全文获取类型
收费全文 | 1460篇 |
免费 | 125篇 |
国内免费 | 33篇 |
专业分类
1618篇 |
出版年
2023年 | 13篇 |
2022年 | 31篇 |
2021年 | 39篇 |
2020年 | 30篇 |
2019年 | 46篇 |
2018年 | 70篇 |
2017年 | 42篇 |
2016年 | 68篇 |
2015年 | 94篇 |
2014年 | 88篇 |
2013年 | 106篇 |
2012年 | 145篇 |
2011年 | 149篇 |
2010年 | 77篇 |
2009年 | 59篇 |
2008年 | 83篇 |
2007年 | 83篇 |
2006年 | 72篇 |
2005年 | 41篇 |
2004年 | 57篇 |
2003年 | 35篇 |
2002年 | 40篇 |
2001年 | 21篇 |
2000年 | 17篇 |
1999年 | 19篇 |
1998年 | 11篇 |
1997年 | 3篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 7篇 |
1991年 | 2篇 |
1990年 | 5篇 |
1989年 | 8篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1969年 | 1篇 |
1964年 | 1篇 |
排序方式: 共有1618条查询结果,搜索用时 0 毫秒
141.
142.
Zhou Q Xiao J Jiang D Wang R Vembaiyan K Wang A Smith CD Xie C Chen W Zhang J Tian X Jones PP Zhong X Guo A Chen H Zhang L Zhu W Yang D Li X Chen J Gillis AM Duff HJ Cheng H Feldman AM Song LS Fill M Back TG Chen SR 《Nature medicine》2011,17(8):1003-1009
Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol's actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients. 相似文献
143.
144.
In the Drosophila circadian clock, the CLOCK/CYCLE complex activates the period and timeless genes that negatively feedback on CLOCK/CYCLE activity. The 24-h pace of this cycle depends on the stability of the clock proteins. RING-domain E3 ubiquitin ligases have been shown to destabilize PERIOD or TIMELESS. Here we identify a clock function for the circadian trip (ctrip) gene, which encodes a HECT-domain E3 ubiquitin ligase. ctrip expression in the brain is mostly restricted to clock neurons and its downregulation leads to long-period activity rhythms in constant darkness. This altered behaviour is associated with high CLOCK levels and persistence of phosphorylated PERIOD during the subjective day. The control of CLOCK protein levels does not require PERIOD. Thus, CTRIP seems to regulate the pace of the oscillator by controlling the stability of both the activator and the repressor of the feedback loop. 相似文献
145.
Rodríguez-Rigueiro T Valladares-Ayerbes M Haz-Conde M Blanco M Aparicio G Fernández-Puente P Blanco FJ Lorenzo MJ Aparicio LA Figueroa A 《Proteomics》2011,11(12):2555-2559
Most of the archived pathological specimens in hospitals are kept as formalin-fixed paraffin-embedded tissues (FFPE) for long-term preservation. Up to now, these samples are only used for immunohistochemistry in a clinical routine as it is difficult to recover intact protein from these FFPE tissues. Here, we report a novel, short time-consuming and cost-effective method to extract full-length, non-degraded proteins from FFPE tissues. This procedure is combined with an effective and non-toxic deparaffinisation process and an extraction method based on antigen-retrieval, high concentration of SDS and high temperature. We have obtained enough intact protein to be detected by Western blotting analysis. This technique will allow utilising these stored FFPE tissues in several applications for protein analysis helping to advance the translational studies in cancer and other diseases. 相似文献
146.
Thirant C Varlet P Lipecka J Le Gall M Broussard C Chafey P Studler JM Lacombe J Lions S Guillaudeau A Camoin L Daumas-Duport C Junier MP Chneiweiss H 《Proteomics》2011,11(21):4139-4154
Gliomas are primary tumors of the human central nervous system with unknown mechanisms of progression. Isocitrate dehydrogenase-1 (IDH1) mutation is frequent in diffuse gliomas such as oligodendrogliomas. To gain insights into the physiopathology of oligodendrogliomas that have a better prognosis than other diffuse gliomas, we combined microdissection, 2-D DIGE and MS/MS focusing on proteome alterations associated with IDH1 mutation. We first compared tumor tissues (TT) and minimally infiltrated parenchymal tissues (MIT) of four IDH1-mutated oligodendrogliomas to verify whether proteins specific to oligodendroglioma tumor cells could be identified from one patient to another. This study resulted in identification of 68 differentially expressed proteins, with functions related to growth of tumor cells in a nervous parenchyma. We then looked for proteins distinctly expressed in TT harboring either mutant (oligodendrogliomas, n=4) or wild-type IDH1 (oligodendroglial component of malignant glio-neuronal tumors, n=4). This second analysis resulted in identification of distinct proteome patterns composed of 42 proteins. Oligodendrogliomas with a mutant IDH1 had noteworthy enhanced expression of enzymes controlling aerobic glycolysis and detoxification, and anti-apoptosis proteins. In addition, the mutant IDH1 migrated differently from the wild-type IDH1 form. Comparative proteomic analysis might thus be suitable to identify proteome alterations associated with a well-defined mutation. 相似文献
147.
