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121.
Dale Fitch Michelle Kaiser Laura Parker-Barua 《Systemic Practice and Action Research》2012,25(5):417-439
This paper presents a framework that addresses a public child welfare agency??s need for a highly trained child welfare workforce with specialized competencies, situating these competencies within the human services educational profession??s accreditation standards, while simultaneously meeting the learning needs of professionals returning to school for additional graduate training. The framework integrates three disparate literatures. The first that frames employees returning to a university setting for additional education and training as a human resources benefit. The second body of literature that addresses the annual review of employee performance via employment assessment systems. And the final body that examines parallel organizational processes related to the development of a product, in our case, a professional with a graduate degree. The framework, developed using a soft system methodology approach, and evaluated by means of an electronic portfolio, integrates these three bodies of literature and allows for the real time curricular and agency assessment of competency achievement. While using a professional graduate training program as an exemplar, implications for broader systemic practice are discussed. 相似文献
122.
Campbell PJ Yachida S Mudie LJ Stephens PJ Pleasance ED Stebbings LA Morsberger LA Latimer C McLaren S Lin ML McBride DJ Varela I Nik-Zainal SA Leroy C Jia M Menzies A Butler AP Teague JW Griffin CA Burton J Swerdlow H Quail MA Stratton MR Iacobuzio-Donahue C Futreal PA 《Nature》2010,467(7319):1109-1113
Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection. 相似文献
123.
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
124.
Castets M Broutier L Molin Y Brevet M Chazot G Gadot N Paquet A Mazelin L Jarrosson-Wuilleme L Scoazec JY Bernet A Mehlen P 《Nature》2012,482(7386):534-537
The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis. 相似文献
125.
Banerji S Cibulskis K Rangel-Escareno C Brown KK Carter SL Frederick AM Lawrence MS Sivachenko AY Sougnez C Zou L Cortes ML Fernandez-Lopez JC Peng S Ardlie KG Auclair D Bautista-Piña V Duke F Francis J Jung J Maffuz-Aziz A Onofrio RC Parkin M Pho NH Quintanar-Jurado V Ramos AH Rebollar-Vega R Rodriguez-Cuevas S Romero-Cordoba SL Schumacher SE Stransky N Thompson KM Uribe-Figueroa L Baselga J Beroukhim R Polyak K Sgroi DC Richardson AL Jimenez-Sanchez G Lander ES Gabriel SB Garraway LA Golub TR 《Nature》2012,486(7403):405-409
126.
I Cho S Yamanishi L Cox BA Methé J Zavadil K Li Z Gao D Mahana K Raju I Teitler H Li AV Alekseyenko MJ Blaser 《Nature》2012,488(7413):621-626
Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation. 相似文献
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