全文获取类型
收费全文 | 1600篇 |
免费 | 13篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 23篇 |
理论与方法论 | 10篇 |
现状及发展 | 882篇 |
研究方法 | 151篇 |
综合类 | 540篇 |
自然研究 | 8篇 |
出版年
2018年 | 25篇 |
2017年 | 17篇 |
2016年 | 22篇 |
2015年 | 16篇 |
2014年 | 22篇 |
2013年 | 19篇 |
2012年 | 60篇 |
2011年 | 74篇 |
2010年 | 39篇 |
2009年 | 18篇 |
2008年 | 86篇 |
2007年 | 72篇 |
2006年 | 82篇 |
2005年 | 68篇 |
2004年 | 60篇 |
2003年 | 59篇 |
2002年 | 54篇 |
2001年 | 35篇 |
2000年 | 49篇 |
1999年 | 30篇 |
1996年 | 12篇 |
1994年 | 19篇 |
1990年 | 10篇 |
1989年 | 10篇 |
1987年 | 10篇 |
1985年 | 13篇 |
1984年 | 17篇 |
1983年 | 12篇 |
1982年 | 14篇 |
1981年 | 13篇 |
1980年 | 28篇 |
1979年 | 17篇 |
1978年 | 20篇 |
1977年 | 19篇 |
1976年 | 20篇 |
1975年 | 21篇 |
1973年 | 28篇 |
1972年 | 28篇 |
1971年 | 34篇 |
1970年 | 31篇 |
1969年 | 26篇 |
1968年 | 30篇 |
1967年 | 24篇 |
1966年 | 31篇 |
1965年 | 22篇 |
1964年 | 16篇 |
1963年 | 15篇 |
1961年 | 13篇 |
1956年 | 12篇 |
1947年 | 11篇 |
排序方式: 共有1614条查询结果,搜索用时 828 毫秒
951.
Lukasz Wujak Ralph T. Böttcher Oleg Pak Helena Frey Elie El Agha Ying Chen Sigrid Schmitt Saverio Bellusci Liliana Schaefer Norbert Weissmann Reinhard Fässler Malgorzata Wygrecka 《Cellular and molecular life sciences : CMLS》2018,75(9):1671-1685
Low density lipoprotein receptor-related protein (LRP) 1 modulates cell adhesion and motility under normal and pathological conditions. Previous studies documented that LRP1 binds several integrin receptors and mediates their trafficking to the cell surface and endocytosis. However, the mechanism by which LRP1 may regulate integrin activation remains unknown. Here we report that LRP1 promotes the activation and subsequent degradation of β1 integrin and thus supports cell adhesion, spreading, migration and integrin signaling on fibronectin. LRP1 interacts with surface β1 integrin, binds the integrin activator kindlin2 and stimulates β1 integrin–kindlin2 complex formation. Specifically, serine 76 in the LRP1 cytoplasmic tail is crucial for the interaction with kindlin2, β1 integrin activation and cell adhesion. Interestingly, a loss of LRP1 induces the accumulation of several integrin receptors on the cell surface. Following internalization, intracellular trafficking of integrins is driven by LRP1 in a protein kinase C- and class II myosin-dependent manner. Ultimately, LRP1 dictates the fate of endocytosed β1 integrin by directing it down the pathway of lysosomal and proteasomal degradation. We propose that LRP1 mediates cell adhesion by orchestrating a multi-protein pathway to activate, traffic and degrade integrins. Thus, LRP1 may serve as a focal point in the integrin quality control system to ensure a firm connection to the extracellular matrix. 相似文献
952.
Sonja A. Kirsch Andreas Kugemann Armando Carpaneto Rainer A. Böckmann Petra Dietrich 《Cellular and molecular life sciences : CMLS》2018,75(20):3803-3815
Mammalian two-pore channels (TPCs) are activated by the low-abundance membrane lipid phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) present in the endo-lysosomal system. Malfunction of human TPC1 or TPC2 (hTPC) results in severe organellar storage diseases and membrane trafficking defects. Here, we compared the lipid-binding characteristics of hTPC2 and of the PI(3,5)P2-insensitive TPC1 from the model plant Arabidopsis thaliana. Combination of simulations with functional analysis of channel mutants revealed the presence of an hTPC2-specific lipid-binding pocket mutually formed by two channel regions exposed to the cytosolic side of the membrane. We showed that PI(3,5)P2 is simultaneously stabilized by positively charged amino acids (K203, K204, and K207) in the linker between transmembrane helices S4 and S5 and by S322 in the cytosolic extension of S6. We suggest that PI(3,5)P2 cross links two parts of the channel, enabling their coordinated movement during channel gating. 相似文献
953.
