全文获取类型
收费全文 | 2138篇 |
免费 | 183篇 |
出版年
2023年 | 18篇 |
2022年 | 28篇 |
2021年 | 60篇 |
2020年 | 32篇 |
2019年 | 70篇 |
2018年 | 71篇 |
2017年 | 70篇 |
2016年 | 80篇 |
2015年 | 141篇 |
2014年 | 123篇 |
2013年 | 143篇 |
2012年 | 202篇 |
2011年 | 169篇 |
2010年 | 116篇 |
2009年 | 92篇 |
2008年 | 111篇 |
2007年 | 93篇 |
2006年 | 84篇 |
2005年 | 81篇 |
2004年 | 90篇 |
2003年 | 65篇 |
2002年 | 75篇 |
2001年 | 25篇 |
2000年 | 14篇 |
1999年 | 15篇 |
1998年 | 11篇 |
1997年 | 11篇 |
1996年 | 9篇 |
1995年 | 7篇 |
1993年 | 13篇 |
1992年 | 15篇 |
1991年 | 13篇 |
1990年 | 10篇 |
1989年 | 13篇 |
1988年 | 11篇 |
1987年 | 11篇 |
1986年 | 5篇 |
1985年 | 13篇 |
1984年 | 7篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1980年 | 8篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1977年 | 8篇 |
1975年 | 8篇 |
1974年 | 6篇 |
1973年 | 9篇 |
1971年 | 4篇 |
1969年 | 4篇 |
排序方式: 共有2321条查询结果,搜索用时 192 毫秒
991.
Macchioni L Davidescu M Mannucci R Francescangeli E Nicoletti I Roberti R Corazzi L 《Biochimica et biophysica acta》2011,1811(3):203-208
The mitochondrial electron transport chain is a source of oxygen superoxide anion (O(2)(-)) that is dismutated to H(2)O(2). Although low levels of ROS are physiologically synthesized during respiration, their increase contributes to cell injury. Therefore, an efficient machinery for H(2)O(2) disposal is essential in mitochondria. In this study, the ability of brain mitochondria to acquire cardiolipin (CL), phosphatidylglycerol (PG), and phosphatidylserine (PS) in vitro through a fusion process was exploited to investigate lipid effects on ROS. MTT assay, oxygen consumption, and respiratory ratio indicated that the acquired phospholipids did not alter mitochondrial respiration and O(2)(-) production from succinate. However, in CL-enriched mitochondria, H(2)O(2) levels where 27% and 47% of control in the absence and in the presence of antimycin A, respectively, suggesting an increase in H(2)O(2) elimination. Concomitantly, cytochrome c (cyt c) was released outside mitochondria. Since free oxidized cyt c acquired peroxidase activity towards H(2)O(2) upon interaction with CL in vitro, a contribution of cyt c to H(2)O(2) disposal in mitochondria through CL conferred peroxidase activity is plausible. In this model, the accompanying CL peroxidation should weaken cyt c-CL interactions, favouring the detachment and release of the protein. Neither cyt c peroxidase activity was elicited by PS in vitro, nor cyt c release was observed in PS-enriched mitochondria, although H(2)O(2) levels were significantly decreased, suggesting a cyt c-independent role of PS in ROS metabolism in mitochondria. 相似文献
992.
993.
994.
Recently, we identified desmoglein 2 (DSG2) as the main receptor for a group of species B adenoviruses (Ads), including Ad3, a serotype that is widely distributed in the human population (H. Wang et al., Nat. Med. 17:96-104, 2011). In this study, we have attempted to delineate structural details of the Ad3 interaction with DSG2. For CAR- and CD46-interacting Ad serotypes, attachment to cells can be completely blocked by an excess of recombinant fiber knob protein, while soluble Ad3 fiber knob only inefficiently blocks Ad3 infection. We found that the DSG2-interacting domain(s) within Ad3 is formed by several fiber knob domains that have to be in the spatial constellation that is present in viral particles. Based on this finding, we generated a small recombinant, self-dimerizing protein containing the Ad3 fiber knob (Ad3-K/S/Kn). Ad3-K/S/Kn bound to DSG2 with high affinity and blocked Ad3 infection. We demonstrated by confocal immunofluorescence and transmission electron microscopy analyses that Ad3-K/S/Kn, through its binding to DSG2, triggered the transient opening of intercellular junctions in epithelial cells. The pretreatment of epithelial cells with Ad3-K/S/Kn resulted in increased access to receptors that are localized in or masked by epithelial junctions, e.g., CAR or Her2/neu. Ad3-K/S/Kn treatment released CAR from tight junctions and thus increased the transduction of epithelial cells by a serotype Ad5-based vector. Furthermore, the pretreatment of Her2/neu-positive breast cancer cells with Ad3-K/S/Kn increased the killing of cancer cells by the Her2/neu-targeting monoclonal antibody trastuzumab (Herceptin). This study widens our understanding of how Ads achieve high avidity to their receptors and the infection of epithelial tissue. The small recombinant protein Ad3-K/S/Kn has practical implications for the therapy of epithelial cancer and gene/drug delivery to normal epithelial tissues. 相似文献
995.
