses have provided new insights into disease states and suggested novel intervention strategies. Here we review the functions assigned to those IAP proteins that act at the intersection of cell death regulation and inflammatory signaling.Apoptosis represents a fundamental biological process that relies on the activation of caspases. Inhibitor of apoptosis (IAP) proteins represent a group of negative regulators of both caspases and cell death. Although best known for their ability to regulate caspases and cell death, it is now clear that they function as arbiters of diverse biological processes (Gyrd-Hansen and Meier 2010). Most prominently, IAPs control ubiquitin (Ub)-dependent signaling events that regulate activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways that in turn drive expression of genes important for inflammation, immunity, cell migration, and cell survival. IAPs thereby function as E3 Ub ligases, mediating the transfer of Ub from E2s to target substrates. This in turn modulates the signaling process through regulating protein stability as well as via nondegradative means (see below for details). Many of the cellular processes controlled by IAPs are frequently deregulated in cancer and, directly or indirectly, contribute to disease initiation, tumor maintenance, and/or progression, making IAPs obvious targets for anticancer therapy (LaCasse et al. 2008). Accordingly, small pharmacological inhibitors of IAPs, frequently referred to as Smac-mimetics (SM), were developed and are currently undergoing clinical trials for the treatment of cancer (LaCasse et al. 2008). The use of SMs in preclinical tumor models and clinical trials has provided compelling evidence for the therapeutic benefit of IAP inhibition. 相似文献
32.
Thomas Spallek Martina Beck Sara Ben Khaled Susanne Salomon Gildas Bourdais Swen Schellmann Silke Robatzek 《PLoS genetics》2013,9(12)
The plant immune receptor FLAGELLIN SENSING 2 (FLS2) is present at the plasma membrane and is internalized following activation of its ligand flagellin (flg22). We show that ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT (ESCRT)-I subunits play roles in FLS2 endocytosis in Arabidopsis. VPS37-1 co-localizes with FLS2 at endosomes and immunoprecipitates with the receptor upon flg22 elicitation. Vps37-1 mutants are reduced in flg22-induced FLS2 endosomes but not in endosomes labeled by Rab5 GTPases suggesting a defect in FLS2 trafficking rather than formation of endosomes. FLS2 localizes to the lumen of multivesicular bodies, but this is altered in vps37-1 mutants indicating compromised endosomal sorting of FLS2 by ESCRT-I loss-of-function. VPS37-1 and VPS28-2 are critical for immunity against bacterial infection through a role in stomatal closure. Our findings identify that VPS37-1, and likewise VPS28-2, regulate late FLS2 endosomal sorting and reveals that ESCRT-I is critical for flg22-activated stomatal defenses involved in plant immunity. 相似文献
33.
Thomas Jans Erika Graf Christian Jacob Ulrike Zwanzger Silke Groß-Lesch Swantje Matthies Evgeniy Perlov Klaus Hennighausen Melanie Jung Michael Rösler Monika Schulte-Altedorneburg Alexander von Gontard Susann Hänig Esther Sobanski Barbara Alm Luise Poustka Lucia Bliznak Michael Colla Laura Gentschow Roland Burghardt Harriet Salbach-Andrae Katja Becker Martin Holtmann Christine Freitag Andreas Warnke Alexandra Philipsen 《Attention deficit and hyperactivity disorders》2013,5(1):29-40
34.
Background
The number of patients seeking health care is a central indicator that may serve several different purposes: (1) as a proxy for the impact on the burden of the primary care system; (2) as a starting point to estimate the number of persons ill with influenza; (3) as the denominator data for the calculation of case fatality rate and the proportion hospitalized (severity indicators); (4) for economic calculations. In addition, reliable estimates of burden of disease and on the health care system are essential to communicate the impact of influenza to health care professionals, public health professionals and to the public.Methodology/Principal Findings
Using German syndromic surveillance data, we have developed a novel approach to describe the seasonal variation of medically attended acute respiratory infections (MAARI) and estimate the excess MAARI attributable to influenza. The weekly excess inside a period of influenza circulation is estimated as the difference between the actual MAARI and a MAARI-baseline, which is established using a cyclic regression model for counts. As a result, we estimated the highest ARI burden within the last 10 years for the influenza season 2004/05 with an excess of 7.5 million outpatient visits (CI95% 6.8–8.0). In contrast, the pandemic wave 2009 accounted for one third of this burden with an excess of 2.4 million (CI95% 1.9–2.8). Estimates can be produced for different age groups, different geographic regions in Germany and also in real time during the influenza waves. 相似文献35.
