全文获取类型
收费全文 | 611篇 |
免费 | 6篇 |
国内免费 | 5篇 |
专业分类
系统科学 | 6篇 |
教育与普及 | 3篇 |
理论与方法论 | 8篇 |
现状及发展 | 64篇 |
研究方法 | 101篇 |
综合类 | 410篇 |
自然研究 | 30篇 |
出版年
2022年 | 1篇 |
2021年 | 2篇 |
2020年 | 2篇 |
2019年 | 3篇 |
2018年 | 1篇 |
2017年 | 5篇 |
2016年 | 8篇 |
2015年 | 3篇 |
2014年 | 5篇 |
2013年 | 17篇 |
2012年 | 85篇 |
2011年 | 110篇 |
2010年 | 17篇 |
2009年 | 7篇 |
2008年 | 73篇 |
2007年 | 55篇 |
2006年 | 36篇 |
2005年 | 44篇 |
2004年 | 34篇 |
2003年 | 49篇 |
2002年 | 45篇 |
1999年 | 6篇 |
1998年 | 4篇 |
1996年 | 2篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1985年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
排序方式: 共有622条查询结果,搜索用时 15 毫秒
101.
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
102.
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
103.
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
104.
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
105.
High-level circuits in the brain that control the direction of gaze are intimately linked with the control of visual spatial attention. Immediately before an animal directs its gaze towards a stimulus, both psychophysical sensitivity to that visual stimulus and the responsiveness of high-order neurons in the cerebral cortex that represent the stimulus increase dramatically. Equivalent effects on behavioural sensitivity and neuronal responsiveness to visual stimuli result from focal electrical microstimulation of gaze control centres in monkeys. Whether the gaze control system modulates neuronal responsiveness in sensory modalities other than vision is unknown. Here we show that electrical microstimulation applied to gaze control circuitry in the forebrain of barn owls regulates the gain of midbrain auditory responses in an attention-like manner. When the forebrain circuit was activated, midbrain responses to auditory stimuli at the location encoded by the forebrain site were enhanced and spatial selectivity was sharpened. The same stimulation suppressed responses to auditory stimuli represented at other locations in the midbrain map. Such space-specific, top-down regulation of auditory responses by gaze control circuitry in the barn owl suggests that the central nervous system uses a common strategy for dynamically regulating sensory gain that applies across modalities, brain areas and classes of vertebrate species. This approach provides a path for discovering mechanisms that underlie top-down gain control in the central nervous system. 相似文献
106.
107.
LU XiuPing GUI YiJie XIAO BingGuang LI YongPing TONG ZhiJun LIU Yun BAI XueFei WU WeiRen XIA Ling HUTTNER Eric KILIAN Adrzej FAN LongJiang 《科学通报(英文版)》2013,58(6):641-648
Tobacco(Nicotiana tabacum) is one of the most economically important nonfood crops,and flue-cured tobacco accounts for approximately 80% of world tobacco production.An extremely narrow genetic diversity in the tobacco pool has led to a low efficiency of PCR-based molecular markers(such as AFLP and SSR).Diversity Arrays Technology(DArT) is a high-throughput hybridisation-based marker system that has been developed in many plants including wheat,which,like tobacco,has a complex genome.In this study,we developed a tobacco DArT chip that included 7680 representative sequence tags based on typical tobacco accessions.The 1076 DArT markers of flue-cured tobacco were identified and most(82.1%) of their polymorphism information contents(PICs) were greater than 0.4.An integrated linkage map that included 851 markers(238 DArT and 613 SSR),which is the highest density map of flue-cured tobacco to date,was constructed.This chip-based DArT system provides an alternative in high-throughput marker genotyping for tobacco. 相似文献
108.
In 1994, University of Southern California computer scientist Dr. Leonard Adleman solved the Hamiltonian path problem using DNA as a computational mechanism. He proved the principle that DNA computing could be used to solve computationally complex problems. Because of the limitations in discovery time, resource requirements, and sequence mismatches, DNA computing has not yet become a commonly accepted practice. However, advancements are continually being discovered that are evolving the field of DNA computing. Practical applications of DNA are not restricted to computation alone. This research presents a novel approach in which DNA could be used as a means of storing files. Through the use of multiple sequence alignment combined with intelligent heuristics, the most probabilistic file contents can be determined with minimal errors. 相似文献
109.
110.