全文获取类型
收费全文 | 1600篇 |
免费 | 152篇 |
出版年
2023年 | 12篇 |
2022年 | 19篇 |
2021年 | 57篇 |
2020年 | 26篇 |
2019年 | 36篇 |
2018年 | 45篇 |
2017年 | 43篇 |
2016年 | 66篇 |
2015年 | 99篇 |
2014年 | 129篇 |
2013年 | 130篇 |
2012年 | 139篇 |
2011年 | 125篇 |
2010年 | 93篇 |
2009年 | 75篇 |
2008年 | 96篇 |
2007年 | 85篇 |
2006年 | 93篇 |
2005年 | 68篇 |
2004年 | 59篇 |
2003年 | 60篇 |
2002年 | 47篇 |
2001年 | 7篇 |
2000年 | 12篇 |
1999年 | 13篇 |
1998年 | 7篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 8篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 13篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1980年 | 6篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1973年 | 3篇 |
1927年 | 1篇 |
排序方式: 共有1752条查询结果,搜索用时 296 毫秒
151.
Demozay D Rocchi S Mas JC Grillo S Pirola L Chavey C Van Obberghen E 《The Journal of biological chemistry》2004,279(8):6261-6270
Phosphatidylinositol 3-kinase signaling regulates the expression of several genes involved in lipid and glucose homeostasis; deregulation of these genes may contribute to insulin resistance and progression toward type 2 diabetes. By employing RNA arbitrarily primed-PCR to search for novel phosphatidylinositol 3-kinase-regulated genes in response to insulin in isolated rat adipocytes, we identified fatty aldehyde dehydrogenase (FALDH), a key component of the detoxification pathway of aldehydes arising from lipid peroxidation events. Among these latter events are oxidative stresses associated with insulin resistance and diabetes. Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice. FALDH mRNA levels were 4-fold decreased in streptozotocin-treated rats, suggesting that FALDH deregulation occurs both in hyperinsulinemic insulin-resistant state and hypoinsulinemic type 1 diabetes models. Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation. Considering the detoxifying role of FALDH, its deregulation in insulin-resistant and type 1 diabetic models may contribute to the lipid-derived oxidative stress. To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes. Ectopic expression of FALDH significantly decreased reactive oxygen species production in cells treated by 4-hydroxynonenal, the major lipid peroxidation product, suggesting that FALDH protects against oxidative stress associated with lipid peroxidation. Taken together, our observations illustrate the importance of FALDH in insulin action and its deregulation in states associated with altered insulin signaling. 相似文献
152.
Luppi PH Gervasoni D Boissard R Verret L Goutagny R Peyron C Salvert D Leger L Barbagli B Fort P 《Archives italiennes de biologie》2004,142(4):397-411
This paper is dedicated to our mentor, Michel Jouvet who inspired our career and transmitted to us his passion for the study of the mechanisms responsible for paradoxical sleep genesis and also that of its still mysterious functions. We expose in the following the progresses in the knowledge in this field brought during 40 years by Michel Jouvet and his team and more recently by the members of a new CNRS laboratory in which we aim to pursue in the path opened by Michel Jouvet. 相似文献
153.
Báfica A Scanga CA Schito M Chaussabel D Sher A 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(12):7229-7234
Immune activation of HIV gene expression as a consequence of the host response to coinfecting pathogens has been implicated as an important factor in AIDS progression. Immune responsiveness to many of the infectious agents associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR). Therefore, TLR-pathogen interactions could play an indirect role in regulating HIV-associated disease. In this review, we summarize emerging evidence for the influence of TLR recognition on HIV gene activation and AIDS progression. 相似文献
154.
Diseases such as type 2 diabetes, Alzheimer's and Parkinson's are associated with the formation of amyloid. The transmissible spongiform encephalopathies, such as variant Creutzfeldt-Jakob disease, are believed to result from infectious forms of amyloid proteins termed prions. The ability of amyloid to initiate spontaneously and in the case of prions, to transfer successfully from one host to another, has been hard to fully rationalize. In this paper we use a mathematical model to explore the idea that it might be a combination of the presence of the prion/amyloid form and a change in the state of the host that allows the amyloid/prion to successfully initiate and propagate itself. We raise the intriguing possibility that potentially infectious amyloid may lie dormant in an apparently healthy individual awaiting a change in the state of the host or transmittal to a new more susceptible host. On this basis we make an analogy between prion/amyloid disease development and the two-hit model of cancer progression. We additionally raise the possibility that infectious amyloid strains may be characterized by a size distribution of length or radius. 相似文献
155.
Damien Sanlaville Capucine Delnatte Jean-Franois Mougenot Joris-Robert Vermeesch Claude Houdayer Marie-Christine de
Blois David Genevieve Olivier Goulet Jean-Pierre Fryns Francis Jaubert Michel Vekemans Stanislas Lyonnet Serge Romana Charis Eng Dominique Stoppa-Lyonnet 《American journal of human genetics》2006,79(3):596-597
156.
