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Sudhir Agrawal Zhiwei Jiang Qiuyan Zhao Denise Shaw Daisy Sun Carl Saxinger 《Nucleosides, nucleotides & nucleic acids》2013,32(7-9):927-936
Abstract Antisense oligonucleotides are being studied as novel therapeutic agents. To further improve the properties of antisense oligonucleotides, we have synthesized phosphorothioate oligonucleotides containing methylphosphonate linkages at the 5′-end, the 3′-end, or in the center, and have evaluated the impact of these linkages on the biophysical properties, biological properties, and some of the safety parameters. 相似文献
3.
Ana P. Bou?as Letícia A. Brondani Bianca M. Souza Natália E. Lemos Fernanda S. de Oliveira Luis H. Canani Daisy Crispim 《PloS one》2013,8(12)
Background
The rs1990760 polymorphism of interferon induced with helicase C domain 1 (IFIH1) has been associated with type 1 diabetes mellitus (T1DM). Here, we investigated whether this polymorphism is associated with T1DM or its clinical characteristics in a Brazilian population, and if IFIH1 gene expression in mononuclear cells from T1DM patients differs according to the genotypes of this polymorphism. A meta-analysis was also conducted to evaluate if the rs1990760 polymorphism is associated with T1DM.Methods
Frequencies of the rs1990760 polymorphism were analyzed in 527 T1DM patients and in 517 healthy subjects. IFIH1 gene expressions according to genotypes were measured in a sub-sample of 26 T1DM patients by quantitative real-time PCR.Results
Our data show the association of the A allele with risk to T1DM under a dominant model of inheritance [odds ratio (OR) = 1.421, P = 0.037], adjusting for ethnicity. The meta-analysis revealed significant association between the rs199760A allele and risk for T1DM for all analyzed inheritance models. Surprisingly, T1DM patients carrying the A allele showed lower levels of systolic (P = 0.001) and diastolic (P = 1×10−10) blood pressures as compared to G/G carriers. Furthermore, the A/A genotype seems to be associated with protection to arterial hypertension (AH) after adjustment for covariates (OR = 0.339, P = 0.019). IFIH1 gene expression in mononuclear cells from 26 T1DM patients did not differ among genotypes (P = 0.274). Nevertheless, IFIH1 gene expression was increased in mononuclear cells from T1DM patients with AH as compared with T1DM patients without AH [6.7 (1.7–2.0) vs. 1.8 (1.3–7.1) arbitrary units; P = 0.036]. The association with blood pressures and AH was not observed in patients with type 2 diabetes mellitus.Conclusions
Our results indicate that the rs1990760 polymorphism is associated with T1DM. Interestingly, the rs1990760 A allele seems to be associated with protection for AH in T1DM patients. Further studies are needed to confirm the association with AH. 相似文献4.
Xiaoyu Yang Wei Xu Svetlana Dukleska Sabrina Benchaar Selina Mengisen Valentyn Antochshuk Jason Cheung Leslie Mann Zulfia Babadjanova Jason Rowand Rico Gunawan Alexander McCampbell Maribel Beaumont David Meininger Daisy Richardson Alexandre Ambrogelly 《MABS-AUSTIN》2013,5(5):787-794
Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2−8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples. We present here three case studies reflecting three typical outcomes: (1) no major or unexpected degradation is found and the study results are used to inform early identification of degradation pathways and potential critical quality attributes within the Quality by Design framework defined by US Food and Drug Administration guidance documents; (2) identification of specific degradation pathway(s) that do not affect potency of the molecule, with subsequent definition of proper process control and formulation strategies; and (3) identification of degradation that affects potency, resulting in program termination and reallocation of resources. 相似文献
5.
