全文获取类型
收费全文 | 776篇 |
免费 | 60篇 |
出版年
2024年 | 3篇 |
2023年 | 3篇 |
2022年 | 10篇 |
2021年 | 12篇 |
2020年 | 9篇 |
2019年 | 6篇 |
2018年 | 8篇 |
2017年 | 8篇 |
2016年 | 19篇 |
2015年 | 50篇 |
2014年 | 39篇 |
2013年 | 43篇 |
2012年 | 64篇 |
2011年 | 55篇 |
2010年 | 40篇 |
2009年 | 43篇 |
2008年 | 65篇 |
2007年 | 59篇 |
2006年 | 44篇 |
2005年 | 42篇 |
2004年 | 40篇 |
2003年 | 43篇 |
2002年 | 32篇 |
2001年 | 14篇 |
2000年 | 10篇 |
1999年 | 12篇 |
1998年 | 9篇 |
1997年 | 8篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 4篇 |
1993年 | 5篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1978年 | 1篇 |
1976年 | 2篇 |
1972年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有836条查询结果,搜索用时 15 毫秒
91.
92.
Rellick SL O'Leary H Piktel D Walton C Fortney JE Akers SM Martin KH Denvir J Boskovic G Primerano DA Vos J Bailey N Gencheva M Gibson LF 《PloS one》2012,7(2):e30758
Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche. 相似文献
93.
Huynh TP Mah V Sampson VB Chia D Fishbein MC Horvath S Alavi M Wu DC Harper J Sarafian T Dubinett SM Langhans SA Goodglick L Rajasekaran AK 《American journal of physiology. Lung cellular and molecular physiology》2012,302(11):L1150-L1158
Diminished Na,K-ATPase expression has been reported in several carcinomas and has been linked to tumor progression. However, few studies have determined whether Na,K-ATPase function and expression are altered in lung malignancies. Because cigarette smoke (CS) is a major factor underlying lung carcinogenesis and progression, we investigated whether CS affects Na,K-ATPase activity and expression in lung cell lines. Cells exposed to CS in vitro showed a reduction of Na,K-ATPase activity. We detected the presence of reactive oxygen species (ROS) in cells exposed to CS before Na,K-ATPase inhibition, and neutralization of ROS restored Na,K-ATPase activity. We further determined whether Na,K-ATPase expression correlated with increasing grades of lung adenocarcinoma and survival of patients with smoking history. Immunohistochemical analysis of lung adenocarcinoma tissues revealed reduced Na,K-ATPase expression with increasing tumor grade. Using tissue microarray containing lung adenocarcinomas of patients with known smoking status, we found that high expression of Na,K-ATPase correlated with better survival. For the first time, these data demonstrate that CS is associated with loss of Na,K-ATPase function and expression in lung carcinogenesis, which might contribute to disease progression. 相似文献
94.
Retnoningrum DS Pramesti HT Santika PY Valerius O Asjarie S Suciati T 《Protein expression and purification》2012,84(2):188-194
Codons in the open reading frame (ORF) encoding for human bone morphogenetic protein-2 (hBMP-2) were optimized to reach high level expression in Escherichia coli. The optimization was done by the computer programs DNA works and DNA Star according to Thermodynamically Balanced Inside Out (TBIO) approach. The ORF consisting of 342 base pairs (bp) was assembled using two-steps Polymerase Chain Reaction, cloned into a pGEM-T vector with a mutation rate of 6.38 bp per kb and transformed into E. coli JM109. After a DNA sequence confirmation, mutation-free ORF was subcloned into pET32b and transformed into E. coli BL21(DE3). The rhBMP-2 was produced as a thioredoxin-his-tag fusion protein at relatively high level, approximately 60% of total intracellular proteins as inclusion bodies (IB), with a yield of 1.39 g per liter culture. Solubilization of IB gave soluble monomer rhBMP-2 with a recovery of 13.6% and refolding of soluble rhBMP-2 produced dimeric forms with a yield of 8.7%. The size and identity of the purified rhBMP-2 was confirmed by nano-LC-MS/MS2 analysis. Our work demonstrates for the first time that by using TBIO approach, a codon-optimized ORF encoding for rhBMP-2 protein can be expressed at high level in E. coli expression system. 相似文献
95.
