全文获取类型
收费全文 | 48230篇 |
免费 | 3895篇 |
国内免费 | 6篇 |
专业分类
52131篇 |
出版年
2023年 | 229篇 |
2021年 | 403篇 |
2020年 | 337篇 |
2019年 | 337篇 |
2018年 | 921篇 |
2017年 | 973篇 |
2016年 | 1083篇 |
2015年 | 1065篇 |
2014年 | 1227篇 |
2013年 | 2091篇 |
2012年 | 3287篇 |
2011年 | 3596篇 |
2010年 | 1877篇 |
2009年 | 1291篇 |
2008年 | 2938篇 |
2007年 | 3043篇 |
2006年 | 2827篇 |
2005年 | 2528篇 |
2004年 | 2411篇 |
2003年 | 2286篇 |
2002年 | 2282篇 |
2001年 | 1568篇 |
2000年 | 1820篇 |
1999年 | 977篇 |
1998年 | 475篇 |
1997年 | 376篇 |
1996年 | 454篇 |
1995年 | 386篇 |
1994年 | 415篇 |
1993年 | 362篇 |
1992年 | 412篇 |
1991年 | 351篇 |
1990年 | 323篇 |
1989年 | 303篇 |
1988年 | 280篇 |
1987年 | 297篇 |
1986年 | 249篇 |
1985年 | 343篇 |
1984年 | 412篇 |
1983年 | 361篇 |
1982年 | 331篇 |
1981年 | 317篇 |
1980年 | 274篇 |
1979年 | 266篇 |
1978年 | 281篇 |
1977年 | 251篇 |
1976年 | 251篇 |
1975年 | 301篇 |
1974年 | 226篇 |
1973年 | 223篇 |
排序方式: 共有10000条查询结果,搜索用时 20 毫秒
991.
992.
Bengt Fellström Faiez Zannad Roland Schmieder Hallvard Holdaas Alan Jardine Helen Rose Wim Wilpshaar 《Trials》2005,6(1):1-8
Background
Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular events. Multiple risk factors for atherosclerosis are present in ESRD and may contribute to the increased risk of cardiovascular mortality in this population. In contrast to patients with normal renal function, the benefits of modifying lipid levels on cardiovascular outcomes in patients with ESRD on haemodialysis have yet to be confirmed in large prospective randomised trials. A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events (AURORA) will be the first large-scale international trial to assess the effects of statin therapy on cardiovascular morbidity and mortality in ESRD patients on chronic haemodialysis.Methods
More than 2,750 ESRD patients who have been receiving chronic haemodialysis treatment for at least 3 months have been randomised (1:1), irrespective of baseline lipid levels, to treatment with rosuvastatin 10 mg or placebo. The primary study endpoint is the time to a major cardiovascular event (first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Secondary endpoints include all-cause mortality, major cardiovascular event-free survival time, time to cardiovascular death, time to non-cardiovascular death, cardiovascular interventions, tolerability of treatment and health economic costs per life-year saved. Study medication will be given until 620 subjects have experienced a major cardiovascular event.Conclusion
Our hypothesis is that results from AURORA will establish the clinical efficacy and tolerability of rosuvastatin in patients with ESRD receiving chronic haemodialysis and guide the optimal management of this expanding population. 相似文献993.
Afshar K Willard FS Colombo K Siderovski DP Gönczy P 《Development (Cambridge, England)》2005,132(20):4449-4459
Understanding of the mechanisms governing spindle positioning during asymmetric division remains incomplete. During unequal division of one-cell stage C. elegans embryos, the Galpha proteins GOA-1 and GPA-16 act in a partially redundant manner to generate pulling forces along astral microtubules. Previous work focused primarily on GOA-1, whereas the mechanisms by which GPA-16 participates in this process are not well understood. Here, we report that GPA-16 is present predominantly at the cortex of one-cell stage embryos. Using co-immunoprecipitation and surface plasmon resonance binding assays, we find that GPA-16 associates with RIC-8 and GPR-1/2, two proteins known to be required for pulling force generation. Using spindle severing as an assay for pulling forces, we demonstrate that inactivation of the Gbeta protein GPB-1 renders GPA-16 and GOA-1 entirely redundant. This suggests that the two Galpha proteins can activate the same pathway and that their dual presence is normally needed to counter Gbetagamma. Using nucleotide exchange assays, we establish that whereas GPR-1/2 acts as a guanine nucleotide dissociation inhibitor (GDI) for GPA-16, as it does for GOA-1, RIC-8 does not exhibit guanine nucleotide exchange factor (GEF) activity towards GPA-16, in contrast to its effect on GOA-1. We establish in addition that RIC-8 is required for cortical localization of GPA-16, whereas it is not required for that of GOA-1. Our analysis demonstrates that this requirement toward GPA-16 is distinct from the known function of RIC-8 in enabling interaction between Galpha proteins and GPR-1/2, thus providing novel insight into the mechanisms of asymmetric spindle positioning. 相似文献
994.
Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease 总被引:3,自引:0,他引:3
Heider U Hofbauer LC Zavrski I Kaiser M Jakob C Sezer O 《Biochemical and biophysical research communications》2005,338(2):687-693
Increased bone resorption is a major characteristic of multiple myeloma and is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta, and SDF-1alpha, which also increase osteoclast activity. On the other hand, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g., the Wnt inhibitors DKK-1 and sFRP-2. Moreover, they inhibit differentiation of osteoblast precursors and induce apoptosis in osteoblasts. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression. 相似文献
995.
The haemoglobin (Hb) of Daphnia magna acclimated to different oxygen conditions was sampled, and in its natively assembled state it was separated by chromatofocusing. The Hb isoforms were analysed for their subunit composition under denaturating conditions by two-dimensional gel electrophoresis. The Hb system is suggested to consist of three predominant Hb aggregates, which are characterised by a specific subunit composition and synthesised in response to different ambient oxygen conditions. In normoxia, a dominant Hb aggregate (DmHbI) with a pI of 4.4-4.6 was composed of subunits B, C, E, F and G. In severe hypoxia, a different dominant Hb isoform (DmHbIII) with a pI of 5.7-5.9 was composed of subunits A, B, C, D, E and F. Further analyses in moderate hypoxia provided evidence for a third Hb isoform (DmHbII) composed of subunits B, C, D, E and F. Sequence alignment and homology modelling of the tertiary structure of the D. magna Hb domains 1 and 2 revealed functionally relevant substitutions of amino acid residues at positions B10, E7 and E11, which determine the functional properties of D. magna haemoglobin in terms of haem contact, oxygen binding and affinity. Both domains are predicted to possess the common haemoglobin fold, but helices C and D are not properly formed, and helix G is interrupted by a short coil. 相似文献
996.
Rolletschek H Nguyen TH Häusler RE Rutten T Göbel C Feussner I Radchuk R Tewes A Claus B Klukas C Linemann U Weber H Wobus U Borisjuk L 《The Plant journal : for cell and molecular biology》2007,51(3):468-484
The glucose-6-phosphate/phosphate translocator (GPT) acts as an importer of carbon into the plastid. Despite the potential importance of GPT for storage in crop seeds, its regulatory role in biosynthetic pathways that are active during seed development is poorly understood. We have isolated GPT1 from Vicia narbonensis and studied its role in seed development using a transgenic approach based on the seed-specific legumin promoter LeB4. GPT1 is highly expressed in vegetative sink tissues, flowers and young seeds. In the embryo, localized upregulation of GPT1 at the onset of storage coincides with the onset of starch accumulation. Embryos of transgenic plants expressing antisense GPT1 showed a significant reduction (up to 55%) in the specific transport rate of glucose-6-phosphate as determined using proteoliposomes prepared from embryos. Furthermore, amyloplasts developed later and were smaller in size, while the expression of genes encoding plastid-specific translocators and proteins involved in starch biosynthesis was decreased. Metabolite analysis and stable isotope labelling demonstrated that starch biosynthesis was also reduced, although storage protein biosynthesis increased. This metabolic shift was characterized by upregulation of genes related to nitrogen uptake and protein storage, morphological variation of the protein-storing vacuoles, and a crude protein content of mature seeds of transgenics that was up to 30% higher than in wild-type. These findings provide evidence that (1) the prevailing level of GPT1 abundance/activity is rate-limiting for the synthesis of starch in developing seeds, (2) GPT1 exerts a controlling function on assimilate partitioning into storage protein, and (3) GPT1 is essential for the differentiation of embryonic plastids and seed maturation. 相似文献
997.
Structural organization and a standardized nomenclature for plant endo-1,4-beta-glucanases (cellulases) of glycosyl hydrolase family 9 下载免费PDF全文
998.
Hinney A Nguyen TT Scherag A Friedel S Brönner G Müller TD Grallert H Illig T Wichmann HE Rief W Schäfer H Hebebrand J 《PloS one》2007,2(12):e1361
Background
Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity.Methodology/Principal Findings
a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10−7, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (CI) 1.22–2.27; ORTT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium.Conclusions/Significance
Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings. 相似文献999.
Systemic vasculitis, an inflammatory necrotizing disease of the blood vessel walls, can occur secondary to autoimmune diseases, including connective tissue diseases. Various pathogenic mechanisms have been implicated in the induction of vasculitis, including cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation. This inflammatory activity is believed to contribute to accelerated atherosclerosis, and also leads to increased risk for cardiovascular events in patients with rheumatoid arthritis and systemic lupus erythematosus. Endothelial cell activation is a common pathogenic pathway in the systemic vasculitis associated with rheumatoid arthritis and systemic lupus erythematosus, with elevated levels of endothelin-1 potentially inducing vascular dysregulation. 相似文献
1000.