全文获取类型
收费全文 | 642篇 |
免费 | 70篇 |
出版年
2021年 | 8篇 |
2020年 | 4篇 |
2019年 | 4篇 |
2018年 | 5篇 |
2017年 | 9篇 |
2016年 | 8篇 |
2015年 | 20篇 |
2014年 | 24篇 |
2013年 | 32篇 |
2012年 | 29篇 |
2011年 | 35篇 |
2010年 | 25篇 |
2009年 | 24篇 |
2008年 | 25篇 |
2007年 | 32篇 |
2006年 | 29篇 |
2005年 | 16篇 |
2004年 | 28篇 |
2003年 | 26篇 |
2002年 | 18篇 |
2001年 | 14篇 |
2000年 | 23篇 |
1999年 | 22篇 |
1998年 | 11篇 |
1997年 | 7篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 12篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1991年 | 13篇 |
1990年 | 9篇 |
1989年 | 8篇 |
1988年 | 9篇 |
1987年 | 11篇 |
1986年 | 10篇 |
1985年 | 9篇 |
1984年 | 19篇 |
1983年 | 9篇 |
1982年 | 7篇 |
1981年 | 10篇 |
1980年 | 8篇 |
1978年 | 10篇 |
1976年 | 9篇 |
1974年 | 7篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1968年 | 3篇 |
1934年 | 3篇 |
1931年 | 3篇 |
排序方式: 共有712条查询结果,搜索用时 15 毫秒
71.
Hog1 mitogen-activated protein kinase phosphorylation targets the yeast Fps1 aquaglyceroporin for endocytosis, thereby rendering cells resistant to acetic acid 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Aquaporins and aquaglyceroporins form the membrane channels that mediate fluxes of water and small solute molecules into and out of cells. Eukaryotes often use mitogen-activated protein kinase (MAPK) cascades for the intracellular signaling of stress. This study reveals an aquaglyceroporin being destabilized by direct MAPK phosphorylation and also a stress resistance being acquired through this channel loss. Hog1 MAPK is transiently activated in yeast exposed to high, toxic levels of acetic acid. This Hog1 then phosphorylates the plasma membrane aquaglyceroporin, Fps1, a phosphorylation that results in Fps1 becoming ubiquitinated and endocytosed and then degraded in the vacuole. As Fps1 is the membrane channel that facilitates passive diffusional flux of undissociated acetic acid into the cell, this loss downregulates such influx in low-pH cultures, where acetic acid (pKa, 4.75) is substantially undissociated. Consistent with this downregulation of the acid entry generating resistance, sensitivity to acetic acid is seen with diverse mutational defects that abolish endocytic removal of Fps1 from the plasma membrane (loss of Hog1, loss of the soluble domains of Fps1, a T231A S537A double mutation of Fps1 that prevents its in vivo phosphorylation, or mutations generating a general loss of endocytosis of cell surface proteins [doa4Delta and end3Delta]). Remarkably, targetting of Fps1 for degradation may be the major requirement for an active Hog1 in acetic acid resistance, since Hog1 is largely dispensable for such resistance when the cells lack Fps1. Evidence is presented that in unstressed cells, Hog1 exists in physical association with the N-terminal cytosolic domain of Fps1. 相似文献
72.
73.
Piper DE Jackson S Liu Q Romanow WG Shetterly S Thibault ST Shan B Walker NP 《Structure (London, England : 1993)》2007,15(5):545-552
Proprotein convertase subtilisin kexin type 9 (PCSK9) has been shown to be involved in the regulation of extracellular levels of the low-density lipoprotien receptor (LDLR). Although PCSK9 is a subtilase, it has not been shown to degrade the LDLR, and its LDLR-lowering mechanism remains uncertain. Here we report the crystal structure of human PCSK9 at 2.3 A resolution. PCSK9 has subtilisin-like pro- and catalytic domains, and the stable interaction between these domains prevents access to PCSK9's catalytic site. The C-terminal domain of PCSK9 has a novel protein fold and may mediate protein-protein interactions. The structure of PCSK9 provides insight into its biochemical characteristics and biological function. 相似文献
74.
Hse1, a component of the yeast Hrs-STAM ubiquitin-sorting complex, associates with ubiquitin peptidases and a ligase to control sorting efficiency into multivesicular bodies
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Ubiquitinated integral membrane proteins are delivered to the interior of the lysosome/vacuole for degradation. This process relies on specific ubiquitination of potential cargo and recognition of that Ub-cargo by sorting receptors at multiple compartments. We show that the endosomal Hse1-Vps27 sorting receptor binds to ubiquitin peptidases and the ubiquitin ligase Rsp5. Hse1 is linked to Rsp5 directly via a PY element within its C-terminus and through a novel protein Hua1, which recruits a complex of Rsp5, Rup1, and Ubp2. The SH3 domain of Hse1 also binds to the deubiquitinating protein Ubp7. Functional analysis shows that when both modes of Rsp5 association with Hse1 are altered, sorting of cargo that requires efficient ubiquitination for entry into the MVB is blocked, whereas sorting of cargo containing an in-frame addition of ubiquitin is normal. Further deletion of Ubp7 restores sorting of cargo when the Rsp5:Hse1 interaction is compromised suggesting that both ubiquitin ligases and peptidases associate with the Hse1-Vps27 sorting complex to control the ubiquitination status and sorting efficiency of cargo proteins. Additionally, we find that disruption of UBP2 and RUP1 inhibits MVB sorting of some cargos suggesting that Rsp5 requires association with Ubp2 to properly ubiquitinate cargo for efficient MVB sorting. 相似文献
75.
