全文获取类型
收费全文 | 6479篇 |
免费 | 62篇 |
国内免费 | 86篇 |
专业分类
系统科学 | 100篇 |
丛书文集 | 124篇 |
教育与普及 | 225篇 |
理论与方法论 | 18篇 |
现状及发展 | 582篇 |
研究方法 | 991篇 |
综合类 | 4581篇 |
自然研究 | 6篇 |
出版年
2018年 | 8篇 |
2017年 | 22篇 |
2016年 | 18篇 |
2015年 | 13篇 |
2014年 | 26篇 |
2013年 | 26篇 |
2012年 | 470篇 |
2011年 | 546篇 |
2010年 | 160篇 |
2009年 | 115篇 |
2008年 | 532篇 |
2007年 | 513篇 |
2006年 | 584篇 |
2005年 | 625篇 |
2004年 | 421篇 |
2003年 | 422篇 |
2002年 | 357篇 |
2001年 | 289篇 |
2000年 | 442篇 |
1999年 | 125篇 |
1998年 | 46篇 |
1997年 | 28篇 |
1996年 | 17篇 |
1995年 | 10篇 |
1994年 | 15篇 |
1993年 | 27篇 |
1992年 | 23篇 |
1991年 | 19篇 |
1990年 | 32篇 |
1989年 | 31篇 |
1988年 | 12篇 |
1987年 | 26篇 |
1986年 | 20篇 |
1985年 | 21篇 |
1984年 | 30篇 |
1983年 | 25篇 |
1982年 | 22篇 |
1981年 | 19篇 |
1980年 | 9篇 |
1979年 | 11篇 |
1971年 | 10篇 |
1970年 | 13篇 |
1966年 | 15篇 |
1959年 | 48篇 |
1958年 | 101篇 |
1957年 | 54篇 |
1956年 | 46篇 |
1955年 | 51篇 |
1954年 | 55篇 |
1948年 | 24篇 |
排序方式: 共有6627条查询结果,搜索用时 62 毫秒
131.
Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase 总被引:1,自引:0,他引:1
Guarani V Deflorian G Franco CA Krüger M Phng LK Bentley K Toussaint L Dequiedt F Mostoslavsky R Schmidt MH Zimmermann B Brandes RP Mione M Westphal CH Braun T Zeiher AM Gerhardt H Dimmeler S Potente M 《Nature》2011,473(7346):234-238
Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses. 相似文献
132.
Complement factor H binds malondialdehyde epitopes and protects from oxidative stress 总被引:2,自引:0,他引:2
Weismann D Hartvigsen K Lauer N Bennett KL Scholl HP Charbel Issa P Cano M Brandstätter H Tsimikas S Skerka C Superti-Furga G Handa JT Zipfel PF Witztum JL Binder CJ 《Nature》2011,478(7367):76-81
Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases. 相似文献
133.
Lee X Goulden ML Hollinger DY Barr A Black TA Bohrer G Bracho R Drake B Goldstein A Gu L Katul G Kolb T Law BE Margolis H Meyers T Monson R Munger W Oren R Paw U KT Richardson AD Schmid HP Staebler R Wofsy S Zhao L 《Nature》2011,479(7373):384-387
Deforestation in mid- to high latitudes is hypothesized to have the potential to cool the Earth's surface by altering biophysical processes. In climate models of continental-scale land clearing, the cooling is triggered by increases in surface albedo and is reinforced by a land albedo-sea ice feedback. This feedback is crucial in the model predictions; without it other biophysical processes may overwhelm the albedo effect to generate warming instead. Ongoing land-use activities, such as land management for climate mitigation, are occurring at local scales (hectares) presumably too small to generate the feedback, and it is not known whether the intrinsic biophysical mechanism on its own can change the surface temperature in a consistent manner. Nor has the effect of deforestation on climate been demonstrated over large areas from direct observations. Here we show that surface air temperature is lower in open land than in nearby forested land. The effect is 0.85 ± 0.44 K (mean ± one standard deviation) northwards of 45° N and 0.21 ± 0.53 K southwards. Below 35° N there is weak evidence that deforestation leads to warming. Results are based on comparisons of temperature at forested eddy covariance towers in the USA and Canada and, as a proxy for small areas of cleared land, nearby surface weather stations. Night-time temperature changes unrelated to changes in surface albedo are an important contributor to the overall cooling effect. The observed latitudinal dependence is consistent with theoretical expectation of changes in energy loss from convection and radiation across latitudes in both the daytime and night-time phase of the diurnal cycle, the latter of which remains uncertain in climate models. 相似文献
134.
