全文获取类型
收费全文 | 730篇 |
免费 | 69篇 |
出版年
2020年 | 5篇 |
2019年 | 8篇 |
2018年 | 6篇 |
2017年 | 7篇 |
2016年 | 14篇 |
2015年 | 10篇 |
2014年 | 14篇 |
2013年 | 27篇 |
2012年 | 39篇 |
2011年 | 35篇 |
2010年 | 30篇 |
2009年 | 11篇 |
2008年 | 26篇 |
2007年 | 27篇 |
2006年 | 31篇 |
2005年 | 29篇 |
2004年 | 26篇 |
2003年 | 29篇 |
2002年 | 31篇 |
2001年 | 26篇 |
2000年 | 21篇 |
1999年 | 31篇 |
1998年 | 14篇 |
1997年 | 8篇 |
1996年 | 9篇 |
1994年 | 11篇 |
1993年 | 8篇 |
1992年 | 18篇 |
1991年 | 15篇 |
1990年 | 14篇 |
1989年 | 11篇 |
1988年 | 14篇 |
1987年 | 9篇 |
1986年 | 14篇 |
1985年 | 13篇 |
1984年 | 14篇 |
1983年 | 15篇 |
1982年 | 7篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 16篇 |
1978年 | 6篇 |
1977年 | 11篇 |
1976年 | 4篇 |
1975年 | 6篇 |
1974年 | 7篇 |
1971年 | 6篇 |
1970年 | 6篇 |
1969年 | 4篇 |
1968年 | 4篇 |
排序方式: 共有799条查询结果,搜索用时 15 毫秒
191.
Marchetti L Sabbieti MG Agas D Menghi M Materazzi G Menghi G Hurley MM 《Journal of cellular biochemistry》2006,97(6):1379-1392
Previous studies showed that prostaglandin F2alpha (PGF2alpha) stimulated fibroblast growth factor-2 (FGF-2) and fibroblast growth factor receptor 2 (FGFR2) cytosolic and nuclear accumulation, however, the endocytic pathway has not been elucidated. This study demonstrates that although PGF2alpha increased the formation of clathrin-coated structures in Py1a rat osteoblasts, they were not involved in FGF-2 and FGFR2 trafficking. PGF2alpha increased binding of FGF-2 and FGFR2 and co-localization of reactive sites in addition to nuclear translocation at the nuclear pore complex level. FGF-2 and FGFR2 were in close spatial correlation with importin beta, further supporting nuclear import of the FGF-2/FGFR2 complex. Immunogold and immunofluorescence techniques as well as Western blotting demonstrated increased importin beta protein labeling in response to PGF2alpha. Similar to PGF2alpha, phorbol 12-myristate 13-acetate (PMA) also increased importin beta protein. These data strongly suggest that prostaglandins may regulate osteoblast metabolism via FGF-2/FGFR2/importin beta nuclear trafficking. 相似文献
192.
193.
Dongshin Kim Elisa Monaco Aaron Maki Alecsandra Sobreira de Lima Hyun Joon Kong Walter L. Hurley Matthew B. Wheeler 《Cell and tissue research》2010,341(3):359-370
Advances in bioengineering, material chemistry, and developmental biology have led to the design of three-dimensional (3D) culture systems that better resemble the surrounding structure and chemistry of the in situ niches of cells in tissues. This study was designed to characterize and compare porcine adipose-derived stem cells (ADSC) and bone-marrow-derived stem cells (BMSC) induced to differentiate toward osteogenic and adipogenic lineages in vitro by using a 3D alginate hydrogel. The morphology and gene expression of the two cell populations during differentiation were analyzed. Both ADSC and BMSC showed morphological evidence of osteogenic and adipogenic differentiation. Expression patterns of genes characteristic of the onset of osteogenic differentiation (ALP, COL1A1, SPARC, SPP1) were low at the beginning of culture and generally increased during the period of differentiation up to 28 days in culture. Expression of genes associated with adipogenic differentiation (ACSL1, ADFP, ADIPOQ, CD36, DBI, DGAT2, PPARG, SCD) was consistently increased in ADSC cultured in alginate hydrogel relative to the start of differentiation. However, adipogenic gene expression of BMSC cultured in alginate hydrogel was more limited when compared with that of ADSC. Evaluation of cell numbers (via the MTT staining assay) suggested a greater viability of BMSC under osteogenic conditions in alginate hydrogels than under adipogenic conditions, whereas ADSC had greater viability under adipogenic conditions than under osteogenic conditions. This study thus provides an important initial evaluation of ADSC and BMSC seeded and differentiated toward the osteogenic and adipogenic cell lineages in a 3D alginate hydrogel in vitro. 相似文献
194.
