全文获取类型
收费全文 | 198篇 |
免费 | 12篇 |
专业分类
210篇 |
出版年
2022年 | 3篇 |
2018年 | 2篇 |
2016年 | 2篇 |
2015年 | 2篇 |
2014年 | 4篇 |
2013年 | 8篇 |
2012年 | 9篇 |
2011年 | 14篇 |
2010年 | 9篇 |
2009年 | 4篇 |
2008年 | 4篇 |
2007年 | 7篇 |
2006年 | 8篇 |
2005年 | 3篇 |
2004年 | 6篇 |
2003年 | 7篇 |
2002年 | 9篇 |
2001年 | 8篇 |
2000年 | 8篇 |
1999年 | 15篇 |
1998年 | 3篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1992年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 6篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1981年 | 4篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1973年 | 2篇 |
1972年 | 5篇 |
1971年 | 1篇 |
1970年 | 4篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1967年 | 2篇 |
1966年 | 1篇 |
1965年 | 1篇 |
1961年 | 1篇 |
1939年 | 1篇 |
排序方式: 共有210条查询结果,搜索用时 15 毫秒
21.
Rod and cone photoreceptors project from the outer retinal surface into a
carbohydrate-rich interphotoreceptor matrix (IPM). Unique IPM
glycoconjugates are distributed around rods and cones. Wheat germ
agglutinin (WGA) strongly decorates the rod matrix domains and weakly
decorates the cone matrix domains. This study characterizes the major
WGA-binding glycoprotein in the human IPM, which we refer to as SPACR
(sialoprotein associated with cones and rods). SPACR, which has a molecular
weight of 147 kDa, was isolated and purified from the IPM by lectin
affinity chromatography. A polyclonal antibody to SPACR was prepared that
colocalizes in tissue preparations with WGA-binding domains in the IPM.
Sequential digestion of SPACR with N- and O- glycosidases results in a
systematic increase in electrophorectic mobility, indicating the presence
of both N- and O-linked glycoconjugates. Complete deglycosylation results
in a reduction in the relative molecular mass of SPACR by about 30%.
Analysis of lectin binding allowed us to identify some of the structural
characteristics of SPACR glycoconjugates. Treatment with neuraminidase
exposes Galbeta1- 3GalNAc disaccharide as indicated by positive peanut
agglutinin (PNA) staining, accompanied by the loss of WGA staining. Maackia
amurensis agglutinins (MAA-1 and MAA-2), specific for sialic acid in
alpha2-3 linkage to Gal, bind SPACR, while Sambucus nigra agglutinin (SNA),
specific for alpha2-6 linked sialic acid, does not, indicating that the
dominant glycoconjugate determinant on SPACR is the O-linked carbohydrate,
NeuAcalpha2-3Galbeta1-3GalNAc. The abundance of sialic acid in SPACR
suggests that this glycoprotein may contribute substantially to the
polyanionic nature of the IPM. The carbohydrate chains present on SPACR
could also provide sites for extensive crosslinking and participate in the
formation of the ordered IPM lattice that surrounds the elongate
photoreceptors projecting from the outer retinal surface.
相似文献
22.
The recent structure determinations of the mammalian effector enzyme adenylyl cyclase reveal the structure of its catalytic core, provide new insights into its catalytic mechanism and suggest how diverse signaling molecules regulate its activity. 相似文献
23.
A variety of methods are commonly used to quantify animal home ranges using location data acquired with telemetry. High‐volume location data from global positioning system (GPS) technology provide researchers the opportunity to identify various intensities of use within home ranges, typically quantified through utilization distributions (UDs). However, the wide range of variability evident within UDs constructed with modern home range estimators is often overlooked or ignored during home range comparisons, and challenges may arise when summarizing distributional shifts among multiple UDs. We describe an approach to gain additional insight into home range changes by comparing UDs across isopleths and summarizing comparisons into meaningful results. To demonstrate the efficacy of this approach, we used GPS location data from 16 bighorn sheep (Ovis canadensis) to identify distributional changes before and after habitat alterations, and we discuss advantages in its application when comparing home range size, overlap, and joint‐space use. We found a consistent increase in bighorn sheep home range size when measured across home range levels, but that home range overlap and similarity values decreased when examined at increasing core levels. Our results highlight the benefit of conducting multiscale assessments when comparing distributions, and we encourage researchers to expand comparative home range analyses to gain a more comprehensive evaluation of distributional changes and to evaluate comparisons across home range levels. 相似文献
24.
25.
JG Hansen W Gao J Dupuis GT O’Connor W Tang M Kowgier A Sood SA Gharib LJ Palmer M Fornage SR Heckbert BM Psaty SL Booth SUNLIGHT Consortium Patricia A Cassano 《Respiratory research》2015,16(1)
Background
Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.Methods
We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.Results
We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).Conclusions
Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users. 相似文献26.
