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排序方式: 共有1409条查询结果,搜索用时 453 毫秒
51.
Roniel Cabrera Miguel Ararat Yiling Xu Todd Brusko Clive Wasserfall Mark A. Atkinson Lung Ji Chang Chen Liu David R. Nelson 《Cancer immunology, immunotherapy : CII》2013,62(4):737-746
Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25? effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from peripheral mononuclear cells of HCC patients to determine immune reactivity by thymidine incorporation, ELISA and flow cytometry. Teff cultured alone or with Treg were supplemented with different concentrations of sorafenib. The effects of sorafenib on Teff responses were dose-dependent. Pharmacologic doses of sorafenib decreased Teff activation by down regulating CD25 surface expression. In contrast, sub-pharmacologic concentrations of sorafenib resulted in Teff activation. These low doses of sorafenib in the Teff cultures led to a significant increase in Teff proliferation, IL2 secretion and up-regulation of CD25 expression on the cell surface. In addition, low doses of sorafenib in the suppression Teff/Treg cocultures restored Teff responses by eliminating Treg suppression. The loss of Treg suppressive function correlated with an increase in IL2 and IL6 secretion. Our findings show that sub-pharmacologic doses of sorafenib impact subsets of T cells differently, selectively increasing Teff activation while blocking Treg function. In conclusion, this study describes novel immune activating properties of low doses of sorafenib by promoting immune responsiveness in patients with HCC. 相似文献
52.
Although environmental modification by ecosystem engineers influences species distributions and abundances and ecological process rates, general determinants of the environmental states of engineered landscapes are not well understood. Here we develop a general, spatially implicit model of engineered landscapes that includes parameters driving engineer populations (demographics, environmental modification) and environmental decay. We show that average environmental states and heterogeneities of landscapes are the result of a balance between parameters determining engineering rates and decay rates that can be expressed as a net engineering ratio (NER). This ratio highlights the need to include environmental decay in ecosystem engineering studies. Moreover, it defines a significant engineer as one that can alter the environment despite decay and generates expectations for different kinds of effects on the engineer, other species and ecological processes depending on ratio values. Finally, it suggests that, in general, decay places limits as to what can be inferred about engineer population dynamics from environmental dynamics and vice versa. 相似文献
53.
54.
Shari L. Wiseman Yoshio Shimizu Clive Palfrey Angus C. Nairn 《The Journal of biological chemistry》2013,288(24):17803-17811
Protein translation and degradation are critical for proper protein homeostasis, yet it remains unclear how these processes are dynamically regulated, or how they may directly balance or synergize with each other. An important translational control mechanism is the Ca2+/calmodulin-dependent phosphorylation of eukaryotic elongation factor-2 (eEF-2) by eukaryotic elongation factor-2 kinase (EF2K), which inhibits elongation of nascent polypeptide chains during translation. We previously described a reduction of EF2K activity in PC12 cells treated with NGF or forskolin. Here, we show that both forskolin- and IGF-1-mediated reductions of EF2K activity in PC12 cells are due to decreased EF2K protein levels, and this is attenuated by application of the proteasome inhibitor, MG132. We further demonstrate that proteasome-mediated degradation of EF2K occurs in response to A2A-type adenosine receptor stimulation, and that activation of protein kinase A (PKA) or phospho-mimetic mutation of the previously characterized PKA site, Ser-499, were sufficient to induce EF2K turnover in PC12 cells. A similar EF2K degradation mechanism was observed in primary neurons and HEK cells. Expression of a dominant-negative form of Cul1 in HEK cells demonstrated that EF2K levels are regulated by an SCF-type ubiquitin E3 ligase. Specifically, EF2K binds to the F-box proteins, βTRCP1 and βTRCP2, and βTRCP regulates EF2K levels and polyubiquitylation. We propose that the proteasomal degradation of EF2K provides a mechanistic link between activity-dependent protein synthesis and degradation. 相似文献
55.