International Consortium for Blood Pressure Genome-Wide Association Studies Ehret GB Munroe PB Rice KM Bochud M Johnson AD Chasman DI Smith AV Tobin MD Verwoert GC Hwang SJ Pihur V Vollenweider P O'Reilly PF Amin N Bragg-Gresham JL Teumer A Glazer NL Launer L Zhao JH Aulchenko Y Heath S Sõber S Parsa A Luan J Arora P Dehghan A Zhang F Lucas G Hicks AA Jackson AU Peden JF Tanaka T Wild SH Rudan I Igl W Milaneschi Y Parker AN Fava C Chambers JC Fox ER Kumari M Go MJ van der Harst P Kao WH 《Nature》2011,478(7367):103-109
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. 相似文献
135.
Cederwall B Moradi FG Bäck T Johnson A Blomqvist J Clément E de France G Wadsworth R Andgren K Lagergren K Dijon A Jaworski G Liotta R Qi C Nyakó BM Nyberg J Palacz M Al-Azri H Algora A de Angelis G Ataç A Bhattacharyya S Brock T Brown JR Davies P Di Nitto A Dombrádi Z Gadea A Gál J Hadinia B Johnston-Theasby F Joshi P Juhász K Julin R Jungclaus A Kalinka G Kara SO Khaplanov A Kownacki J La Rana G Lenzi SM Molnár J Moro R Napoli DR Singh BS Persson A Recchia F Sandzelius M Scheurer JN Sletten G 《Nature》2011,469(7328):68-71
Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus (92)Pd. Gamma rays emitted following the (58)Ni((36)Ar,2n)(92)Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis. 相似文献
136.
Zaratiegui M Vaughn MW Irvine DV Goto D Watt S Bähler J Arcangioli B Martienssen RA 《Nature》2011,469(7328):112-115
Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats. 相似文献
137.
Lord C Bhandari D Menon S Ghassemian M Nycz D Hay J Ghosh P Ferro-Novick S 《Nature》2011,473(7346):181-186
How the directionality of vesicle traffic is achieved remains an important unanswered question in cell biology. The Sec23p/Sec24p coat complex sorts the fusion machinery (SNAREs) into vesicles as they bud from the endoplasmic reticulum (ER). Vesicle tethering to the Golgi begins when the tethering factor TRAPPI binds to Sec23p. Where the coat is released and how this event relates to membrane fusion is unknown. Here we use a yeast transport assay to demonstrate that an ER-derived vesicle retains its coat until it reaches the Golgi. A Golgi-associated kinase, Hrr25p (CK1δ orthologue), then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and dephosphorylation are needed for vesicle fusion and budding, respectively. Additionally, we show that Sec23p interacts in a sequential manner with different binding partners, including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi traffic and prevent the back-fusion of a COPII vesicle with the ER. These events are conserved in mammalian cells. 相似文献
138.
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development 总被引:1,自引:0,他引:1
Kang TW Yevsa T Woller N Hoenicke L Wuestefeld T Dauch D Hohmeyer A Gereke M Rudalska R Potapova A Iken M Vucur M Weiss S Heikenwalder M Khan S Gil J Bruder D Manns M Schirmacher P Tacke F Ott M Luedde T Longerich T Kubicka S Zender L 《Nature》2011,479(7374):547-551
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells. 相似文献
139.
Voineagu I Wang X Johnston P Lowe JK Tian Y Horvath S Mill J Cantor RM Blencowe BJ Geschwind DH 《Nature》2011,474(7351):380-384
140.
Oxysterols direct immune cell migration via EBI2 总被引:1,自引:0,他引:1
Hannedouche S Zhang J Yi T Shen W Nguyen D Pereira JP Guerini D Baumgarten BU Roggo S Wen B Knochenmuss R Noël S Gessier F Kelly LM Vanek M Laurent S Preuss I Miault C Christen I Karuna R Li W Koo DI Suply T Schmedt C Peters EC Falchetto R Katopodis A Spanka C Roy MO Detheux M Chen YA Schultz PG Cho CY Seuwen K Cyster JG Sailer AW 《Nature》2011,475(7357):524-527
Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response. 相似文献