全文获取类型
收费全文 | 722篇 |
免费 | 53篇 |
出版年
2021年 | 10篇 |
2020年 | 8篇 |
2019年 | 7篇 |
2018年 | 14篇 |
2017年 | 14篇 |
2016年 | 20篇 |
2015年 | 32篇 |
2014年 | 27篇 |
2013年 | 45篇 |
2012年 | 47篇 |
2011年 | 35篇 |
2010年 | 40篇 |
2009年 | 25篇 |
2008年 | 41篇 |
2007年 | 29篇 |
2006年 | 40篇 |
2005年 | 32篇 |
2004年 | 29篇 |
2003年 | 18篇 |
2002年 | 20篇 |
2001年 | 21篇 |
2000年 | 24篇 |
1999年 | 18篇 |
1997年 | 6篇 |
1993年 | 3篇 |
1992年 | 11篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1989年 | 3篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 9篇 |
1985年 | 9篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 5篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1975年 | 3篇 |
1974年 | 5篇 |
1973年 | 7篇 |
1972年 | 6篇 |
1971年 | 3篇 |
1970年 | 7篇 |
1969年 | 8篇 |
1968年 | 8篇 |
1967年 | 3篇 |
1965年 | 5篇 |
排序方式: 共有775条查询结果,搜索用时 125 毫秒
71.
Olsson M Ahlin S Olsson B Svensson PA Ståhlman M Borén J Carlsson LM Sjöholm K 《PloS one》2011,6(5):e19609
Obesity and obesity co-morbidities are associated with a low grade inflammation and elevated serum levels of acute phase proteins, including serum amyloid A (SAA). In the non-acute phase in humans, adipocytes are major producers of SAA but the function of adipocyte-derived SAA is unknown. To clarify the role of adipocyte-derived SAA, a transgenic mouse model expressing human SAA1 (hSAA) in adipocytes was established. hSAA expression was analysed using real-time PCR analysis. Male animals were challenged with a high fat (HF) diet. Plasma samples were subjected to fast protein liquid chromatography (FPLC) separation. hSAA, cholesterol and triglyceride content were measured in plasma and in FPLC fractions. Real-time PCR analysis confirmed an adipose tissue-specific hSAA gene expression. Moreover, the hSAA gene expression was not influenced by HF diet. However, hSAA plasma levels in HF fed animals (37.7±4.0 µg/mL, n = 7) were increased compared to those in normal chow fed animals (4.8±0.5 µg/mL, n = 10; p<0.001), and plasma levels in the two groups were in the same ranges as in obese and lean human subjects, respectively. In FPLC separated plasma samples, the concentration of hSAA peaked in high-density lipoprotein (HDL) containing fractions. In addition, cholesterol distribution over the different lipoprotein subfractions as assessed by FPLC analysis was similar within the two experimental groups. The established transgenic mouse model demonstrates that adipose tissue produced hSAA enters the circulation, resulting in elevated plasma levels of hSAA. This new model will enable further studies of metabolic effects of adipose tissue-derived SAA. 相似文献
72.
Why do Nogo/Nogo‐66 receptor gene knockouts result in inferior regeneration compared to treatment with neutralizing agents? 总被引:15,自引:0,他引:15
IN-1, the monoclonal antibody against the exon 3-encoded N-terminal domain of Nogo-A, and the Nogo-66 receptor (NgR) antagonist NEP1-40 have both shown efficacy in promoting regeneration in animal spinal cord injury models, the latter even when administered subcutaneously 1 week after injury. These results are supportive of the hypothesis that the Nogo-NgR axis is a major path for inhibition of spinal cord axonal regeneration and uphold the promises of these neutralizing agents in clinical applications. However, mice with targeted disruption of Nogo and NgR have, surprisingly, only modest regenerative capacity (if any) compared with treatment with IN-1 or NEP1-40. Disruption of the Nogo gene by various groups yielded results ranging from significant regenerative improvement in young mice to no improvement. Likewise, knockout of NgR produced some improvement in raphespinal and rubrospinal axonal regeneration, but not that of corticospinal neurons. Other than invoking possible differences in genetic background, we suggest here some possible and testable explanations for the above phenomena. These possibilities include effects of IN-1 and NEP1-40 on the CNS beyond neutralization of Nogo and NgR functions, and the latter's possible role in the CNS beyond that of neuronal growth inhibition. 相似文献
73.