Diabetic retinopathy is a disease of the retinal microvasculature that develops as a complication of diabetes mellitus and constitutes a major cause of blindness in adults of all ages. Diabetic retinopathy is characterized by the loss of capillary cells leading to increased vasopermeability, ischemia, and hypoxia that trigger the excessive formation of new blood vessels in the retina. The influence of the pituitary gland in the pathophysiology of diabetic retinopathy was recognized nearly six decades ago, but the contribution of pituitary hormones to this disease remains unclear. Recent studies have shown that the pituitary hormone prolactin is proteolytically cleaved to vasoinhibins, a family of peptides with potent antivasopermeability, vasoconstrictive, and antiangiogenic actions that can protect the eye against the deleterious effects of the diabetic state. In this review, we summarize what is known about the changes in the circulating levels of prolactin and vasoinhibins during diabetes and diabetic retinopathy as well as the implications of these changes for the development and progression of the disease with particular attention to hyperprolactinemia in pregnancy and postpartum. We discuss the effects of prolactin and vasoinhibins that may impact diabetic retinopathy and suggest these hormones as important targets for therapeutic interventions. 相似文献
27.
Birnbaum RA O'Marcaigh A Wardak Z Zhang YY Dranoff G Jacks T Clapp DW Shannon KM 《Molecular cell》2000,5(1):189-195
The NF1 tumor suppressor gene encodes neurofibromin, a GTPase-activating protein (GAP) for p21ras (Ras). Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML). Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD. Human JMML and murine Nf1-deficient cells are hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose cultures. We generated hematopoietic cells deficient in both Nf1 and Gmcsf to test whether GM-CSF is required to drive excessive proliferation of Nf1-/- cells in vivo. Here we show that GM-CSF play a central role in establishing and maintaining the MPD and that recipients engrafted with Nf1-/- Gmcsf-/- hematopoietic cells are hypersensitive to exogenous GM-CSF. 相似文献
28.
Kelly M. Clapp Hwei-Ming Peng Gary J. Jenkins Michael J. Ford Yoshihiro Morishima Miranda Lau Yoichi Osawa 《The Journal of biological chemistry》2012,287(51):42601-42610
Nitric-oxide synthase, a cytochrome P450-like hemoprotein enzyme, catalyzes the synthesis of nitric oxide, a critical signaling molecule in a variety of physiological processes. Our laboratory has discovered that certain drugs suicide-inactivate neuronal nitric-oxide synthase (nNOS) and lead to the preferential ubiquitination of the inactivated nNOS by an Hsp70- and CHIP (C terminus of Hsc70-interacting protein)-dependent process. To further understand the process by which altered nNOS is recognized, ubiquitinated, and proteasomally degraded, we examined the sites of ubiquitination on nNOS. We utilized an in vitro ubiquitination system containing purified E1, E2 (UbcH5a), Hsp70, and CHIP that recapitulates the ability of the cells to selectively recognize and ubiquitinate the altered forms of nNOS. LC-MS/MS analysis of the tryptic peptides obtained from the in vitro ubiquitinated nNOS identified 12 ubiquitination sites. Nine of the sites were within the oxygenase domain and two were in the calmodulin-binding site, which links the oxygenase and reductase domains, and one site was in the reductase domain. Mutational analysis of the lysines in the calmodulin-binding site revealed that Lys-739 is a major site for poly-ubiquitination of nNOS in vitro and regulates, in large part, the CHIP-dependent degradation of nNOS in HEK293 cells, as well as in in vitro studies with fraction II. Elucidating the exact site of ubiquitination is an important step in understanding how chaperones recognize and trigger degradation of nNOS. 相似文献
29.
30.
C Clapp L Portt C Khoury S Sheibani G Norman P Ebner R Eid H Vali C A Mandato F Madeo M T Greenwood 《Cell death & disease》2012,3(7):e348
Expression of human Bax, a cardinal regulator of mitochondrial membrane permeabilization, causes death in yeast. We screened a human cDNA library for suppressors of Bax-mediated yeast death and identified human 14-3-3β/α, a protein whose paralogs have numerous chaperone-like functions. Here, we show that, yeast cells expressing human 14-3-3β/α are able to complement deletion of the endogenous yeast 14-3-3 and confer resistance to a variety of different stresses including cadmium and cycloheximide. The expression of 14-3-3β/α also conferred resistance to death induced by the target of rapamycin inhibitor rapamycin and by starvation for the amino acid leucine, conditions that induce autophagy. Cell death in response to these autophagic stimuli was also observed in the macroautophagic-deficient atg1Δ and atg7Δ mutants. Furthermore, 14-3-3β/α retained its ability to protect against the autophagic stimuli in these autophagic-deficient mutants arguing against so called ‘autophagic death''. In line, analysis of cell death markers including the accumulation of reactive oxygen species, membrane integrity and cell surface exposure of phosphatidylserine indicated that 14-3-3β/α serves as a specific inhibitor of apoptosis. Finally, we demonstrate functional conservation of these phenotypes using the yeast homolog of 14-3-3: Bmh1. In sum, cell death in response to multiple stresses can be counteracted by 14-3-3 proteins. 相似文献