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41.
Xuetao Sun Abdul Momen Jun Wu Hossein Noyan Renke Li Rüdiger von Harsdorf Mansoor Husain 《The Journal of biological chemistry》2014,289(24):16924-16935
p27Kip1 (p27), a key regulator of cell division, has been implicated in autophagy of cancer cells. However, its role in autophagy, the evolutionarily conserved catabolic process that enables cells to remove unwanted proteins and damaged organelles, had not been examined in the heart. Here we report that ectopic delivery of a p27 fusion protein (TAT-p27) was sufficient to induce autophagy in neonatal rat ventricular cardiomyocytes in vitro, under basal conditions and after glucose deprivation. Conversely, lentivirus-delivered shRNA against p27 successfully reduced p27 levels and suppressed basal and glucose-deprived levels of autophagy in cardiomyocytes in vitro. Glucose deprivation mimics myocardial ischemia and induces apoptosis in cardiomyocytes. During glucose deprivation, TAT-p27 inhibited apoptosis, whereas down-regulation of p27 decreased survival of cardiomyocytes. However, inhibition of autophagy by pharmacological (3-methyladenine, chloroquine, or bafilomycin A1) or genetic approaches (siRNA-mediated knockdown of Atg5) sensitized cardiomyocytes to glucose deprivation-induced apoptosis, even in the presence of TAT-p27. TAT-p27 was also able to provoke greater levels of autophagy in resting and fasting cardiomyocytes in vivo. Further, TAT-p27 enhanced autophagy and repressed cardiomyocytes apoptosis, improved cardiac function, and reduced infarct size following myocardial infarction. Again, these effects were lost when cardiac autophagy in vivo was blocked by chloroquine. Taken together, these data show that p27 positively regulates cardiac autophagy in vitro and in vivo, at rest and after metabolic stress, and that TAT-p27 inhibits apoptosis by promoting autophagy in glucose-deprived cardiomyocytes in vitro and in post-myocardial infarction hearts in vivo. 相似文献
42.
Wang X Hu Q Mansoor A Lee J Wang Z Lee T From AH Zhang J 《American journal of physiology. Heart and circulatory physiology》2006,290(4):H1393-H1405
In an established swine model of severe left ventricular (LV) hypertrophy (LVH), the bioenergetic and functional consequences of transplanting autologous mesenchymal stem cells (MSCs) overexpressing vascular endothelial growth factor (VEGF-MSCs) into the LV were evaluated; transplantation was accomplished by infusion of VEGF-MSCs into the interventricular cardiac vein. Specifically, the hypertrophic response to aortic banding was compared in seven pigs treated with 30 million VEGF-MSCs, eight pigs treated with 30 million MSCs without VEGF modification, and 19 untreated LVH pigs. Eight pigs without banding or cell transplantation (normal) were also studied. Four weeks postbanding, LV wall thickening (MRI), myocardial blood flow (MBF), high-energy phosphate levels ((31)P magnetic resonance spectroscopy), and hemodynamic measurements were obtained under basal conditions and during a catecholamine-induced high cardiac workstate (HCW). Although 9 of 19 untreated banded pigs developed clinical evidence of biventricular failure, no MSCs-treated animal developed heart failure. MSCs engraftment was present in both cell transplant groups, and both baseline and HCW MBF values were significantly increased in hearts receiving VEGF-MSCs compared with other groups (P < 0.05). During HCW, cardiac inotropic reserve (defined as the percent increase of rate pressure product at HCW relative to baseline) was normal in the VEGF-MSCs group and significantly decreased in all other banded groups. Additionally, during HCW, the myocardial energetic state [reflected by the phosphocreatine-to-ATP ratio (PCr/ATP)] of VEGF-MSCs-treated hearts remained stable, whereas in all other groups, PCr/ATP decreased significantly from baseline values (P < 0.05, each group). Myocardial von Willebrand factor and VEGF mRNA expressions and myocardial capillary density were significantly increased in VEGF-MSCs-treated hearts (P < 0.05). Hence, in the pressure-overloaded LV, transplantation of VEGF-MSCs prevents LV decompensation, induces neovascularization, attenuates hypertrophy, and improves MBF, myocardial bioenergetic characteristics, and contractile performance. 相似文献
43.
Yang LL Arab S Liu P Stewart DJ Husain M 《Canadian journal of physiology and pharmacology》2005,83(1):47-62
Endothelin-1 has emerged as an important participant in the pathophysiology of a variety of cardiovascular diseases, where it may act on endocrine, paracrine and autocrine bases. Here we review its regulated biosynthesis, receptor-mediated signaling, and functional consequences in the heart, with particular emphasis on cardiac development and disease. Exploring published data employing molecular genetic mouse models of endothelin dysregulation, we highlight its heretofore underappreciated role as a pro-inflammatory cytokine. We also present novel micro-array data from one such mouse model, which implicate the specific downstream pathways that may mediate endothelin-1's effects. 相似文献
44.
45.
o-Phthalaldehyde activates the Ca(2+) release mechanism from skeletal muscle sarcoplasmic reticulum.
