全文获取类型
收费全文 | 1078篇 |
免费 | 83篇 |
专业分类
1161篇 |
出版年
2023年 | 6篇 |
2022年 | 15篇 |
2021年 | 22篇 |
2020年 | 11篇 |
2019年 | 15篇 |
2018年 | 28篇 |
2017年 | 14篇 |
2016年 | 31篇 |
2015年 | 64篇 |
2014年 | 65篇 |
2013年 | 68篇 |
2012年 | 92篇 |
2011年 | 75篇 |
2010年 | 48篇 |
2009年 | 47篇 |
2008年 | 59篇 |
2007年 | 66篇 |
2006年 | 52篇 |
2005年 | 62篇 |
2004年 | 42篇 |
2003年 | 40篇 |
2002年 | 51篇 |
2001年 | 4篇 |
2000年 | 8篇 |
1998年 | 8篇 |
1996年 | 18篇 |
1995年 | 5篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 9篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1987年 | 7篇 |
1986年 | 5篇 |
1985年 | 11篇 |
1984年 | 9篇 |
1983年 | 6篇 |
1981年 | 9篇 |
1980年 | 3篇 |
1978年 | 6篇 |
1976年 | 7篇 |
1975年 | 2篇 |
1974年 | 4篇 |
1973年 | 7篇 |
1972年 | 2篇 |
1971年 | 3篇 |
1970年 | 2篇 |
1969年 | 4篇 |
1968年 | 5篇 |
1953年 | 2篇 |
排序方式: 共有1161条查询结果,搜索用时 15 毫秒
41.
Celia van der Merwe Ben Loos Chrisna Swart Craig Kinnear Franclo Henning Lize van der Merwe Komala Pillay Nolan Muller Dan Zaharie Lize Engelbrecht Jonathan Carr Soraya Bardien 《Biochemical and biophysical research communications》2014
Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies. 相似文献
42.
Chiou TT Bonhomme B Jin H Miralles CP Xiao H Fu Z Harvey RJ Harvey K Vicini S De Blas AL 《The Journal of biological chemistry》2011,286(25):22456-22468
Collybistin promotes submembrane clustering of gephyrin and is essential for the postsynaptic localization of gephyrin and γ-aminobutyric acid type A (GABA(A)) receptors at GABAergic synapses in hippocampus and amygdala. Four collybistin isoforms are expressed in brain neurons; CB2 and CB3 differ in the C terminus and occur with and without the Src homology 3 (SH3) domain. We have found that in transfected hippocampal neurons, all collybistin isoforms (CB2(SH3+), CB2(SH3-), CB3(SH3+), and CB3(SH3-)) target to and concentrate at GABAergic postsynapses. Moreover, in non-transfected neurons, collybistin concentrates at GABAergic synapses. Hippocampal neurons co-transfected with CB2(SH3-) and gephyrin developed very large postsynaptic gephyrin and GABA(A) receptor clusters (superclusters). This effect was accompanied by a significant increase in the amplitude of miniature inhibitory postsynaptic currents. Co-transfection with CB2(SH3+) and gephyrin induced the formation of many (supernumerary) non-synaptic clusters. Transfection with gephyrin alone did not affect cluster number or size, but gephyrin potentiated the clustering effect of CB2(SH3-) or CB2(SH3+). Co-transfection with CB2(SH3-) or CB2(SH3+) and gephyrin did not affect the density of presynaptic GABAergic terminals contacting the transfected cells, indicating that collybistin is not synaptogenic. Nevertheless, the synaptic superclusters induced by CB2(SH3-) and gephyrin were accompanied by enlarged presynaptic GABAergic terminals. The enhanced clustering of gephyrin and GABA(A) receptors induced by collybistin isoforms was not accompanied by enhanced clustering of neuroligin 2. Moreover, during the development of GABAergic synapses, the clustering of gephyrin and GABA(A) receptors preceded the clustering of neuroligin 2. We propose a model in which the SH3- isoforms play a major role in the postsynaptic accumulation of GABA(A) receptors and in GABAergic synaptic strength. 相似文献
43.
