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排序方式: 共有1720条查询结果,搜索用时 15 毫秒
171.
172.
Patten IS Rana S Shahul S Rowe GC Jang C Liu L Hacker MR Rhee JS Mitchell J Mahmood F Hess P Farrell C Koulisis N Khankin EV Burke SD Tudorache I Bauersachs J del Monte F Hilfiker-Kleiner D Karumanchi SA Arany Z 《Nature》2012,485(7398):333-338
Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM. 相似文献
173.
John Earman 《Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics》2011,42(2):81-97
The importance of the Unruh effect lies in the fact that, together with the related (but distinct) Hawking effect, it serves to link the three main branches of modern physics: thermal/statistical physics, relativity theory/gravitation, and quantum physics. However, different researchers can have in mind different phenomena when they speak of “the Unruh effect” in flat spacetime and its generalization to curved spacetimes. Three different approaches are reviewed here. They are shown to yield results that are sometimes concordant and sometimes discordant. The discordance is disconcerting only if one insists on taking literally the definite article in “the Unruh effect.” It is argued that the role of linking different branches of physics is better served by taking “the Unruh effect” to designate a family of related phenomena. The relation between the Hawking effect and the generalized Unruh effect for curved spacetimes is briefly discussed. 相似文献
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Beddington J Cooper CL Field J Goswami U Huppert FA Jenkins R Jones HS Kirkwood TB Sahakian BJ Thomas SM 《Nature》2008,455(7216):1057-1060
Countries must learn how to capitalize on their citizens' cognitive resources if they are to prosper, both economically and socially. Early interventions will be key. 相似文献
177.
Mouquet H Scheid JF Zoller MJ Krogsgaard M Ott RG Shukair S Artyomov MN Pietzsch J Connors M Pereyra F Walker BD Ho DD Wilson PC Seaman MS Eisen HN Chakraborty AK Hope TJ Ravetch JV Wardemann H Nussenzweig MC 《Nature》2010,467(7315):591-595
During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV. 相似文献
178.
Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M 《Nature》2006,444(7122):1083-1087
Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours. 相似文献
179.
Oleksiewicz U Liloglou T Field JK Xinarianos G 《Cellular and molecular life sciences : CMLS》2011,68(23):3869-3883
Since the discovery of cytoglobin (Cygb) a decade ago, growing amounts of data have been gathered to characterise Cygb biochemistry,
functioning and implication in human pathologies. Its molecular roles remain under investigation, but nitric oxide dioxygenase
and lipid peroxidase activities have been demonstrated. Cygb expression increases in response to various stress conditions
including hypoxia, oxidative stress and fibrotic stimulation. When exogenously overexpressed, Cygb revealed cytoprotection
against these factors. Cygb was shown to be upregulated in fibrosis and neurodegenerative disorders and downregulated in multiple
cancer types. CYGB was also found within the minimal region of a hereditary tylosis with oesophageal cancer syndrome, and its expression was
reduced in tylotic samples. Recently, Cygb has been shown to inhibit cancer cell growth in vitro, thus confirming its suggested
tumour suppressor role. This article aims to review the biochemical and functional aspects of Cygb, its involvement in various
pathological conditions and potential clinical utility. 相似文献
180.