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101.
102.
Valentin Magidson Jie He Jeffrey G. Ault Christopher B. O’Connell Nachen Yang Irina Tikhonenko Bruce F. McEwen Haixin Sui Alexey Khodjakov 《The Journal of cell biology》2016,212(3):307-319
Kinetochores attach chromosomes to the spindle microtubules and signal the spindle assembly checkpoint to delay mitotic exit until all chromosomes are attached. Light microscopy approaches aimed to indirectly determine distances between various proteins within the kinetochore (termed Delta) suggest that kinetochores become stretched by spindle forces and compact elastically when the force is suppressed. Low Delta is believed to arrest mitotic progression in taxol-treated cells. However, the structural basis of Delta remains unknown. By integrating same-kinetochore light microscopy and electron microscopy, we demonstrate that the value of Delta is affected by the variability in the shape and size of outer kinetochore domains. The outer kinetochore compacts when spindle forces are maximal during metaphase. When the forces are weakened by taxol treatment, the outer kinetochore expands radially and some kinetochores completely lose microtubule attachment, a condition known to arrest mitotic progression. These observations offer an alternative interpretation of intrakinetochore tension and question whether Delta plays a direct role in the control of mitotic progression. 相似文献
103.
Neuraminidase 1 is a negative regulator of lysosomal exocytosis 总被引:1,自引:0,他引:1
Yogalingam G Bonten EJ van de Vlekkert D Hu H Moshiach S Connell SA d'Azzo A 《Developmental cell》2008,15(1):74-86
Lysosomal exocytosis is a Ca2+-regulated mechanism that involves proteins responsible for cytoskeletal attachment and fusion of lysosomes with the plasma membrane. However, whether luminal lysosomal enzymes contribute to this process remains unknown. Here we show that neuraminidase NEU1 negatively regulates lysosomal exocytosis in hematopoietic cells by processing the sialic acids on the lysosomal membrane protein LAMP-1. In macrophages from NEU1-deficient mice, a model of the disease sialidosis, and in patients' fibroblasts, oversialylated LAMP-1 enhances lysosomal exocytosis. Silencing of LAMP-1 reverts this phenotype by interfering with the docking of lysosomes at the plasma membrane. In neu1-/- mice the excessive exocytosis of serine proteases in the bone niche leads to inactivation of extracellular serpins, premature degradation of VCAM-1, and loss of bone marrow retention. Our findings uncover an unexpected mechanism influencing lysosomal exocytosis and argue that exacerbations of this process form the basis for certain genetic diseases. 相似文献
104.
F. C. Connell P. Ostergaard C. Carver G. Brice N. Williams S. Mansour P. S. Mortimer Steve Jeffery Lymphoedema Consortium 《Human genetics》2009,124(6):625-631
Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant
inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary lymphoedema and more specifically in those with a phenotype that resembles Milroy disease.
This study aims to address this issue and thereby delineate the Milroy disease phenotype. Fifty-two patients with primary
lymphoedema were analysed for mutations in the coding regions of VEGFR3. Patients were divided into four groups: Typical Milroy disease with family history (group I), typical Milroy disease with
no family history (group II), atypical Milroy disease (group III), and complex primary lymphoedema (group IV). Results demonstrated
that with rigorous phenotyping the likelihood of detecting VEGFR3 mutations is optimised. Mutation prevalence is 75% in typical Milroy patients with a family history (group I) and 68% if
positive family history is not a diagnostic criterion. A positive family history is not essential in Milroy disease. The likelihood
of detecting VEGFR3 mutations in patients who have a phenotype which is not typical of Milroy disease is very small (<5%). For the 22 mutation
positive patients, 14 novel VEGFR3 mutations were identified, two of which were in exon 22 and one in exon 17, confirming that these exons should be included
in VEGFR3 analysis. No mutations were found outside the kinase domains, showing that analysis of this part of the gene is not useful
for Milroy disease patients. VEGFC, which encodes the ligand for VEGFR3, was sequenced in all patients with typical Milroy disease (groups I and II) and no
mutations were identified.
F. C. Connell and P. Ostergaard contributed equally to this work.
An erratum to this article can be found at 相似文献
105.
Matthew O’Connell Wayne Zeller James Burgeson Rama K. Mishra Jose Ramirez Alex S. Kiselyov Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(3):778-782
A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP3 receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE2 and fits into an internally generated EP3 pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs. 相似文献
106.
The roles of weather variability and sunspots in the occurrence of cyanobacteria blooms, were investigated using cyanobacteria
cell data collected from the Fred Haigh Dam, Queensland, Australia. Time series generalized linear model and classification
and regression tree (CART) model were used in the analysis. Data on notified cell numbers of cyanobacteria and weather variables
over the periods 2001 and 2005 were provided by the Australian Department of Natural Resources and Water, and Australian Bureau
of Meteorology, respectively. The results indicate that monthly minimum temperature (relative risk [RR]: 1.13, 95% confidence
interval [CI]: 1.02–1.25) and rainfall (RR: 1.11; 95% CI: 1.03–1.20) had a positive association, but relative humidity (RR:
0.94; 95% CI: 0.91–0.98) and wind speed (RR: 0.90; 95% CI: 0.82–0.98) were negatively associated with the cyanobacterial numbers,
after adjustment for seasonality and auto-correlation. The CART model showed that the cyanobacteria numbers were best described
by an interaction between minimum temperature, relative humidity, and sunspot numbers. When minimum temperature exceeded 18°C
and relative humidity was under 66%, the number of cyanobacterial cells rose by 2.15-fold. We conclude that weather variability
and sunspot activity may affect cyanobacteria blooms in dams. 相似文献
107.
