全文获取类型
收费全文 | 1952篇 |
免费 | 340篇 |
国内免费 | 24篇 |
出版年
2024年 | 9篇 |
2023年 | 81篇 |
2022年 | 71篇 |
2021年 | 118篇 |
2020年 | 92篇 |
2019年 | 118篇 |
2018年 | 93篇 |
2017年 | 95篇 |
2016年 | 110篇 |
2015年 | 104篇 |
2014年 | 146篇 |
2013年 | 215篇 |
2012年 | 93篇 |
2011年 | 114篇 |
2010年 | 54篇 |
2009年 | 61篇 |
2008年 | 67篇 |
2007年 | 78篇 |
2006年 | 65篇 |
2005年 | 54篇 |
2004年 | 69篇 |
2003年 | 60篇 |
2002年 | 44篇 |
2001年 | 35篇 |
2000年 | 37篇 |
1999年 | 41篇 |
1998年 | 25篇 |
1997年 | 21篇 |
1996年 | 19篇 |
1995年 | 14篇 |
1994年 | 9篇 |
1993年 | 16篇 |
1992年 | 20篇 |
1991年 | 9篇 |
1990年 | 7篇 |
1989年 | 2篇 |
1988年 | 5篇 |
1987年 | 3篇 |
1986年 | 8篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1975年 | 3篇 |
1972年 | 1篇 |
排序方式: 共有2316条查询结果,搜索用时 31 毫秒
991.
Apoptosis at a distance: remote activation of caspase-3 occurs early after myocardial infarction 总被引:4,自引:0,他引:4
Schwarz K Simonis G Yu X Wiedemann S Strasser RH 《Molecular and cellular biochemistry》2006,281(1-2):45-54
Objective: After an acute myocardial infarction, the viable myocardium remote from the infarct zone is subjected to ventricular remodeling.
Besides hypertrophy, processes of apoptosis may contribute to these remodeling processes. Reports on apoptosis in this area
have been doubted because they were mainly based on in-situ nick-end DNA labeling (TUNEL) measurements, with questionable specifity. Moreover, the time course of initiation of these
processes has not been characterized. Therefore the goals of this study were to (1) reliably determine if in the remote area
of the infarcted heart apoptosis may be initiated using highly specific biochemical markers and (2) evaluate the time course
of such an activation.
Methods: A well-defined model, regional myocardial infarction induced by ligation of the left anterior coronary artery in rats in vivo, was used. Heart and lung wet weights, the left ventricular end-diastolic pressure (LVEDP), and the serum level of the atrial
natriuretic propeptide (proANP) were determined from 1 day up to 4 weeks as indicators of developing heart failure. In transmural
biopsies from the non-ischemic left ventricular wall of the infarcted heart, the activation of caspase-3, the bcl-2/bax ratio
(Western blot analysis), and the DNA laddering (LM-PCR) were determined.
Results: Although heart- and lung weights did not increase before 1 week after infarction, proANP levels were elevated already 1 day
after myocardial infarction suggesting early sub-clinical heart failure. The activity of caspase-3 increased significantly
to 160± 20% compared to sham operated controls as early as 1 day after ligation and remained elevated over the entire time
course. In parallel, the bcl-2/bax ratio shifted toward the pro-apoptotic bax. Moreover, these clear and specific biochemical
indicators of apoptosis in the remote area of the infarcted heart were paralleled by the fragmentation of genomic DNA.
Conclusion: These data demonstrate that apoptotic markers are activated in the surviving zone of the heart remote from the infarct area
as early as 1 day after myocardial infarction with persistence for up to 4 weeks. This activation coincides with early markers
of heart failure. The exact regulation of this apoptotic process remains to be elucidated.
Parts of this study were presented at the Annual Meetings of the American College of Cardiology 2002. 相似文献
992.
目前,人工肝支持系统正在成为急性肝衰竭患者体外有效的肝支持治疗手段,其中以生物人工肝为主附加血或血浆灌流组成的体外组合型人工肝辅助装置最为人们关注,主要包含肝酶类、肝细胞成分、肝组织片及培养肝细胞系统等,其中又以对肝细胞培养系统的研究最为广泛。本文综述了国内外有关肝细胞的来源、培养方式、所需肝细胞数量等问题的研究进展。 相似文献
993.