Helminth genome projects: all or nothing 总被引:1,自引:0,他引:1
74.
Widespread gamma-secretase activity in the cell, but do we need it at the mitochondria? 总被引:1,自引:0,他引:1
gamma-Secretase cleavage of the amyloid precursor protein already subjected to a prior beta-secretase cleavage generates beta-amyloid (Abeta) peptide fragments, which are major constituents of the amyloid plagues found in Alzheimer's disease brain tissues. gamma-Secretase activity and components of the gamma-secretase complex are found in the endoplasmic reticulum-Golgi intermediate compartment, the Golgi, the trans-Golgi network, the plasma membrane, the endosomal-lysosomal system and recently, the mitochondria. Abeta fragments have been shown to be neurotoxic, leading to mitochondrial dysfunction and enhanced apoptotic cell death. However, if Abeta fragments are indeed detrimental to neurons, the widespread presence of enzymatic activity that would result in their generation in the cell appears to make little sense. The presence of a gamma-secretase complex in the mitochondrion, an organelle that is particularly susceptible to Abeta toxicity, is even more puzzling. Emerging evidence suggests that both secreted and intracellular Abeta fragments have endogenous functions. Also, while the fibrillogenic Abeta1-42 is clearly neurotoxic, the more abundant and soluble Abeta1-40 is an antioxidant and could potentially be neuroprotective in several ways. A "physiological" amount of Abeta1-40 production by cellular gamma-secretase activity may be part of the neuron's natural counter against oxidative damage, in addition to endogenous roles in neuronal survival and modulation of synaptic transmission. In any case, whether Abeta is produced locally in the mitochondria and the function for mitochondrial Abeta, if produced, is yet unclear. 相似文献
75.
During chemical denaturation different intermediate states are populated or suppressed due to the nature of the denaturant used. Chemical denaturation by guanidine-HCl (GuHCl) of human carbonic anhydrase II (HCA II) leads to a three-state unfolding process (Cm,NI=1.0 and Cm,IU=1.9 M GuHCl) with formation of an equilibrium molten-globule intermediate that is stable at moderate concentrations of the denaturant (1-2 M) with a maximum at 1.5 M GuHCl. On the contrary, urea denaturation gives rise to an apparent two-state unfolding transition (Cm=4.4 M urea). However, 8-anilino-1-naphthalene sulfonate (ANS) binding and decreased refolding capacity revealed the presence of the molten globule in the middle of the unfolding transition zone, although to a lesser extent than in GuHCl. Cross-linking studies showed the formation of moderate oligomer sized (300 kDa) and large soluble aggregates (>1000 kDa). Inclusion of 1.5 M NaCl to the urea denaturant to mimic the ionic character of GuHCl leads to a three-state unfolding behavior (Cm,NI=3.0 and Cm,IU=6.4 M urea) with a significantly stabilized molten-globule intermediate by the chloride salt. Comparisons between NaCl and LiCl of the impact on the stability of the various states of HCA II in urea showed that the effects followed what could be expected from the Hofmeister series, where Li+ is a chaotropic ion leading to decreased stability of the native state. Salt addition to the completely urea unfolded HCA II also led to an aggregation prone unfolded state, that has not been observed before for carbonic anhydrase. Refolding from this state only provided low recoveries of native enzyme. 相似文献
76.
