排序方式: 共有100条查询结果,搜索用时 46 毫秒
81.
F Odoardi C Sie K Streyl VK Ulaganathan C Schläger D Lodygin K Heckelsmiller W Nietfeld J Ellwart WE Klinkert C Lottaz M Nosov V Brinkmann R Spang H Lehrach M Vingron H Wekerle C Flügel-Koch A Flügel 《Nature》2012,488(7413):675-679
The blood–brain barrier (BBB) and the environment of the central nervous system (CNS) guard the nervous tissue from peripheral immune cells. In the autoimmune disease multiple sclerosis, myelin-reactive T-cell blasts are thought to transgress the BBB and create a pro-inflammatory environment in the CNS, thereby making possible a second autoimmune attack that starts from the leptomeningeal vessels and progresses into the parenchyma. Using a Lewis rat model of experimental autoimmune encephalomyelitis, we show here that contrary to the expectations of this concept, T-cell blasts do not efficiently enter the CNS and are not required to prepare the BBB for immune-cell recruitment. Instead, intravenously transferred T-cell blasts gain the capacity to enter the CNS after residing transiently within the lung tissues. Inside the lung tissues, they move along and within the airways to bronchus-associated lymphoid tissues and lung-draining mediastinal lymph nodes before they enter the blood circulation from where they reach the CNS. Effector T cells transferred directly into the airways showed a similar migratory pattern and retained their full pathogenicity. On their way the T cells fundamentally reprogrammed their gene-expression profile, characterized by downregulation of their activation program and upregulation of cellular locomotion molecules together with chemokine and adhesion receptors. The adhesion receptors include ninjurin 1, which participates in T-cell intravascular crawling on cerebral blood vessels. We detected that the lung constitutes a niche not only for activated T cells but also for resting myelin-reactive memory T cells. After local stimulation in the lung, these cells strongly proliferate and, after assuming migratory properties, enter the CNS and induce paralytic disease. The lung could therefore contribute to the activation of potentially autoaggressive T cells and their transition to a migratory mode as a prerequisite to entering their target tissues and inducing autoimmune disease. 相似文献
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Krassimira Angelova Angelo Felline Moon Lee Manish Patel David Puett Francesca Fanelli 《Cellular and molecular life sciences : CMLS》2011,68(7):1227-1239
The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic
gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants,
combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible
for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids
in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active
states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular
sides in both functional states with emphasis on the active one. In this respect, non-conservative loss-of-function mutations
of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding
domain and G protein recognition regions. 相似文献
84.
André Ferreira da Silva Francesca Romana Mariotti Valdemar Máximo Silvia Campello 《Cellular and molecular life sciences : CMLS》2014,71(12):2313-2324
Mitochondria are highly dynamic and functionally versatile organelles that continuously fragment and fuse in response to different physiological needs of the cell. The list of proteins that strictly regulate the morphology of these organelles is constantly growing, adding new players every day and new pieces to the comprehension and elucidation of this complex machinery. The structural complexity of mitochondria is only paralled by their functional versatility. Indeed, changes in mitochondria shape play critical roles in vertebrate development programmed cell death and in various processes of normal cell physiology, such as calcium signaling, reactive oxygen species production, and lifespan. Here, we present the latest findings on the regulation of mitochondrial dynamics and some of their physiological roles, focusing on cell migration. In cells where migration represents a crucial function in their physiology, such as T and tumoral metastatic cells, mitochondria need to be fragmented and recruited to specific subcellular regions to make movement possible. In depth analysis of this role of mitochondrial dynamics should help in identifying potential targeted therapy against cancer or in improving the immune system’s efficiency. 相似文献
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This paper traces the reception of Babylonian astronomy into the history of science, beginning in early to mid twentieth century when cuneiform astronomical sources became available to the scholarly public. The dominant positivism in philosophy of science of this time influenced criteria employed in defining and demarcating science by historians, resulting in a persistently negative assessment of the nature of knowledge evidenced in cuneiform sources. Ancient Near Eastern astronomy (and astrology) was deemed pre- or non-scientific, and even taken to reflect a stage in the evolution of thought before the emergence of science (in ancient Greece). Two principal objections are examined: first, that the Near East produced merely practical as opposed to theoretical knowledge and, second, that astronomy was in the service of astrology and religion. As the notion of a universal scientific method has been dismantled by post-positivists and constructivists of the second half of the twentieth century, an interest in varieties of intellectual and cultural contexts for science has provided a new ground for the re-consideration of Babylonian astronomical texts as science developed here. 相似文献
87.
Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response
88.
Viviana Volta Anne Beugnet Simone Gallo Laura Magri Daniela Brina Elisa Pesce Piera Calamita Francesca Sanvito Stefano Biffo 《Cellular and molecular life sciences : CMLS》2013,70(8):1439-1450
The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus. 相似文献
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Steinberg KM Antonacci F Sudmant PH Kidd JM Campbell CD Vives L Malig M Scheinfeldt L Beggs W Ibrahim M Lema G Nyambo TB Omar SA Bodo JM Froment A Donnelly MP Kidd KK Tishkoff SA Eichler EE 《Nature genetics》2012,44(8):872-880
The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2') lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps. 相似文献