排序方式: 共有43条查询结果,搜索用时 0 毫秒
31.
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
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Gudbjartsson DF Sulem P Stacey SN Goldstein AM Rafnar T Sigurgeirsson B Benediktsdottir KR Thorisdottir K Ragnarsson R Sveinsdottir SG Magnusson V Lindblom A Kostulas K Botella-Estrada R Soriano V Juberías P Grasa M Saez B Andres R Scherer D Rudnai P Gurzau E Koppova K Kiemeney LA Jakobsdottir M Steinberg S Helgason A Gretarsdottir S Tucker MA Mayordomo JI Nagore E Kumar R Hansson J Olafsson JH Gulcher J Kong A Thorsteinsdottir U Stefansson K 《Nature genetics》2008,40(7):886-891
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation. 相似文献
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Large recurrent microdeletions associated with schizophrenia 总被引:1,自引:0,他引:1
Stefansson H Rujescu D Cichon S Pietiläinen OP Ingason A Steinberg S Fossdal R Sigurdsson E Sigmundsson T Buizer-Voskamp JE Hansen T Jakobsen KD Muglia P Francks C Matthews PM Gylfason A Halldorsson BV Gudbjartsson D Thorgeirsson TE Sigurdsson A Jonasdottir A Jonasdottir A Bjornsson A Mattiasdottir S Blondal T Haraldsson M Magnusdottir BB Giegling I Möller HJ Hartmann A Shianna KV Ge D Need AC Crombie C Fraser G Walker N Lonnqvist J Suvisaari J Tuulio-Henriksson A Paunio T Toulopoulou T 《Nature》2008,455(7210):232-236
Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. 相似文献
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A Kong ML Frigge G Masson S Besenbacher P Sulem G Magnusson SA Gudjonsson A Sigurdsson A Jonasdottir A Jonasdottir WS Wong G Sigurdsson GB Walters S Steinberg H Helgason G Thorleifsson DF Gudbjartsson A Helgason OT Magnusson U Thorsteinsdottir K Stefansson 《Nature》2012,488(7412):471-475
Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20?×?10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5?years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism. 相似文献
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Lithium attenuates drug-induced hyperactivity in rats 总被引:1,自引:0,他引:1
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Solar wind dynamic pressure and electric field as the main factors controlling Saturn's aurorae 总被引:1,自引:0,他引:1
Crary FJ Clarke JT Dougherty MK Hanlon PG Hansen KC Steinberg JT Barraclough BL Coates AJ Gérard JC Grodent D Kurth WS Mitchell DG Rymer AM Young DT 《Nature》2005,433(7027):720-722
The interaction of the solar wind with Earth's magnetosphere gives rise to the bright polar aurorae and to geomagnetic storms, but the relation between the solar wind and the dynamics of the outer planets' magnetospheres is poorly understood. Jupiter's magnetospheric dynamics and aurorae are dominated by processes internal to the jovian system, whereas Saturn's magnetosphere has generally been considered to have both internal and solar-wind-driven processes. This hypothesis, however, is tentative because of limited simultaneous solar wind and magnetospheric measurements. Here we report solar wind measurements, immediately upstream of Saturn, over a one-month period. When combined with simultaneous ultraviolet imaging we find that, unlike Jupiter, Saturn's aurorae respond strongly to solar wind conditions. But in contrast to Earth, the main controlling factor appears to be solar wind dynamic pressure and electric field, with the orientation of the interplanetary magnetic field playing a much more limited role. Saturn's magnetosphere is, therefore, strongly driven by the solar wind, but the solar wind conditions that drive it differ from those that drive the Earth's magnetosphere. 相似文献
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Mixing in fluids is a rapidly developing area in fluid mechanics, being an important industrial and environmental problem. The mixing of liquids at low Reynolds numbers is usually quite weak in simple flows, and it requires special devices to be efficient. Recently, the problem of mixing was solved analytically for a simple case of random flow, known as the Batchelor regime. Here we demonstrate experimentally that very viscous liquids containing a small amount of high-molecular-weight polymers can be mixed quite efficiently at very low Reynolds numbers, for a simple flow in a curved channel. A polymer concentration of only 0.001% suffices. The presence of the polymers leads to an elastic instability and to irregular flow, with velocity spectra corresponding to the Batchelor regime. Our detailed observations of the mixing in this regime enable us to confirm several important theoretical predictions: the probability distributions of the concentration exhibit exponential tails, moments of the distribution decay exponentially along the flow, and the spatial correlation function of concentration decays logarithmically. 相似文献