全文获取类型
收费全文 | 1296篇 |
免费 | 235篇 |
国内免费 | 4篇 |
出版年
2022年 | 15篇 |
2021年 | 29篇 |
2020年 | 22篇 |
2019年 | 32篇 |
2018年 | 45篇 |
2017年 | 52篇 |
2016年 | 42篇 |
2015年 | 89篇 |
2014年 | 62篇 |
2013年 | 96篇 |
2012年 | 92篇 |
2011年 | 81篇 |
2010年 | 87篇 |
2009年 | 54篇 |
2008年 | 61篇 |
2007年 | 56篇 |
2006年 | 65篇 |
2005年 | 53篇 |
2004年 | 64篇 |
2003年 | 50篇 |
2002年 | 50篇 |
2001年 | 23篇 |
2000年 | 16篇 |
1999年 | 12篇 |
1998年 | 19篇 |
1997年 | 15篇 |
1996年 | 9篇 |
1995年 | 13篇 |
1994年 | 13篇 |
1993年 | 7篇 |
1991年 | 13篇 |
1990年 | 10篇 |
1989年 | 8篇 |
1988年 | 8篇 |
1987年 | 7篇 |
1986年 | 13篇 |
1985年 | 7篇 |
1984年 | 17篇 |
1983年 | 14篇 |
1982年 | 15篇 |
1981年 | 13篇 |
1980年 | 11篇 |
1979年 | 6篇 |
1978年 | 8篇 |
1977年 | 8篇 |
1976年 | 8篇 |
1975年 | 6篇 |
1973年 | 6篇 |
1969年 | 5篇 |
1965年 | 4篇 |
排序方式: 共有1535条查询结果,搜索用时 15 毫秒
911.
912.
The present study was designed to investigate the effect of intracerebroventricular infusion of norepinephrine (NE) on the secretion of luteinizing hormone-releasing hormone (LH-RH) into the hypophysial portal blood of steroid-primed ovariectomized rats. Saline infusion into the third ventricle caused no significant change in LH-RH levels. NE infusion (20 micrograms) resulted in a significant release of LH-RH (p less than 0.05) into the portal blood 10-30 min later. This endogenous LH-RH was similar to synthetic LH-RH when characterized by thin-layer chromatography. LH secretion in similarly treated rats but with intact portal vessels, also was significantly elevated (p less than 0.05) at 20 and 40 min after the start of NE infusion. These results show that NE stimulated the secretion of LH-RH into the hypophysial portal blood and this correlated with an enhanced release of LH. 相似文献
913.
Brian E. Ford Bruce Sun James Carpino Elizabeth S. Chapler Jane Ching Yoon Choi Kevin Jhun Jung D. Kim Gregory G. Lallos Rachelle Morgenstern Shalini Singh Sai Theja John J. Dennehy 《PloS one》2014,9(11)
Viruses readily mutate and gain the ability to infect novel hosts, but few data are available regarding the number of possible host range-expanding mutations allowing infection of any given novel host, and the fitness consequences of these mutations on original and novel hosts. To gain insight into the process of host range expansion, we isolated and sequenced 69 independent mutants of the dsRNA bacteriophage Φ6 able to infect the novel host, Pseudomonas pseudoalcaligenes. In total, we found at least 17 unique suites of mutations among these 69 mutants. We assayed fitness for 13 of 17 mutant genotypes on P. pseudoalcaligenes and the standard laboratory host, P. phaseolicola. Mutants exhibited significantly lower fitnesses on P. pseudoalcaligenes compared to P. phaseolicola. Furthermore, 12 of the 13 assayed mutants showed reduced fitness on P. phaseolicola compared to wildtype Φ6, confirming the prevalence of antagonistic pleiotropy during host range expansion. Further experiments revealed that the mechanistic basis of these fitness differences was likely variation in host attachment ability. In addition, using computational protein modeling, we show that host-range expanding mutations occurred in hotspots on the surface of the phage''s host attachment protein opposite a putative hydrophobic anchoring domain. 相似文献
914.
915.
916.
917.
918.
TRPV4 is a mechanically activated Ca(2+)-passing channel implicated in the sensing of forces, including those acting on bones. To date, 33 mutations are known to affect human bone development to different extents. The spectrum of these skeletal dysplasias (SD) ranges from dominantly inherited mild brachylomia (BO) to neonatal lethal forms of metatropic dysplasia (MD). Complexities of the results from fluorescence and electrophysiological studies have led to questions on whether channel activity is a good predictor of disease severity. Here we report on a systematic examination of 14 TRPV4 mutant alleles covering the entire SD spectrum. Expressed in Xenopus oocyte and without any stimulation, the wild-type channel had a ~1% open probability (Po) while those of most of the lethal MD channels approached 100%. All mutant channels had higher basal open probabilities, which limited their further increase by agonist or hypotonicity. The magnitude of this limitation revealed a clear correlation between the degree of over-activity (the molecular phenotype) and the severity of the disease over the entire spectrum (the biological phenotype). Thus, while other factors are at play, our results are consistent with the increased TRPV4 basal activity being a critical determinant of the severity of skeletal dysplasia. We discuss how the channel over-activity may lead to the "gain-of-function" phenotype and speculate that the function of wild-type TRPV4 may be secondary in normal bone development but crucial in an acute process such as fracture repair in the adult. 相似文献
919.
Carrasco LR Lee LK Lee VJ Ooi EE Shepard DS Thein TL Gan V Cook AR Lye D Ng LC Leo YS 《PLoS neglected tropical diseases》2011,5(12):e1426
Background
Dengue illness causes 50–100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact of dengue in higher resourced countries or the cost-effectiveness of potential dengue vaccines in such settings.Methods and Findings
We estimate the direct and indirect costs of dengue from hospitalized and ambulatory cases in Singapore. We consider inter alia the impacts of dengue on the economy using the human-capital and the friction cost methods. Disease burden was estimated using disability-adjusted life years (DALYs) and the cost-effectiveness of a potential vaccine program was evaluated. The average economic impact of dengue illness in Singapore from 2000 to 2009 in constant 2010 US$ ranged between $0.85 billion and $1.15 billion, of which control costs constitute 42%–59%. Using empirically derived disability weights, we estimated an annual average disease burden of 9–14 DALYs per 100 000 habitants, making it comparable to diseases such as hepatitis B or syphilis. The proportion of symptomatic dengue cases detected by the national surveillance system was estimated to be low, and to decrease with age. Under population projections by the United Nations, the price per dose threshold for which vaccines stop being more cost-effective than the current vector control program ranged from $50 for mass vaccination requiring 3 doses and only conferring 10 years of immunity to $300 for vaccination requiring 2 doses and conferring lifetime immunity. The thresholds for these vaccine programs to not be cost-effective for Singapore were $100 and $500 per dose respectively.Conclusions
Dengue illness presents a serious economic and disease burden in Singapore. Dengue vaccines are expected to be cost-effective if reasonably low prices are adopted and will help to reduce the economic and disease burden of dengue in Singapore substantially. 相似文献920.
Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3'UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26-47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk. 相似文献