Christiane Segarra Daisy Bougard Mohammed Moudjou Hubert Laude Vincent Béringue Joliette Coste 《PloS one》2013,8(7)
Background
Variant Creutzfeldt-Jakob disease (vCJD) is a neurodegenerative infectious disorder, characterized by a prominent accumulation of pathological isoforms of the prion protein (PrPTSE) in the brain and lymphoid tissues. Since the publication in the United Kingdom of four apparent vCJD cases following transfusion of red blood cells and one apparent case following treatment with factor VIII, the presence of vCJD infectivity in the blood seems highly probable. For effective blood testing of vCJD individuals in the preclinical or clinical phase of infection, it is considered necessary that assays detect PrPTSE concentrations in the femtomolar range.Methodology/Principal Findings
We have developed a three-step assay that firstly captures PrPTSE from infected blood using a plasminogen-coated magnetic-nanobead method prior to its serial amplification via protein misfolding cyclic amplification (PMCA) and specific PrPTSE detection by western blot. We achieved a PrPTSE capture yield of 95% from scrapie-infected material. We demonstrated the possibility of detecting PrPTSE in white blood cells, in buffy coat and in plasma isolated from the blood of scrapie-infected sheep collected at the pre-clinical stage of the disease. The test also allowed the detection of PrPTSE in human plasma spiked with a 10−8 dilution of vCJD-infected brain homogenate corresponding to the level of sensitivity (femtogram) required for the detection of the PrPTSE in asymptomatic carriers. The 100% specificity of the test was revealed using a blinded panel comprising 96 human plasma samples.Conclusion/Significance
We have developed a sensitive and specific amplification assay allowing the detection of PrPTSE in the plasma and buffy coat fractions of blood collected at the pre-clinical phase of the disease. This assay represents a good candidate as a confirmatory assay for the presence of PrPTSE in blood of patients displaying positivity in large scale screening tests. 相似文献6.
Approaches to homozygosity mapping and exome sequencing for the identification of novel types of CDG
Gert Matthijs Daisy Rymen María Beatriz Bistué Millón Erika Souche Valérie Race 《Glycoconjugate journal》2013,30(1):67-76
In the past decade, the identification of most genes involved in Congenital Disorders of Glycosylation (CDG) (type I) was achieved by a combination of biochemical, cell biological and glycobiological investigations. This has been truly successful for CDG-I, because the candidate genes could be selected on the basis of the homology of the synthetic pathway of the dolichol linked oligosaccharide in human and yeast. On the contrary, only a few CDG-II defects were elucidated, be it that some of the discoveries represent wonderful breakthroughs, like e.g, the identification of the COG defects. In general, many rare genetic defects have been identified by positional cloning. However, only a few types of CDG have effectively been elucidated by linkage analysis and so-called reverse genetics. The reason is that the families were relatively small and could—except for CDG-PMM2—not be pooled for analysis. Hence, a large number of CDG cases has long remained unsolved because the search for the culprit gene was very laborious, due to the heterogeneous phenotype and the myriad of candidate defects. This has changed when homozygosity mapping came of age, because it could be applied to small (consanguineous) families. Many novel CDG genes have been discovered in this way. But the best has yet to come: what we are currently witnessing, is an explosion of novel CDG defects, thanks to exome sequencing: seven novel types were published over a period of only two years. It is expected that exome sequencing will soon become a diagnostic tool, that will continuously uncover new facets of this fascinating group of diseases. 相似文献
7.
B. V. Agboton D. Salifu Z. Seguni M. E. Sijaona S. Shomari S. Ekesi N. K. Maniania 《Journal of Applied Entomology》2013,137(10):782-789
Cashew (Anacardium occidentale) is an economically important cash crop for many rural households in Tanzania. However, its production is constrained by some insect pests and diseases. As a prerequisite for the development of a more sustainable integrated insect pest and disease management strategy for cashew, information on the biology and ecology of the key insect pests and diseases in a changing environment, and on influencing biotic and abiotic factors, is needed. Surveys were conducted in the major cashew nut‐producing areas of Tanzania for two seasons: August to December, 2009, and August to December, 2010. Data on number of infested and infected shoots by key insect pests and diseases, natural enemies and associated farmer practices, namely synthetic pesticide use and intercropping systems, were collected from different subzones within agroecological zones. Our data showed that abundance and diversity of key cashew insect pests and diseases were influenced by agroecological zones and subzones. Intercropping was more commonly practised in the northern than in the southern zone. Agrochemicals were most frequently used in the southern agroecological zone and affected the occurrence of natural enemies, notably the weaver ant that was more abundant in the northern zone. Furthermore, our findings revealed that Helopeltis sp. and the powdery mildew remained the major constraints to cashew nut production in Tanzania. 相似文献
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Elhaseen Elamin Ad Masclee Kati Juuti-Uusitalo Sven van IJzendoorn Freddy Troost Harm-Jan Pieters Jan Dekker Daisy Jonkers 《PloS one》2013,8(3)