全文获取类型
收费全文 | 463篇 |
免费 | 44篇 |
出版年
2022年 | 4篇 |
2021年 | 4篇 |
2019年 | 2篇 |
2018年 | 6篇 |
2017年 | 2篇 |
2016年 | 5篇 |
2015年 | 8篇 |
2014年 | 12篇 |
2013年 | 20篇 |
2012年 | 27篇 |
2011年 | 32篇 |
2010年 | 24篇 |
2009年 | 20篇 |
2008年 | 20篇 |
2007年 | 26篇 |
2006年 | 40篇 |
2005年 | 19篇 |
2004年 | 19篇 |
2003年 | 23篇 |
2002年 | 26篇 |
2001年 | 10篇 |
2000年 | 10篇 |
1999年 | 13篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 2篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1977年 | 4篇 |
1976年 | 11篇 |
1975年 | 6篇 |
1974年 | 11篇 |
1973年 | 8篇 |
1969年 | 2篇 |
1968年 | 4篇 |
排序方式: 共有507条查询结果,搜索用时 15 毫秒
41.
Characterization of the tyrosine kinases RAFTK/Pyk2 and FAK in nerve growth factor-induced neuronal differentiation 总被引:2,自引:0,他引:2
The related adhesion focal tyrosine kinase (RAFTK), a member of the focal adhesion kinase (FAK) family and highly expressed in brain, is a key mediator of various extracellular signals that elevate intracellular Ca(2+) concentration. We investigated RAFTK and FAK signaling upon nerve growth factor (NGF) stimulation of PC12 cells. NGF induced the tyrosine phosphorylation of RAFTK in a time- and dose-dependent manner, whereas no change in the tyrosine phosphorylation of FAK was observed. Chemical inhibition showed that RAFTK phosphorylation was inhibited by blocking phospholipase Cgamma activity or intracellular Ca(2+). Blocking of extracellular Ca(2+) or phosphatidylinositol 3-kinase activity partially reduced the phosphorylation of RAFTK. In addition, disruption of actin polymerization abolished RAFTK phosphorylation, indicating that an intact actin-based cytoskeletal organization is required for RAFTK phosphorylation. The focal adhesion molecule paxillin was co-immunoprecipitated with RAFTK, and its tyrosine phosphorylation was increased in a Ca(2+)-dependent manner upon NGF stimulation. Confocal microscopic analysis demonstrated that RAFTK translocated from the cytoplasm to potential neurite initiation sites at the cell periphery, where RAFTK co-localized with paxillin and bundled actin in the early phase (within 5 min) of NGF stimulation, whereas FAK co-localized with paxillin at "point contacts," which are the primary cell adhesion sites in neuronal cells. Significant distribution of RAFTK was observed in the neurites and growth cones of differentiated PC12 cells. Furthermore, potassium depolarization induced the tyrosine phosphorylation of both RAFTK and paxillin in an intracellular Ca(2+)-dependent manner in the differentiated PC12 cells. Taken together, these results demonstrate that RAFTK is involved in NGF-induced cytoskeletal organization and may play a role in neurite and growth cone function(s). 相似文献
42.
Ganju RK Brubaker SA Chernock RD Avraham S Groopman JE 《The Journal of biological chemistry》2000,275(23):17263-17268
The beta-chemokine receptor CCR5 has been shown to modulate cell migration, proliferation, and immune functions and to serve as a co-receptor for the human immunodeficiency virus. We and others have shown that CCR5 activates related adhesion focal tyrosine kinase (RAFTK)/Pyk2/CAK-beta. In this study, we further characterize the signaling molecules activated by CCR5 upon binding to its cognate ligand, macrophage inflammatory protein-1beta (MIP1beta). We observed enhanced tyrosine phosphorylation of the phosphatases SHP1 and SHP2 upon MIP1beta stimulation of CCR5 L1.2 transfectants and T-cells derived from peripheral blood mononuclear cells. Furthermore, we observed that SHP1 associated with RAFTK. However, using a dominant-negative phosphatase-binding mutant of RAFTK (RAFTK(m906)), we found that RAFTK does not mediate SHP1 or SHP2 phosphorylation. SHP1 and SHP2 also associated with the adaptor protein Grb2 and the Src-related kinase Syk. Pretreatment of CCR5 L1.2 transfectants or T-cells with the phosphatase inhibitor orthovanadate markedly abolished MIP1beta-induced chemotaxis. Syk was also activated upon MIP1beta stimulation of CCR5 L1.2 transfectants or T-cells and associated with RAFTK. Overexpression of a dominant-negative Src-binding mutant of RAFTK (RAFTK(m402)) significantly attenuated Syk activation, whereas overexpression of wild-type RAFTK enhanced Syk activity, indicating that RAFTK acts upstream of CCR5-mediated Syk activation. Taken together, these results suggest that MIP1beta stimulation mediated by CCR5 induces the formation of a signaling complex consisting of RAFTK, Syk, SHP1, and Grb2. 相似文献
43.