56.
Nafisa-Katrin Seich al Basatena Clive J. Hoggart Lachlan J. Coin Paul F. O’Reilly 《Genetics》2013,193(1):243-253
In recent years it has emerged that structural variants have a substantial impact on genomic variation. Inversion polymorphisms represent a significant class of structural variant, and despite the challenges in their detection, data on inversions in the human genome are increasing rapidly. Statistical methods for inferring parameters such as the recombination rate and the selection coefficient have generally been developed without accounting for the presence of inversions. Here we exploit new software for simulating inversions in population genetic data, invertFREGENE, to assess the potential impact of inversions on such methods. Using data simulated by invertFREGENE, as well as real data from several sources, we test whether large inversions have a disruptive effect on widely applied population genetics methods for inferring recombination rates, for detecting selection, and for controlling for population structure in genome-wide association studies (GWAS). We find that recombination rates estimated by LDhat are biased downward at inversion loci relative to the true contemporary recombination rates at the loci but that recombination hotspots are not falsely inferred at inversion breakpoints as may have been expected. We find that the integrated haplotype score (iHS) method for detecting selection appears robust to the presence of inversions. Finally, we observe a strong bias in the genome-wide results of principal components analysis (PCA), used to control for population structure in GWAS, in the presence of even a single large inversion, confirming the necessity to thin SNPs by linkage disequilibrium at large physical distances to obtain unbiased results. 相似文献
57.
Jessica Worthington Wilmer Mitchell Lyons Kristen E. Lee Clive A. McAlpine Frank N. Carrick 《Molecular ecology》2013,22(14):3752-3765
Landscape genetics offers a powerful approach to understanding species' dispersal patterns. However, a central obstacle is to account for ecological processes operating at multiple spatial scales, while keeping research outcomes applicable to conservation management. We address this challenge by applying a novel multilevel regression approach to model landscape drivers of genetic structure at both the resolution of individuals and at a spatial resolution relevant to management (i.e. local government management areas: LGAs) for the koala (Phascolartos cinereus) in Australia. Our approach allows for the simultaneous incorporation of drivers of landscape‐genetic relationships operating at multiple spatial resolutions. Using microsatellite data for 1106 koalas, we show that, at the individual resolution, foliage projective cover (FPC) facilitates high gene flow (i.e. low resistance) until it falls below approximately 30%. Out of six additional land‐cover variables, only highways and freeways further explained genetic distance after accounting for the effect of FPC. At the LGA resolution, there was significant variation in isolation‐by‐resistance (IBR) relationships in terms of their slopes and intercepts. This was predominantly explained by the average resistance distance among LGAs, with a weaker effect of historical forest cover. Rates of recent landscape change did not further explain variation in IBR relationships among LGAs. By using a novel multilevel model, we disentangle the effect of landscape resistance on gene flow at the fine resolution (i.e. among individuals) from effects occurring at coarser resolutions (i.e. among LGAs). This has important implications for our ability to identify appropriate scale‐dependent management actions. 相似文献
58.
