全文获取类型
收费全文 | 4367篇 |
免费 | 389篇 |
国内免费 | 1篇 |
专业分类
4757篇 |
出版年
2022年 | 39篇 |
2021年 | 50篇 |
2020年 | 49篇 |
2019年 | 42篇 |
2018年 | 48篇 |
2017年 | 41篇 |
2016年 | 95篇 |
2015年 | 161篇 |
2014年 | 178篇 |
2013年 | 259篇 |
2012年 | 314篇 |
2011年 | 299篇 |
2010年 | 171篇 |
2009年 | 159篇 |
2008年 | 232篇 |
2007年 | 248篇 |
2006年 | 245篇 |
2005年 | 219篇 |
2004年 | 222篇 |
2003年 | 190篇 |
2002年 | 204篇 |
2001年 | 72篇 |
2000年 | 65篇 |
1999年 | 68篇 |
1998年 | 47篇 |
1997年 | 43篇 |
1996年 | 33篇 |
1995年 | 27篇 |
1994年 | 33篇 |
1993年 | 44篇 |
1992年 | 48篇 |
1991年 | 43篇 |
1990年 | 41篇 |
1989年 | 40篇 |
1988年 | 50篇 |
1987年 | 37篇 |
1986年 | 31篇 |
1985年 | 30篇 |
1984年 | 38篇 |
1983年 | 35篇 |
1982年 | 35篇 |
1981年 | 28篇 |
1980年 | 34篇 |
1979年 | 27篇 |
1978年 | 24篇 |
1977年 | 25篇 |
1976年 | 32篇 |
1975年 | 27篇 |
1974年 | 34篇 |
1971年 | 19篇 |
排序方式: 共有4757条查询结果,搜索用时 15 毫秒
51.
Marie Maraninchi Delphine Feron Ingrid Fruitier‐Arnaudin Audrey Bégu‐Le Corroller Juan P. Nogueira Julien Mancini René Valéro Jean M. Piot Bernard Vialettes 《Obesity (Silver Spring, Md.)》2013,21(2):378-381
Objective:
Hemorphin peptides exhibit biological activities that interfere with the endorphin system, the inflammatory response, and blood‐pressure control. VV‐hemorphin‐7 and LVV‐hemorphin‐7 peptides exert a hypotensive effect, in particular, by inhibiting the renin–angiotensin system. Furthermore, levels of circulating hemorphin‐7 peptides have been found to be decreased in diseases such as type 1 and type 2 diabetes.Design and Methods:
Because type 2 diabetes and obesity share common features, such as insulin resistance, microinflammation, high glomerular‐filtration rate (GFR), and cardiovascular risk, we evaluated serum VV‐hemorphin‐7 like immunoreactivity (VVH7‐i.r.) levels, using an enzyme‐linked immunosorbent assay method, on a group of 54 obese subjects without diabetes or hypertension, compared with a group of 33 healthy normal‐weight subjects.Results:
Circulating VVH7‐i.r. levels were significantly decreased in the obese group compared with the control group (1.98 ± 0.19 vs. 4.86 ± 0.54 µmol/l, respectively, P < 0.01), and a significant negative correlation between VVH7‐i.r. and diastolic blood pressure (DBP) was found in obese patients (r = ?0.35, P = 0.011). There was no significant correlation between VVH7‐i.r. level and insulin resistance, metabolic syndrome, or GFR.Conclusions:
The decreased serum hemorphin‐7 found in obese subjects, as in diabetes, may contribute to the development of hypertension and to the cardiovascular risk associated with these metabolic diseases.52.
