全文获取类型
收费全文 | 346篇 |
免费 | 26篇 |
专业分类
372篇 |
出版年
2022年 | 2篇 |
2021年 | 7篇 |
2020年 | 2篇 |
2019年 | 5篇 |
2018年 | 9篇 |
2017年 | 4篇 |
2016年 | 6篇 |
2015年 | 8篇 |
2014年 | 12篇 |
2013年 | 14篇 |
2012年 | 9篇 |
2011年 | 14篇 |
2010年 | 14篇 |
2009年 | 9篇 |
2008年 | 15篇 |
2007年 | 20篇 |
2006年 | 22篇 |
2005年 | 17篇 |
2004年 | 18篇 |
2003年 | 14篇 |
2002年 | 10篇 |
2001年 | 16篇 |
2000年 | 9篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 5篇 |
1994年 | 2篇 |
1992年 | 8篇 |
1991年 | 7篇 |
1990年 | 2篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 7篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1969年 | 4篇 |
1968年 | 3篇 |
排序方式: 共有372条查询结果,搜索用时 15 毫秒
21.
Palmer S Campen CA Allan GF Rybczynski P Haynes-Johnson D Hutchins A Kraft P Kiddoe M Lai M Lombardi E Pedersen P Hodgen G Combs DW 《The Journal of steroid biochemistry and molecular biology》2000,75(1):33-42
We have characterized a series of nonsteroidal progesterone receptor ligands, the tetrahydropyridazines. Compounds in this series, exemplified by RWJ 26819, demonstrate high affinity and unprecedented specificity for the progesterone receptor relative to other steroid hormone receptors. Like steroidal progestins, RWJ 26819 induces binding of the receptor to a progesterone response element in vitro, and stimulates gene expression in and proliferation of T47D human breast cancer cells. When administered to rabbits orally or subcutaneously, the compound induces histological changes in the uterine lining comparable to those induced by levonorgestrel. It also inhibits ovulation in monkeys. Though less potent in cells and in animal models than would be predicted from binding affinity alone, their enhanced selectivity suggests that they could be effectively used in a clinical setting. Most of the tetrahydropyridazines synthesized are progestin agonists or mixed agonists and antagonists in vitro; however, one compound with antagonist activity in the rabbit uterine transformation assay has been identified. 相似文献
22.
Mingzhang Gao Min Wang Kathy D. Miller Gary D. Hutchins Qi-Huang Zheng 《Bioorganic & medicinal chemistry》2010,18(6):2099-2106
Cannabinoids have been recently proposed as a new family of potential antitumor agents, and cannabinoid receptor 2 (CB2) is believed to be over-expressed in tumor cells. This study was designed to develop new radioligands for imaging of CB2 receptor in cancer using biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled 2-oxoquinoline and 2-chloroquinoline derivatives, [11C]6a–d and [11C]9a–d, were prepared by O-[11C]methylation of their corresponding precursors using [11C]CH3OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 40–50% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 15–20 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 111–185 GBq/μmol. Radioligand binding assays indicated compounds 6f, 6b, and 9f display potent in vitro binding affinities with nanomolar Ki values and at least 100–2000-fold selectivity for CB2. 相似文献
23.
Fei X Zheng QH Liu X Wang JQ Sun HB Mock BH Stone KL Miller KD Sledge GW Hutchins GD 《Bioorganic & medicinal chemistry letters》2003,13(13):2217-2222
Novel matrix metalloproteinase (MMP) inhibitor radiotracers, (S)-3-methyl-2-(2',3',4'-methoxybiphenyl-4-sulfonylamino)-butyric acid [(11)C]methyl ester (1a-c), (S)-3-methyl-2-(2',3',4'-fluorobiphenyl-4-sulfonylamino)-butyric acid [(11)C]methyl ester (1d-f), and (S)-3-methyl-2-(4'-nitrobiphenyl-4-sulfonylamino)-butyric acid [(11)C]methyl ester (1g), a series of substituted biphenylsulfonamide derivatives, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer imaging agents. 相似文献
24.