J J Abramson S P Mullen S Koehler D Mansoor P Anderson C C Wamser T J Swan T G Favero 《Archives of biochemistry and biophysics》2001,391(2):235-244
o-Phthalaldehyde (OPA) is a bifunctional reagent that forms an isoindole derivative by reacting with cysteine and lysine residues separated by approximately 0.3 nm. OPA inhibits sarcoplasmic reticulum (SR) Ca(2+)-ATPase activity at low micromolar concentrations and induces Ca(2+) release from actively loaded SR vesicles by activating the ryanodine receptor from fast twitch skeletal muscle. Both ryanodine binding and single-channel activity show a biphasic concentration dependence. At low OPA concentrations (<100 microM), ryanodine binding and single channel activity are stimulated, while at higher concentrations, a time-dependent sequential activation and inhibition of receptor binding is observed. Activation is characterized by a Ca(2+)-independent increase in maximal receptor occupancy. Data are presented to support a model in which Ca(2+) channel and ryanodine binding activity are enhanced due to an intramolecular cross-linking of nearby lysine and nonhyperreactive cysteine residues. OPA complexation with endogenous lysine residue(s) is critical for receptor activation. 相似文献
46.
47.
Haider MA Olander JE Arnold RF Marous DR McLamb AJ Thompson KC Woodruff WR Haugh JM 《Biomechanics and modeling in mechanobiology》2011,10(6):915-924
A phenomenological mixture model is presented for interactions between biosynthesis of extracellular matrix (ECM) constituents
and ECM linking in a scaffold seeded with chondrocytes. A system of three ordinary differential equations for average apparent
densities of unlinked ECM, linked ECM and scaffold is developed along with associated initial conditions for scaffold material
properties. Equations for unlinked ECM synthesis and ECM linking include an inhibitory mechanism where associated rates decrease
as unlinked ECM concentration in the interstitial fluid increases. Linking rates are proposed to depend on average porosity
in the evolving tissue construct. The resulting initial value problem contains nine independent parameters that account for
scaffold biomaterial properties and interacting mechanisms in the engineered system. Effects of parameter variations on model
variables are analyzed relative to a baseline case with emphasis on the evolution of solid phase apparent density, which is
often correlated with the compressive elastic modulus of the tissue construct. The new model provides an additional quantitative
framework for assessing and optimizing the design of engineered cell-scaffold systems and guiding strategies for articular
cartilage tissue engineering. 相似文献
48.
49.
Muazzam AG Qureshi S Mansoor A Ali L Iqbal M Siddiqi S Khan KM Mazhar K 《Genetic vaccines and therapy》2011,9(1):14-6
Background
A recently discovered occult HCV entity reported by various investigators seems to be highly controversial. Especially, the clinical significance of these findings remains uncertain. For optimal outcome of antiviral therapy, investigation of occult HCV needs a broad-based probe in order to investigate the results of viral therapy and its host/viral interaction. The current study was aimed at determining the prevalence of occult HCV in peripheral blood lymphocytes of predominantly genotype 3 HCV-infected patients after completion of antiviral therapy and to investigate long term outcomes in the presence or absence of PBMC positivity.Method
A total of 151 chronic, antiHCV and serum RNA-positive patients were enrolled in the study. Patients with a complete virological response at the end of treatment were screened for the presence of viral RNA in their PBMCs and were followed for up to one year for the presence of serum and PBMC viral genomic RNA.Results
Out of 151 patients, 104 (70%) responded to the prescribed interferon treatment and showed viral-clearance from serum. These were screened for the presence of genomic RNA in their PBMCs. Sixteen samples were PBMC-positive for viral RNA at the end of treatment (EOT). All these patients had also cleared the virus from peripheral blood cells after the 6-12 month follow-up study.Conclusion
True occult hepatitis C virus does not exist in our cohort. Residual viremia at the EOT stage merely reflects a difference in viral kinetics in various compartments that remains a target of immune response even after the end of antiviral therapy and is eventually cleared out at the sustained viral response (SVR). 相似文献50.
Larson SD Plopper CG Baker G Tarkington BK Decile KC Pinkerton K Mansoor JK Hyde DM Schelegle ES 《American journal of physiology. Lung cellular and molecular physiology》2004,287(2):L286-L295
Mucous cell hypersecretion and increased neuropeptide production play a role in the exacerbation of symptoms associated with asthma. The source of these neuropeptides have been confined to the contributions of small afferent nerves or possibly neuroendocrine cells. We tested the hypothesis that repeated exposure to allergen would alter the sources and abundance of neuropeptides in airways. Right middle lobes from rats (8 wk old) exposed to 2.5% ovalbumin (OVA) for five episodes (30 min each) or filtered air were inflation fixed with paraformaldehyde. The lobes were dissected to expose the airway tree, permeabilized with DMSO, and incubated in antibody to rat calcitonin gene-related peptide (CGRP), followed with a fluorochrome-labeled second antibody. CGRP-positive structures were imaged via confocal microscopy. Airways were later embedded in plastic and sectioned for cell identification. In animals challenged with OVA, CGRP-positive cells, not neuroendocrine or neuronal in origin (confirmed by a lack of protein gene product 9.5 signal), were recorded along the axial path. In section, this fluorescent signal was localized to granules within epithelial cells. Alcian blue/periodic acid-Schiff staining of these same sections positively identify these cells as mucous cells. Mucous cells of animals not challenged with OVA were not positive for CGRP. We conclude that episodic allergen exposure results in the accumulation of CGRP within mucous cells, creating a new source for the release of this neuropeptide within the airway. 相似文献