全文获取类型
收费全文 | 738篇 |
免费 | 76篇 |
专业分类
814篇 |
出版年
2022年 | 5篇 |
2021年 | 14篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 7篇 |
2017年 | 10篇 |
2016年 | 21篇 |
2015年 | 26篇 |
2014年 | 33篇 |
2013年 | 52篇 |
2012年 | 69篇 |
2011年 | 37篇 |
2010年 | 44篇 |
2009年 | 30篇 |
2008年 | 46篇 |
2007年 | 60篇 |
2006年 | 45篇 |
2005年 | 39篇 |
2004年 | 34篇 |
2003年 | 37篇 |
2002年 | 44篇 |
2001年 | 10篇 |
2000年 | 3篇 |
1999年 | 15篇 |
1998年 | 5篇 |
1997年 | 12篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 4篇 |
1992年 | 7篇 |
1991年 | 11篇 |
1990年 | 5篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1973年 | 3篇 |
1972年 | 4篇 |
1967年 | 1篇 |
排序方式: 共有814条查询结果,搜索用时 46 毫秒
81.
Altered integration of matrilin-3 into cartilage extracellular matrix in the absence of collagen IX 下载免费PDF全文
Budde B Blumbach K Ylöstalo J Zaucke F Ehlen HW Wagener R Ala-Kokko L Paulsson M Bruckner P Grässel S 《Molecular and cellular biology》2005,25(23):10465-10478
The matrilins are a family of four noncollagenous oligomeric extracellular matrix proteins with a modular structure. Matrilins can act as adapters which bridge different macromolecular networks. We therefore investigated the effect of collagen IX deficiency on matrilin-3 integration into cartilage tissues. Mice harboring a deleted Col9a1 gene lack synthesis of a functional protein and produce cartilage fibrils completely devoid of collagen IX. Newborn collagen IX knockout mice exhibited significantly decreased matrilin-3 and cartilage oligomeric matrix protein (COMP) signals, particularly in the cartilage primordium of vertebral bodies and ribs. In the absence of collagen IX, a substantial amount of matrilin-3 is released into the medium of cultured chondrocytes instead of being integrated into the cell layer as in wild-type and COMP-deficient cells. Gene expression of matrilin-3 is not affected in the absence of collagen IX, but protein extraction from cartilage is greatly facilitated. Matrilin-3 interacts with collagen IX-containing cartilage fibrils, while fibrils from collagen IX knockout mice lack matrilin-3, and COMP-deficient fibrils exhibit an intermediate integration. In summary, the integration of matrilin-3 into cartilage fibrils occurs both by a direct interaction with collagen IX and indirectly with COMP serving as an adapter. Matrilin-3 can be considered as an interface component, capable of interconnecting macromolecular networks and mediating interactions between cartilage fibrils and the extrafibrillar matrix. 相似文献
82.
Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia 下载免费PDF全文
Cho YJ Zhang B Kaartinen V Haataja L de Curtis I Groffen J Heisterkamp N 《Molecular and cellular biology》2005,25(13):5777-5785
Numerous studies indirectly implicate Rac GTPases in cancer. To investigate if Rac3 contributes to normal or malignant cell function, we generated rac3 null mutants through gene targeting. These mice were viable, fertile, and lacked an obvious external phenotype. This shows Rac3 function is dispensable for embryonic development. Bcr/Abl is a deregulated tyrosine kinase that causes chronic myelogenous leukemia and Ph-positive acute lymphoblastic leukemia in humans. Vav1, a hematopoiesis-specific exchange factor for Rac, was constitutively tyrosine phosphorylated in primary lymphomas from Bcr/Abl P190 transgenic mice, suggesting inappropriate Rac activation. rac3 is expressed in these malignant hematopoietic cells. Using lysates from BCR/ABL transgenic mice that express or lack rac3, we detected the presence of activated Rac3 but not Rac1 or Rac2 in the malignant precursor B-lineage lymphoblasts. In addition, in female P190 BCR/ABL transgenic mice, lack of rac3 was associated with a longer average survival. These data are the first to directly show a stimulatory role for Rac in leukemia in vivo. Moreover, our data suggest that interference with Rac3 activity, for example, by using geranyl-geranyltransferase inhibitors, may provide a positive clinical benefit for patients with Ph-positive acute lymphoblastic leukemia. 相似文献
83.