Athanassopoulos P Vaessen LM Balk AH Weimar W Sharma HS Bogers AJ 《Cell biochemistry and biophysics》2006,44(1):83-101
Chemokines and their receptors have been implicated in the pathogenesis of different forms of heart failure (HF). We examined
CC-and CXC-chemokine receptor expression in fresh peripheral blood leukocyte populations from 24 end-stage HF patients consisting
of coronary artery disease (CAD; n=6) and hypertrophic cardiomyopathy (HCM; n=7) or idiopathic dilated cardiomyopathy (IDCM; n=8) or valvular disease (VD; n=3) and compared the data with 18 healthy controls. Levels of CCR1, 2, 3, 4, 5, and 7, and CXCR1, 2, 3, and 4 were measured
by flow cytometry, and the expression profile was assessed as molecules of equivalent soluble fluorochrome units as well as
frequency (percentage) of CD3+, CD4+, and CD8+ T cells and monocytes or granulocytes. Frequency of CD3+ CXCR4+, CD3+ CXCR1+, and CD3+ CXCR3+ cells was significantly increased in HF patients, whereas only CCR7 and CXCR4 expression levels were elevated on CD3+ cells. Both CD4+ CXCR4+ and CD8+ CXCR4+ cell frequencies were significantly increased irrespective of cardiac disease etiology. Elevated CCR7 expression was less
pronounced on CD4+ than CD8+ cells in patients with CAD and IDCM. Expression of CXCR4 on CD8+ cells was upregulated substantially, regardless of the cause of disease. CD8+ CXCR1+ and CD8+ CXCR3+ but not CD4+ CXCR1+ or CD4+ CXCR3+ cells were increased in the HF patients with IDCM and CAD, respectively. Expression of CXCR1 or CXCR3 on both CD4+ and CD8+ cells did not differ in all the groups. For monocytes, frequency of CD14+ CCR1+ and CD14+ CCR2+ cells was significantly decreased in CAD patients, whereas, increase in CD14+ CXCR4+ cell frequency was accompanied with elevated CXCR4 expression. On granulocytes, CXCR1 and CXCR2 receptors were downregulated
in all patients, compared with controls. Our results suggest that the altered expression profile of CC- and CXC-chemokine
receptors on circulating leukocyte populations involves enhanced activation of the immune system, perhaps as part of the pathogenic
mechanisms in HF. Modulation of the chemokine network could offer interesting novel therapeutic modalities for end-stage HF. 相似文献
994.
BACKGROUND: The hamster strain CHF147 presents a progressive dilated cardiomyopathy (DCM) due to a large deletion of the delta-sarcoglycan gene that leads to heart failure. This cardiomyopathy induces premature death. We have previously shown that a short-term treatment using IGF-1 preserves cardiac structure and improves function of the CHF147 hamster. METHODS: In the current study, we measured long-term effects of short-term treatment with recombinant human IGF-1 (rhIGF-1) in CHF147 hamsters. CHF147 hamsters (7-8 months old) were implanted under the skin with an osmotic pump filled either with saline or with recombinant human IGF-1 at a total dose of 25 microg. The osmotic pump allowed a continuous delivery of the protein for a mean duration of 19 days. RESULTS: We observed a significant increase in overall survival, as well as preservation of cardiac function, in the rhIGF-1-treated group. At the time of death, hearts of treated animals did not present any macroscopical or histological differences compared to those of sham hamsters. These results show that rhIGF-1 treatment slows down the evolution of the DCM in the CHF147 hamster. Moreover, the low dose treatment did not increase IGF-1 serum levels. CONCLUSIONS: This study is the first one reporting beneficial effects of IGF-1 treatment on survival of an animal model presenting DCM. Our results raise hopes for a new therapeutic approach of this pathology. 相似文献
995.
Christopher Rose 《Journal of neurochemistry》2006,97(S1):11-15
996.