Wertz X Schoëvaërt D Maitournam H Chassignet P Schwartz L 《Comptes rendus biologies》2006,329(2):79-85
Mechanical stresses play a key role in regulating cell growth and cell differentiation. Using mechanical and physiological data available in the literature, we are able to construct a growth curve of a child, which we compare to the standard curve. It appears likely that the impact of hormones on pubertal growth rate sprout followed by growth arrest can be solely explained by increased mechanical stresses. The uptake of hormones by the muscles results in increased mechanical stress on the chondrocyte before and at the puberty, resulting in a peak in growth followed by growth cessation. 相似文献
157.
Stephen J. Newman Ian W. Wright Ben M. Rome Michael C. Mackie Paul D. Lewis Rik C. Buckworth Aaron C. Ballagh Rod N. Garrett Jason Stapley Damien Broderick Jennifer R. Ovenden David J. Welch 《Environmental Biology of Fishes》2010,89(3-4):357-367
The stable isotopes of δ18O and δ13C in sagittal otolith carbonates were used to determine the stock structure of Grey Mackerel, Scomberomorus semifasciatus. Otoliths were collected from Grey Mackerel at ten locations representing much of their distributional and fisheries range across northern Australia from 2005 to 2007. Across this broad range (~ 6500 km), fish from four broad locations—Western Australia (S1), Northern Territory and Gulf of Carpentaria (S2, S3, S4, S5, S6, S7), Queensland east coast mid and north sites (S8, S9) and Queensland east coast south site (S10)—had stable isotope values that were significantly different indicating stock separation. Otolith stable isotopes differed more between locations than among years within a location, indicating temporal stability across years. The spatial separation of these populations indicates a complex stock structure across northern Australia. Stocks of S. semifasciatus appear to be associated with large coastal embayments. These results indicate that optimal fisheries management may require a review of the current spatial arrangements, particularly in relation to the evidence of shared stocks in the Gulf of Carpentaria. Furthermore, as the population of S. semifasciatus in Western Australia exhibited high spatial separation from those at all the other locations examined, further research activities should focus on investigating additional locations within Western Australia for an enhanced determination of stock delineation. 相似文献
158.
Chuang-Rung Chang Cara Marie Manlandro Damien Arnoult Julia Stadler Ammon E. Posey R. Blake Hill Craig Blackstone 《The Journal of biological chemistry》2010,285(42):32494-32503
Mitochondria dynamically fuse and divide within cells, and the proper balance of fusion and fission is necessary for normal mitochondrial function, morphology, and distribution. Drp1 is a dynamin-related GTPase required for mitochondrial fission in mammalian cells. It harbors four distinct domains: GTP-binding, middle, insert B, and GTPase effector. A lethal mutation (A395D) within the Drp1 middle domain was reported in a neonate with microcephaly, abnormal brain development, optic atrophy, and lactic acidemia (Waterham, H. R., Koster, J., van Roermund, C. W., Mooyer, P. A., Wanders, R. J., and Leonard, J. V. (2007) N. Engl. J. Med. 356, 1736–1741). Mitochondria within patient-derived fibroblasts were markedly elongated, but the molecular mechanisms underlying these findings were not demonstrated. Because the middle domain is particularly important for the self-assembly of some dynamin superfamily proteins, we tested the hypothesis that this A395D mutation, and two other middle domain mutations (G350D, G363D) were important for Drp1 tetramerization, higher order assembly, and function. Although tetramerization appeared largely intact, each of these mutations compromised higher order assembly and assembly-dependent stimulation of Drp1 GTPase activity. Moreover, mutant Drp1 proteins exhibited impaired localization to mitochondria, indicating that this higher order assembly is important for mitochondrial recruitment, retention, or both. Overexpression of these middle domain mutants markedly inhibited mitochondrial division in cells. Thus, the Drp1 A395D lethal defect likely resulted in impaired higher order assembly of Drp1 at mitochondria, leading to decreased fission, elongated mitochondria, and altered cellular distribution of mitochondria. 相似文献
159.
The mechanisms by which epithelial cells regulate the presence of microvilli on their apical surface are largely unknown. A potential regulator is EBP50/NHERF1 (ERM-binding phosphoprotein of 50 kD/Na(+)-H(+) exchanger regulatory factor), a microvillar scaffolding protein with two PDZ domains followed by a C-terminal ezrin-binding domain. Using RNAi and expression of RNAi-resistant EBP50 mutants we systematically show that EBP50 is necessary for microvillar assembly and requires that EBP50 has both a functional first PDZ domain and an ezrin-binding site. Expression of mutants mimicking Cdc2 or PKC phosphorylation are nonfunctional in microvillar assembly. Biochemical analysis reveals that these mutants are defective in PDZ1 accessibility when PDZ2 is occupied, and can be rendered functional in vivo by additional mutation of PDZ2. EBP50 is not necessary for mitotic cell microvilli, and PKC activation causes a rearrangement of microvilli on cells due to phosphorylation-dependent loss of EBP50 function. Thus, EBP50 is a critical factor that regulates microvilli assembly and whose activity is regulated by signaling pathways and occupation of its PDZ2 domain. 相似文献
160.