Jeffrey W. Peng Celia A. Schiffer Ping Xu Wilfred F. van Gunsteren Richard R. Ernst 《Journal of biomolecular NMR》1996,8(4):453-476
Summary The influence of water binding on the conformational dynamics of the cyclic decapeptide antamanide dissolved in the model lipophilic environment chloroform is investigated by NMR relaxation measurements. The water-peptide complex has a lifetime of 35 s at 250 K, which is longer than typical lifetimes of water-peptide complexes reported in aqueous solution. In addition, there is a rapid intracomplex mobility that probably involves librational motions of the bound water or water molecules hopping between different binding sites. Water binding restricts the flexibility of antamanide. The experimental findings are compared with GROMOS molecular dynamics simulations of antamanide with up to eight bound water molecules. Within the simulation time of 600 ps, no water molecule leaves the complex. Additionally, the simulations show a reduced flexibility for the complex in comparison with uncomplexed antamanide. Thus, there is a qualitative agreement between the experimental NMR results and the computer simulations. 相似文献
44.
45.
Ecological zoogeography of the bats of Paraguay 总被引:1,自引:0,他引:1
Celia López-González 《Journal of Biogeography》2004,31(1):33-45
Aim To relate the composition of bat assemblages in Paraguay to environmental factors (vegetation) and to test the hypothesis that the observed patterns of distribution of Paraguayan mammals is ultimately due to soils and geological features. Location Paraguay. Methods Museum specimens were used to create a data base of 3762 individuals of forty-eight species collected in twenty-six 50 × 50 km sites distributed throughout the country. Proportion of each of sixteen vegetation types per site was estimated from vegetation maps. Vegetation and bat data were related using canonical correspondence analysis (CCA) and Mantel tests. The same analyses were performed with the bat data grouped in terms of trophic strategies. Results A significant relationship was found between composition of vegetation and composition of bat assemblages. CCA ordination arranged plant associations and bat assemblages into three distinct groups: Dry Chaco, Floodable Lands and Eastern Paraguay, which correspond to the major characteristics of the Paraguayan vegetation, geology and soils. Frugivorous bats were restricted to Eastern Paraguay and Floodable Lands, whereas most insectivore and omnivore species occur across the entire country. However, the maximum abundance of insectivorous and omnivorous species within each genus indicates that there is at least a partial segregation of species to one of the three regions, and in those cases where the maximum abundance of congeneric species coincide, those species differ considerably in size. Main conclusions The Paraguayan bat fauna is a composite of species from various South American biomes, with no endemic species. However, species are not randomly distributed across the country despite the lack of geographical barriers and the high dispersal capabilities of bats. Instead, species presence at any given site is strongly associated with vegetation patterns that are ultimately the result of the geological history of the area. This correlation can be explained partially in terms of habitat suitability and resource availability. Additionally, results suggest that interspecific interactions are also an important component in determining the composition of a given bat assemblage. 相似文献
46.
Zafar U. Khan Antonia Gutiérrez Celia P. Miralles Angel L. De Blas 《Neurochemical research》1996,21(2):147-159
Subunit-specific antibodies to all the γ subunit isoforms described in mammalian brain (γ1, γ2S, γL, and γ3) have been made. The proportion of GABAA receptors containing each γ subunit isoform in various brain regions has been determined by quantitative immunoprecipitation.
In all tested regions of the rat brain, the γ1, and γ3 subunits are present in considerable smaller proportion of GABAA receptor than the γ2 subunit. Immunocytochemistry shows that γ1 immunoreactivity concentrates in the stratum oriens and stratum radiatum of the CA1 region of the hippocampus. In the dentate
gyrus, γ1 immunoreactivity concentrates on the outer 2/3 of the molecular layer coinciding with the localization of the axospinous
synapses of the perforant pathway. In contrast, γ3 immunoreactivity concentrates on the basket cells and other GABAergic local circuit neurons of the hilus. These cells are
also rich in γ2S. In the cerebellu, γ1 immunolabeling was localized on the Bergmann glia. The γ2S and γ2L subunits are differentially expressed in various brain regions. Thus the γ2S is highly expressed in the olfactory bulb and hippocampus whereas the γ2L is very abundant in inferior colliculus and cerebellum, particularly in Purkinje cells, as immunocytochemistry, in situ hybridization
and immunoprecipitation techniques have revealed. The γ2S and γ2L coexist in some brain areas and cell types. Moreover, the γ2S and γ2L subunits can coexist in the same GABAA receptor pentamer. We have shown that this is the case in some GABAA receptors expressed in cerebellar granule cells. These GABAA receptors also have α and β subunits forming the pentamer. Immunoblots have shown that the rat γ1, γ2S, γ2L and γ3 subunits are peptides of 47, 45, 47 and 44 kDa respectively. Results also indicate that there are aging-related changes in
the expression of the γ2S and γ2L subunits in various brain regions which suggest the existence of aging-related changes in the subunit composition of the
GABAA receptors which in turn might lead to changes in receptor pharmacology. The results obtained with the various γ subunit isoforms
are discussed in terms of the high molecular and binding heterogeneity of the native GABAA receptors in brain.