Daniel P. Kloer Raul Rojas Viorica Ivan Kengo Moriyama Thijs van Vlijmen Namita Murthy Rodolfo Ghirlando Peter van der Sluijs James H. Hurley Juan S. Bonifacino 《The Journal of biological chemistry》2010,285(10):7794-7804
The Hermansky-Pudlak syndrome (HPS) is a genetic hypopigmentation and bleeding disorder caused by defective biogenesis of lysosome-related organelles (LROs) such as melanosomes and platelet dense bodies. HPS arises from mutations in any of 8 genes in humans and 16 genes in mice. Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. Analytical ultracentrifugation reveals that this complex has a molecular mass of 146 kDa, equivalent to that of the native complex and to the sum of the predicted molecular masses of HPS1 and HPS4. This indicates that HPS1 and HPS4 interact directly in the absence of any other protein as part of BLOC-3. Limited proteolysis and deletion analyses show that both subunits interact with one another throughout most of their lengths with the sole exception of a long, unstructured loop in the central part of HPS4. An interaction screen reveals a specific and strong interaction of BLOC-3 with the GTP-bound form of the endosomal GTPase, Rab9. This interaction is mediated by HPS4 and the switch I and II regions of Rab9. These characteristics indicate that BLOC-3 might function as a Rab9 effector in the biogenesis of LROs. 相似文献
195.
Martin A. Baraibar Barry B. Muhoberac Holly J. Garringer Thomas D. Hurley Ruben Vidal 《The Journal of biological chemistry》2010,285(3):1950-1956
Mutations in the coding sequence of the ferritin light chain (FTL) gene cause a
neurodegenerative disease known as neuroferritinopathy or hereditary
ferritinopathy, which is characterized by the presence of intracellular
inclusion bodies containing the mutant FTL polypeptide and by abnormal
accumulation of iron in the brain. Here, we describe the x-ray crystallographic
structure and report functional studies of ferritin homopolymers formed from the
mutant FTL polypeptide p.Phe167SerfsX26, which has a C terminus that is altered
in amino acid sequence and length. The structure was determined and refined to
2.85 Å resolution and was very similar to the wild type between
residues Ile-5 and Arg-154. However, instead of the E-helices normally present
in wild type ferritin, the C-terminal sequences of all 24 mutant subunits showed
substantial amounts of disorder, leading to multiple C-terminal polypeptide
conformations and a large disruption of the normally tiny 4-fold axis pores.
Functional studies underscored the importance of the mutant C-terminal sequence
in iron-induced precipitation and revealed iron mishandling by soluble mutant
FTL homopolymers in that only wild type incorporated iron when in direct
competition in solution with mutant ferritin. Even without competition, the
amount of iron incorporation over the first few minutes differed severalfold.
Our data suggest that disruption at the 4-fold pores may lead to direct iron
mishandling through attenuated iron incorporation by the soluble form of mutant
ferritin and that the disordered C-terminal polypeptides may play a major role
in iron-induced precipitation and formation of ferritin inclusion bodies in
hereditary ferritinopathy. 相似文献
196.
Beno?t Renvoisé Rell L. Parker Dong Yang Joanna C. Bakowska James H. Hurley Craig Blackstone 《Molecular biology of the cell》2010,21(19):3293-3303
Hereditary spastic paraplegias (HSPs, SPG1-46) are inherited neurological disorders characterized by lower extremity spastic weakness. Loss-of-function SPG20 gene mutations cause an autosomal recessive HSP known as Troyer syndrome. The SPG20 protein spartin localizes to lipid droplets and endosomes, and it interacts with tail interacting protein 47 (TIP47) as well as the ubiquitin E3 ligases atrophin-1-interacting protein (AIP)4 and AIP5. Spartin harbors a domain contained within microtubule-interacting and trafficking molecules (MIT) at its N-terminus, and most proteins with MIT domains interact with specific ESCRT-III proteins. Using yeast two-hybrid and in vitro surface plasmon resonance assays, we demonstrate that the spartin MIT domain binds with micromolar affinity to the endosomal sorting complex required for transport (ESCRT)-III protein increased sodium tolerance (Ist)1 but not to ESCRT-III proteins charged multivesicular body proteins 1–7. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells by small interfering RNA significantly decreases the number of cells where spartin is present at midbodies. Depletion of spartin does not affect Ist1 localization to midbodies but markedly impairs cytokinesis. A structure-based amino acid substitution in the spartin MIT domain (F24D) blocks the spartin–Ist1 interaction. Spartin F24D does not localize to the midbody and acts in a dominant-negative manner to impair cytokinesis. These data suggest that Ist1 interaction is important for spartin recruitment to the midbody and that spartin participates in cytokinesis. 相似文献
197.
The mammalian retromer complex consists of SNX1, SNX2, Vps26, Vps29 and Vps35, and retrieves lysosomal enzyme receptors from endosomes to the trans-Golgi network. The structure of human Vps26A at 2.1-A resolution reveals two curved beta-sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235-246, near the tip of the C-terminal domain. The loop is phylogenetically conserved and provides a mechanism for Vps26 integration into the complex that leaves the rest of the structure free for engagements with membranes and for conformational changes. Hydrophobic residues and a glycine in this loop are required for integration into the retromer complex and endosomal localization of human Vps26, and for the function of yeast Vps26 in carboxypeptidase Y sorting. 相似文献
198.
199.
200.