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排序方式: 共有121条查询结果,搜索用时 234 毫秒
81.
Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality; it results from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Humans have a paralogue, SMN2, whose exon 7 is predominantly skipped, but the limited amount of functional, full-length SMN protein expressed from SMN2 cannot fully compensate for a lack of SMN1. SMN is important for the biogenesis of spliceosomal small nuclear ribonucleoprotein particles, but downstream splicing targets involved in pathogenesis remain elusive. There is no effective SMA treatment, but SMN restoration in spinal cord motor neurons is thought to be necessary and sufficient. Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported in severe SMA mouse models and patients, reflecting autonomic dysfunction or direct effects in cardiac tissues. Here we compared systemic versus CNS restoration of SMN in a severe mouse model. We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection. Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median lifespan by 25 fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals expression, leading to a pronounced reduction in circulating insulin-like growth factor 1 (IGF1), and ASO-10-27 treatment restored IGF1 to normal levels. These results suggest that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate. 相似文献
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83.
We present a cointegration analysis on the triangle (USD–DEM, USD–JPY, DEM–JPY) of foreign exchange rates using intra‐day data. A vector autoregressive model is estimated and evaluated in terms of out‐of‐sample forecast accuracy measures. Its economic value is measured on the basis of trading strategies that account for transaction costs. We show that the typical seasonal volatility in high‐frequency data can be accounted for by transforming the underlying time scale. Results are presented for the original and the modified time scales. We find that utilizing the cointegration relation among the exchange rates and the time scale transformation improves forecasting results. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
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Geert J. P. L. Kops Adrian T. Saurin Patrick Meraldi 《Cellular and molecular life sciences : CMLS》2010,67(13):2145-2161
Genomic stability requires error-free chromosome segregation during mitosis. Chromosome congression to the spindle equator
precedes chromosome segregation in anaphase and is a hallmark of metazoan mitosis. Here we review the current knowledge and
concepts on the processes that underlie chromosome congression, including initial attachment to spindle microtubules, biorientation,
and movements, from the perspective of the kinetochore. 相似文献
87.
Yvonne G. J. van Helden Sandra G. Heil Frederik J. van Schooten Evelien Kramer Susanne Hessel Jaume Amengual Joan Ribot Katja Teerds Adrian Wyss Georg Lietz M. Luisa Bonet Johannes von Lintig Roger W. L. Godschalk Jaap Keijer 《Cellular and molecular life sciences : CMLS》2010,67(12):2039-2056
Beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ?/?) mice accumulate beta-carotene (BC) similarly to humans, whereas wild-type (Bcmo1 +/+) mice efficiently cleave BC. Bcmo1 ?/? mice are therefore suitable to investigate BC-induced alterations in gene expression in lung, assessed by microarray analysis. Bcmo1 ?/? mice receiving control diet had increased expression of inflammatory genes as compared to BC-supplemented Bcmo1 ?/? mice and Bcmo1 +/+ mice that received either control or BC-supplemented diets. Differential gene expression in Bcmo1 ?/? mice was confirmed by real-time quantitative PCR. Histochemical analysis indeed showed an increase in inflammatory cells in lungs of control Bcmo1 ?/? mice. Supported by metabolite and gene-expression data, we hypothesize that the increased inflammatory response is due to an altered BC metabolism, resulting in an increased vitamin A requirement in Bcmo1 ?/? mice. This suggests that effects of BC may depend on inter-individual variations in BC-metabolizing enzymes, such as the frequently occurring human polymorphisms in BCMO1. 相似文献
88.
Northcott PA Shih DJ Peacock J Garzia L Morrissy AS Zichner T Stütz AM Korshunov A Reimand J Schumacher SE Beroukhim R Ellison DW Marshall CR Lionel AC Mack S Dubuc A Yao Y Ramaswamy V Luu B Rolider A Cavalli FM Wang X Remke M Wu X Chiu RY Chu A Chuah E Corbett RD Hoad GR Jackman SD Li Y Lo A Mungall KL Nip KM Qian JQ Raymond AG Thiessen NT Varhol RJ Birol I Moore RA Mungall AJ Holt R Kawauchi D Roussel MF Kool M Jones DT Witt H Fernandez-L A Kenney AM Wechsler-Reya RJ Dirks P Aviv T 《Nature》2012,488(7409):49-56
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy. 相似文献
89.
Envelope structure of Semliki Forest virus reconstructed from cryo-electron micrographs 总被引:25,自引:0,他引:25
The basic principles of the architecture of many viral protein shells have been successfully established from electron microscopy and X-ray data, but enveloped viruses have been more difficult to study because they resist crystallization and are easily deformed when prepared for electron microscopy. To avoid the limitations of conventional techniques when applied to enveloped viruses, we have used a cryo-electron microscopy method in which unfixed and unstained viruses are observed in an unsupported thin layer of vitrified suspension. Because of electron beam damage, the many different views required for high-resolution three-dimensional reconstruction cannot be obtained from a tilt series of the same particle. The images of many differently oriented viruses are combined using a novel reconstruction method, 'reconstruction by optimized series expansion' (ROSE). The structure of the envelope of Semliki Forest virus has been reconstructed to 3.5-nm resolution. The T = 4 geometry of the surface lattice, the shape of the trimeric spikes and their arrangement on the lipid bilayer are visualized. 相似文献
90.
A common mechanism of action for three mood-stabilizing drugs 总被引:21,自引:0,他引:21
Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment. 相似文献