Pain in nonhuman animals is a difficult concept to identify and measure. This article briefly describes the consequences of pain in animals on the farm and explains the reasons for the minimal use of analgesics in farmed animals. Pain can have implications for both animal welfare and economics. The reasons for a low use of analgesics in farmed animals include the lack of recognition of animal pain owing to the apparent lack of anthropomorphically identifiable behavioral changes, concern over human food safety, and lack of research efforts to develop safe analgesics for farm use. Treatment cost relative to the benefits expected is another hindering factor. Interventions to minimize pain must begin with developing objective and practical measures for pain identification and measurement at the farm level. A suggested use of a combination of different behavioral and physiological indicators would help to identify pain in animals. To facilitate continued usage of the methodologies on the farm it also is necessary to evaluate the economic implication of the pain alleviation intervention. 相似文献
84.
von Bonsdorff-Nikander A Lievonen S Christiansen L Karjalainen M Rantanen J Yliruusi J 《AAPS PharmSciTech》2005,6(3):E413-E420
The aim of this research was to describe the thermal behavior of β-sitosterol crystals in oil-suspensions with a focus on
the role of water during heating. The suspensions were prepared by recrystallization in order to achieve a microcrystalline
particle size. The structural changes together with the mechanical properties of the suspensions during heating were studied
by using variable temperature X-ray powder diffractometry (VT-XRPD), differential scanning calorimetry (DSC), and dynamic
mechanical analysis (DMA). Hydrated β-sitosterol crystals in an oil-suspension, dehydrated, despite the composition of the
suspensions, at low temperatures. At high β-sitosterol concentration, the monohydrate crystal form changed partially to a
hemihydrated form, and when only a small amount of water was initially incorporated, the hemihydrate crystal form dehydrated
to a mostly anhydrate crystal form. The released water, which was immiscible in the surrounding oil, caused the recrystallization
of hydrated β-sitosterol during cooling. This procedure indicated a reversible dehydration process. Structural and thermal
analysis of β-sitosterol crystals in suspensions, together with mechanical analysis made it possible to understand various
physical changes during heating.
Published: October 19, 2005 相似文献
85.
Franzke CW Tasanen K Borradori L Huotari V Bruckner-Tuderman L 《The Journal of biological chemistry》2004,279(23):24521-24529
Collagen XVII/BP180, an epithelial adhesion molecule, belongs to the group of collagenous transmembrane proteins, which are characterized by ectodomain shedding. We recently showed that ADAMs can cleave collagen XVII, but also that furin participates in this process (Franzke, C. W., Tasanen, K., Sch?cke, H., Zhou, Z., Tryggvason, K., Mauch, C., Zigrino, P., Sunnarborg, S., Lee, D. C., Fahrenholz, F., and Bruckner-Tuderman, L. (2002) EMBO J. 21, 5026-5035). To define the cleavage region in the juxtamembranous NC16A linker domain and assess its structure and requirements for shedding, we constructed deletion mutants of the NC16A domain, expressed them in COS-7 cells, and analyzed their structural integrity and shedding behavior. A mutant lacking the furin consensus sequence was shed in a normal manner, demonstrating that furin does not cleave collagen XVII but rather activates ADAMs (a disintegrin and metalloproteinase). Large deletions of the NC16A domain prevented shedding, and analysis of defined smaller deletions pointed to the stretch of amino acid residues 528-547 as important for sheddase recognition and cleavage. Secondary protein structure predictions showed that deletion of this stretch resulted in an NC16A domain with a positive net charge and an amphipathic alpha-helix, which can cause conformational changes in the collagen XVII homotrimer. Assessment of triple-helix folding of the mutants revealed a lower thermal stability of all non-shed variants than of wild-type collagen XVII or the shed mutants. In contrast, deletion of the putative nucleation site for triple-helix folding of collagenous transmembrane proteins did not affect folding of collagen XVII. The data indicate that the conformation of the NC16A domain and steric availability of the cleavage site influence shedding and is important for folding of collagen XVII. 相似文献
86.
Pihlajamaa T Lankinen H Ylöstalo J Valmu L Jäälinoja J Zaucke F Spitznagel L Gösling S Puustinen A Mörgelin M Peränen J Maurer P Ala-Kokko L Kilpelaïnen I 《The Journal of biological chemistry》2004,279(23):24265-24273
The N-terminal NC4 domain of collagen IX is a globular structure projecting away from the surface of the cartilage collagen fibril. Several interactions have been suggested for this domain, reflecting its location and its characteristic high isoelectric point. In an attempt to characterize the NC4 domain in more detail, we set up a prokaryotic expression system to produce the domain. The purified 27.5-kDa product was analyzed for its glycosaminoglycan-binding potential by surface plasmon resonance and solid-state assays. The results show that the NC4 domain of collagen IX specifically binds heparin with a K(d) of 0.6 microm, and the full-length recombinant collagen IX has an even stronger interaction with heparin, with an apparent K(d) of 3.6 nm. The heparin-binding site of the NC4 domain was located in the extreme N terminus, containing a heparin-binding consensus sequence, whereas electron microscopy suggested the presence of at least three additional heparin-binding sites on full-length collagen IX. The NC4 domain was also shown to bind cartilage oligomeric matrix protein. This interaction and the association of cartilage oligomeric matrix protein with other regions of collagen IX were found to be heparin-competitive. Circular dichroism analyses of the NC4 domain indicated the presence of stabilizing disulfide bonds and a thermal denaturation point of about 80 degrees C. The pattern of disulfide bond formation within the NC4 domain was identified by tryptic peptide mass mapping of the NC4 in native and reduced states. A similar pattern was demonstrated for the NC4 domain of full-length recombinant collagen IX. 相似文献
87.
