排序方式: 共有127条查询结果,搜索用时 26 毫秒
91.
Birmingham CL Canadien V Kaniuk NA Steinberg BE Higgins DE Brumell JH 《Nature》2008,451(7176):350-354
Listeria monocytogenes is an intracellular bacterial pathogen that replicates rapidly in the cytosol of host cells during acute infection. Surprisingly, these bacteria were found to occupy vacuoles in liver granuloma macrophages during persistent infection of severe combined immunodeficient (SCID) mice. Here we show that L. monocytogenes can replicate in vacuoles within macrophages. In livers of SCID mice infected for 21 days, we observed bacteria in large LAMP1(+) compartments that we termed spacious Listeria-containing phagosomes (SLAPs). SLAPs were also observed in vitro, and were found to be non-acidic and non-degradative compartments that are generated in an autophagy-dependent manner. The replication rate of bacteria in SLAPs was found to be reduced compared to the rate of those in the cytosol. Listeriolysin O (LLO, encoded by hly), a pore-forming toxin essential for L. monocytogenes virulence, was necessary and sufficient for SLAP formation. A L. monocytogenes mutant with low LLO expression was impaired for phagosome escape but replicated slowly in SLAPs over a 72 h period. Therefore, our studies reveal a role for LLO in promoting L. monocytogenes replication in vacuoles and suggest a mechanism by which this pathogen can establish persistent infection in host macrophages. 相似文献
92.
Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project 总被引:2,自引:0,他引:2
ENCODE Project Consortium Birney E Stamatoyannopoulos JA Dutta A Guigó R Gingeras TR Margulies EH Weng Z Snyder M Dermitzakis ET Thurman RE Kuehn MS Taylor CM Neph S Koch CM Asthana S Malhotra A Adzhubei I Greenbaum JA Andrews RM Flicek P Boyle PJ Cao H Carter NP Clelland GK Davis S Day N Dhami P Dillon SC Dorschner MO Fiegler H Giresi PG Goldy J Hawrylycz M Haydock A Humbert R James KD Johnson BE Johnson EM Frum TT Rosenzweig ER Karnani N Lee K Lefebvre GC Navas PA Neri F Parker SC Sabo PJ 《Nature》2007,447(7146):799-816
93.
In situ phosphatization and reductive cell division have recently been discovered within the vacuolate sulphur-oxidizing bacteria. Here we show that certain Neoproterozoic Doushantuo Formation (about 600 million years bp) microfossils, including structures previously interpreted as the oldest known metazoan eggs and embryos, can be interpreted as giant vacuolate sulphur bacteria. Sulphur bacteria of the genus Thiomargarita have sizes and morphologies similar to those of many Doushantuo microfossils, including symmetrical cell clusters that result from multiple stages of reductive division in three planes. We also propose that Doushantuo phosphorite precipitation was mediated by these bacteria, as shown in modern Thiomargarita-associated phosphogenic sites, thus providing the taphonomic conditions that preserved other fossils known from the Doushantuo Formation. 相似文献
94.
Laurie CC Laurie CA Rice K Doheny KF Zelnick LR McHugh CP Ling H Hetrick KN Pugh EW Amos C Wei Q Wang LE Lee JE Barnes KC Hansel NN Mathias R Daley D Beaty TH Scott AF Ruczinski I Scharpf RB Bierut LJ Hartz SM Landi MT Freedman ND Goldin LR Ginsburg D Li J Desch KC Strom SS Blot WJ Signorello LB Ingles SA Chanock SJ Berndt SI Le Marchand L Henderson BE Monroe KR Heit JA de Andrade M Armasu SM Regnier C Lowe WL Hayes MG Marazita ML Feingold E Murray JC Melbye M Feenstra B Kang JH Wiggs JL 《Nature genetics》2012,44(6):642-650
We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18). 相似文献
95.
Kote-Jarai Z Olama AA Giles GG Severi G Schleutker J Weischer M Campa D Riboli E Key T Gronberg H Hunter DJ Kraft P Thun MJ Ingles S Chanock S Albanes D Hayes RB Neal DE Hamdy FC Donovan JL Pharoah P Schumacher F Henderson BE Stanford JL Ostrander EA Sorensen KD Dörk T Andriole G Dickinson JL Cybulski C Lubinski J Spurdle A Clements JA Chambers S Aitken J Gardiner RA Thibodeau SN Schaid D John EM Maier C Vogel W Cooney KA Park JY Cannon-Albright L Brenner H Habuchi T Zhang HW Lu YJ Kaneva R 《Nature genetics》2011,43(8):785-791
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified. 相似文献
96.
Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ Greenway SC Stram DO Le Marchand L Kolonel LN Frasco M Wong D Pooler LC Ardlie K Oakley-Girvan I Whittemore AS Cooney KA John EM Ingles SA Altshuler D Henderson BE Reich D 《Nature genetics》2007,39(5):638-644
After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein. 相似文献
97.
98.
Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy 总被引:1,自引:0,他引:1
P Koppikar N Bhagwat O Kilpivaara T Manshouri M Adli T Hricik F Liu LM Saunders A Mullally O Abdel-Wahab L Leung A Weinstein S Marubayashi A Goel M Gönen Z Estrov BL Ebert G Chiosis SD Nimer BE Bernstein S Verstovsek RL Levine 《Nature》2012,489(7414):155-159
The identification of somatic activating mutations in JAK2 (refs?1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors. 相似文献
99.
An integrated encyclopedia of DNA elements in the human genome 总被引:4,自引:0,他引:4
ENCODE Project Consortium BE Bernstein E Birney I Dunham ED Green C Gunter M Snyder 《Nature》2012,489(7414):57-74
100.
Tomlins SA Laxman B Dhanasekaran SM Helgeson BE Cao X Morris DS Menon A Jing X Cao Q Han B Yu J Wang L Montie JE Rubin MA Pienta KJ Roulston D Shah RB Varambally S Mehra R Chinnaiyan AM 《Nature》2007,448(7153):595-599
Recently, we identified recurrent gene fusions involving the 5' untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers. Whereas TMPRSS2-ERG fusions are predominant, fewer TMPRSS2-ETV1 cases have been identified than expected on the basis of the frequency of high (outlier) expression of ETV1 (refs 3-13). Here we explore the mechanism of ETV1 outlier expression in human prostate tumours and prostate cancer cell lines. We identified previously unknown 5' fusion partners in prostate tumours with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15orf21), and a strongly expressed housekeeping gene (HNRPA2B1). To study aberrant activation of ETV1, we identified two prostate cancer cell lines, LNCaP and MDA-PCa 2B, that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-megabase prostate-specific region at 14q13.3-14q21.1 in both LNCaP cells (cryptic insertion) and MDA-PCa 2B cells (balanced translocation). Because the common factor of these rearrangements is aberrant ETV1 overexpression, we recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in the mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrates that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Subversion of active genomic regulatory elements may serve as a more generalized mechanism for carcinoma development. Furthermore, the identification of androgen-repressed and insensitive 5' fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer. 相似文献