Human immunodeficiency virus type 1 Nef associates with lipid rafts to downmodulate cell surface CD4 and class I major histocompatibility complex expression and to increase viral infectivity 总被引:2,自引:0,他引:2 下载免费PDF全文
Alexander M Bor YC Ravichandran KS Hammarskjöld ML Rekosh D 《Journal of virology》2004,78(4):1685-1696
Lipid rafts are membrane microdomains that are functionally distinct from other membrane regions. We have shown that 10% of human immunodeficiency virus type 1 (HIV-1) Nef expressed in SupT1 cells is present in lipid rafts and that this represents virtually all of the membrane-associated Nef. To determine whether raft targeting, rather than simply membrane localization, has functional significance, we created a Nef fusion protein (LAT-Nef) containing the N-terminal 35 amino acids from LAT, a protein that is exclusively localized to rafts. Greater than 90% of the LAT-Nef protein was found in the raft fraction. In contrast, a mutated form, lacking two cysteine palmitoylation sites, showed less than 5% raft localization. Both proteins were equally expressed and targeted nearly exclusively to membranes. The LAT-Nef protein was more efficient than its nonraft mutant counterpart at downmodulating both cell surface CD4 and class I major histocompatibility complex (MHC) expression, as well as in enhancing first-round infectivity and being incorporated into virus particles. This demonstrates that targeting of Nef to lipid rafts is mechanistically important for all of these functions. Compared to wild-type Nef, LAT-Nef downmodulated class I MHC nearly as effectively as the wild-type Nef protein, but was only about 60% as effective for CD4 downmodulation and 30% as effective for infectivity enhancement. Since the LAT-Nef protein was found entirely in rafts while the wild-type Nef protein was distributed 10% in rafts and 90% in the soluble fraction, our results suggest that class I MHC downmodulation by Nef may be performed exclusively by raft-bound Nef. In contrast, CD4 downmodulation and infectivity enhancement may require a non-membrane-bound Nef component as well as the membrane-bound form. 相似文献
77.
78.
79.
The reactions of [Pt2(μ-S)2(PPh3)4] with excess PbBr2 or PbI2 in methanolic suspension result in the formation of the neutral lead(II) halide adducts [Pt2(μ-S)2(PPh3)4PbX2] (X = Br, I). The X-ray structure determination of the lead iodide adduct reveals an essentially tetrahedral lead(II) centre, which is a rare coordination geometry for lead(II), which almost invariably is hemidirected, with a stereochemically active lone pair. In contrast, the structure of the PbBr2 adduct, although suffering from some disorder, shows a more typical, distorted arrangement of ligands; these results are discussed in terms of the tendency for soft, bulky ligands to promote symmetric, holodirected geometries. The ESI mass spectra of the adducts are reported, and yield [M−halide]+ ions. 相似文献
80.
Caspases are essential in animal programmed cell death both as initiator and executioner proteases. Plants do not have close caspase homologues, but several instances of caspase-like proteolytic activity have been demonstrated in connection with programmed cell death in plants. It was asked if caspase-like proteases are involved during development of the barley caryopsis. The presence of a caspase-6-like proteolytic activity that preferentially cleaved the sequence VEID was demonstrated. A range of protease inhibitors was tested and only caspase-specific inhibitors showed major inhibitory effects. The profile of VEIDase activity in developing starchy endosperm, embryo, and whole caryopsis was measured and showed a general trend of higher activity in young, rapidly developing tissues. The VEIDase activity was localized in vivo to vesicles, shown to be autophagosomes, in randomly distributed cells of the starchy endosperm. The VEIDase activity detected in barley caryopsis is similar to activities described previously in mammals, spruce, yeast, and thale cress. In mammals, spruce, and yeast, VEIDase activity has been shown to be positively correlated with the occurrence of programmed cell death. Several manifestations of programmed cell death exist in developing barley caryopsis, indicating a connection between VEIDase activity and developmental programmed cell death in barley. 相似文献