Palmer CG Hsieh HJ Reed EF Lonnqvist J Peltonen L Woodward JA Sinsheimer JS 《American journal of human genetics》2006,79(4):710-715
Schizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype-matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22-2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia. 相似文献
88.
Niiranen K Keinänen TA Pirinen E Heikkinen S Tusa M Fatrai S Suppola S Pietilä M Uimari A Laakso M Alhonen L Jänne J 《Journal of cellular and molecular medicine》2006,10(4):933-945
The N(1)-acetylation of spermidine or spermine by spermidine/spermine N(1)-acetyltransferase (SSAT) is the ratecontrolling enzymatic step in the polyamine catabolism. We have now generated SSAT knockout (SSAT-KO) mice, which confirmed our earlier results with SSATdeficient embryonic stem (ES) cells showing only slightly affected polyamine homeostasis, mainly manifested as an elevated molar ratio of spermidine to spermine in most tissues indicating the indispensability of SSAT for the spermidine backconversion.Contrary to SSAT deficient ES cells, polyamine pools in SSAT-KO mice remained almost unchanged in response to N(1),N(11)-diethylnorspermine (DENSPM) treatment compared to a significant reduction of the polyamine pools in the wild-type animals and ES cells. Furthermore, SSATKO mice were more sensitive to the toxicity exerted by DENSPM in comparison with wild-type mice. The latter finding indicates that inducible SSAT plays an essential role in vivo in DENSPM treatmentevoked polyamine depletion, but a controversial role in toxicity of DENSPM. Surprisingly, liver polyamine pools were depleted similarly in wild-type and SSAT-KO mice in response to carbon tetrachloride treatment. Further characterization of SSAT knockout mice revealed insulin resistance at old age which supported the role of polyamine catabolism in glucose metabolism detected earlier with our SSAT overexpressing mice displaying enhanced basal metabolic rate, high insulin sensitivity and improved glucose tolerance. Therefore SSAT knockout mice might serve as a novel mouse model for type 2 diabetes. 相似文献
89.
Leena S. Patel Cheryl K. Mitchell William P. Dubinsky John O'Brien 《Cell communication & adhesion》2006,13(1):41-54
Gap-junctional coupling among neurons is subject to regulation by a number of neurotransmitters including nitric oxide. We studied the mechanisms by which NO regulates coupling in cells expressing Cx35, a connexin expressed in neurons throughout the central nervous system. NO donors caused potent uncoupling of HeLa cells stably transfected with Cx35. This effect was mimicked by Bay 21-4272, an activator of guanylyl cyclase. A pharmacological analysis indicated that NO-induced uncoupling involved both PKG-dependent and PKG-independent pathways. PKA was involved in both pathways, suggesting that PKG-dependent uncoupling may be indirect. In vitro, PKG phosphorylated Cx35 at three sites: Ser110, Ser276, and Ser289. A mutational analysis indicated that phosphorylation on Ser110 and Ser276, sites previously shown also to be phosphorylated by PKA, had a significant influence on regulation. Ser289 phosphorylation had very limited effects. We conclude that NO can regulate coupling through Cx35 and that regulation is indirect in HeLa cells. 相似文献
90.
Franzke CW Has C Schulte C Huilaja L Tasanen K Aumailley M Bruckner-Tuderman L 《The Journal of biological chemistry》2006,281(40):30260-30268
Collagen XVII, a type II transmembrane protein in hemidesmosomes, is involved in the anchorage of stratified epithelia to the underlying mesenchyme. Its functions are regulated by ectodomain shedding, and its genetic defects lead to epidermal detachment in junctional epidermolysis bullosa (JEB), a heritable skin fragility syndrome, but the molecular disease mechanisms remain elusive. Here we used a spontaneously occurring homozygous COL17A1 deletion mutant in JEB to discern glycosylation of collagen XVII. The mutation truncated the distal ectodomain and positioned the only N-glycosylation site 34 amino acids from the newly formed C terminus, which impaired efficient N-glycosylation. Immunofluorescence staining of authentic JEB keratinocytes and of COS-7 cells transfected with the mutant indicated intracellular accumulation of collagen XVII precursor molecules. Cell surface biotinylation and quantification of ectodomain shedding demonstrated that only about 15% of the truncated collagen XVII reached the cell surface. The cell surface-associated molecules were N-glycosylated in a normal manner, in contrast to the molecules retained within the cells, indicating that N-glycosylation of the ectodomain is required for targeting of collagen XVII to the plasma membrane and that reduced accessibility of the N-glycosylation site negatively regulates this process. Functional consequences of the strong reduction of collagen XVII on the cell surface included scattered deposition of cell adhesion molecule laminin 5 into the extracellular environment and, as a consequence of faulty collagen XVII-laminin ligand interactions, aberrant motility of the mutant cells. 相似文献