Abhineet M. Sharma Breanna Baraff John T. Hutchins Michelle K. Wong G. Kai Blaisdell Monica L. Cooper Kent M. Daane Rodrigo P. P. Almeida 《PloS one》2015,10(11)
Some diseases manifest as one characteristic set of symptoms to the host, but can be caused by multiple pathogens. Control treatments based on plant symptoms can make it difficult to effectively manage such diseases, as the biology of the underlying pathogens can vary. Grapevine leafroll disease affects grapes worldwide, and is associated with several viral species in the family Closteroviridae. Whereas some of the viruses associated with this disease are transmitted by insect vectors, others are only graft-transmissible. In three regions of California, we surveyed vineyards containing diseased vines and screened symptomatic plants for all known viral species associated with grapevine leafroll disease. Relative incidence of each virus species differed among the three regions regions, particularly in relation to species with known vectors compared with those only known to be graft-transmitted. In one region, the pathogen population was dominated by species not known to have an insect vector. In contrast, populations in the other surveyed regions were dominated by virus species that are vector-transmissible. Our survey did not detect viruses associated with grapevine leafroll disease at some sites with characteristic disease symptoms. This could be explained either by undescribed genetic diversity among these viruses that prevented detection with available molecular tools at the time the survey was performed, or a misidentification of visual symptoms that may have had other underlying causes. Based on the differences in relative prevalence of each virus species among regions and among vineyards within regions, we expect that region and site-specific management strategies are needed for effective disease control. 相似文献
25.
Michael Mazanek Elisabeth Roitinger Otto Hudecz James R.A. Hutchins Björn Hegemann Goran Mitulović Thomas Taus Christoph Stingl Jan-Michael Peters Karl Mechtler 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(5-6):515-524
The selective enrichment of phosphorylated peptides prior to reversed-phase separation and mass spectrometric detection significantly improves the analytical results in terms of higher number of detected phosphorylation sites and spectra of higher quality. Metal oxide chromatography (MOC) has been recently described for selective phosphopeptide enrichment (Pinkse et al., 2004 [1]; Larsen et al., 2005 [2]; Kweon and Hakansson, 2006 [3]; Cantin et al., 2007 [4]; Collins et al., 2007 [5]). In the present work we have tested the effect of a modified loading solvent containing a novel acid mix and optimized wash conditions on the efficiency of TiO2-based phosphopeptide enrichment in order to improve our previously published method (Mazanek et al., 2007 [6]). Applied to a test mixture of synthetic and BSA-derived peptides, the new method showed improved selectivity for phosphopeptides, whilst retaining a high recovery rate. Application of the new enrichment method to digested purified protein complexes resulted in the identification of a significantly higher number of phosphopeptides as compared to the previous method. Additionally, we have compared the performance of TiO2 and ZrO2 columns for the isolation and identification of phosphopeptides from purified protein complexes and found that for our test set, both media performed comparably well. In summary, our improved method is highly effective for the enrichment of phosphopeptides from purified protein complexes prior to mass spectrometry, and is suitable for large-scale phosphoproteomic projects that aim to elucidate phosphorylation-dependent cellular processes. 相似文献
26.
Lai CM Yu MJ Brankov M Barnett NL Zhou X Redmond TM Narfstrom K Rakoczy PE 《Genetic vaccines and therapy》2004,2(1):3
Background
Leber's congenital amaurosis (LCA) is a severe form of retinal dystrophy. Mutations in the RPE65 gene, which is abundantly expressed in retinal pigment epithelial (RPE) cells, account for approximately 10–15% of LCA cases. In this study we used the high turnover, and rapid breeding and maturation time of the Rpe65 -/- knockout mice to assess the efficacy of using rAAV-mediated gene therapy to replace the disrupted RPE65 gene. The potential for rAAV-mediated gene treatment of LCA was then analyzed by determining the pattern of RPE65 expression, the physiological and histological effects that it produced, and any improvement in visual function. 相似文献27.
Nathan G Walworth Michael D Lee Egor Dolzhenko Fei-Xue Fu Andrew D Smith Eric A Webb David A Hutchins 《Molecular biology and evolution》2021,38(3):927
A major challenge in modern biology is understanding how the effects of short-term biological responses influence long-term evolutionary adaptation, defined as a genetically determined increase in fitness to novel environments. This is particularly important in globally important microbes experiencing rapid global change, due to their influence on food webs, biogeochemical cycles, and climate. Epigenetic modifications like methylation have been demonstrated to influence short-term plastic responses, which ultimately impact long-term adaptive responses to environmental change. However, there remains a paucity of empirical research examining long-term methylation dynamics during environmental adaptation in nonmodel, ecologically important microbes. Here, we show the first empirical evidence in a marine prokaryote for long-term m5C methylome modifications correlated with phenotypic adaptation to CO2, using a 7-year evolution experiment (1,000+ generations) with the biogeochemically important marine cyanobacterium Trichodesmium. We identify m5C methylated sites that rapidly changed in response to high (750 µatm) CO2 exposure and were maintained for at least 4.5 years of CO2 selection. After 7 years of CO2 selection, however, m5C methylation levels that initially responded to high-CO2 returned to ancestral, ambient CO2 levels. Concurrently, high-CO2 adapted growth and N2 fixation rates remained significantly higher than those of ambient CO2 adapted cell lines irrespective of CO2 concentration, a trend consistent with genetic assimilation theory. These data demonstrate the maintenance of CO2-responsive m5C methylation for 4.5 years alongside phenotypic adaptation before returning to ancestral methylation levels. These observations in a globally distributed marine prokaryote provide critical evolutionary insights into biogeochemically important traits under global change. 相似文献
28.
