全文获取类型
收费全文 | 9743篇 |
免费 | 796篇 |
国内免费 | 9篇 |
出版年
2023年 | 40篇 |
2022年 | 70篇 |
2021年 | 172篇 |
2020年 | 115篇 |
2019年 | 113篇 |
2018年 | 163篇 |
2017年 | 130篇 |
2016年 | 271篇 |
2015年 | 413篇 |
2014年 | 509篇 |
2013年 | 633篇 |
2012年 | 775篇 |
2011年 | 764篇 |
2010年 | 453篇 |
2009年 | 444篇 |
2008年 | 598篇 |
2007年 | 645篇 |
2006年 | 610篇 |
2005年 | 532篇 |
2004年 | 534篇 |
2003年 | 515篇 |
2002年 | 512篇 |
2001年 | 111篇 |
2000年 | 80篇 |
1999年 | 117篇 |
1998年 | 147篇 |
1997年 | 104篇 |
1996年 | 94篇 |
1995年 | 104篇 |
1994年 | 87篇 |
1993年 | 82篇 |
1992年 | 89篇 |
1991年 | 39篇 |
1990年 | 48篇 |
1989年 | 35篇 |
1988年 | 39篇 |
1987年 | 23篇 |
1986年 | 33篇 |
1985年 | 32篇 |
1984年 | 27篇 |
1983年 | 27篇 |
1982年 | 37篇 |
1981年 | 29篇 |
1980年 | 22篇 |
1979年 | 20篇 |
1978年 | 12篇 |
1977年 | 25篇 |
1976年 | 17篇 |
1974年 | 8篇 |
1973年 | 13篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Cyclosporin A (CsA) generates superoxide in smooth muscle cells. Our earlier studies have demonstrated that the increase in the vasopressin type 1 receptor induced in vascular smooth muscle cells in the presence of CsA is probably due to superoxide (Krauskopf et al., J Biol Chem 278, 41685-41690, 2003). This increase in vasopressin receptor is likely at the base of increased vascular responsiveness to vasoconstrictor hormones and hypertension induced by CsA. Here, we demonstrate that CsA produces superoxide. In addition, our data show that superoxide generation does not originate from the major cellular superoxide generating systems NAD(P)H oxidase or xanthine oxidase. Our results suggest that the side effects of CsA could be diminished with the help of SOD mimetic drugs. 相似文献
992.
993.
Huard K Bourgeois P Rhainds D Falstrault L Cohn JS Brissette L 《The international journal of biochemistry & cell biology》2005,37(6):1308-1318
Plasma low- and high-density lipoproteins (LDL and HDL) are cleared from the circulation by specific receptors and are either totally degraded or their cholesteryl esters (CE) are selectively delivered to cells by receptors such as the scavenger receptor class B type I (SR-BI). The aim of the present study was to define the effect of apoC-II and apoC-III on the uptake of LDL and HDL by HepG2 cells. Stable transformants were obtained with sense or antisense strategies that secrete 47-294% the normal level of apoC-II or 60-200% that of apoC-III. Different levels of secreted apoC-II or apoC-III had little effect on LDL and HDL protein degradation by HepG2 cells. However, compared to controls, cells under-expressing apoC-II showed a 160% higher capacity to selectively take up HDL-CE, while cells under-expressing apoC-III demonstrated 70 and 160% higher capacity to take up CE from LDL and HDL, respectively. In experiments conducted with exogenously added apoC-II or apoC-III, no significant effect was observed on lipoprotein-protein association/degradation; however, LDL-CE and HDL-CE selective uptake was significantly reduced in a dose-dependent manner. These results indicate that apoC-II and apoC-III inhibit CE-selective uptake. 相似文献
994.
Altered responses in skeletal muscle protein turnover during aging in anabolic and catabolic periods
Attaix D Mosoni L Dardevet D Combaret L Mirand PP Grizard J 《The international journal of biochemistry & cell biology》2005,37(10):1962-1973
One of the most important effects of aging is sarcopenia, which is associated with impaired locomotion and general weakness. In addition, there is increased susceptibility to illness in aging, which often results in muscle wasting episodes. In such instances, the mobilization of muscle proteins provides free amino acids that are used for energetic purpose, the synthesis of acute phase proteins, and the immune response. However, since muscle protein mass is already depleted, the ability of the aged organism to recover from stress is impaired. Therefore, elucidating the mechanisms that result in sarcopenia is of obvious importance. Age-related changes in protein synthesis and proteolysis are rather small and our current methodology does not enable one to establish unequivocally whether sarcopenia results from depressed protein synthesis, increased proteolysis or both. By contrast, in anabolic and catabolic periods, a number of dysregulations in muscle protein turnover became clearly apparent. The aim of this review is to provide an overview of such altered responses to nutrients and catabolic treatments, which may ultimately contribute to explain sarcopenia. This includes impaired recovery in catabolic states, impaired anabolic effects of nutrients, in particular leucine, and a lack of regulation of the ubiquitin-proteasome proteolytic system. These alterations are discussed with respect to modifications in the insulin/IGF-1 axis and glucocorticoid related effects. 相似文献
995.
