全文获取类型
收费全文 | 252篇 |
免费 | 0篇 |
专业分类
系统科学 | 1篇 |
教育与普及 | 1篇 |
理论与方法论 | 13篇 |
现状及发展 | 86篇 |
研究方法 | 48篇 |
综合类 | 102篇 |
自然研究 | 1篇 |
出版年
2020年 | 1篇 |
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 3篇 |
2014年 | 1篇 |
2013年 | 6篇 |
2012年 | 20篇 |
2011年 | 25篇 |
2010年 | 7篇 |
2009年 | 4篇 |
2008年 | 10篇 |
2007年 | 21篇 |
2006年 | 11篇 |
2005年 | 14篇 |
2004年 | 17篇 |
2003年 | 13篇 |
2002年 | 11篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 5篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1995年 | 4篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1978年 | 6篇 |
1977年 | 3篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 5篇 |
1970年 | 3篇 |
1969年 | 4篇 |
1968年 | 3篇 |
1967年 | 3篇 |
1966年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有252条查询结果,搜索用时 140 毫秒
211.
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron 总被引:1,自引:0,他引:1
Louis-Dit-Picard H Barc J Trujillano D Miserey-Lenkei S Bouatia-Naji N Pylypenko O Beaurain G Bonnefond A Sand O Simian C Vidal-Petiot E Soukaseum C Mandet C Broux F Chabre O Delahousse M Esnault V Fiquet B Houillier P Bagnis CI Koenig J Konrad M Landais P Mourani C Niaudet P Probst V Thauvin C Unwin RJ Soroka SD Ehret G Ossowski S Caulfield M;International Consortium for Blood Pressure 《Nature genetics》2012,44(4):456-60, S1-3
Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure. 相似文献
212.
Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes 总被引:1,自引:0,他引:1
Bonnefond A Clément N Fawcett K Yengo L Vaillant E Guillaume JL Dechaume A Payne F Roussel R Czernichow S Hercberg S Hadjadj S Balkau B Marre M Lantieri O Langenberg C Bouatia-Naji N;Meta-Analysis of Glucose Insulin-Related Traits Consortium 《Nature genetics》2012,44(3):297-301
Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT(2)) increase type 2 diabetes (T2D) risk(1,2). Although the strongest association signal was highly significant (P < 1 × 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of ~1.10-1.15)(1-3). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 × 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 × 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 × 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk. 相似文献
213.
214.
W Zhou EA Otto A Cluckey R Airik TW Hurd M Chaki K Diaz FP Lach GR Bennett HY Gee AK Ghosh S Natarajan S Thongthip U Veturi SJ Allen S Janssen G Ramaswami J Dixon F Burkhalter M Spoendlin H Moch MJ Mihatsch J Verine R Reade H Soliman M Godin D Kiss G Monga G Mazzucco K Amann F Artunc RC Newland T Wiech S Zschiedrich TB Huber A Friedl GG Slaats JA Joles R Goldschmeding J Washburn RH Giles S Levy A Smogorzewska F Hildebrandt 《Nature genetics》2012,44(8):910-915
Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD. 相似文献
215.
Delous M Baala L Salomon R Laclef C Vierkotten J Tory K Golzio C Lacoste T Besse L Ozilou C Moutkine I Hellman NE Anselme I Silbermann F Vesque C Gerhardt C Rattenberry E Wolf MT Gubler MC Martinovic J Encha-Razavi F Boddaert N Gonzales M Macher MA Nivet H Champion G Berthélémé JP Niaudet P McDonald F Hildebrandt F Johnson CA Vekemans M Antignac C Rüther U Schneider-Maunoury S Attié-Bitach T Saunier S 《Nature genetics》2007,39(7):875-881
Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder. 相似文献
216.
A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition 总被引:1,自引:0,他引:1
Ropero S Fraga MF Ballestar E Hamelin R Yamamoto H Boix-Chornet M Caballero R Alaminos M Setien F Paz MF Herranz M Palacios J Arango D Orntoft TF Aaltonen LA Schwartz S Esteller M 《Nature genetics》2006,38(5):566-569
Disruption of histone acetylation patterns is a common feature of cancer cells, but very little is known about its genetic basis. We have identified truncating mutations in one of the primary human histone deacetylases, HDAC2, in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. The presence of the HDAC2 frameshift mutation causes a loss of HDAC2 protein expression and enzymatic activity and renders these cells more resistant to the usual antiproliferative and proapoptotic effects of histone deacetylase inhibitors. As such drugs may serve as therapeutic agents for cancer, our findings support the use of HDAC2 mutational status in future pharmacogenetic treatment of these individuals. 相似文献
217.
218.
Crosnier C Bustamante LY Bartholdson SJ Bei AK Theron M Uchikawa M Mboup S Ndir O Kwiatkowski DP Duraisingh MT Rayner JC Wright GJ 《Nature》2011,480(7378):534-537
Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor-ligand interactions involved are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways. Here, we show that we have identified a receptor-ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Ok(a-) erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor-ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies. 相似文献
219.
Suppression of lung adenocarcinoma progression by Nkx2-1 总被引:1,自引:0,他引:1
220.
Abbot P Abe J Alcock J Alizon S Alpedrinha JA Andersson M Andre JB van Baalen M Balloux F Balshine S Barton N Beukeboom LW Biernaskie JM Bilde T Borgia G Breed M Brown S Bshary R Buckling A Burley NT Burton-Chellew MN Cant MA Chapuisat M Charnov EL Clutton-Brock T Cockburn A Cole BJ Colegrave N Cosmides L Couzin ID Coyne JA Creel S Crespi B Curry RL Dall SR Day T Dickinson JL Dugatkin LA El Mouden C Emlen ST Evans J Ferriere R Field J Foitzik S Foster K Foster WA Fox CW Gadau J Gandon S 《Nature》2011,471(7339):E1-4; author reply E9-10
Arising from M. A. Nowak, C. E. Tarnita & E. O. Wilson 466, 1057-1062 (2010); Nowak et al. reply. Nowak et al. argue that inclusive fitness theory has been of little value in explaining the natural world, and that it has led to negligible progress in explaining the evolution of eusociality. However, we believe that their arguments are based upon a misunderstanding of evolutionary theory and a misrepresentation of the empirical literature. We will focus our comments on three general issues. 相似文献