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排序方式: 共有274条查询结果,搜索用时 31 毫秒
31.
Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis 总被引:13,自引:0,他引:13
Giorgio M Migliaccio E Orsini F Paolucci D Moroni M Contursi C Pelliccia G Luzi L Minucci S Marcaccio M Pinton P Rizzuto R Bernardi P Paolucci F Pelicci PG 《Cell》2005,122(2):221-233
Reactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biological significance and the underlying molecular mechanisms remain undetermined. P66Shc is a genetic determinant of life span in mammals, which regulates ROS metabolism and apoptosis. We report here that p66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling molecules for apoptosis. For this function, p66Shc utilizes reducing equivalents of the mitochondrial electron transfer chain through the oxidation of cytochrome c. Redox-defective mutants of p66Shc are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals. 相似文献
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Richter SN Gatto B Tabarrini O Fravolini A Palumbo M 《Bioorganic & medicinal chemistry letters》2005,15(19):4247-4251
Structural modifications introduced in 6-amino-quinolones to increase antiviral activity can strongly affect cytotoxicity to host cells. By competition to Tat-TAR complex and binding experiments to viral and cellular DNA and RNA structures, we show that the nature of the substituent at position 7 modifies drug affinity and specificity for the nucleic acid. Interestingly, the basicity of the above substituent modulates chelation of the quinolone template to magnesium ions, which, in turn, critically affects the potency and target selectivity in the antiviral quinolone family. 相似文献
34.
Migliaccio M Raj K Menzel O Rufer N 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(6):3335-3343
Human T lymphocytes can be numerically expanded in vitro only to a limited extent. The cyclin-dependent kinase inhibitor p16(INK4a) is essential in the control of cellular proliferation, and its expression, in epithelial cells, is associated with irreversible growth arrest. Using long-term cultured CD8+ T lymphocytes, we have investigated the role of the p16/pRb pathway in the regulation of T cell proliferation and senescence. In this study, we describe at least two mechanisms that cause replicative growth arrest in cultured lymphocytes. The first one depends on the expression of p16(INK4a) and is directly responsible for the exit of a significant proportion of CD8+ T cells from the proliferative population. This induced p16 expression pattern is observed during each round of mitogen stimulation and is not related to activation-induced cell death. Importantly, knocking down p16(INK4a) expression allows increased proliferation of T cells. The second one is a phenomenon that resembles human fibroblast senescence, but is independent of p16(INK4a) and of telomere attrition. Interestingly, virtually all pRb proteins in the senescent population are found in the active form. Our data indicate that newly synthesized p16(INK4a) limits the proliferation of T lymphocytes that respond to mitogen, but is not required for the loss of mitogen responsiveness called senescence. 相似文献
35.
Orsini F Migliaccio E Moroni M Contursi C Raker VA Piccini D Martin-Padura I Pelliccia G Trinei M Bono M Puri C Tacchetti C Ferrini M Mannucci R Nicoletti I Lanfrancone L Giorgio M Pelicci PG 《The Journal of biological chemistry》2004,279(24):25689-25695
P66Shc regulates life span in mammals and is a critical component of the apoptotic response to oxidative stress. It functions as a downstream target of the tumor suppressor p53 and is indispensable for the ability of oxidative stress-activated p53 to induce apoptosis. The molecular mechanisms underlying the apoptogenic effect of p66Shc are unknown. Here we report the following three findings. (i) The apoptosome can be properly activated in vitro in the absence of p66Shc only if purified cytochrome c is supplied. (ii) Cytochrome c release after oxidative signals is impaired in the absence of p66Shc. (iii) p66Shc induces the collapse of the mitochondrial trans-membrane potential after oxidative stress. Furthermore, we showed that a fraction of cytosolic p66Shc localizes within mitochondria where it forms a complex with mitochondrial Hsp70. Treatment of cells with ultraviolet radiation induced the dissociation of this complex and the release of monomeric p66Shc. We propose that p66Shc regulates the mitochondrial pathway of apoptosis by inducing mitochondrial damage after dissociation from an inhibitory protein complex. Genetic and biochemical evidence suggests that mitochondria regulate life span through their effects on the energetic metabolism (mitochondrial theory of aging). Our data suggest that mitochondrial regulation of apoptosis might also contribute to life span determination. 相似文献
36.
Brendan P. Kelly Oriana H. Badajos Mervi Kunnasranta John R. Moran Micaela Martinez-Bakker Douglas Wartzok Peter Boveng 《Polar Biology》2010,33(8):1095-1109
Population structure and patterns of habitat use among ringed seals (Phoca hispida) are poorly known, in part because seasonal movements have not been adequately documented. We monitored the movements of
98 ringed seals in the Beaufort and Chukchi seas between 1990 and 2006 using three forms of telemetry. In the winter—spring
period (when the seals were occupying shorefast ice), we used radio and ultra-sonic tags to track movements above and below
the ice, respectively. We used satellite-linked transmitters in summer and fall (when the seals ranged away from their winter
sites) to track at-sea movements. In the shorefast ice habitat, the home ranges of 27 adult males ranged from <1 to 13.9 km2 (median = 0.628) while the home ranges of 28 adult females ranged from <1 to 27.9 km2 (median = 0.652). The 3-dimensional volumes used by 9 seals tracked acoustically under the ice averaged 0.07 (SD = 0.04) km3 for subadults and adult males and 0.13 (SD = 0.04) km3 for adult females. Three of the radio-tracked seals and 9 tracked by satellite ranged up to 1,800 km from their winter/spring
home ranges in summer but returned to the same small (1–2 km2) sites during the ice-bound months in the following year. The restricted movements of ringed seals during the ice-bound season—including
the breeding season—limits their foraging activities for most of the year and may minimize gene flow within the species. 相似文献
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Migliaccio M Alves PM Romero P Rufer N 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(4):2173-2182
Human Ag-specific CD8(+) T lymphocytes are heterogeneous and include functionally distinct populations. In this study, we report that at least two distinct mechanisms control the expansion of circulating naive, memory, and effector CD8(+) T lymphocytes when exposed to mitogen or Ag stimulation. The first one leads to apoptosis and occurs shortly after in vitro stimulation. Susceptibility to cell death is prominent among primed T cell subsets, and it is inversely correlated with the size of the ex vivo Bcl-2(high) population within these subsets. Importantly, the Bcl-2(high) phenotype is associated to the proportion of responsive CD8(+) T cells, independently of their differentiation stage. The second one depends on the expression of newly synthesized cyclin-dependent kinase inhibitor p16(INK4a) that occurs in a significant fraction of T cells that had been actively cycling, leading to their cell cycle arrest upon stimulation. Strikingly, accumulation of p16(INK4a) protein preferentially occurs in naive as opposed to primed derived T lymphocytes and is not related to apoptosis. Significant levels of p16 are readily detectable in a small number of ex vivo CD8(+) T cells. Our observations reveal that activation-induced p16 expression represents an alternative process to apoptosis, limiting the proliferation potential of activated naive derived T lymphocytes. 相似文献
39.
Recent advances have increased excitement about the potential for therapeutic production of red blood cells (RBCs) in vitro. However, generation of RBCs in the large numbers required for transfusion remains a significant challenge. In this article, we summarize recent progress in producing RBCs from various cell sources, and discuss the hurdles that remain for translation into the clinical arena. 相似文献
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