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151.
Anderson CA Boucher G Lees CW Franke A D'Amato M Taylor KD Lee JC Goyette P Imielinski M Latiano A Lagacé C Scott R Amininejad L Bumpstead S Baidoo L Baldassano RN Barclay M Bayless TM Brand S Büning C Colombel JF Denson LA De Vos M Dubinsky M Edwards C Ellinghaus D Fehrmann RS Floyd JA Florin T Franchimont D Franke L Georges M Glas J Glazer NL Guthery SL Haritunians T Hayward NK Hugot JP Jobin G Laukens D Lawrance I Lémann M Levine A Libioulle C Louis E McGovern DP Milla M Montgomery GW 《Nature genetics》2011,43(3):246-252
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. 相似文献
152.
Caroline Lonez Marc F. Lensink Emilie Kleiren Jean-Marie Vanderwinden Jean-Marie Ruysschaert Michel Vandenbranden 《Cellular and molecular life sciences : CMLS》2010,67(3):483-494
Addition of co-lipids into cationic lipid formulations is considered as promoting cell delivery of DNA by enhancing fusion
processes with cell membranes. Here, by combining FRET and confocal microscopy, we demonstrate that some cationic lipids do
not require a co-lipid to fuse efficiently with cells. These cationic lipids are able to self-organize into bilayers that
are stable enough to form liposomes, while presenting some destabilizing properties reminiscent of the conically shaped fusogenic
co-lipid, DOPE. We therefore analyzed the resident lipid structures in cationic bilayers by molecular dynamics simulations,
clustering the individual lipid structures into populations of similarly shaped molecules, as opposed to the classical approach
of using the static packing parameter to define the lipid shapes. Comparison of fusogenic properties with these lipid populations
suggests that the ratio of cylindrical versus conical lipid populations correlates with the ability to fuse with cell membranes. 相似文献
153.
Bidart M Ricard N Levet S Samson M Mallet C David L Subileau M Tillet E Feige JJ Bailly S 《Cellular and molecular life sciences : CMLS》2012,69(2):313-324
Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase
1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has
recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning
BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating
form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary
epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma
(1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and
fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during
mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood.
We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells.
Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active
(60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state. 相似文献
154.
TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome 总被引:1,自引:0,他引:1
C Boileau DC Guo N Hanna ES Regalado D Detaint L Gong M Varret SK Prakash AH Li H d'Indy AC Braverman B Grandchamp CS Kwartler L Gouya RL Santos-Cortez M Abifadel SM Leal C Muti J Shendure MS Gross MJ Rieder A Vahanian DA Nickerson JB Michel;National Heart Lung Blood Institute 《Nature genetics》2012,44(8):916-921
A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta. 相似文献
155.
AID is required for germinal center-derived lymphomagenesis 总被引:1,自引:0,他引:1
Pasqualucci L Bhagat G Jankovic M Compagno M Smith P Muramatsu M Honjo T Morse HC Nussenzweig MC Dalla-Favera R 《Nature genetics》2008,40(1):108-112
Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL. 相似文献
156.
Benzinou M Creemers JW Choquet H Lobbens S Dina C Durand E Guerardel A Boutin P Jouret B Heude B Balkau B Tichet J Marre M Potoczna N Horber F Le Stunff C Czernichow S Sandbaek A Lauritzen T Borch-Johnsen K Andersen G Kiess W Körner A Kovacs P Jacobson P Carlsson LM Walley AJ Jørgensen T Hansen T Pedersen O Meyre D Froguel P 《Nature genetics》2008,40(8):943-945
Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity. 相似文献
157.
Julien SG Dubé N Read M Penney J Paquet M Han Y Kennedy BP Muller WJ Tremblay ML 《Nature genetics》2007,39(3):338-346
We investigated the role of protein tyrosine phosphatase 1B (PTP1B) in mammary tumorigenesis using both genetic and pharmacological approaches. It has been previously shown that transgenic mice with a deletion mutation in the region of Erbb2 encoding its extracellular domain (referred to as NDL2 mice, for 'Neu deletion in extracellular domain 2') develop mammary tumors that progress to lung metastasis. However, deletion of PTP1B activity in the NDL2 transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor results in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in the mammary gland leads to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTB1B occurs through the attenuation of both the MAP kinase (MAPK) and Akt pathways. This report provides a rationale for the development of PTP1B as a new therapeutic target in breast cancer. 相似文献
158.
Franke A McGovern DP Barrett JC Wang K Radford-Smith GL Ahmad T Lees CW Balschun T Lee J Roberts R Anderson CA Bis JC Bumpstead S Ellinghaus D Festen EM Georges M Green T Haritunians T Jostins L Latiano A Mathew CG Montgomery GW Prescott NJ Raychaudhuri S Rotter JI Schumm P Sharma Y Simms LA Taylor KD Whiteman D Wijmenga C Baldassano RN Barclay M Bayless TM Brand S Büning C Cohen A Colombel JF Cottone M Stronati L Denson T De Vos M D'Inca R Dubinsky M Edwards C Florin T Franchimont D Gearry R 《Nature genetics》2010,42(12):1118-1125
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10??). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease. 相似文献
159.
Michel Puech 《Foundations of Science》2017,22(2):269-274
Several trends in contemporary philosophy have revived the question of the good life. This article addresses the more elaborate notion of an “art of living” in the specific context of the technosphere on the basis of recent works in philosophy of technology. It also brings ideas from Asian philosophy and from Buddhism in particular into the discussion. The focus is on the notion of non-confrontation, which could lead to a decisive change in the methods and scope of technology assessment within the humanities. The art of living in the technosphere emerges as an existential virtuosity that pertains to practical wisdom. 相似文献