Al-Qatati A Winter PW Wolf-Ringwall AL Chatterjee PB Van Orden AK Crans DC Roess DA Barisas BG 《Cell biochemistry and biophysics》2012,62(3):441-450
We have examined the association of insulin receptors (IR) and downstream signaling molecules with membrane microdomains in
rat basophilic leukemia (RBL-2H3) cells following treatment with insulin or tris(2-pyridinecarbxylato)chromium(III) (Cr(pic)3). Single-particle tracking demonstrated that individual IR on these cells exhibited reduced lateral diffusion and increased
confinement within 100 nm-scale membrane compartments after treatment with either 200 nM insulin or 10 μM Cr(pic)3. These treatments also increased the association of native IR, phosphorylated insulin receptor substrate 1 and phosphorylated
AKT with detergent-resistant membrane microdomains of characteristically high buoyancy. Confocal fluorescence microscopic
imaging of Di-4-ANEPPDHQ labeled RBL-2H3 cells also showed that plasma membrane lipid order decreased following treatment
with Cr(pic)3 but was not altered by insulin treatment. Fluorescence correlation spectroscopy demonstrated that Cr(pic)3 did not affect IR cell-surface density or compete with insulin for available binding sites. Finally, Fourier transform infrared
spectroscopy indicated that Cr(pic)3 likely associates with the lipid interface in reverse-micelle model membranes. Taken together, these results suggest that
activation of IR signaling in a cellular model system by both insulin and Cr(pic)3 involves retention of IR in specialized nanometer-scale membrane microdomains but that the insulin-like effects of Cr(pic)3 are due to changes in membrane lipid order rather than to direct interactions with IR. 相似文献
96.
Stephanie von Hinke Kessler Scholder George Davey Smith Debbie A. Lawlor Carol Propper Frank Windmeijer 《Economics & Human Biology》2012,10(4):405-418
The literature that examines the relationship between child or adolescent Body Mass Index (BMI) and academic attainment generally finds mixed results. This may be due to the use of different data sets, conditioning variables, or methodologies: studies either use an individual fixed effects (FE) approach and/or an instrumental variable (IV) specification. Using one common dataset, the Avon Longitudinal Study of Parents and Children, and a common set of controls, this paper compares the different approaches (including using different types of IV's), discusses their appropriateness, and contrasts their findings. We show that, although the results differ depending on the approach, most estimates cannot be statistically distinguished from OLS, nor from each other. Examining the potential violations of key assumptions of the different approaches and comparing their point estimates, we conclude that fat mass is unlikely to be causally related to academic achievement in adolescence. 相似文献
97.
Beekman JM van der Poel CE van der Linden JA van den Berg DL van den Berghe PV van de Winkel JG Leusen JH 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(6):3938-3945
Filamin A, or actin-binding protein 280, is a ubiquitously expressed cytosolic protein that interacts with intracellular domains of multiple receptors to control their subcellular distribution, and signaling capacity. In this study, we document interaction between FcgammaRI, a high-affinity IgG receptor, and filamin A by yeast two-hybrid techniques and coimmunoprecipitation. Both proteins colocalized at the plasma membrane in monocytes, but dissociated upon FcgammaRI triggering. The filamin-deficient cell line M2 and a filamin-reconstituted M2 subclone (A7), were used to further study FcgammaRI-filamin interactions. FcgammaRI transfection in A7 cells with filamin resulted in high plasma membrane expression levels. In filamin-deficient M2 cells and in filamin RNA-interference studies, FcgammaRI surface expression was consistently reduced. FcgammaRI localized to LAMP-1-positive vesicles in the absence of filamin as shown by confocal microscopy indicative for lysosomal localization. Mouse IgG2a capture experiments suggested a transient membrane expression of FcgammaRI before being transported to the lysosomes. These data support a pivotal role for filamin in FcgammaRI surface expression via retention of FcgammaRI from a default lysosomal pathway. 相似文献
98.
