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排序方式: 共有183条查询结果,搜索用时 15 毫秒
71.
Johannessen CM Boehm JS Kim SY Thomas SR Wardwell L Johnson LA Emery CM Stransky N Cogdill AP Barretina J Caponigro G Hieronymus H Murray RR Salehi-Ashtiani K Hill DE Vidal M Zhao JJ Yang X Alkan O Kim S Harris JL Wilson CJ Myer VE Finan PM Root DE Roberts TM Golub T Flaherty KT Dummer R Weber BL Sellers WR Schlegel R Wargo JA Hahn WC Garraway LA 《Nature》2010,468(7326):968-972
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies. 相似文献
72.
73.
Christina M. Dobson Samuel J. Hempel Stephanie H. Stalnaker Ryan Stuart Lance Wells 《Cellular and molecular life sciences : CMLS》2013,70(16):2849-2857
Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity of proteins. Here we discuss the importance of one type of glycosylation, specifically O-mannosylation and its relationship to a number of human diseases. The most widely studied O-mannose modified protein is alpha-dystroglycan (α-DG). Recent studies have focused intensely on α-DG due to the severity of diseases associated with its improper glycosylation. O-mannosylation of α-DG is involved in cancer metastasis, arenavirus entry, and multiple forms of congenital muscular dystrophy [1, 2]. In this review, we discuss the structural and functional characteristics of O-mannose-initiated glycan structures on α-DG, enzymes involved in the O-mannosylation pathway, and the diseases that are a direct result of disruptions within this pathway. 相似文献
74.
Prediction of central nervous system embryonal tumour outcome based on gene expression. 总被引:75,自引:0,他引:75
Scott L Pomeroy Pablo Tamayo Michelle Gaasenbeek Lisa M Sturla Michael Angelo Margaret E McLaughlin John Y H Kim Liliana C Goumnerova Peter M Black Ching Lau Jeffrey C Allen David Zagzag James M Olson Tom Curran Cynthia Wetmore Jaclyn A Biegel Tomaso Poggio Shayan Mukherjee Ryan Rifkin Andrea Califano Gustavo Stolovitzky David N Louis Jill P Mesirov Eric S Lander Todd R Golub 《Nature》2002,415(6870):436-442
Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis. 相似文献
75.
Morin RD Mendez-Lago M Mungall AJ Goya R Mungall KL Corbett RD Johnson NA Severson TM Chiu R Field M Jackman S Krzywinski M Scott DW Trinh DL Tamura-Wells J Li S Firme MR Rogic S Griffith M Chan S Yakovenko O Meyer IM Zhao EY Smailus D Moksa M Chittaranjan S Rimsza L Brooks-Wilson A Spinelli JJ Ben-Neriah S Meissner B Woolcock B Boyle M McDonald H Tam A Zhao Y Delaney A Zeng T Tse K Butterfield Y Birol I Holt R Schein J Horsman DE Moore R Jones SJ Connors JM Hirst M Gascoyne RD Marra MA 《Nature》2011,476(7360):298-303
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. 相似文献
76.
77.
Grbić M Van Leeuwen T Clark RM Rombauts S Rouzé P Grbić V Osborne EJ Dermauw W Ngoc PC Ortego F Hernández-Crespo P Diaz I Martinez M Navajas M Sucena É Magalhães S Nagy L Pace RM Djuranović S Smagghe G Iga M Christiaens O Veenstra JA Ewer J Villalobos RM Hutter JL Hudson SD Velez M Yi SV Zeng J Pires-daSilva A Roch F Cazaux M Navarro M Zhurov V Acevedo G Bjelica A Fawcett JA Bonnet E Martens C Baele G Wissler L Sanchez-Rodriguez A Tirry L Blais C Demeestere K Henz SR Gregory TR Mathieu J 《Nature》2011,479(7374):487-492
78.
Mills RE Walter K Stewart C Handsaker RE Chen K Alkan C Abyzov A Yoon SC Ye K Cheetham RK Chinwalla A Conrad DF Fu Y Grubert F Hajirasouliha I Hormozdiari F Iakoucheva LM Iqbal Z Kang S Kidd JM Konkel MK Korn J Khurana E Kural D Lam HY Leng J Li R Li Y Lin CY Luo R Mu XJ Nemesh J Peckham HE Rausch T Scally A Shi X Stromberg MP Stütz AM Urban AE Walker JA Wu J Zhang Y Zhang ZD Batzer MA Ding L Marth GT McVean G Sebat J Snyder M Wang J Ye K Eichler EE Gerstein MB Hurles ME Lee C McCarroll SA 《Nature》2011,470(7332):59-65
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies. 相似文献
79.
Szabo E Rampalli S Risueño RM Schnerch A Mitchell R Fiebig-Comyn A Levadoux-Martin M Bhatia M 《Nature》2010,468(7323):521-526
80.