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1.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with autosomal dominant hypercholesterolemia, a state of elevated levels of LDL (low-density lipoprotein) cholesterol. Autosomal dominant hypercholesterolemia can result in severe implications such as stroke and coronary heart disease. The inhibition of PCSK9 function by therapeutic antibodies that block interaction of PCSK9 with the epidermal growth factor-like repeat A domain of LDL receptor (LDLR) was shown to successfully lower LDL cholesterol levels in clinical studies. Here we present data on the identification, structural and biophysical characterization and in vitro and in vivo pharmacology of a PCSK9 antibody (mAb1). The X-ray structure shows that mAb1 binds the module 1 of the C-terminal domain (CTD) of PCSK9. It blocks access to an area bearing several naturally occurring gain-of-function and loss-of-function mutations. Although the antibody does not inhibit binding of PCSK9 to epidermal growth factor-like repeat A, it partially reverses PCSK9-induced reduction of the LDLR and LDL cholesterol uptake in a cellular assay. mAb1 is also effective in lowering serum levels of LDL cholesterol in cynomolgus monkeys in vivo. Complete loss of PCSK9 is associated with insufficient liver regeneration and increased risk of hepatitis C infections. Blocking of the CTD is sufficient to partially inhibit PCSK9 function. Antibodies binding the CTD of PCSK9 may thus be advantageous in patients that do not tolerate complete inhibition of PCSK9.  相似文献   
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Nowadays, particulate matter, especially that with small dimension as PM10, PM2.5 and PM1, is the air quality indicator most commonly associated with a number of adverse health effects. In this paper it is analyzed the impact that a natural event, such as the transport of Saharan dust, can have on increasing the particulate matter concentration in Sicily.Consulting the data of daily PM10 concentration, acquired by air quality monitoring network belonging to “Agenzia Regionale Protezionedell’ Ambiente” (Environmental Protection Regional Agency), it was possible to analyze the trend from 2013 to 2015. The days, in which the limit value was exceeded, were subjected to combined analysis. It was based on three models: interpretations of the air masses back-trajectories, using the atmospheric model HYSPLIT (HYbrid Single-Particle Lagrangian Integrated trajectory); on the calculation of the concentration on the ground and at high altitude particulate applying DREAM model (Dust REgional atmospheric model) and on the calculation of the concentration of mineral aerosols according to the atmospheric optical thickness (AOT) applying NAAPS model (Navy Aerosol Analysis and Prediction System).The daily limit value exceedances were attributed to the transport of Saharan dust events exclusively when the three models were in agreement with each other. Identifying the natural events, it was possible to quantify the contribution of the Saharan dust and consequently the reduction of the exceedances number. To quantify the contribution of Saharan dust on daily PM10 concentration, it was calculated the regional background in according to precautionary approach recommended by “Guidance on the quantification of the contribution of natural sources under the EU Air Quality Directive 2008/50/EC”, when the application of the method cannot be validated with chemical analysis, as in this case. In this study is obtained, as the most important quantitative goal, the convergence of the three models to the same result. So, is evident that exceedances of the daily limit value that occurred from 2013 to 2015 in Sicily can be attributed, in most cases, to the Saharan dust intrusion.  相似文献   
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Polyomavirus BK (BKV) infection is an important cause of renal allograft failure. Viral microRNAs are known to play a crucial role in viral replication. This study investigated the expression of BKV-encoded microRNAs (miR-B1) in patients with polyomavirus-associated nephropathy (PVAN) and their role in viral replication. Following BKV infection in renal proximal tubular cells, the 3p and 5p miR-B1 levels were significantly increased. Cells transfected with the vector containing the miR-B1 precursor (the miR-B1 vector) showed a significant increase in expression of 3p and 5p miR-B1 and decrease in luciferase activity of a reporter containing the 3p and 5p miR-B1 binding sites, compared to cells transfected