Sylvia Kamphuis Kolbrún Hrafnkelsdóttir Mark R Klein Wilco de Jager Margje H Haverkamp Jolanda HM van Bilsen Salvatore Albani Wietse Kuis Marca HM Wauben Berent J Prakken 《Arthritis research & therapy》2007,8(6):R178
Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by chronic joint inflammation. Knowing
which antigens drive the autoreactive T-cell response in JIA is crucial for the understanding of disease pathogenesis and
additionally may provide targets for antigen-specific immune therapy. In this study, we tested 9 self-peptides derived from
joint-related autoantigens for T-cell recognition (T-cell proliferative responses and cytokine production) in 36 JIA patients
and 15 healthy controls. Positive T-cell proliferative responses (stimulation index ≥2) to one or more peptides were detected
in peripheral blood mononuclear cells (PBMC) of 69% of JIA patients irrespective of major histocompatibility complex (MHC)
genotype. The peptides derived from aggrecan, fibrillin, and matrix metalloproteinase (MMP)-3 yielded the highest frequency
of T-cell proliferative responses in JIA patients. In both the oligoarticular and polyarticular subtypes of JIA, the aggrecan
peptide induced T-cell proliferative responses that were inversely related with disease duration. The fibrillin peptide, to
our knowledge, is the first identified autoantigen that is primarily recognized in polyarticular JIA patients. Finally, the
epitope derived from MMP-3 elicited immune responses in both subtypes of JIA and in healthy controls. Cytokine production
in short-term peptide-specific T-cell lines revealed production of interferon-γ (aggrecan/MMP-3) and interleukin (IL)-17 (aggrecan)
and inhibition of IL-10 production (aggrecan). Here, we have identified a triplet of self-epitopes, each with distinct patterns
of T-cell recognition in JIA patients. Additional experiments need to be performed to explore their qualities and role in
disease pathogenesis in further detail. 相似文献
76.
77.
78.
Adam T. Piper Costantino Manes Fabio Siniscalchi Andrea Marion Rosalind M. Wright Paul S. Kemp 《Proceedings. Biological sciences / The Royal Society》2015,282(1811)
Anthropogenic structures (e.g. weirs and dams) fragment river networks and restrict the movement of migratory fish. Poor understanding of behavioural response to hydrodynamic cues at structures currently limits the development of effective barrier mitigation measures. This study aimed to assess the effect of flow constriction and associated flow patterns on eel behaviour during downstream migration. In a field experiment, we tracked the movements of 40 tagged adult European eels (Anguilla anguilla) through the forebay of a redundant hydropower intake under two manipulated hydrodynamic treatments. Interrogation of fish trajectories in relation to measured and modelled water velocities provided new insights into behaviour, fundamental for developing passage technologies for this endangered species. Eels rarely followed direct routes through the site. Initially, fish aligned with streamlines near the channel banks and approached the intake semi-passively. A switch to more energetically costly avoidance behaviours occurred on encountering constricted flow, prior to physical contact with structures. Under high water velocity gradients, fish then tended to escape rapidly back upstream, whereas exploratory ‘search’ behaviour was common when acceleration was low. This study highlights the importance of hydrodynamics in informing eel behaviour. This offers potential to develop behavioural guidance, improve fish passage solutions and enhance traditional physical screening. 相似文献
79.
Paik J Fierce Y Mai PO Phelps SR McDonald T Treuting P Drivdahl R Brabb T LeBoeuf R O'Brien KD Maggio-Price L 《Comparative medicine》2011,61(4):330-338
Murine norovirus (MNV) is prevalent in rodent facilities in the United States. Because MNV has a tropism for macrophages and dendritic cells, we hypothesized that it may alter phenotypes of murine models of inflammatory diseases, such as obesity and atherosclerosis. We examined whether MNV infection influences phenotypes associated with diet-induced obesity and atherosclerosis by using Ldlr(-/-) mice. Male Ldlr(-/-) mice were maintained on either a diabetogenic or high-fat diet for 16 wk, inoculated with either MNV or vehicle, and monitored for changes in body weight, blood glucose, glucose tolerance, and insulin sensitivity. Influence of MNV on atherosclerosis was analyzed by determining aortic sinus lesion area. Under both dietary regimens, MNV-infected and control mice gained similar amounts of weight and developed similar degrees of insulin resistance. However, MNV infection was associated with significant increases in aortic sinus lesion area and macrophage content in Ldlr(-/-) mice fed a high-fat diet but not those fed a diabetogenic diet. In conclusion, MNV infection exacerbates atherosclerosis in Ldlr(-/-) mice fed a high-fat diet but does not influence obesity- and diabetes-related phenotypes. Increased lesion size was associated with increased macrophages, suggesting that MNV may influence macrophage activation or accumulation in the lesion area. 相似文献
80.