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91.
92.
The Amazon basin in transition 总被引:7,自引:0,他引:7
Davidson EA de Araújo AC Artaxo P Balch JK Brown IF C Bustamante MM Coe MT DeFries RS Keller M Longo M Munger JW Schroeder W Soares-Filho BS Souza CM Wofsy SC 《Nature》2012,481(7381):321-328
Agricultural expansion and climate variability have become important agents of disturbance in the Amazon basin. Recent studies have demonstrated considerable resilience of Amazonian forests to moderate annual drought, but they also show that interactions between deforestation, fire and drought potentially lead to losses of carbon storage and changes in regional precipitation patterns and river discharge. Although the basin-wide impacts of land use and drought may not yet surpass the magnitude of natural variability of hydrologic and biogeochemical cycles, there are some signs of a transition to a disturbance-dominated regime. These signs include changing energy and water cycles in the southern and eastern portions of the Amazon basin. 相似文献
93.
Wu X Northcott PA Dubuc A Dupuy AJ Shih DJ Witt H Croul S Bouffet E Fults DW Eberhart CG Garzia L Van Meter T Zagzag D Jabado N Schwartzentruber J Majewski J Scheetz TE Pfister SM Korshunov A Li XN Scherer SW Cho YJ Akagi K MacDonald TJ Koster J McCabe MG Sarver AL Collins VP Weiss WA Largaespada DA Collier LS Taylor MD 《Nature》2012,482(7386):529-533
Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies. 相似文献
94.
95.
Chromatin-modifying enzymes as modulators of reprogramming 总被引:2,自引:0,他引:2
Onder TT Kara N Cherry A Sinha AU Zhu N Bernt KM Cahan P Marcarci BO Unternaehrer J Gupta PB Lander ES Armstrong SA Daley GQ 《Nature》2012,483(7391):598-602
96.
S Neph J Vierstra AB Stergachis AP Reynolds E Haugen B Vernot RE Thurman S John R Sandstrom AK Johnson MT Maurano R Humbert E Rynes H Wang S Vong K Lee D Bates M Diegel V Roach D Dunn J Neri A Schafer RS Hansen T Kutyavin E Giste M Weaver T Canfield P Sabo M Zhang G Balasundaram R Byron MJ MacCoss JM Akey MA Bender M Groudine R Kaul JA Stamatoyannopoulos 《Nature》2012,489(7414):83-90
97.
Smith CC Wang Q Chin CS Salerno S Damon LE Levis MJ Perl AE Travers KJ Wang S Hunt JP Zarrinkar PP Schadt EE Kasarskis A Kuriyan J Shah NP 《Nature》2012,485(7397):260-263
Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts. 相似文献
98.
Song K Nam YJ Luo X Qi X Tan W Huang GN Acharya A Smith CL Tallquist MD Neilson EG Hill JA Bassel-Duby R Olson EN 《Nature》2012,485(7400):599-604
99.
Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested, do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-alpha and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings. 相似文献
100.
Human cytomegalovirus (HCMV) prevents the display of class I major histocompatibility complex (MHC) peptide complexes at the surface of infected cells as a means of escaping immune detection. Two HCMV-encoded immunoevasins, US2 and US11, induce the dislocation of class I MHC heavy chains from the endoplasmic reticulum membrane and target them for proteasomal degradation in the cytosol. Although the outcome of the dislocation reactions catalysed is similar, US2 and US11 operate differently: Derlin-1 is a key component of the US11 but not the US2 pathway. So far, proteins essential for US2-dependent dislocation have not been identified. Here we compare interacting partners of wild-type US2 with those of a dislocation-incompetent US2 mutant, and identify signal peptide peptidase (SPP) as a partner for the active form of US2. We show that a decrease in SPP levels by RNA-mediated interference inhibits heavy-chain dislocation by US2 but not by US11. Our data implicate SPP in the US2 pathway and indicate the possibility of a previously unknown function for this intramembrane-cleaving aspartic protease in dislocation from the endoplasmic reticulum. 相似文献