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71.
Alpha-synuclein and Parkinson's disease 总被引:6,自引:0,他引:6
The involvement of alpha-synuclein in neurodegenerative diseases was first suspected after the isolation of an alpha-synuclein fragment (NAC) from amyloid plaques in Alzheimer's disease (AD). Later, two different alpha-synuclein mutations were shown to be associated with autosomal-dominant Parkinson's disease (PD), but only in a small number of families. However, the discovery that alpha-synuclein is a major component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD, confirmed its role in PD pathogenesis. Pathological aggregation of the protein might be responsible for neurodegeneration. In addition, soluble oligomers of alpha-synuclein might be even more toxic than the insoluble fibrils found in Lewy bodies. Multiple factors have been shown to accelerate alpha-synuclein aggregation in vitro. Therapeutic strategies aimed to prevent this aggregation are therefore envisaged. Although little has been learned about its normal function, alpha-synuclein appears to interact with a variety of proteins and membrane phospholipids, and may therefore participate in a number of signaling pathways. In particular, it may play a role in regulating cell differentiation, synaptic plasticity, cell survival, and dopaminergic neurotransmission. Thus, pathological mechanisms based on disrupted normal function are also possible. 相似文献
72.
73.
Stevanin G Herman A Dürr A Jodice C Frontali M Agid Y Brice A 《Nature genetics》2000,24(3):213; author reply 215
74.
Suhre K Wallaschofski H Raffler J Friedrich N Haring R Michael K Wasner C Krebs A Kronenberg F Chang D Meisinger C Wichmann HE Hoffmann W Völzke H Völker U Teumer A Biffar R Kocher T Felix SB Illig T Kroemer HK Gieger C Römisch-Margl W Nauck M 《Nature genetics》2011,43(6):565-569
We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria. 相似文献
75.
A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2 总被引:1,自引:0,他引:1
Cébe Suarez S Pieren M Cariolato L Arn S Hoffmann U Bogucki A Manlius C Wood J Ballmer-Hofer K 《Cellular and molecular life sciences : CMLS》2006,63(17):2067-2077
The development of functional blood and lymphatic vessels requires spatio-temporal coordination of the production and release
of growth factors such as vascular endothelial growth factors (VEGFs). VEGF family proteins are produced in multiple isoforms
with distinct biological properties and bind to three types of VEGF receptors. A VEGF-A splice variant, VEGF-A165b, has recently been isolated from kidney epithelial cells. This variant is identical to VEGF-A165 except for the last six amino acids encoded by an alternative exon. VEGF-A165b and VEGF-A165 bind VEGF receptors 1 and 2 with similar affinity. VEGF-A165b elicits drastically reduced activity in angiogenesis assays and even counteracts signaling by VEGF-A165. VEGF-A165b weakly binds to heparan sulfate and does not interact with neuropilin-1, a coreceptor for VEGF receptor 2. To determine
the molecular basis for altered signaling by VEGF-A165b we measured VEGF receptor 2 and ERK kinase activity in endothelial cells in culture. VEGF-A165 induced strong and sustained activation of VEGF receptor 2 and ERK-1 and −2, while activation by VEGF-A165b was only weak and transient. Taken together these data show that VEGF-A165b has attenuated signaling potential through VEGF receptor 2 defining this new member of the VEGF family as a partial receptor
agonist.
Received 31 May 2006; received after revision 26 June 2006; accepted 14 July 2006 相似文献
76.
77.
KU Ludwig E Mangold S Herms S Nowak H Reutter A Paul J Becker R Herberz T Alchawa E Nasser AC Böhmer M Mattheisen MA Alblas S Barth N Kluck C Lauster B Braumann RH Reich A Hemprich S Pötzsch B Blaumeiser N Daratsianos T Kreusch JC Murray ML Marazita I Ruczinski AF Scott TH Beaty FJ Kramer TF Wienker RP Steegers-Theunissen M Rubini PA Mossey P Hoffmann C Lange S Cichon P Propping M Knapp MM Nöthen 《Nature genetics》2012,44(9):968-971
We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P(NSCLP) = 6.51 × 10(-11); homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84-3.16). 相似文献
78.
79.
Hoffmann AA Montgomery BL Popovici J Iturbe-Ormaetxe I Johnson PH Muzzi F Greenfield M Durkan M Leong YS Dong Y Cook H Axford J Callahan AG Kenny N Omodei C McGraw EA Ryan PA Ritchie SA Turelli M O'Neill SL 《Nature》2011,476(7361):454-457
Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency <30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation. 相似文献
80.
Climate change and evolutionary adaptation 总被引:6,自引:0,他引:6
Evolutionary adaptation can be rapid and potentially help species counter stressful conditions or realize ecological opportunities arising from climate change. The challenges are to understand when evolution will occur and to identify potential evolutionary winners as well as losers, such as species lacking adaptive capacity living near physiological limits. Evolutionary processes also need to be incorporated into management programmes designed to minimize biodiversity loss under rapid climate change. These challenges can be met through realistic models of evolutionary change linked to experimental data across a range of taxa. 相似文献