Genomic organization, chromosomal localization and regulation of expression of the neuronal nuclear matrix protein NRP/B in human brain tumors 总被引:5,自引:0,他引:5
The nuclear matrix and its role in cell physiology are largely unknown, and the discovery of any matrix constituent whose expression is tissue- and/or cell-specific offers a new avenue of exploration. Studies of the novel neuronal nuclear matrix protein, NRP/B, reveal that it is an early and highly specific marker of neuronal induction and development in vertebrates, since its expression is restricted mainly to the developing and mature nervous system. These studies also show that NRP/B is involved in neuronal differentiation. To further examine the structure-function of NRP/B, we have cloned and characterized the murine Nrp/b gene. The murine gene consists of four exons interrupted by three introns that span 7.6kb of DNA. The complete open reading frame is localized in exon 3, suggesting that NRP/B is highly conserved during evolution. Chromosomal analysis shows that NRP/B is localized to chromosome 13 in mouse and chromosome 5q12-13 in human.Since our previous studies demonstrated that NRP/B is expressed in primary hippocampal neurons but not in primary astrocytes, we have characterized NRP/B mRNA and protein expression in various brain cell lines and in human brain tumors. Abundant expression of NRP/B mRNA and protein was observed in human neuroblastoma cell lines (IMR32, SKN-MC, SKN-SH), in glioblastoma cell lines (A172, T98G, U87-MG, U118-MG, U138-MG, and U373-MG), in neuroglioma (H4) and astrocytoma cell lines (CCF-STTG1 and SW1088). Confocal analysis of NRP/B in U87-MG glioblastoma cells indicated nuclear localization of NRP/B. NRP/B expression was also observed in human primary brain tumors including glioblastoma multiformae and astrocytomas (total of five cases). These results suggest that NRP/B expression is upregulated in human brain tumors including glioblastomas and astrocytomas, while under normal conditions NRP/B expression is restricted to neurons. This study implicates a role for NRP/B in brain tumor development. 相似文献
44.
Yael Ben Shabat Avraham Shitzer Dusan Fiala 《International journal of biometeorology》2014,58(6):1007-1015
Wind chill equivalent temperatures (WCETs) were estimated by a modified Fiala’s whole body thermoregulation model of a clothed person. Facial convective heat exchange coefficients applied in the computations concurrently with environmental radiation effects were taken from a recently derived human-based correlation. Apart from these, the analysis followed the methodology used in the derivation of the currently used wind chill charts. WCET values are summarized by the following equation: $$ \mathrm{WCET}=12.87+0.5334\ast {T}_o-\left(12.66-0.4414\ast {T}_o\right)\ast {U}_{reported}{}^{0.1228} $$ Results indicate consistently lower estimated facial skin temperatures and consequently higher WCETs than those listed in the literature and used by the North American weather services. Calculated dynamic facial skin temperatures were additionally applied in the estimation of probabilities for the occurrence of risks of frostbite. Predicted weather combinations for probabilities of “Practically no risk of frostbite for most people,” for less than 5 % risk at wind speeds above 40 km h?1, were shown to occur at air temperatures above ?10 °C compared to the currently published air temperature of ?15 °C. At air temperatures below ?35 °C, the presently calculated weather combination of 40 km h?1/?35 °C, at which the transition for risks to incur a frostbite in less than 2 min, is less conservative than that published: 60 km h?1/?40 °C. The present results introduce a fundamentally improved scientific basis for estimating facial skin temperatures, wind chill temperatures and risk probabilities for frostbites over those currently practiced. 相似文献
45.
46.
Nangia-Makker P Nakahara S Hogan V Raz A 《Journal of bioenergetics and biomembranes》2007,39(1):79-84
During the past decade, extensive progress has been made toward understanding the molecular basis for the regulation of apoptosis.
In mammalian cells undergoing apoptosis, two distinct mechanisms or pathways are operated and are triggered by cell death
stimuli from intra- or extra-cellular environments, namely the intrinsic or extrinsic pathways, resulting in mitochondrial
membrane depolarization. Several lines of evidence from our laboratories and others have indicated that galectin-3 plays an
important role in these pathways by binding to various ligands. Here the authors provide a brief discussion on the role of
endogenous or extra-cellular galectin-3 in the regulation of apoptosis and how it could be used as a therapeutic target using
natural plant products as its functional inhibitors. 相似文献
47.
