全文获取类型
收费全文 | 124篇 |
免费 | 0篇 |
专业分类
系统科学 | 1篇 |
理论与方法论 | 1篇 |
现状及发展 | 20篇 |
研究方法 | 25篇 |
综合类 | 71篇 |
自然研究 | 6篇 |
出版年
2019年 | 1篇 |
2018年 | 1篇 |
2017年 | 4篇 |
2014年 | 1篇 |
2013年 | 3篇 |
2012年 | 14篇 |
2011年 | 17篇 |
2010年 | 4篇 |
2009年 | 2篇 |
2008年 | 11篇 |
2007年 | 14篇 |
2006年 | 10篇 |
2005年 | 9篇 |
2004年 | 5篇 |
2003年 | 7篇 |
2002年 | 10篇 |
2000年 | 1篇 |
1990年 | 2篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1983年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有124条查询结果,搜索用时 93 毫秒
31.
Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes 总被引:1,自引:0,他引:1
Gudmundsson J Sulem P Steinthorsdottir V Bergthorsson JT Thorleifsson G Manolescu A Rafnar T Gudbjartsson D Agnarsson BA Baker A Sigurdsson A Benediktsdottir KR Jakobsdottir M Blondal T Stacey SN Helgason A Gunnarsdottir S Olafsdottir A Kristinsson KT Birgisdottir B Ghosh S Thorlacius S Magnusdottir D Stefansdottir G Kristjansson K Bagger Y Wilensky RL Reilly MP Morris AD Kimber CH Adeyemo A Chen Y Zhou J So WY Tong PC Ng MC Hansen T Andersen G Borch-Johnsen K Jorgensen T Tres A Fuertes F 《Nature genetics》2007,39(8):977-983
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes. 相似文献
32.
Saether BE Lande R Engen S Weimerskirch H Lillegård M Altwegg R Becker PH Bregnballe T Brommer JE McCleery RH Merilä J Nyholm E Rendell W Robertson RR Tryjanowski P Visser ME 《Nature》2005,436(7047):99-102
Theoretical studies have shown that variation in density regulation strongly influences population dynamics, yet our understanding of factors influencing the strength of density dependence in natural populations still is limited. Consequently, few general hypotheses have been advanced to explain the large differences between species in the magnitude of population fluctuations. One reason for this is that the detection of density regulation in population time series is complicated by time lags induced by the life history of species that make it difficult to separate the relative contributions of intrinsic and extrinsic factors to the population dynamics. Here we use population time series for 23 bird species to estimate parameters of a stochastic density-dependent age-structured model. We show that both the strength of total density dependence in the life history and the magnitude of environmental stochasticity, including transient fluctuations in age structure, increase with generation time. These results indicate that the relationships between demographic and life-history traits in birds translate into distinct population dynamical patterns that are apparent only on a scale of generations. 相似文献
33.
It has recently been shown that RNA interference can be induced in cultured mammalian cells by delivery of short interfering RNAs (siRNAs). Here we describe a method for efficient in vivo delivery of siRNAs to organs of postnatal mice and demonstrate effective and specific inhibition of transgene expression in a variety of organs. 相似文献
34.
35.
Inuzuka H Shaik S Onoyama I Gao D Tseng A Maser RS Zhai B Wan L Gutierrez A Lau AW Xiao Y Christie AL Aster J Settleman J Gygi SP Kung AL Look T Nakayama KI DePinho RA Wei W 《Nature》2011,471(7336):104-109
The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL. 相似文献
36.
Vacic V McCarthy S Malhotra D Murray F Chou HH Peoples A Makarov V Yoon S Bhandari A Corominas R Iakoucheva LM Krastoshevsky O Krause V Larach-Walters V Welsh DK Craig D Kelsoe JR Gershon ES Leal SM Dell Aquila M Morris DW Gill M Corvin A Insel PA McClellan J King MC Karayiorgou M Levy DL DeLisi LE Sebat J 《Nature》2011,471(7339):499-503
37.
Thorgeirsson TE Geller F Sulem P Rafnar T Wiste A Magnusson KP Manolescu A Thorleifsson G Stefansson H Ingason A Stacey SN Bergthorsson JT Thorlacius S Gudmundsson J Jonsson T Jakobsdottir M Saemundsdottir J Olafsdottir O Gudmundsson LJ Bjornsdottir G Kristjansson K Skuladottir H Isaksson HJ Gudbjartsson T Jones GT Mueller T Gottsäter A Flex A Aben KK de Vegt F Mulders PF Isla D Vidal MJ Asin L Saez B Murillo L Blondal T Kolbeinsson H Stefansson JG Hansdottir I Runarsdottir V Pola R Lindblad B 《Nature》2008,452(7187):638-642
Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases. 相似文献
38.
Gudbjartsson DF Arnar DO Helgadottir A Gretarsdottir S Holm H Sigurdsson A Jonasdottir A Baker A Thorleifsson G Kristjansson K Palsson A Blondal T Sulem P Backman VM Hardarson GA Palsdottir E Helgason A Sigurjonsdottir R Sverrisson JT Kostulas K Ng MC Baum L So WY Wong KS Chan JC Furie KL Greenberg SM Sale M Kelly P MacRae CA Smith EE Rosand J Hillert J Ma RC Ellinor PT Thorgeirsson G Gulcher JR Kong A Thorsteinsdottir U Stefansson K 《Nature》2007,448(7151):353-357
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart. 相似文献
39.
40.
The mineral magnetite (Fe(3)O(4)) undergoes a complex structural distortion and becomes electrically insulating at temperatures less than 125 kelvin. Verwey proposed in 1939 that this transition is driven by a charge ordering of Fe(2+) and Fe(3+) ions, but the ground state of the low-temperature phase has remained contentious because twinning of crystal domains hampers diffraction studies of the structure. Recent powder diffraction refinements and resonant X-ray studies have led to proposals of a variety of charge-ordered and bond-dimerized ground-state models. Here we report the full low-temperature superstructure of magnetite, determined by high-energy X-ray diffraction from an almost single-domain, 40-micrometre grain, and identify the emergent order. The acentric structure is described by a superposition of 168 atomic displacement waves (frozen phonon modes), all with amplitudes of less than 0.24 ?ngstr?ms. Distortions of the FeO(6) octahedra show that Verwey's hypothesis is correct to a first approximation and that the charge and Fe(2+) orbital order are consistent with a recent prediction. However, anomalous shortening of some Fe-Fe distances suggests that the localized electrons are distributed over linear three-Fe-site units, which we call 'trimerons'. The charge order and three-site distortions induce substantial off-centre atomic displacements and couple the resulting large electrical polarization to the magnetization. Trimerons may be important quasiparticles in magnetite above the Verwey transition and in other transition metal oxides. 相似文献