Tsvetelina Batsalova Ingrid Lindh Johan B?cklund Balik Dzhambazov Rikard Holmdahl 《Arthritis research & therapy》2012,14(6):R237
Introduction
Immune responses against collagen type II (CII) are crucial for the development of collagen-induced arthritis (CIA). The aim of the present study was to evaluate and compare the CII-directed T cell and antibody specificity at different time points in the course of CIA using two mouse strains on the B10 genetic background - B10.Q, expressing Aq MHC class II molecules, and B10.DR4.Ncf1*/*, expressing human rheumatoid arthritis-associated MHC II DR4 molecules (DRA*0101/DRB*0401).Methods
B10.Q and B10.DR4.Ncf1*/* mice were immunized with CII emulsified in adjuvant and development of CIA was assessed. T cells from draining lymph nodes were restimulated in vitro with CII peptides and interferon-gamma (IFN-γ) levels in culture supernatants were evaluated by ELISA. CII-specific antibody levels in serum samples were measured by ELISA.Results
At four different CIA time points we analyzed T cell specificity to the immunodominant CII epitope 259-273 (CII259-273) and several posttranslationally modified forms of CII259-273 as well as antibody responses to three B cell immunodominant epitopes on CII (C1, U1, J1). Our data show that CII-specific T and B cell responses increase dramatically after disease onset in both strains and are sustained during the disease course. Concerning anti-CII antibody fine specificity, during all investigated stages of CIA the B10.Q mice responded predominantly to the C1 epitope, whereas the B10.DR4.Ncf1*/* mice also recognized the U1 epitope. In the established disease phase, T cell reactivity toward the galactosylated CII259-273 peptide was similar between the DR4- and the Aq-expressing strains whereas the response to the non-modified CII peptide was dramatically enhanced in the DR4 mice compared with the B10.Q. In addition, we show that the difference in the transgenic DR4-restricted T cell specificity to CII259-273 is not dependent on the degree of glycosylation of the collagen used for immunization.Conclusions
The present study provides important evaluation of CII-specific immune responses at different phases during CIA development as well as a comparative analysis between two CIA mouse models. We indicate significant differences in CII T cell and antibody specificities between the two strains and highlight a need for improved humanized B10.DR4 mouse model for rheumatoid arthritis. 相似文献53.
Litjens SH Koster J Kuikman I van Wilpe S de Pereda JM Sonnenberg A 《Molecular biology of the cell》2003,14(10):4039-4050
Plectin is a major component of the cytoskeleton and links the intermediate filament system to hemidesmosomes by binding to the integrin beta4 subunit. Previously, a binding site for beta4 was mapped on the actin-binding domain (ABD) of plectin and binding of beta4 and F-actin to plectin was shown to be mutually exclusive. Here we show that only the ABDs of plectin and dystonin bind to beta4, whereas those of other actin-binding proteins do not. Mutations of the ABD of plectin-1C show that Q131, R138, and N149 are critical for tight binding of the ABD to beta4. These residues form a small cavity, occupied by a well-ordered water molecule in the crystal structure. The beta4 binding pocket partly overlaps with the actin-binding sequence 2 (ABS2), previously shown to be essential for actin binding. Therefore, steric interference may render binding of beta4 and F-actin to plectin mutually exclusive. Finally, we provide evidence indicating that the residues preceding the ABD in plectin-1A and -1C, although unable to mediate binding to beta4 themselves, modulate the binding activity of the ABD for beta4. These studies demonstrate the unique property of the plectin-ABD to bind to both F-actin and beta4, and explain why several other ABD-containing proteins that are expressed in basal keratinocytes are not recruited into hemidesmosomes. 相似文献
54.