Brixius K Song Q Malick A Boelck B Addicks K Bloch W Mehlhorn U Schwinger RH 《Life sciences》2006,79(13):1234-1241
Nebivolol is a highly selective beta(1)-adrenoceptor blocker with additional vasodilatory properties, which may be due to an endothelial-dependent beta(3)-adrenergic activation of the endothelial nitric oxide synthase (eNOS). beta(3)-adrenergic eNOS activation has been described in human myocardium and is increased in human heart failure. Therefore, this study investigated whether nebivolol may induce an eNOS activation in cardiac tissue. Immunohistochemical stainings were performed using specific antibodies against eNOS translocation and eNOS serine(1177) phosphorylation in rat isolated cardiomyocytes, human right atrial tissue (coronary bypass-operation), left ventricular non-failing (donor hearts) and failing myocardium after application of the beta-adrenoceptor blockers nebivolol, metoprolol and carvedilol, as well as after application of BRL 37344, a specific beta(3)-adrenoceptor agonist. BRL 37344 (10 microM) significantly increased eNOS activity in all investigated tissues (either via translocation or phosphorylation or both). None of the beta-blockers (each 10 microM), including nebivolol, increased either translocation or phosphorylation in any of the investigated tissues. In human failing myocardium, nebivolol (10 microM) decreased eNOS activity. In conclusion, nebivolol shows a tissue-specific eNOS activation. Nebivolol does not activate the endothelial eNOS in end-stage human heart failure and may thus reduce inhibitory effects of NO on myocardial contractility and on oxidative stress formation. This mode of action may be of advantage when treating heart failure patients. 相似文献
997.
M. Gherghiceanu M. E. Hinescu L. M. Popescu 《Journal of cellular and molecular medicine》2009,13(1):202-206
We compared, by transmission electron microscopy (TEM), the ultrastructure of interstitial Cajal-like cells (ICLC) in normal mammalian myocardium versus caveolin-1 null mice. TEM showed that myocardial ICLCs of caveolin-1-deficient mice retain their main ultrastructural characteristics, for example, location among cardiomyocytes, close vicinity to nerves and/or blood capillaries, specialized cell-to-cell junctions, presence of 2–3 typical processes, which are very long (several tens of micrometres), but are very thin (0.1–0.2 μm) and moniliform. However, the most striking modification of myocardial ICLC in caveolin-1 KO mice was the absence of caveolae . Beyond this main observation, three other findings could be reported: (1) the absence of caveolae in capillary endothelium, (2) persistence of (some) caveolae at the level of cardiomyocte sarcolemma or vascular smooth muscle cell sarcolemma and (3) (un)expected ultrastructural modifications such as increased thickness of capillary basement membrane and increased autophagy of several cardiomyocytes. 相似文献
998.
转化生长因子-β(transforming growth factor-β,TGF-β)作用复杂,广泛参与哺乳动物的各种病理生理过程如影响细胞的增殖分化、参与心力衰竭发展。TGF-β信号通路关键的信号传导分子为胞浆蛋白Smads。TGF-β诱导分化心肌成纤维细胞,刺激胶原蛋白等细胞间质成分的合成,促进细胞间质的沉积和抑制弹性蛋白酶等的分泌,刺激蛋白酶抑制剂的表达,从而抑制Ⅰ型胶原成分的降解,促进心肌纤维化发展,进一步了解TGF-β/Smads通路转导蛋白的作用及机制,通过抑制TGF-β/Smads通路转导蛋白作为治疗新靶点为最终防止心力衰竭提供了新的思路。 相似文献
999.
1000.
MicroRNAs (miRNAs) are a class of 21- to 25-nucleotide non-coding RNAs, some of which are important gene regulators involved in folliculogenesis. In this study, we used CCK-8, real-time PCR and Western blot assays to demonstrate that miR-145 inhibits mouse granulosa cell (mGC) proliferation. Combined with the results of luciferase reporter assays that studied the 3′-untranslated region of ACVRIB mRNA, these assays identified ACVRIB as a direct target of miR-145. The ectopic expression of miR-145 reduced the levels of both ACVRIB mRNA and protein and also interfered with activin-induced Smad2 phosphorylation. Altogether, this study revealed that miR-145 suppresses mGC proliferation by targeting ACVRIB. 相似文献