with the miR-B1-mutated vector. Transfection of the miR-B1 expression vector or the 3p and 5p miR-B1 oligonucleotides inhibited expression of TAg. TAg-enhanced promoter activity and BKV replication were inhibited by miR-B1. In contrast, inhibition of miR-B1 expression by addition of miR-B1 antagomirs or silencing of Dicer upregulated the expression of TAg and VP1 proteins in BKV-infected cells. Importantly, patients with PVAN had significantly higher levels of 3p and 5p miR-B1 compared to renal transplant patients without PVAN. In conclusion, we demonstrated that (1) miR-B1 expression was upregulated during BKV infection and (2) miR-B1 suppressed TAg-mediated autoregulation of BKV replication. Use of miR-B1 can be evaluated as a potential treatment strategy against BKV infection.  相似文献   
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This study investigates Pb isotope ratios at low concentrations (parts per billion; ppb) in tree rings and soils in the Northern Athabasca Oil Sands Region (NAOSR), western Canada, to evaluate if: (1) climatic conditions influence on tree-ring Pb assimilation; and (2) such low Pb content allows inferring the regional Pb depositional history.Our results reflect the influence of winter snow cover and the importance of minimum temperature and precipitation in spring and summer on the bioavailability of Pb and its passive assimilation by trees in sub-arctic semi-humid climatic conditions. Winter conditions can influence the state of root systems that subsequently impacts the following growth period, while spring and summer conditions likely control microbial processes and water source, and may thus impact Pb assimilation by trees. Thus, the results of tree-ring Pb concentrations show interesting correlation with cumulated snow from November of the previous year to February (ρ = 0.53; P < 0.01; n = 36). Likewise, the 206Pb/207Pb ratios inversely correlate with minimum temperature from April to September (ρ = −0.67; P < 0.01; n = 40) and precipitation from May to August (ρ = −0.42; P < 0.01; n = 36). The isotopic results also suggest that the effects of climatic variations are superimposed by regional industrial Pb deposition: Western North American Aerosols (WNAA) and fugitive dust from the oil sands mining operations appear to be the most likely sources.Importantly, this study suggests that even at low Pb concentrations, tree-ring Pb isotopes are modulated by climatic conditions and potential input of regional and long-range transport of airborne Pb. These interpretations open the possibility of using Pb isotopes as an environmental tool for inferring the pollution history in remote regions, and improving our understanding of its natural cycle through the forest environment.  相似文献   
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黄土丘陵区生物土壤结皮表面糙度特征及影响因素   总被引:1,自引:0,他引:1  
地表糙度是影响地表径流和侵蚀过程的重要属性.生物结皮在干旱半干旱区广泛分布,是地表糙度的影响因子之一.本文采用链条法测定了黄土丘陵区不同发育阶段生物结皮表面糙度特征,分析了不同发育阶段生物结皮表面糙度对坡向、土壤含水量和冻融作用的响应及其与各理化性质的相关性,初步探索了生物结皮对地表糙度的影响及其相关因素.结果表明: 生物结皮显著改变地表糙度,随着生物结皮从藻结皮向藓结皮演替,其糙度先降低后增加,生物结皮发育形成10年以后,其表面糙度基本趋于稳定;研究区早期形成的藻结皮表面糙度较裸土降低47.0%,深色藻结皮(藓类盖度<20%)较裸土降低20.4%,混生结皮(藓类盖度为20%~60%)和苔藓结皮(藓类盖度>70%)表面糙度与深色藻结皮基本一致;坡向对发育10年以上的生物结皮表面糙度的影响不显著;土壤含水量影响地表糙度特征.研究区浅色藻结皮表面糙度随水分变化较为剧烈;随着生物结皮发育,深色藻结皮、混生结皮和苔藓结皮表面糙度随水分的变化趋于平缓.冻融增加了生物结皮表面糙度.浅色藻结皮经两次冻融后表面糙度增加29.7%;深色藻结皮、混生结皮和藓结皮表面糙度的影响需经过反复冻融才有所体现.生物结皮表面糙度与藓结皮盖度呈显著正相关(P<0.1).  相似文献   
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几种沙漠地区野生药用植物资源及其引种栽培   总被引:3,自引:0,他引:3  
几种沙漠地区野生药用植物资源及其引种栽培尹林克(中国科学院吐鲁番沙漠植物园,新疆吐鲁番838008)Resourcesofseveralspeciesofwildmedicinalplantsindesertregionandtheirintrodu...  相似文献   
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The noncoding region between tRNAPro and the large conserved sequence block is the most variable region in the mammalian mitochondrial DNA D-loop region. This variable region (ca. 270 bp) of four species of Equus, including Mongolian and Japanese native domestic horses as well as Przewalskii's (or Mongolian) wild horse, were sequenced. These data were compared with our recently published Thoroughbred horse mitochondrial DNA sequences. The evolutionary rate of this region among the four species of Equus was estimated to be 2–4 × 10–8 per site per year. Phylogenetic trees of Equus species demonstrate that Przewalskii's wild horse is within the genetic variation among the domestic horse. This suggests that the chromosome number change (probably increase) of the Przewalskii's wild horse occurred rather recently.Correspondence to: N. Ishida  相似文献   
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