Oberholzer A John T Kohl B Gust T Müller RD La Face D Hutchins B Zreiqat H Ertel W Schulze-Tanzil G 《Cell and tissue research》2007,328(2):383-390
Gene transfer into cultured chondrocytes by using adenoviral vectors has potential applications in treating cartilage disorders.
The present study was undertaken to compare and optimize two chondrocyte culture conditions for adenoviral transduction efficacy
by using primary human articular chondrocytes cultivated either directly in a monolayer condition or as outgrowths from alginate-stored
chondrocyte cultures. Isolated primary chondrocytes from human articular cartilage were either immediately transduced with
an EGFP (enhanced green fluorescent protein)-gene-bearing adenoviral vector (1,000 and 3,000 virus particles/cell) or cultured
in alginate before transduction. Immunohistochemistry and flow cytometric analysis were employed to determine the expression
of extracellular matrix proteins and of the αvβ5 integrin receptor involved in adenoviral cell entry. Monolayer chondrocytes
exhibited moderate transduction rates (mean 22.2% and 46.9% EGFP-positive cells at 1,000 and 3,000 virus particles/cell by
72 h post-transduction), whereas alginate-derived chondrocytes revealed significantly higher transduction efficacies (95.7%
and 99%). Both monolayer and alginate-derived chondrocytes expressed αvβ5 integrin, type II collagen and cartilage proteoglycans.
The mean fluorescence intensity of type II collagen was significantly higher in the alginate-derived chondrocytes, whereas
that of αvβ5 integrin was higher in the monolayer chondrocytes. Our results indicate that transduction efficacy is independent
of αvβ5 integrin expression levels in chondrocytes. Moreover, adenoviral transduction of alginate-derived chondrocytes is
more efficient than that for monolayer chondrocytes and may be a suitable tool to achieve sufficient numbers of transduced
and differentiated chondrocytes for experimental applications and cartilage repair.
Dr. Gundula Schulze-Tanzil is supported by a grant awarded by the Rahel Hirsh Foundation from the Charité Medical Schools
Berlin. The study was supported by a grant from the Deutsche Arthrosehilfe e.V. 相似文献
29.
Liu D Brockman JM Dass B Hutchins LN Singh P McCarrey JR MacDonald CC Graber JH 《Nucleic acids research》2007,35(1):234-246
Gene expression and processing during mouse male germ cell maturation (spermatogenesis) is highly specialized. Previous reports have suggested that there is a high incidence of alternative 3′-processing in male germ cell mRNAs, including reduced usage of the canonical polyadenylation signal, AAUAAA. We used EST libraries generated from mouse testicular cells to identify 3′-processing sites used at various stages of spermatogenesis (spermatogonia, spermatocytes and round spermatids) and testicular somatic Sertoli cells. We assessed differences in 3′-processing characteristics in the testicular samples, compared to control sets of widely used 3′-processing sites. Using a new method for comparison of degenerate regulatory elements between sequence samples, we identified significant changes in the use of putative 3′-processing regulatory sequence elements in all spermatogenic cell types. In addition, we observed a trend towards truncated 3′-untranslated regions (3′-UTRs), with the most significant differences apparent in round spermatids. In contrast, Sertoli cells displayed a much smaller trend towards 3′-UTR truncation and no significant difference in 3′-processing regulatory sequences. Finally, we identified a number of genes encoding mRNAs that were specifically subject to alternative 3′-processing during meiosis and postmeiotic development. Our results highlight developmental differences in polyadenylation site choice and in the elements that likely control them during spermatogenesis. 相似文献
30.
Zheng QH Gao M Mock BH Wang S Hara T Nazih R Miller MA Receveur TJ Lopshire JC Groh WJ Zipes DP Hutchins GD DeGrado TR 《Bioorganic & medicinal chemistry letters》2007,17(8):2220-2224
The high-affinity choline transporter (CHT1) system is an attractive target for the development of positron emission tomography (PET) biomarkers to probe brain, cardiac, and cancer diseases. An efficient and convenient synthesis of new radiolabeled CHT1 inhibitors [(11)C]hemicholinium-3 and [(18)F]hemicholinium-3 by solid-phase extraction (SPE) technique using a cation-exchange CM Sep-Pak cartridge has been well developed. The preliminary evaluation of both tracers through biodistribution studies in 9L-glioma rats has been performed, and the uptakes in the heart and tumor were observed, while very low brain uptake was seen. 相似文献