Kohlhaas CF Morrow VA Jhakra N Patil V Connell JM Petrie JR Salt IP 《Biochemical and biophysical research communications》2011,412(4):747-751
Insulin stimulates endothelial NO synthesis, at least in part mediated by phosphorylation and activation of endothelial NO synthase at Ser1177 and Ser615 by Akt. We have previously demonstrated that insulin-stimulated NO synthesis is inhibited under high culture glucose conditions, without altering Ca(2+)-stimulated NO synthesis or insulin-stimulated phosphorylation of eNOS. This indicates that stimulation of endothelial NO synthase phosphorylation may be required, yet not sufficient, for insulin-stimulated nitric oxide synthesis. In the current study we investigated the role of supply of the eNOS substrate, L-arginine as a candidate parallel mechanism underlying insulin-stimulated NO synthesis in cultured human aortic endothelial cells. Insulin rapidly stimulated L-arginine transport, an effect abrogated by incubation with inhibitors of phosphatidylinositol-3'-kinase or infection with adenoviruses expressing a dominant negative mutant Akt. Furthermore, supplementation of endothelial cells with extracellular L-arginine enhanced insulin-stimulated NO synthesis, an effect reversed by co-incubation with the L-arginine transport inhibitor, L-lysine. Basal L-arginine transport was significantly increased under high glucose culture conditions, yet insulin-stimulated L-arginine transport remained unaltered. The increase in L-arginine transport elicited by high glucose was independent of the expression of the cationic amino acid transporters, hCAT1 and hCAT2 and not associated with any changes in the activity of ERK1/2, Akt or protein kinase C (PKC). We propose that rapid stimulation of L-arginine transport contributes to insulin-stimulated NO synthesis in human endothelial cells, yet attenuation of this is unlikely to underlie the inhibition of insulin-stimulated NO synthesis under high glucose conditions. 相似文献
108.
Christine F. Kohlhaas Valerie A. Morrow Neelam Jhakra Vrushali Patil John M.C. Connell John R. Petrie Ian P. Salt 《Biochemical and biophysical research communications》2011,(4):747
Insulin stimulates endothelial NO synthesis, at least in part mediated by phosphorylation and activation of endothelial NO synthase at Ser1177 and Ser615 by Akt. We have previously demonstrated that insulin-stimulated NO synthesis is inhibited under high culture glucose conditions, without altering Ca2+-stimulated NO synthesis or insulin-stimulated phosphorylation of eNOS. This indicates that stimulation of endothelial NO synthase phosphorylation may be required, yet not sufficient, for insulin-stimulated nitric oxide synthesis. In the current study we investigated the role of supply of the eNOS substrate, l-arginine as a candidate parallel mechanism underlying insulin-stimulated NO synthesis in cultured human aortic endothelial cells. Insulin rapidly stimulated l-arginine transport, an effect abrogated by incubation with inhibitors of phosphatidylinositol-3′-kinase or infection with adenoviruses expressing a dominant negative mutant Akt. Furthermore, supplementation of endothelial cells with extracellular l-arginine enhanced insulin-stimulated NO synthesis, an effect reversed by co-incubation with the l-arginine transport inhibitor, l-lysine. Basal l-arginine transport was significantly increased under high glucose culture conditions, yet insulin-stimulated l-arginine transport remained unaltered. The increase in l-arginine transport elicited by high glucose was independent of the expression of the cationic amino acid transporters, hCAT1 and hCAT2 and not associated with any changes in the activity of ERK1/2, Akt or protein kinase C (PKC). We propose that rapid stimulation of L-arginine transport contributes to insulin-stimulated NO synthesis in human endothelial cells, yet attenuation of this is unlikely to underlie the inhibition of insulin-stimulated NO synthesis under high glucose conditions. 相似文献
109.
Connell AF 《Plastic and reconstructive surgery》2011,128(4):848-852
This feasibility study represents the first report of a new carbon dioxide-based tissue expander designed to allow gradual controlled expansion and to eliminate the need for percutaneous injections. Seven patients underwent implantation with a total of 10 (three bilateral) tissue expanders. After intraoperative filling by the surgeon and wound healing, small doses of carbon dioxide were administered on a daily basis by the patient by means of a hand-held dosage controller leading to gradual, incremental expansion. Rapid expansion during the active dosing phase and flexibility to meet individual patient needs during expansion were demonstrated with all subjects. These patients achieved full expansion in an average of 15 days. All seven patients were able to use the device safely and with ease at home, leading to successful tissue expansion and permanent breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. 相似文献
110.
The likelihood that coupled dynamical systems will completely synchronize, or become “coherent”, is often of great applied
interest. Previous work has established conditions for local stability of coherent solutions and global attractivity of coherent
manifolds in a variety of spatially explicit models. We consider models of communities coupled by dispersal and explore intermediate
regimes in which it can be shown that states in phase space regions of positive measure are attracted to coherent solutions.
Our methods yield rigorous and practically useful coherence criteria that facilitate useful analyses of ecological and epidemiological
problems. 相似文献