全文获取类型
收费全文 | 488篇 |
免费 | 1篇 |
国内免费 | 3篇 |
专业分类
系统科学 | 2篇 |
理论与方法论 | 2篇 |
现状及发展 | 112篇 |
研究方法 | 38篇 |
综合类 | 332篇 |
自然研究 | 6篇 |
出版年
2018年 | 2篇 |
2015年 | 1篇 |
2014年 | 2篇 |
2013年 | 6篇 |
2012年 | 20篇 |
2011年 | 25篇 |
2010年 | 12篇 |
2009年 | 1篇 |
2008年 | 17篇 |
2007年 | 17篇 |
2006年 | 20篇 |
2005年 | 24篇 |
2004年 | 32篇 |
2003年 | 19篇 |
2002年 | 11篇 |
2001年 | 13篇 |
2000年 | 16篇 |
1999年 | 8篇 |
1994年 | 1篇 |
1992年 | 8篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1986年 | 13篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1983年 | 8篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 11篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1976年 | 7篇 |
1975年 | 9篇 |
1974年 | 13篇 |
1973年 | 11篇 |
1972年 | 12篇 |
1971年 | 12篇 |
1970年 | 18篇 |
1969年 | 8篇 |
1968年 | 14篇 |
1967年 | 14篇 |
1966年 | 11篇 |
1965年 | 8篇 |
1963年 | 1篇 |
1959年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有492条查询结果,搜索用时 37 毫秒
391.
Oladapo E. Olaniru Attilio Pingitore Stefanie Giera Xianhua Piao Ramón Castañera González Peter M. Jones Shanta J. Persaud 《Cellular and molecular life sciences : CMLS》2018,75(21):4007-4019
Aims
G-protein coupled receptor 56 (GPR56) is the most abundant islet-expressed G-protein coupled receptor, suggesting a potential role in islet function. This study evaluated islet expression of GPR56 and its endogenous ligand collagen III, and their effects on β-cell function.Methods
GPR56 and collagen III expression in mouse and human pancreas sections was determined by fluorescence immunohistochemistry. Effects of collagen III on β-cell proliferation, apoptosis, intracellular calcium ([Ca2+]i) and insulin secretion were determined by cellular BrdU incorporation, caspase 3/7 activities, microfluorimetry and radioimmunoassay, respectively. The role of GPR56 in islet vascularisation and innervation was evaluated by immunohistochemical staining for CD31 and TUJ1, respectively, in pancreases from wildtype (WT) and Gpr56?/? mice, and the requirement of GPR56 for normal glucose homeostasis was determined by glucose tolerance tests in WT and Gpr56?/? mice.Results
Immunostaining of mouse and human pancreases revealed that GPR56 was expressed by islet β-cells while collagen III was confined to the peri-islet basement membrane and islet capillaries. Collagen III protected β-cells from cytokine-induced apoptosis, triggered increases in [Ca2+]i and potentiated glucose-induced insulin secretion from WT islets but not from Gpr56?/? islets. Deletion of GPR56 did not affect glucose-induced insulin secretion in vitro and it did not impair glucose tolerance in adult mice. GPR56 was not required for normal islet vascularisation or innervation.Conclusion
We have demonstrated that collagen III improves islet function by increasing insulin secretion and protecting against apoptosis. Our data suggest that collagen III may be effective in optimising islet function to improve islet transplantation outcomes, and GPR56 may be a target for the treatment of type 2 diabetes.392.
Ferreira MA O'Donovan MC Meng YA Jones IR Ruderfer DM Jones L Fan J Kirov G Perlis RH Green EK Smoller JW Grozeva D Stone J Nikolov I Chambert K Hamshere ML Nimgaonkar VL Moskvina V Thase ME Caesar S Sachs GS Franklin J Gordon-Smith K Ardlie KG Gabriel SB Fraser C Blumenstiel B Defelice M Breen G Gill M Morris DW Elkin A Muir WJ McGhee KA Williamson R MacIntyre DJ MacLean AW St CD Robinson M Van Beck M Pereira AC Kandaswamy R McQuillin A Collier DA Bass NJ Young AH Lawrence J Ferrier IN 《Nature genetics》2008,40(9):1056-1058
To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder. 相似文献
393.