Margret Rave-Fränk Ihtzaz Ahmed Malik Hans Christiansen Naila Naz Sadaf Sultan Ahmad Amanzada Martina Blaschke Silke Cameron Shakil Ahmad Clemens Friedrich Hess Giuliano Ramadori Federico Moriconi 《Radiation and environmental biophysics》2013,52(3):321-338
The liver is considered a radiosensitive organ. However, in rats, high single-dose irradiation (HDI) showed only mild effects. Consequences of fractionated irradiation (FI) in such an animal model have not been studied so far. Rats were exposed to selective liver FI (total dose 60 Gy, 2 Gy/day) or HDI (25 Gy) and were killed three months after the end of irradiation. To study acute effects, HDI-treated rats were additionally killed at several time points between 1 and 48 h. Three months after irradiation, no differences between FI and HDI treatment were found for macroscopically detectable small “scars” on the liver surface and for an increased number of neutrophil granulocytes distributed in the portal fields and through the liver parenchyma. As well, no changes in HE-stained tissues or clear signs of fibrosis were found around the portal vessels. Differences were seen for the number of bile ducts being increased in FI- but not in HDI-treated livers. Serum levels indicative of liver damage were determined for alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (γGT) and lactate dehydrogenase (LDH). A significant increase of AP was detected only after FI while HDI led to the significant increases of AST and LDH serum levels. By performing RT-PCR, we detected up-regulation of matrix metalloproteinases, MMP-2, MMP-9, MMP-14, and of their inhibitors, TIMP-1, TIMP-2 and TIMP-3, shortly after HDI, but not at 3 month after FI or HDI. Overall, we saw punctual differences after FI and HDI, and a diffuse formation of small scars at the liver surface. Lack of “provisional clot”-formation and absence of recruitment of mononuclear phagocytes could be one explanation for scar formation as incomplete repair response to irradiation. 相似文献
36.
Jan Fischer Jörg W. Schneider John-Paul M. Hodnett David K. Elliott Gary D. Johnson Silke Voigt 《Historical Biology》2013,25(6):710-727
δ18OP values and 87Sr/86Sr ratios were determined on disarticulated xenacanthiform, hybodontid and ctenacanthid shark tooth material from several Early Permian (Sakmarian–Kungurian) continental bone beds of northern Texas and southern Oklahoma as well as from the marine Middle Permian (Roadian) of northern Arizona. The δ18OP values derived from the teeth of bone beds are in the range of 17.6–23.5‰ VSMOW, and are mostly depleted in 18O by 0.5–5‰ relative to proposed coeval marine δ18OP values. This indicates an adaptation to freshwater habitats on the Early Permian coastal plain by several sharks. Distinctly higher δ18OP values from two bone beds are attributed to significant evaporative enrichment in 18O in flood plain ponds. 87Sr/86Sr ratios of around 0.71077 are notably more radiogenic than 87Sr/86Sr of contemporaneous seawater. In contrast, the isotopic composition of teeth from the marine Kaibab Formation is characterised by low δ18OP values in the range of 13.4–15.6‰ VSMOW while 87Sr/86Sr ratios of around 0.70821 are closer to the Roadian seawater value. The distinctly depleted δ18OP values cannot be readily explained by fluvially affected freshening in a nearshore marine environment, so a diagenetic alteration of the Kaibab material seems to be more likely, excluding it from further interpretation. 相似文献
37.
The plasma membrane-localised FLAGELLIN SENSING 2 (FLS2) receptor is an important component of plant immunity against potentially pathogenic bacteria, acting to recognise the conserved flg22 peptide of flagellin. FLS2 shares the common structure of transmembrane receptor kinases with a receptor-like ectodomain composed of leucine-rich repeats (LRR) and an active intracellular kinase domain. Upon ligand binding, FLS2 dimerises with the regulatory LRR-receptor kinase BRI1-associated kinase 1, which in turn triggers downstream signalling cascades. Although lacking crystal structure data, recent advances have been made in our understanding of flg22 recognition based on structural and functional analyses of FLS2. These studies have revealed critical regions/residues of FLS2 and post-translational modifications that regulate the abundance and activity of this receptor. In this review, we present the current knowledge on the structural mechanism of the FLS2–flg22 interaction and subsequent receptor-mediated signalling. 相似文献
38.
39.
Václav Šlouf Marcel Fuciman Silke Johanning Eckhard Hofmann Harry A. Frank Tomáš Polívka 《Photosynthesis research》2013,117(1-3):257-265
The major light-harvesting complex of Amphidinium (A.) carterae, chlorophyll-a–chlorophyll-c 2–peridinin–protein complex (acpPC), was studied using ultrafast pump-probe spectroscopy at low temperature (60 K). An efficient peridinin–chlorophyll-a energy transfer was observed. The stimulated emission signal monitored in the near-infrared spectral region was stronger when redder part of peridinin pool was excited, indicating that these peridinins have the S1/ICT (intramolecular charge-transfer) state with significant charge-transfer character. This may lead to enhanced energy transfer efficiency from “red” peridinins to chlorophyll-a. Contrary to the water-soluble antenna of A. carterae, peridinin–chlorophyll-a protein, the energy transfer rates in acpPC were slower under low-temperature conditions. This fact underscores the influence of the protein environment on the excited-state dynamics of pigments and/or the specificity of organization of the two pigment–protein complexes. 相似文献
40.