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991.
Many biological processes are regulated through the selective dephosphorylation of proteins. Protein serine-threonine phosphatases are assembled from catalytic subunits bound to diverse regulatory subunits that provide substrate specificity and subcellular localization. We describe a small molecule, guanabenz, that bound to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the α subunit of translation initiation factor 2 (eIF2α). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2α phosphorylation in human stressed cells, adjusting the protein production rates to levels manageable by available chaperones. This favored protein folding and thereby rescued cells from protein misfolding stress. Thus, regulatory subunits of phosphatases are drug targets, a property used here to restore proteostasis in stressed cells. 相似文献
992.
Griffitts JS Haslam SM Yang T Garczynski SF Mulloy B Morris H Cremer PS Dell A Adang MJ Aroian RV 《Science (New York, N.Y.)》2005,307(5711):922-925
The development of pest resistance threatens the effectiveness of Bacillus thuringiensis (Bt) toxins used in transgenic and organic farming. Here, we demonstrate that (i) the major mechanism for Bt toxin resistance in Caenorhabditis elegans entails a loss of glycolipid carbohydrates; (ii) Bt toxin directly and specifically binds glycolipids; and (iii) this binding is carbohydrate-dependent and relevant for toxin action in vivo. These carbohydrates contain the arthroseries core conserved in insects and nematodes but lacking in vertebrates. We present evidence that insect glycolipids are also receptors for Bt toxin. 相似文献
993.
Bleharski JR Li H Meinken C Graeber TG Ochoa MT Yamamura M Burdick A Sarno EN Wagner M Röllinghoff M Rea TH Colonna M Stenger S Bloom BR Eisenberg D Modlin RL 《Science (New York, N.Y.)》2003,301(5639):1527-1530
Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 toward interleukin-10 and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens. 相似文献
994.
Allen RL Bittner-Eddy PD Grenville-Briggs LJ Meitz JC Rehmany AP Rose LE Beynon JL 《Science (New York, N.Y.)》2004,306(5703):1957-1960
Plants are constantly exposed to attack by an array of diverse pathogens but lack a somatically adaptive immune system. In spite of this, natural plant populations do not often suffer destructive disease epidemics. Elucidating how allelic diversity within plant genes that function to detect pathogens (resistance genes) counteracts changing structures of pathogen genes required for host invasion (pathogenicity effectors) is critical to our understanding of the dynamics of natural plant populations. The RPP13 resistance gene is the most polymorphic gene analyzed to date in the model plant Arabidopsis thaliana. Here we report the cloning of the avirulence gene, ATR13, that triggers RPP13-mediated resistance, and we show that it too exhibits extreme levels of amino acid polymorphism. Evidence of diversifying selection visible in both components suggests that the host and pathogen may be locked in a coevolutionary conflict at these loci, where attempts to evade host resistance by the pathogen are matched by the development of new detection capabilities by the host. 相似文献
995.
Hátún H Sandø AB Drange H Hansen B Valdimarsson H 《Science (New York, N.Y.)》2005,309(5742):1841-1844
During the past decade, record-high salinities have been observed in the Atlantic Inflow to the Nordic Seas and the Arctic Ocean, which feeds the North Atlantic thermohaline circulation (THC). This may counteract the observed long-term increase in freshwater supply to the area and tend to stabilize the North Atlantic THC. Here we show that the salinity of the Atlantic Inflow is tightly linked to the dynamics of the North Atlantic subpolar gyre circulation. Therefore, when assessing the future of the North Atlantic THC, it is essential that the dynamics of the subpolar gyre and its influence on the salinity are taken into account. 相似文献
996.
Substances that accumulate to hazardous levels in living organisms pose environmental and human-health risks, which governments seek to reduce or eliminate. Regulatory authorities identify bioaccumulative substances as hydrophobic, fat-soluble chemicals having high octanol-water partition coefficients (K(OW))(>/=100,000). Here we show that poorly metabolizable, moderately hydrophobic substances with a K(OW) between 100 and 100,000, which do not biomagnify (that is, increase in chemical concentration in organisms with increasing trophic level) in aquatic food webs, can biomagnify to a high degree in food webs containing air-breathing animals (including humans) because of their high octanol-air partition coefficient (K(OA)) and corresponding low rate of respiratory elimination to air. These low K(OW)-high K(OA) chemicals, representing a third of organic chemicals in commercial use, constitute an unidentified class of potentially bioaccumulative substances that require regulatory assessment to prevent possible ecosystem and human-health consequences. 相似文献
997.
Funding bodies are coming to the aid of young scientists with a variety of programs aimed at helping them become independent investigators. 相似文献
998.
Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC 《Science (New York, N.Y.)》2003,301(5638):1374-1377
During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation in human B cells. A majority (55 to 75%) of all antibodies expressed by early immature B cells displayed self-reactivity, including polyreactive and anti-nuclear specificities. Most of these autoantibodies were removed from the population at two discrete checkpoints during B cell development. Inefficient checkpoint regulation would lead to substantial increases in circulating autoantibodies. 相似文献
999.
Rich TH Hopson JA Musser AM Flannery TF Vickers-Rich P 《Science (New York, N.Y.)》2005,307(5711):910-914
A dentary of the oldest known monotreme, the Early Cretaceous Teinolophos trusleri, has an internal mandibular trough, which in outgroups to mammals houses accessory jaw bones, and probable contact facets for angular, coronoid, and splenial bones. Certain of these accessory bones were detached from the mandible to become middle ear bones in mammals. Evidence that the angular (homologous with the mammalian ectotympanic) and the articular and prearticular (homologous with the mammalian malleus) bones retained attachment to the lower jaw in a basal monotreme indicates that the definitive mammalian middle ear evolved independently in living monotremes and therians (marsupials and placentals). 相似文献
1000.
Zhang SY Jouanguy E Ugolini S Smahi A Elain G Romero P Segal D Sancho-Shimizu V Lorenzo L Puel A Picard C Chapgier A Plancoulaine S Titeux M Cognet C von Bernuth H Ku CL Casrouge A Zhang XX Barreiro L Leonard J Hamilton C Lebon P Héron B Vallée L Quintana-Murci L Hovnanian A Rozenberg F Vivier E Geissmann F Tardieu M Abel L Casanova JL 《Science (New York, N.Y.)》2007,317(5844):1522-1527
Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3. 相似文献