Special issue dedicated to Dr. Kinya Kuriyama 相似文献
47.
José S. Carrión Errikarta I. Yll† Michael J. Walker‡ Alfonso J. Legaz‡ Celia Chaín§ Antonio López‡ 《Global Ecology and Biogeography》2003,12(2):119-129
Aim To locate glacial refugia of thermophilous plant species in Spain. Location Two south‐eastern Spanish Neanderthal man sites in Murcia; namely, the inland Cueva Negra del Estrecho del Río Quípar and the coastal Sima de las Palomas del Cabezo Gordo. Methods We use pollen found in cave sediments as a source of palaeobotanical and palaeoecological information. The findings are discussed with regard both to animal remains from both sites, and also to other refugia in south‐eastern Spain and elsewhere in the Iberian Peninsula. Results Both sequences show persistence of abundant mesothermophilous trees during the last glacial stage, suggesting both localities were reservoirs of phytodiversity and woodland species. At both sites, deciduous and evergreen oaks are the most abundant components, followed by a wide variety of deciduous trees and sclerophyllous shrubs, including Ibero‐North African xerothermic scrub near the coast. Conclusions Incomplete information underlies a common misapprehension that Iberian glacial refugia were confined to southernmost parts of the peninsula. A rather different picture of Quaternary refugia emerges from consideration of pollen sequences from caves (and other inputs such as macroscopic charcoal, spatial genetic structure of present‐day populations, faunal remains, and present‐day distribution of thermophilous species). This picture offers a view of numerous viable areas for woodland species in southern Spain, in addition to others in the mountain ranges, both in continental central Spain and those of northern Spain: these stretch from the Mediterranean coast of Catalonia to the westernmost extent of the Bay of Biscay. 相似文献
48.
Miriam Rossi Francesco Caruso Erica J. Crespi Jens Z. Pedersen Gail Nakano Michelle Duong Celia Mckee Sharon Lee Manasi Jiwrajka Charles Caldwell Francis Baffour Dylan Alex Karlin Genevieve Lidoff Stefano Leone Valentina Balducci Jaroslav Miler Sandra Incerpi 《Biochimie》2013
In order to better understand the antioxidant behavior of a series of polyphenolic 2′-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV–vis spectroscopic method indicate that a hydroxyl group in position 5′ induces the highest antioxidant activity. Consequently, 2,2′,5′-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2′,5′-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa−/fa−) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2′,5′-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases. 相似文献
49.
Christopher?Butt Lynette?Peddle Celia?Greenwood Sean?Hamilton Dafna?Gladman Proton?RahmanEmail author 《Arthritis research & therapy》2005,8(1):R27
Recent studies have implicated PTPN22 and tp53 in susceptibility to several autoimmune diseases, including rheumatoid arthritis, suggesting that these genes are important
in maintaining immune homeostasis. Because autoimmune diseases may share similar susceptibility loci, investigation of these
genes in psoriatic arthritis (PsA) is of potential relevance. As a result we investigated known coding polymorphisms in PTPN22 and tp53 in a homogenous Caucasian PsA cohort from Newfoundland, Canada and an admixed Caucasian PsA cohort from Toronto, Canada.
We observed a moderate association of the R620W variant of PTPN22 with PsA in the Toronto population only. Because of the conflicting findings reported regarding the association of PTPN22 with PsA, further studies in other PsA populations are warranted. 相似文献
50.
Dastani Z Hivert MF Timpson N Perry JR Yuan X Scott RA Henneman P Heid IM Kizer JR Lyytikäinen LP Fuchsberger C Tanaka T Morris AP Small K Isaacs A Beekman M Coassin S Lohman K Qi L Kanoni S Pankow JS Uh HW Wu Y Bidulescu A Rasmussen-Torvik LJ Greenwood CM Ladouceur M Grimsby J Manning AK Liu CT Kooner J Mooser VE Vollenweider P Kapur KA Chambers J Wareham NJ Langenberg C Frants R Willems-Vandijk K Oostra BA Willems SM Lamina C Winkler TW Psaty BM Tracy RP Brody J Chen I Viikari J Kähönen M 《PLoS genetics》2012,8(3):e1002607
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance. 相似文献