Anthony J Hayes Debbie Tudor Mari A Nowell Bruce Caterson Clare E Hughes 《The journal of histochemistry and cytochemistry》2008,56(2):125-138
Osteoarthritis is a chronic, debilitating joint disease characterized by progressive destruction of articular cartilage. Recently, a number of studies have identified a chondroprogenitor cell population within articular cartilage with significant potential for repair/regeneration. As yet, there are few robust biomarkers of these cells. In this study, we show that monoclonal antibodies recognizing novel chondroitin sulfate sulfation motif epitopes in glycosaminoglycans on proteoglycans can be used to identify metabolically distinct subpopulations of cells specifically within the superficial zone of the tissue and that flow cytometric analysis can recognize these cell subpopulations. Fluorochrome co-localization analysis suggests that the chondroitin sulfate sulphation motifs are associated with a range of cell and extracellular matrix proteoglycans within the stem cell niche that include perlecan and aggrecan but not versican. The unique distributions of these sulphation motifs within the microenvironment of superficial zone chondrocytes, seems to designate early stages of stem/progenitor cell differentiation and is consistent with these molecules playing a functional role in regulating aspects of chondrogenesis. The isolation and further characterization of these cells will lead to an improved understanding of the role novel chondroitin sulfate sulfation plays in articular cartilage development and may contribute significantly to the field of articular cartilage repair. 相似文献
99.
Two hypotheses, based on previous work on Neandertal anterior and premolar teeth, are investigated here: (1) that estimated molar lateral enamel formation times in Neandertals are likely to fall within the range of modern human population variation, and (2) that perikymata (lateral enamel growth increments) are distributed across cervical and occlusal halves of the crown differently in Neandertals than they are in modern humans. To investigate these hypotheses, total perikymata numbers and the distribution of perikymata across deciles of crown height were compared for Neandertal, northern European, and southern African upper molar mesiobuccal (mb) cusps, lower molar mesiobuccal cusps, and the lower first molar distobuccal (db) cusp. Sample sizes range from five (Neandertal M(1)db) to 29 (southern African M(1)mb). Neandertal mean perikymata numbers were found to differ significantly from those of both modern human samples (with the Neandertal mean higher) only for the M(2)mb. Regression analysis suggests that, with the exception of the M(2)mb, the hypothesis of equivalence between Neandertal and modern human lateral enamel formation time cannot be rejected. For the M(2)mb, regression analysis strongly suggests that this cusp took longer to form in the Neandertal sample than it did in the southern African sample. Plots of perikymata numbers across deciles of crown height demonstrate that Neandertal perikymata are distributed more evenly across the cervical and occlusal halves of molar crowns than they are in the modern human samples. These results are integrated into a discussion of Neandertal and modern human lateral enamel formation across the dentition, with reference to issues of life history and enamel growth processes. 相似文献
100.
Murphy DM Forrest IA Corris PA Johnson GE Small T Jones D Fisher AJ Egan JJ Cawston TE Ward C Lordan JL 《American journal of physiology. Lung cellular and molecular physiology》2008,294(3):L592-L599
Obliterative bronchiolitis (OB), the major cause of chronic lung allograft dysfunction, is characterized by airway neutrophilia, inflammation, and remodeling, with progressive fibroproliferation and obliteration of small airways that ultimately leads to patient death. Statins have potential anti-inflammatory effects and have been demonstrated to confer a survival advantage in lung transplant patients. We postulated that the beneficial effects of simvastatin in lung transplantation are in part due to inhibition of the epithelial production of key mediators of neutrophil chemotaxis, inflammation, and airway remodeling. Our objective was to assess the effect of simvastatin on a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts, with specific reference to airway neutrophilia and remodeling. PBEC cultures were stimulated with IL-17 or transforming growth factor (TGF)-beta, with and without simvastatin. Supernatant levels of factors critical to driving airway neutrophilia and remodeling were measured. IL-17 upregulated IL-8, IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and VEGF, whereas TGF-beta increased IL-6, GM-CSF, matrix metalloproteinase (MMP)-2, and MMP-9. Simvastatin attenuated effects of both IL-17 and TGF-beta. We have demonstrated the ability of simvastatin to attenuate release of airway neutrophilic and remodeling mediators and to inhibit their upregulation by TGF-beta and IL-17. These data illustrate the potential of simvastatin to alleviate neutrophilic airway inflammation and remodeling in the transplanted lung and may have additional relevance to other neutrophilic airway conditions, such as chronic obstructive pulmonary disease. 相似文献