Jiang S Seng S Avraham HK Fu Y Avraham S 《The Journal of biological chemistry》2007,282(16):12319-12329
Oligodendrocytes (OLGs) are generated by progenitor cells that are committed to differentiating into myelin-forming cells of the central nervous system. Rearrangement of the cytoskeleton leading to the extension of cellular processes is essential for the myelination of axons by OLGs. Here, we have characterized a new member of the Kelch-related protein family termed MRP2 (for Mayven-related protein 2) that is specifically expressed in brain. MRP2/KLHL1 is expressed in oligodendrocyte precursors and mature OLGs, and its expression is up-regulated during OLG differentiation. MRP2/KLHL1 expression was abundant during the specific stages of oligodendrocyte development, as identified by A2B5-, O4-, and O1-specific oligodendrocyte markers. MRP2/KLHL1 was localized in the cytoplasm and along the cell processes. Moreover, a direct endogenous association of MRP2/KLHL1 with actin was observed, which was significantly increased in differentiated OLGs compared with undifferentiated OLGs. Overexpression of MRP2/KLHL1 resulted in a significant increase in the process extension of rat OLGs, whereas MRP2/KLHL1 antisense reduced the process length of primary rat OLGs. Furthermore, murine OLGs isolated from MRP2/KLHL1 transgenic mice showed a significant increase in the process extension of OLGs compared with control wild-type murine OLGs. These studies provide insights into the role of MRP2/KLHL1, through its interaction with actin, in the process elongation of OLGs. 相似文献
48.
Hydraulic resistance components of mature apple trees on rootstocks of different vigours 总被引:1,自引:0,他引:1
Dwarfing of fruit trees is often achieved through the use of dwarfing rootstocks. Dwarf trees are characterized by sustained reductions in vegetative growth during the lifetime of the tree. The dwarfing mechanism is not well understood, but it has been hypothesized that hydraulic properties of the rootstock and the graft union are involved. It is hypothesized here that leaf- or stem-specific resistance of at least one hydraulic component of the water transport system would be negatively correlated with rootstock 'vigour', and this could be useful for selection of rootstocks. Hydraulic resistance (R) of fully grown apple trees on a variety of rootstocks of different 'vigours' was measured. Most measurements were with the evaporative flux (EF) method, where water uptake measured with sap flow sensors was related to the pressure gradient from soil (taken as pre-dawn leaf) and midday root (taken as covered root-sucker), stem (from covered leaf), and exposed and shaded leaf water potentials (Psi(l)). R of trees on dwarfing M9 rootstock was compared with that of more vigorous MM106 and MM111 rootstocks in Israel and Vermont, USA. In Israel, M9 consistently had higher leaf-specific hydraulic resistance (R(l)) in the soil to scion stem pathway, but this difference was only significant for one summer. R was larger in M9 between the root and stem, implicating the graft union as the site of increased resistance. In Vermont, R(l) of 9- and 10-year-old trees on six rootstocks of various vigours was not consistently related to vigour, and stem-specific resistance (R(s)) increased with increasing vigour. High pressure flow meter (HPFM) measurements gave a lower R than the EF method in all but one case, perhaps indicating a significant amount of xylem dysfunction in these trees, and demonstrated the increased resistivity of stem sections that included dwarf graft unions as compared with non-graft stem sections. It is concluded that stem- and leaf-specific R are not consistently positively correlated with dwarfing, although the increased resistivity of the graft union in dwarfing rootstocks may influence the transport of water and other elements across the graft union, and therefore be involved in the dwarfing mechanism. 相似文献
49.
Genomic technology has completely changed the way in which we are able to diagnose human genetic mutations. Genomic techniques such as the polymerase chain reaction, linkage analysis, Sanger sequencing, and most recently, massively parallel sequencing, have allowed researchers and clinicians to identify mutations for patients with Pendred syndrome and DFNB4 non-syndromic hearing loss. While thus far most of the mutations have been in the SLC26A4 gene coding for the pendrin protein, other genetic mutations may contribute to these phenotypes as well. Furthermore, mouse models for deafness have been invaluable to help determine the mechanisms for SLC26A4-associated deafness. Further work in these areas of research will help define genotype-phenotype correlations and develop methods for therapy in the future. 相似文献
50.
The discovery of unanticipated microbial diversity in remote, often hostile environments has led to a greater appreciation of the complexity and richness of the natural world. Yellowstone National Park (YNP) has long been a focus of work on taxa that inhabit extreme environments. Here we report the finding of microbial flora that inhabit an unexpected niche: the cavities of bone remnants from a bison carcass in Norris Geyser Basin in YNP. Although bleached white on the surface, the bone cavities are bright green due to the presence of Stichococcus-like trebouxiophyte green algae. The cavities also harbour different fungi and bacteria. Stichococcus species are common lichen photobionts and the Thelebolales fungi present in the bone cavities have previously been found in association with animal remains. Scanning electron microscope analysis suggests the fungi and algae do not form lichen-like associations in the bone. Rather these taxa and the bacteria appear to be opportunists that have colonized an isolated oasis that provides nutrients and protection from desiccation and UV radiation. 相似文献