Background
Extensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages.Methodology/Principal Findings
The frequencies, phenotypes, and functions of peripheral blood and intrahepatic monocyte/macrophage subsets were analyzed in 110 HBeAg positive CHB patients, including 32 immune tolerant (IT) carriers and 78 immune activated (IA) patients. Liver biopsies from 20 IA patients undergoing diagnosis were collected for immunohistochemical analysis. IA patients displayed significant increases in peripheral blood monocytes and intrahepatic macrophages as well as CD16+ subsets, which were closely associated with serum alanine aminotransferase (ALT) levels and the liver histological activity index (HAI) scores. In addition, the increased CD16+ monocytes/macrophages expressed higher levels of the activation marker HLA-DR compared with CD16− monocytes/macrophages. Furthermore, peripheral blood CD16+ monocytes preferentially released inflammatory cytokines and hold higher potency in inducing the expansion of Th17 cells. Of note, hepatic neutrophils also positively correlated with HAI scores.Conclusions
These distinct properties of monocyte/macrophage subpopulations participate in fostering the inflammatory microenvironment and liver damage in CHB patients and further represent a collaborative scenario among different cell types contributing to the pathogenesis of HBV-induced liver disease. 相似文献148.
Ang KC Leow JW Yeap WK Hood S Mahani MC Md-Zain BM 《Genetics and molecular research : GMR》2011,10(2):640-649
Malaysia remains as a crossroad of different cultures and peoples, and it has long been recognized that studying its population history can provide crucial insight into the prehistory of Southeast Asia as a whole. The earliest inhabitants were the Orang Asli in Peninsular Malaysia and the indigenous groups in Sabah and Sarawak. Although they were the earliest migrants in this region, these tribes are divided geographically by the South China Sea. We analyzed DNA sequences of 18 Orang Asli using mitochondrial DNA extracted from blood samples, each representing one sub-tribe, and from five Sarawakian Iban. Mitochondrial DNA was extracted from hair samples in order to examine relationships with the main ethnic groups in Malaysia. The D-loop region and cytochrome b genes were used as the candidate loci. Phylogenetic relationships were investigated using maximum parsimony and neighbor joining algorithms, and each tree was subjected to bootstrap analysis with 1000 replicates. Analyses of the HVS I region showed that the Iban are not a distinct group from the Orang Asli; they form a sub-clade within the Orang Asli. Based on the cytochrome b gene, the Iban clustered with the Orang Asli in the same clade. We found evidence for considerable gene flow between Orang Asli and Iban. We concluded that the Orang Asli, Iban and the main ethnic groups of Malaysia are probably derived from a common ancestor. This is in agreement with a single-route migration theory, but it does not dismiss a two-route migration theory. 相似文献
149.
Deeper in the human cornea proteome using nanoLC-Orbitrap MS/MS: An improvement for future studies on cornea homeostasis and pathophysiology 总被引:1,自引:0,他引:1
Galiacy SD Froment C Mouton-Barbosa E Erraud A Chaoui K Desjardins L Monsarrat B Malecaze F Burlet-Schiltz O 《Journal of Proteomics》2011,75(1):81-92
The cornea is a transparent, avascular, and highly specialized connective tissue that provides the majority of light refraction in the optical system of the eye. The human cornea is composed of several layers interacting in a complex manner and possessing specific functions, like eye protection and optical clearness. Only few proteomic studies of mammalian cornea have been performed leading to the identification of less than 200 proteins in human corneas. The present study explores the proteome of the intact normal human cornea using a shot-gun nanoLC-MS/MS strategy and an LTQ Orbitrap mass spectrometer. A total of 2070 distinct corneal proteins were identified from five human cornea samples, which represents a 14-fold improvement in the number of proteins identified so far for human cornea. This enlarged dataset of human corneal proteins represents a valuable reference library for further studies on cornea homeostasis and pathophysiology. Network and gene ontology analyses were used to determine biological pathways specific of the human cornea. They allowed the identification of subnetworks of putative importance for corneal diseases, like a redox regulation and oxidative stress network constituted of aldehyde and alcohol dehydrogenases, most of them being described for the first time in human cornea. 相似文献
150.
Molecular Ecology Resources Primer Development Consortium Austin JD Bertin A Bórquez JP Cárdenas L Cardoza TB Chapman F De Sousa AC De Souza AP Douglas KC Ellwood SR Ferriol M Garmendia A Gouin N Hargrove J Jasti M Keränen I Knott KE Konec M Kuitunen K Lima MP Linde CC Merle H Oliva ME Pérez M Saarinen E Samollow PB Scarpassa VM Segura I Smith L Trontelj P Valdivia IM Wallwork H Wellenreuther M 《Molecular ecology resources》2011,11(4):757-758
This article documents the addition of 111 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Acipenser oxyrinchus desotoi, Anopheles nuneztovari sensu lato, Asellus aquaticus, Calopteryx splendens, Calopteryx virgo, Centaurea aspera, Centaurea seridis, Chilina dombeyana, Proctoeces cf. lintoni and Pyrenophora teres f. teres. 相似文献