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41.
Silaghi-Dumitrescu R Reeder BJ Nicholls P Cooper CE Wilson MT 《The Biochemical journal》2007,403(3):391-395
Ferryl (Fe(IV)=O) species are involved in key enzymatic processes with direct biomedical relevance; among others, the uncontrolled reactivities of ferryl Mb (myoglobin) and Hb (haemoglobin) have been reported to be central to the pathology of rhabdomyolysis and subarachnoid haemorrhage. Rapid-scan stopped-flow methods have been used to monitor the spectra of the ferryl species in Mb and Hb as a function of pH. The ferryl forms of both proteins display an optical transition with pK approximately 4.7, and this is assigned to protonation of the ferryl species itself. We also demonstrate for the first time a direct correlation between Hb/Mb ferryl reactivity and ferryl protonation status, simultaneously informing on chemical mechanism and toxicity and with broader biochemical implications. 相似文献
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43.
Ramajayam R Giridhar R Yadav MR Djaballah H Shum D Radu C 《Journal of enzyme inhibition and medicinal chemistry》2007,22(6):716-721
Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined. 相似文献
44.
Maria Radu Karen Lyle Klaus P. Hoeflich Olga Villamar-Cruz Hartmut Koeppen Jonathan Chernoff 《Molecular and cellular biology》2015,35(23):3990-4005
p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements, cell proliferation, attachment, and migration in a variety of cellular contexts, including endothelial cells. However, the role of endothelial Pak in embryo development has not been reported, and currently, there is no consensus on the endothelial function of individual Pak isoforms, in particular p21-activated kinase 2 (Pak2), the main Pak isoform expressed in endothelial cells. In this work, we employ genetic and molecular studies that show that Pak2, but not Pak1, is a critical mediator of development and maintenance of endothelial cell function. Endothelial depletion of Pak2 leads to early embryo lethality due to flawed blood vessel formation in the embryo body and yolk sac. In adult endothelial cells, Pak2 depletion leads to severe apoptosis and acute angiogenesis defects, and in adult mice, endothelial Pak2 deletion leads to increased vascular permeability. Furthermore, ubiquitous Pak2 deletion is lethal in adult mice. We show that many of these defects are mediated through a newly unveiled Pak2/Bmk1 pathway. Our results demonstrate that endothelial Pak2 is essential during embryogenesis and also for adult blood vessel maintenance, and they also pinpoint the Bmk1/Erk5 pathway as a critical mediator of endothelial Pak2 signaling. 相似文献
45.
Cardiac‐Specific Disruption of Bin1 in Mice Enables a Model of Stress‐ and Age‐Associated Dilated Cardiomyopathy 下载免费PDF全文
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Psoriasis is a chronic, autoimmune skin disease affecting approximately 2% of the world's population. Clobetasol propionate
which is a superpotent topical corticosteroid is widely used for topical treatment of psoriasis. Conventional dosage forms
like creams and ointments are commonly prefered for the therapy. The purpose of this study was to develop a new topical delivery
system in order to provide the prolonged release of clobetasol propionate and to reduce systemic absorption and side effects
of the drug. Clobetasol propionate loaded-poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared by oil-in-water
emulsion–solvent evaporation technique. Particle size analysis, morphological characterization, DSC and XRD analyses and in vitro drug release studies were performed on the microparticle formulations. Emulgel formulations were prepared as an alternative
for topical delivery of clobetasol propionate. In vitro drug release studies were carried out from the emulgel formulations containing pure drug and drug-loaded microspheres. In
addition, the same studies were performed to determine the drug release from the commercial cream product of clobetasol propionate.
The release of clobetasol propionate from the emulgel formulations was significantly higher than the commercial product. In
addition, the encapsulation of clobetasol propionate in the PLGA microspheres significantly delayed the drug release from
the emulgel formulation. As a result, the decrease in the side effects of clobetasol propionate by the formulation containing
PLGA microspheres is expected. 相似文献
48.
Knezevic I Predescu D Bardita C Wang M Sharma T Keith B Neamu R Malik AB Predescu S 《Journal of cellular and molecular medicine》2011,15(11):2364-2376
Intersectin-1s (ITSN-1s), a five Src homology 3 (SH3) domain-containing protein, is critically required for caveolae and clathrin-mediated endocytosis (CME), due to its interactions with dynamin (dyn). Of the five SH3A-E domains, SH3A is unique because of its high affinity for dyn and potent inhibition of CME. However, the molecular mechanism by which SH3A integrates in the overall function of ITSN-1s to regulate the endocytic process is not understood. Using biochemical and functional approaches as well as high-resolution electron microscopy, we show that SH3A exogenously expressed in human lung endothelial cells caused abnormal endocytic structures, distorted caveolae clusters, frequent staining-dense rings around the caveolar necks and 60% inhibition of caveolae internalization. In vitro studies further revealed that SH3A, similar to full-length ITSN-1s stimulates dyn2 oligomerization and guanosine triphosphatase (GTP)ase activity, effects not detected when other SH3 domains of ITSN-1s were used as controls. Strikingly, in the presence of SH3A, dyn2-dyn2 interactions are stabilized and despite continuous GTP hydrolysis, dyn2 oligomers cannot disassemble. SH3A may hold up caveolae release from the plasma membrane and formation of free-transport vesicles, by prolonging the lifetime of assembled dyn2. Altogether, our results indicate that ITSN-1s, via its SH3A has the unique ability to regulate dyn2 assembly-disassembly and function during endocytosis. 相似文献
49.
Background: A significant proportion of heart failure (HF) patients have preserved ejection fraction (EF). Considering that inflammation and oxidative stress are involved in HF evolution, we investigated lipoprotein-associated phospholipase A2 (LpPLA2), an enzyme involved in these pathophysiologic processes in relation to EF. Methods and results: The study included 208 HF patients and 20 healthy controls. HF patients with preserved EF (HFpEF) represented 42.31% of all HF patients. LpPLA2 activity was significantly increased in HF patients when compared with controls and was higher in HFpEF than in HF with reduced EF patients (HFrEF). The incidence of left ventricular hypertrophy was higher in HFpEF than in HFrEF (EF < 50). Conclusion: Confirming its role as a marker of vascular inflammation, LpPLA2 seems to be a biomarker constantly correlated with HF, regardless of etiology. Elevated plasma values of LpPLA2 in HFpEF are consistent with the exacerbated inflammatory status. 相似文献
50.
Iovita R 《PloS one》2011,6(12):e29029