Plant Effects on Spatial and Temporal Patterns of Nitrogen Cycling in Shortgrass Steppe 总被引:6,自引:0,他引:6
Because of the water-limited nature and discontinuous plant cover of shortgrass steppe, spatial patterns in ecosystem properties
are influenced more by the presence or absence of plants than by plant type. However, plant type may influence temporal patterns
of nutrient cycling between plant and soil. Plants having the carbon-3 (C3) or carbon-4 (C4) photosynthetic pathway differ in phenology as well as other attributes that affect nitrogen (N) cycling. We estimated net
N mineralization rates and traced nitrogen-15 (15N) additions among plant and soil components during May, July, and September of 1995 in native plots of C3 plants, C4 plants, or mixtures of C3 and C4. Net N mineralization was significantly greater in C3 plots than in C4 plots during both July and September. C3 plots retained significantly more 15N in May than did mixed and C4 plots; these differences in
15N retention were due to greater 15N uptake by C3 plants than by C4 plants during May. There were no significant differences in total 15N retention among plant communities for July and September. Soil 15N was influenced more by presence or absence of plants than by type of plant; greater quantities of
15N remained in soil interspaces between plants than in soil directly under plants for July and September. Our results indicate
that plant functional type (C3 versus C4) can affect both the spatial and the temporal patterns of N cycling in shortgrass steppe. Further research is necessary to
determine how these intraseasonal differences translate to longer-term and coarser-scale effects of plants on N cycling, retention,
and storage.
Received 8 December 1997; accepted 6 May 1998. 相似文献
55.
Herr I Gassler N Friess H Büchler MW 《Apoptosis : an international journal on programmed cell death》2007,12(2):271-291
More than a quarter of a century ago, the phenomenon of glucocorticoid-induced apoptosis in the majority of hematological
cells was first recognized. More recently, glucocorticoid-induced antiapoptotic signaling associated with apoptosis resistance
has been identified in cells of epithelial origin, most of malignant solid tumors and some other tissues. Despite these huge
amount of data demonstrating differential pro- and anti-apoptotic effects of glucocortioids, the underlying mechanisms of
cell type specific glucocorticoid signaling are just beginning to be described. This review summarizes our present understanding
of cell type-specific pro- and anti-apoptotic signaling induced by glucocorticoids. In the first section we give a summary
and update of known glucocorticoid-induced pathways mediating apoptosis in hematological cells. We shortly introduce mechanisms
of glucocorticoid resistance of hematological cells. We highlight and discuss the emerging molecular evidence of a general
induction of survival signaling in epithelial cells and carcinoma cells by glucocorticoids. We provide a model for glucocorticoid-induced
resistance in cells growing in a tissue formation. Thus, attachment to the extracellular matrix and cell-cell contacts typical
for e.g. epithelial and tumor cells may be crucially involved in switching the balance of several interacting pathways to
survival upon treatment with glucocorticoids. 相似文献
56.
Rosemarie Swanson 《Bulletin of mathematical biology》1984,46(2):187-203
The structure of the genetic code is related to a Gray code, which is a plausible theoretical model for an amino acid code.
The proposed model implies that the most important factor in shaping the code was the effects of mistakes in translation,
not effects of mutations. Another possible implication is that the preservation of stiffness and flexibility at appropriate
places in a protein chain is as important in protein structure as the appropriate placement of hydrophilic (external) and
hydrophobic (internal) residues. Other results are a simple conceptualization of the relationships among the 20 amino acids
and their relations to their codons. The detailed relationships are summarized in the following ‘similarity alphabet’: ala,
thr, gly, pro, ser; asp, asn, glu, gln, lys; his, arg, trp, tyr, phe; leu, met, ile, val, cys; (ATGPS DNEQK HRWYF LMIVC in
the one-letter code). This alphabet falls into four groups of amino acids: small, external, large, internal. The approximate
relation of the groups to their codons is expressed as: the first base of a codon controls size—a purine means a small amino
acid, a pyrimidine means large; the middle base controls cloisterednes—purine means external, pyrimidine means internal. These
relationships express the minimum change principle upon which the code appears to be founded. 相似文献
57.
58.
