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501.
Stein JL Medland SE Vasquez AA Hibar DP Senstad RE Winkler AM Toro R Appel K Bartecek R Bergmann Ø Bernard M Brown AA Cannon DM Chakravarty MM Christoforou A Domin M Grimm O Hollinshead M Holmes AJ Homuth G Hottenga JJ Langan C Lopez LM Hansell NK Hwang KS Kim S Laje G Lee PH Liu X Loth E Lourdusamy A Mattingsdal M Mohnke S Maniega SM Nho K Nugent AC O'Brien C Papmeyer M Pütz B Ramasamy A Rasmussen J Rijpkema M Risacher SL Roddey JC Rose EJ Ryten M Shen L Sprooten E Strengman E Teumer A 《Nature genetics》2012,44(5):552-561
Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)). 相似文献
502.
KE Holt S Baker FX Weill EC Holmes A Kitchen J Yu V Sangal DJ Brown JE Coia DW Kim SY Choi SH Kim WD da Silveira DJ Pickard JJ Farrar J Parkhill G Dougan NR Thomson 《Nature genetics》2012,44(9):1056-1059
Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery, spreading efficiently via low-dose fecal-oral transmission. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries but is now emerging as a problem in the developing world, seeming to replace the more diverse Shigella flexneri in areas undergoing economic development and improvements in water quality. Classical approaches have shown that S. sonnei is genetically conserved and clonal. We report here whole-genome sequencing of 132 globally distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and that diversified into several distinct lineages with unique characteristics. Our analysis suggests that the majority of this diversification occurred in Europe and was followed by more recent establishment of local pathogen populations on other continents, predominantly due to the pandemic spread of a single, rapidly evolving, multidrug-resistant lineage. 相似文献
503.
Yung Sik Kim 《Studies in history and philosophy of science》2012,43(1):228-231
504.
Jongsung Lee Eunsun Jung Jienny Lee Sungran Huh Young-Soo Kim Yong-Woo Kim Yeong Shik Kim Deokhoon Park 《Cellular and molecular life sciences : CMLS》2010,67(3):467-481
Adipocyte dysfunction is associated with the development of obesity. This study shows that 6-thioinosine inhibits adipocyte
differentiation. The mRNA levels of PPAR γ and C/EBPα, but not C/EBPβ and δ, were reduced by 6-thioinosine. Moreover, the
mRNA levels of PPAR γ target genes (LPL, CD36, aP2, and LXRα) were down-regulated by 6-thioinosine. We also demonstrated that
6-thioinosine inhibits the transactivation activity and the mRNA level of PPAR γ. Additionally, attempts to elucidate a possible
mechanism underlying the 6-thioinosine-mediated effects revealed that 6-thioinosine induced iNOS gene expression without impacting
eNOS expression, and that this was mediated through activation of AP-1, especially, JNK. In addition, 6-thioinosine was found
to operate upstream of MEKK-1 in JNK activation signaling. Taken together, these findings suggest that the inhibition of adipocyte
differentiation by 6-thioinosine occurs primarily through the reduced expression of PPAR γ, which is mediated by upregulation
of iNOS via the activation of JNK. 相似文献
505.
506.
Myosin I is a non-filamentous, single-headed, actin-binding motor protein and is present in a wide range of species from yeast to man. The role of these class I myosins have been studied extensively in simple eukaryotes, showing their role in diverse processes such as actin cytoskeleton organization, cell motility, and endocytosis. Recently, studies in metazoans have begun to reveal more specialized functions of myosin I. It will be a major challenge in the future to examine the physiological functions of each class I myosin in different cell types of metazoans. 相似文献
507.
Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos 总被引:1,自引:0,他引:1
In blastocyst chimeras, embryonic stem (ES) cells contribute to embryonic tissues but not extraembryonic trophectoderm. Conditional activation of HRas1(Q61L) in ES cells in vitro induces the trophectoderm marker Cdx2 and enables derivation of trophoblast stem (TS) cell lines that, when injected into blastocysts, chimerize placental tissues. Erk2, the downstream effector of Ras-mitogen-activated protein kinase (MAPK) signaling, is asymmetrically expressed in the apical membranes of the 8-cell-stage embryo just before morula compaction. Inhibition of MAPK signaling in cultured mouse embryos compromises Cdx2 expression, delays blastocyst development and reduces trophectoderm outgrowth from embryo explants. These data show that ectopic Ras activation can divert ES cells toward extraembryonic trophoblastic fates and implicate Ras-MAPK signaling in promoting trophectoderm formation from mouse embryos. 相似文献
508.
509.
RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis 总被引:3,自引:0,他引:3
Premature fusion of one or more of the cranial sutures (craniosynostosis) in humans causes over 100 skeletal diseases, which occur in 1 of approximately 2,500 live births. Among them is Apert syndrome, one of the most severe forms of craniosynostosis, primarily caused by missense mutations leading to amino acid changes S252W or P253R in fibroblast growth factor receptor 2 (FGFR2). Here we show that a small hairpin RNA targeting the dominant mutant form of Fgfr2 (Fgfr2(S252W)) completely prevents Apert-like syndrome in mice. Restoration of normal FGFR2 signaling is manifested by an alteration of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2), implicating the gene encoding ERK and the genes downstream of it in disease expressivity. Furthermore, treatment of the mutant mice with U0126, an inhibitor of mitogen-activated protein (MAP) kinase kinase 1 and 2 (MEK1/2) that blocks phosphorylation and activation of ERK1/2, significantly inhibits craniosynostosis. These results illustrate a pathogenic role for ERK activation in craniosynostosis resulting from FGFR2 with the S252W substitution and introduce a new concept of small-molecule inhibitor-mediated prevention and therapy for diseases caused by gain-of-function mutations in the human genome. 相似文献
510.
Models and Algorithm for Stochastic Network Designs 总被引:1,自引:0,他引:1
The network design problem (NDP) is one of the most difficult and challenging problems in trans-portation. Traditional NDP models are often posed as a deterministic bilevel program assuming that all relevant inputs are known with certainty. This paper presents three stochastic models for designing transporta-tion networks with demand uncertainty. These three stochastic NDP models were formulated as the expected value model, chance-constrained model, and dependent-chance model in a bilevel programming framew... 相似文献