Herzberg RD Greenlees PT Butler PA Jones GD Venhart M Darby IG Eeckhaudt S Eskola K Grahn T Gray-Jones C Hessberger FP Jones P Julin R Juutinen S Ketelhut S Korten W Leino M Leppänen AP Moon S Nyman M Page RD Pakarinen J Pritchard A Rahkila P Sarén J Scholey C Steer A Sun Y Theisen Ch Uusitalo J 《Nature》2006,442(7105):896-899
A long-standing prediction of nuclear models is the emergence of a region of long-lived, or even stable, superheavy elements beyond the actinides. These nuclei owe their enhanced stability to closed shells in the structure of both protons and neutrons. However, theoretical approaches to date do not yield consistent predictions of the precise limits of the 'island of stability'; experimental studies are therefore crucial. The bulk of experimental effort so far has been focused on the direct creation of superheavy elements in heavy ion fusion reactions, leading to the production of elements up to proton number Z = 118 (refs 4, 5). Recently, it has become possible to make detailed spectroscopic studies of nuclei beyond fermium (Z = 100), with the aim of understanding the underlying single-particle structure of superheavy elements. Here we report such a study of the nobelium isotope 254No, with 102 protons and 152 neutrons--the heaviest nucleus studied in this manner to date. We find three excited structures, two of which are isomeric (metastable). One of these structures is firmly assigned to a two-proton excitation. These states are highly significant as their location is sensitive to single-particle levels above the gap in shell energies predicted at Z = 114, and thus provide a microscopic benchmark for nuclear models of the superheavy elements. 相似文献
394.
DT Jones N Jäger M Kool T Zichner B Hutter M Sultan YJ Cho TJ Pugh V Hovestadt AM Stütz T Rausch HJ Warnatz M Ryzhova S Bender D Sturm S Pleier H Cin E Pfaff L Sieber A Wittmann M Remke H Witt S Hutter T Tzaridis J Weischenfeldt B Raeder M Avci V Amstislavskiy M Zapatka UD Weber Q Wang B Lasitschka CC Bartholomae M Schmidt C von Kalle V Ast C Lawerenz J Eils R Kabbe V Benes P van Sluis J Koster R Volckmann D Shih MJ Betts RB Russell S Coco GP Tonini U Schüller V Hans N Graf YJ Kim C Monoranu 《Nature》2012,488(7409):100-105
Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients. 相似文献
395.
H Pälike MW Lyle H Nishi I Raffi A Ridgwell K Gamage A Klaus G Acton L Anderson J Backman J Baldauf C Beltran SM Bohaty P Bown W Busch JE Channell CO Chun M Delaney P Dewangan T Dunkley Jones KM Edgar H Evans P Fitch GL Foster N Gussone H Hasegawa EC Hathorne H Hayashi JO Herrle A Holbourn S Hovan K Hyeong K Iijima T Ito S Kamikuri K Kimoto J Kuroda L Leon-Rodriguez A Malinverno TC Moore BH Murphy DP Murphy H Nakamura K Ogane C Ohneiser C Richter R Robinson EJ Rohling O Romero K Sawada H Scher 《Nature》2012,488(7413):609-614
Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5?kilometres during the early Cenozoic (approximately 55?million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth. 相似文献
396.
397.
Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli 总被引:48,自引:0,他引:48
In antibodies, a heavy and a light chain variable domain, VH and VL, respectively, pack together and the hypervariable loops on each domain contribute to binding antigen. We find, however, that isolated VH domains with good antigen-binding affinities can also be prepared. Using the polymerase chain reaction, diverse libraries of VH genes were cloned from the spleen genomic DNA of mice immunized with either lysozyme or keyhole-limpet haemocyanin. From these libraries, VH domains were expressed and secreted from Escherichia coli. Binding activities were detected against both antigens, and two VH domains were characterized with affinities for lysozyme in the 20 nM range. Isolated variable domains may offer an alternative to monoclonal antibodies and serve as the key to building high-affinity human antibodies. We suggest the name 'single domain antibodies (dAbs)' for these antigen binding demands. 相似文献
398.
399.
The delayed rise of present-day mammals 总被引:1,自引:0,他引:1
Bininda-Emonds OR Cardillo M Jones KE MacPhee RD Beck RM Grenyer R Price SA Vos RA Gittleman JL Purvis A 《Nature》2007,446(7135):507-512
Did the end-Cretaceous mass extinction event, by eliminating non-avian dinosaurs and most of the existing fauna, trigger the evolutionary radiation of present-day mammals? Here we construct, date and analyse a species-level phylogeny of nearly all extant Mammalia to bring a new perspective to this question. Our analyses of how extant lineages accumulated through time show that net per-lineage diversification rates barely changed across the Cretaceous/Tertiary boundary. Instead, these rates spiked significantly with the origins of the currently recognized placental superorders and orders approximately 93 million years ago, before falling and remaining low until accelerating again throughout the Eocene and Oligocene epochs. Our results show that the phylogenetic 'fuses' leading to the explosion of extant placental orders are not only very much longer than suspected previously, but also challenge the hypothesis that the end-Cretaceous mass extinction event had a major, direct influence on the diversification of today's mammals. 相似文献
400.