Bo Fernholm Michael Norén Sven O. Kullander Andrea M. Quattrini Vincent Zintzen Clive D. Roberts Hin‐Kiu Mok Chien‐Hsien Kuo 《Journal of Zoological Systematics and Evolutionary Research》2013,51(4):296-307
A recent phylogenetic analysis of the Myxinidae based on the 16S rRNA gene resulted in synonymization of Paramyxine with Eptatretus. This created homonymy of Paramyxine fernholmi with Eptatretus fernholmi and Paramyxine wisneri with Eptatretus wisneri. In order to resolve this nomenclatural dilemma, we made a more extensive phylogenetic assessment of the Myxinidae and examined the nomenclature of the family. We used 75 sequences (37 of which new for this study) of a 561 bp fragment of the 16S rRNA gene, representing 33 species, and 72 sequences (37 of which new for this study) of a 687 bp fragment of the cytochrome c oxidase subunit I (COI) gene, representing 23 species, to reconstruct the phylogeny of Myxinidae. The monophyly of the subfamily Myxininae, traditionally characterized by having a single pair of external gill openings, was rejected (0.50 Bayesian posterior probability) by the 16S analysis, but supported by the COI and combined COI+16S analyses (0.99 and 0.81 Bpp, respectively). The monophyly of the subfamily Eptatretinae, characterized by having several pairs of external gill openings, was not supported by the 16S analysis and rejected by the COI and combined COI+16S analysis due to the placement of Eptatretus lopheliae as the earliest branch of Myxinidae (0.71 and 0.57 Bpp, respectively). Eptatretus lopheliae and Eptatretus rubicundus formed a monophyletic group and were allocated to a new genus, Rubicundus, characterized by the presence of an elongated tubular nostril and reddish coloration. A new monotypic subfamily, Rubicundinae, was proposed for Rubicundus. The synonymy of the genera Paramyxine and Quadratus with Eptatretus was confirmed. E. fernholmi is renamed Eptatretus luzonicus. Eptatretus wisneri was renamed Eptatretus bobwisneri. Petromyzon cirrhatus Forster, 1801, Homea banksii Fleming, 1822, and Bdellostoma forsteri Müller, 1836 are synonyms, but no type specimens are known to exist. Petromyzon cirrhatus was designated as type species of Eptatretus, conserving present usage. Gastrobranchus dombeyi Shaw, 1804 has priority over other names for Chilean myxinids. Bdellostoma stoutii was designated as type species of Polistotrema Gill. The validity of the Western Atlantic Myxine limosa as distinct from the Eastern Atlantic Myxine glutinosa was confirmed. 相似文献
59.
Eucalypts face increasing climate stress 总被引:1,自引:0,他引:1
Global climate change is already impacting species and ecosystems across the planet. Trees, although long‐lived, are sensitive to changes in climate, including climate extremes. Shifts in tree species' distributions will influence biodiversity and ecosystem function at scales ranging from local to landscape; dry and hot regions will be especially vulnerable. The Australian continent has been especially susceptible to climate change with extreme heat waves, droughts, and flooding in recent years, and this climate trajectory is expected to continue. We sought to understand how climate change may impact Australian ecosystems by modeling distributional changes in eucalypt species, which dominate or codominate most forested ecosystems across Australia. We modeled a representative sample of Eucalyptus and Corymbia species (n = 108, or 14% of all species) using newly available Representative Concentration Pathway (RCP) scenarios developed for the 5th Assessment Report of the IPCC, and bioclimatic and substrate predictor variables. We compared current, 2025, 2055, and 2085 distributions. Overall, Eucalyptus and Corymbia species in the central desert and open woodland regions will be the most affected, losing 20% of their climate space under the mid‐range climate scenario and twice that under the extreme scenario. The least affected species, in eastern Australia, are likely to lose 10% of their climate space under the mid‐range climate scenario and twice that under the extreme scenario. Range shifts will be lateral as well as polewards, and these east–west transitions will be more significant, reflecting the strong influence of precipitation rather than temperature changes in subtropical and midlatitudes. These net losses, and the direction of shifts and contractions in range, suggest that many species in the eastern and southern seaboards will be pushed toward the continental limit and that large tracts of currently treed landscapes, especially in the continental interior, will change dramatically in terms of species composition and ecosystem structure. 相似文献
60.
Hisham Mohammed Clive D’Santos Aurelien A. Serandour H. Raza Ali Gordon D. Brown Alan Atkins Oscar M. Rueda Kelly A. Holmes Vasiliki Theodorou Jessica L.L. Robinson Wilbert Zwart Amel Saadi Caryn S. Ross-Innes Suet-Feung Chin Suraj Menon John Stingl Carlo Palmieri Carlos Caldas Jason S. Carroll 《Cell reports》2013,3(2):342-349
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