食品包装材料的迁移及安全壁垒研究
3 总被引:4,自引:0,他引:4
食品包装安全是食品安全的重要组成部分,分析研究了欧美食品包装材料安全性法规的整体框架,尤其是关于食品接触包装材料迁移的安全法规,并重点对欧美制定迁移安全法规的依据-食品聚合物包装材料成分迁移的数学模型和实验测试方法进行了探讨. 相似文献
954.
弗雷格从逻辑的角度考察"真",认为"真"不可定义,并认为句子是"真"的作用对象;"真"具有客观性和完全性,它是不可感觉到的存在,其表达只存在于断定句的形式中。弗雷格关于"真"之本体论基础的解读促使他将命题作为逻辑研究的对象。弗雷格求"真"的进路给语言学、哲学和逻辑学的研究带来启迪,而其思想也有不足之处。 相似文献
955.
Suhre K Wallaschofski H Raffler J Friedrich N Haring R Michael K Wasner C Krebs A Kronenberg F Chang D Meisinger C Wichmann HE Hoffmann W Völzke H Völker U Teumer A Biffar R Kocher T Felix SB Illig T Kroemer HK Gieger C Römisch-Margl W Nauck M 《Nature genetics》2011,43(6):565-569
We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria. 相似文献
956.
Kornum BR Kawashima M Faraco J Lin L Rico TJ Hesselson S Axtell RC Kuipers H Weiner K Hamacher A Kassack MU Han F Knudsen S Li J Dong X Winkelmann J Plazzi G Nevsimalova S Hong SC Honda Y Honda M Högl B Ton TG Montplaisir J Bourgin P Kemlink D Huang YS Warby S Einen M Eshragh JL Miyagawa T Desautels A Ruppert E Hesla PE Poli F Pizza F Frauscher B Jeong JH Lee SP Strohl KP Longstreth WT Kvale M Dobrovolna M Ohayon MM Nepom GT Wichmann HE Rouleau GA Gieger C Levinson DF Gejman PV Meitinger T 《Nature genetics》2011,43(1):66-71
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y?? gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10?1?, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases. 相似文献
957.
Nair KS Hmani-Aifa M Ali Z Kearney AL Ben Salem S Macalinao DG Cosma IM Bouassida W Hakim B Benzina Z Soto I Söderkvist P Howell GR Smith RS Ayadi H John SW 《Nature genetics》2011,43(6):579-584
Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people. Although 4 million people are bilaterally blind from ACG, the causative molecular mechanisms of ACG remain to be defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure. Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG. 相似文献
958.
Davis EE Zhang Q Liu Q Diplas BH Davey LM Hartley J Stoetzel C Szymanska K Ramaswami G Logan CV Muzny DM Young AC Wheeler DA Cruz P Morgan M Lewis LR Cherukuri P Maskeri B Hansen NF Mullikin JC Blakesley RW Bouffard GG;NISC Comparative Sequencing Program Gyapay G Rieger S Tönshoff B Kern I Soliman NA Neuhaus TJ Swoboda KJ Kayserili H Gallagher TE Lewis RA Bergmann C Otto EA Saunier S Scambler PJ Beales PL Gleeson JG Maher ER Attié-Bitach T Dollfus H Johnson CA Green ED Gibbs RA Hildebrandt F 《Nature genetics》2011,43(3):189-196
Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ~5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders. 相似文献
959.
Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile 总被引:1,自引:0,他引:1
Kilpeläinen TO Zillikens MC Stančákova A Finucane FM Ried JS Langenberg C Zhang W Beckmann JS Luan J Vandenput L Styrkarsdottir U Zhou Y Smith AV Zhao JH Amin N Vedantam S Shin SY Haritunians T Fu M Feitosa MF Kumari M Halldorsson BV Tikkanen E Mangino M Hayward C Song C Arnold AM Aulchenko YS Oostra BA Campbell H Cupples LA Davis KE Döring A Eiriksdottir G Estrada K Fernández-Real JM Garcia M Gieger C Glazer NL Guiducci C Hofman A Humphries SE Isomaa B Jacobs LC Jula A Karasik D Karlsson MK 《Nature genetics》2011,43(8):753-760
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. 相似文献
960.
Witt H Sahin-Tóth M Landt O Chen JM Kähne T Drenth JP Kukor Z Szepessy E Halangk W Dahm S Rohde K Schulz HU Le Maréchal C Akar N Ammann RW Truninger K Bargetzi M Bhatia E Castellani C Cavestro GM Cerny M Destro-Bisol G Spedini G Eiberg H Jansen JB Koudova M Rausova E Macek M Malats N Real FX Menzel HJ Moral P Galavotti R Pignatti PF Rickards O Spicak J Zarnescu NO Böck W Gress TM Friess H Ockenga J Schmidt H Pfützer R Löhr M Simon P Weiss FU Lerch MM Teich N Keim V Berg T Wiedenmann B Luck W 《Nature genetics》2006,38(6):668-673
Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis. 相似文献