A decline in our ability to successfully treat patients with malaria infections of the parasitic protozoan Plasmodium falciparum with cheap quinoline drugs has led to a huge escalation in morbidity and mortality in recent years. Many approaches have been taken, including classical genetics, reverse genetics and molecular epidemiology, to identify the molecular determinants underlying this resistance. The contribution of the P. falciparum multidrug resistance gene, pfmdr1, to antimalarial resistance has been a source of controversy for over a decade since it was first identified. In the current issue of Molecular Microbiology, Sidhu and colleagues use powerful reverse genetics to demonstrate the importance of commonly occurring alleles of pfmdr1 in conferring resistance to the second-line drugs quinine and sensitivity to the new alternatives mefloquine and artemisinin. They also elegantly highlight the importance of genetic background and epistasis between pfmdr1 and other potential modulators of drug resistance. Such molecular knowledge will facilitate surveillance/monitoring and aid the development of strategies for the reversal of resistance. 相似文献
996.
Bertolino C Macsweeney M Tobin J O'Neill B Sheehan MM Coluccia S Berney H 《Biosensors & bioelectronics》2005,21(4):565-573
The aim of this work was to develop an integrated solution to DNA hybridisation monitoring for diagnostics on a monolithic silicon platform. A fabrication process was developed incorporating a gold initiation electrode patterned directly onto a PIN photodiode detector. Patterned interdigitated type electrodes exhibited the smallest reduction in photodiode sensitivity, therefore these were chosen as the ECL initiator design. A novel DNA hybridisation assay was developed based on the displacement of a partially mismatched complementary strand by a perfectly matched labelled complementary strand. Pre-hybridised thiolated oligonucleotide and unlabelled 25% mismatched oligonucleotide were assembled on the gold initiation electrode. On addition of the labelled perfectly complementary oligonucleotide, the mismatched strands were displaced and a signal was generated. The sensitivity of the photodiode to light emitted at 620 nm, the ruthenium emission wavelength, was determined and subsequently, the diode current response to light generated by flow addition of ruthenium solution was found to be measurable to a concentration of 10 fM. Pre-hybridised duplex DNA, consisting of thiolated oligonucleotide and ruthenium labelled complementary oligonucleotide, was assembled on the gold initiation electrode. The difference between the current measured during flow of buffer and the ECL co-reactant TPA was three orders of magnitude, indicating that DNA assembled on the surface comprised sufficient ruthenium to generate a measurable signal. Finally, the displacement of unlabelled partial mismatch oligonucleotide from the sensor surface was monitored on addition of the ruthenium labelled perfectly complementary oligonucleotide in TPA flow and the measured photodiode current response was up to 50 times greater. 相似文献
997.
998.
Synthesis of a C-terminal modified peptide with an -amido methylketone was efficiently carried out using a backbone-amide-type linker loading with a monofunctionalized diamine, provided that no base such as piperidine or diisopropylethylamine or a reducing agent such as triisopopylsilane was used for the synthetic pathway. The ketoxime-forming chemoselective ligation between a methylketone and an aminooxy was quantitative in 5 h at pH 2. 相似文献
999.
Zirihi GN Grellier P Guédé-Guina F Bodo B Mambu L 《Bioorganic & medicinal chemistry letters》2005,15(10):2637-2640
Bioassay-guided fractionation of the EtOH extract of the stem bark of Funtumia elastica resulted in the isolation of four steroidal alkaloids, holarrhetine (1), conessine (2), holarrhesine (3) and isoconessimine (4). Their structures were determined on the basis of 1D- and 2D-NMR techniques and mass spectrometry. Compounds 1-4 exhibited in vitro antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum with IC50 values ranging from 0.97 to 3.39 microM. They showed weak cytotoxicity against a rat cell line L-6 with IC50 values ranging from 5.13 to 36.55 microM. 相似文献
1000.
Nantermet PG Burgey CS Robinson KA Pellicore JM Newton CL Deng JZ Selnick HG Lewis SD Lucas BJ Krueger JA Miller-Stein C White RB Wong B McMasters DR Wallace AA Lynch JJ Yan Y Chen Z Kuo L Gardell SJ Shafer JA Vacca JP Lyle TA 《Bioorganic & medicinal chemistry letters》2005,15(11):2771-2775
In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h). 相似文献