Elsa Addessi Alessandra Mancini Lara Crescimbene Elisabetta Visalberghi 《International journal of primatology》2011,32(1):83-98
Although numerous studies have examined token-directed behaviors in primates, few have done so in a social context despite the fact that most primate species live in complex groups. Here, we provided capuchin monkeys with a relatively limited budget of tokens, likely to elicit intragroup competition, and, after an overnight delay, we allowed them to exchange tokens while in a group setting. We aimed to 1) evaluate whether social context affects token-directed behaviors of knowledgeable subjects, i.e., subjects already proficient in token exchange before the present study, as well as of naïve subjects, i.e., subjects that never showed exchange behavior before this study; 2) appraise whether capuchins indeed value tokens; and 3) assess whether capuchins can refrain from throwing tokens outside their enclosure when the experimenter is not present. Overall, the social context positively affected high-ranking individuals and negatively affected low-ranking ones. All 6 high-ranking naïve subjects, but none of the 4 low-ranking ones, quickly acquired token exchange behavior, whereas 9 of 12 low-ranking knowledgeable subjects, but only 1 high-ranking knowledgeable subject, never displayed token exchange in social contexts. Thus, competition constrained token exchange in low-ranking subjects and prompted exchange behavior in high-ranking naïve subjects. Capuchins were unable to inhibit the exchange of valueless items when the experimenter was soliciting them and, at the group level, knowledgeable subjects did not exchange more valuable tokens than less valuable (or valueless) ones. However, the 3 high-ranking knowledgeable subjects that exchanged most of the tokens first preferentially exchanged more valuable tokens over less valuable or valueless ones. Finally, capuchins inhibited exchange behavior in the absence of the experimenter, thus recognizing the appropriate conditions in which a successful exchange could occur. 相似文献
996.
Lalor SJ Dungan LS Sutton CE Basdeo SA Fletcher JM Mills KH 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(10):5738-5748
IL-1β plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1β and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1β and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1β or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1β and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1β and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1β and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases. 相似文献
997.
Costa C Tanner G Lodesani M Maistrello L Neumann P 《Journal of invertebrate pathology》2011,108(3):224-225
Interactions between pathogens might contribute to honey bee colony losses. Here we investigated if there is an association between the microsporidian Nosema ceranae and the deformed wing virus (DWV) in different body sections of individual honey bee workers (Apis mellifera ligustica) under exclusion of the vector Varroa destructor. Our data provide correlational evidence for antagonistic interactions between the two pathogens in the midgut of the bees. 相似文献
998.
999.
Mandal M Wei J Zhong P Cheng J Duffney LJ Liu W Yuen EY Twelvetrees AE Li S Li XJ Kittler JT Yan Z 《The Journal of biological chemistry》2011,286(39):33719-33728
Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5, which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and cognitive processes in HD conditions. 相似文献
1000.
Haddad LE Khzam LB Hajjar F Merhi Y Sirois MG 《American journal of physiology. Cell physiology》2011,301(5):C1036-C1045
Several members of the fibroblast growth factor (FGF) family are potent endothelial cell (EC) mitogens and angiogenic factors, and their activities can be mediated by four tyrosine kinase receptors (FGFR1-4). In addition, FGFs can induce the release of inflammatory mediators by ECs and the expression of adhesion molecules at their surface, thereby favoring the recruitment and transvascular migration of inflammatory cells such as neutrophils. Neither the expression nor the biological activities that could be mediated by FGFRs have been investigated in human neutrophils. By biochemical and cytological analyses, we observed that purified circulating human neutrophils from healthy individuals expressed varying levels of FGFRs in their cytosol and at their cytoplasmic membrane. FGFR-2 was identified as the sole cell surface receptor, with FGFR-1 and -4 localizing in the cytosol and FGFR-3 being undetectable. We assessed the capacity of FGF-1 and FGF-2 to induce neutrophil chemotaxis in a modified Boyden microchamber and observed that they increase neutrophil transmigration at 10(-10) and 10(-9) M and by 1.77- and 2.34-fold, respectively, as compared with PBS-treated cells. Treatment with a selective anti-FGFR-2 antibody reduced FGF-1-mediated chemotaxis by 75% and abrogated the effect of FGF-2, while the blockade of FGFR-1 and -4 partially inhibited (15-40%) FGF-chemotactic activities. In summary, our data are the first to report the expression of FGF receptors in human neutrophils, with FGF-1 and FGF-2 promoting neutrophil chemotaxis mainly through FGFR-2 activation. 相似文献