Questions: Is the occurrence of vine species in neotropical rain forests primarily determined by properties of the forest (environmental factors), by properties of the trees (tree species or tree size) or are vines randomly distributed? Location: Maya Biosphere Reserve, Guatemala. Methods: In five 1‐ha plots that span variation from unlogged forest to forest impacted by recurrent human disturbance we recorded the presence of all climbing vine species on every tree. The presence of all free standing vine species and 11 environmental variables were recorded in 100‐m2 subplots. The relationship of host tree diameter and host tree identity on single tree vine species richness was investigated by GLM modelling. Partial redundancy analyses were used to partition the variation in vine species composition on two sources: environmental factors and tree species identity. Results: Single tree vine richness increased with increasing host tree DBH and differed significantly among host species. For climbing vines, the ratio of variation in subplot presence explained by tree species and by environmental variables was ca. 4:1 (in the most disturbed logged plots slightly lower), for free standing vines this ratio varied from 1:2 in the most disturbed logged plots to 9:1 in reserve plots, while a ratio of ca. 1:1 was found for all plots analysed together. Conclusion: Different tree species have different probabilities of being infested by vines. Vines see both the forest and the trees; the environment is more important in earlier developmental stages, properties of individual trees become more important from the time vines start to climb. 相似文献
59.
Ong JM Aoki AM Seigel GM Sacerio I Castellon R Nesburn AB Kenney MC 《Neurochemical research》2003,28(6):883-891
Studies have shown an intimate relationship between cholesterol and retinal diseases; we examined the effects of cholesterol oxides on cultured cells. Using the rat retinal precursor cell line R28 and the human RPE cell line ARPE-19, we investigated the potential cytotoxicity of cholesterol oxides. Cultured R28 and ARPE-19 cells were treated with either 25-hydroxycholesterol and 7-ketocholesterol (0–50 µg/ml). Cell viability was determined by the WST-1 colorimetric assay. Production of reactive oxygen intermediate (ROI) was assessed by a fluorescent probe–based assay (2,7-dichlorodihydrofluorescein diacetate [H2DCFDA]). To detect the presence of apoptosis, DNA fragmentation gel analysis and Hoescht nuclear staining were performed. Both cholesterol oxides tested were toxic in a time- and dose-dependent fashion to the two cell lines used in this study. Treatment of R28 cells with either 25-hydroxycholesterol or 7-ketocholesterol at a concentration of 25 µg/ml resulted in greater than 50% loss of cell viability after 24 h. ARPE-19 cells were slightly less affected, with a loss of cell viability of approximately 20% and 40% after 24 h-exposure of 25-hydroxycholesterol and 7-ketocholesterol, respectively. DNA fragmentation and chromatin condensation demonstrated apoptotic events occurring in 7-ketocholesterol–treated cells. The fluorescent assay for ROI production showed that after an hour of exposure to 7-ketocholesterol, R28 cells responded with increased levels of ROIs, whereas no immediate production of ROIs were detected with treated ARPE-19 cells. These in vitro findings provide evidence that cholesterol oxides can directly damage cultured retinal and RPE cells. The oxysterol-induced oxidative stress in these cells may be a factor in the pathology of retinal degenerative diseases. 相似文献
60.
Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila 总被引:6,自引:0,他引:6
Gunawardena S Her LS Brusch RG Laymon RA Niesman IR Gordesky-Gold B Sintasath L Bonini NM Goldstein LS 《Neuron》2003,40(1):25-40
We tested whether proteins implicated in Huntington's and other polyglutamine (polyQ) expansion diseases can cause axonal transport defects. Reduction of Drosophila huntingtin and expression of proteins containing pathogenic polyQ repeats disrupt axonal transport. Pathogenic polyQ proteins accumulate in axonal and nuclear inclusions, titrate soluble motor proteins, and cause neuronal apoptosis and organismal death. Expression of a cytoplasmic polyQ repeat protein causes adult retinal degeneration, axonal blockages in larval neurons, and larval lethality, but not neuronal apoptosis or nuclear inclusions. A nuclear polyQ repeat protein induces neuronal apoptosis and larval lethality but no axonal blockages. We suggest that pathogenic polyQ proteins cause neuronal dysfunction and organismal death by two non-mutually exclusive mechanisms. One mechanism requires nuclear accumulation and induces apoptosis; the other interferes with axonal transport. Thus, disruption of axonal transport by pathogenic polyQ proteins could contribute to early neuropathology in Huntington's and other polyQ expansion diseases. 相似文献