全文获取类型
收费全文 | 382篇 |
免费 | 37篇 |
出版年
2022年 | 5篇 |
2021年 | 3篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 7篇 |
2015年 | 8篇 |
2014年 | 11篇 |
2013年 | 18篇 |
2012年 | 21篇 |
2011年 | 17篇 |
2010年 | 11篇 |
2009年 | 11篇 |
2008年 | 10篇 |
2007年 | 19篇 |
2006年 | 22篇 |
2005年 | 8篇 |
2004年 | 16篇 |
2003年 | 8篇 |
2002年 | 14篇 |
2001年 | 16篇 |
2000年 | 12篇 |
1999年 | 10篇 |
1997年 | 8篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1992年 | 7篇 |
1991年 | 6篇 |
1990年 | 7篇 |
1989年 | 4篇 |
1988年 | 5篇 |
1986年 | 8篇 |
1985年 | 6篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1981年 | 6篇 |
1977年 | 7篇 |
1976年 | 3篇 |
1973年 | 9篇 |
1972年 | 3篇 |
1970年 | 3篇 |
1969年 | 3篇 |
1968年 | 3篇 |
1967年 | 3篇 |
1965年 | 4篇 |
1961年 | 3篇 |
1950年 | 2篇 |
1941年 | 2篇 |
1908年 | 3篇 |
排序方式: 共有419条查询结果,搜索用时 281 毫秒
51.
Malic enzyme was purified 43-fold from Mucor circinelloides. The enzyme was dependent on Mg2+ or Mn2+ for activity, was not active with Dmalate and had a pH optimum at 7.8. The apparent Km values for malate and NADP+ were 488 ΜM and 41 Μm respectively. The Mr of the native enzyme was 160 kDa. Five metabolic analogues of malate: oxaloacetate, tartronic acid, 1-methylenecyclopropane
trans-2,3-dicarboxyIic acid, malonic acid and glutaric acid, were found to inhibit malic enzyme activity at 10 mM. Four oleaginous
fungi, Mucor circinelloides, Mortierella alpina, Mortierella elongata and Pythium ultimum, were also examined, all possessed
a soluble malic enzyme, two also possessed a microsomal malic enzyme. 相似文献
52.
Winnie Ip Juliana M.F. Silva Hubert Gaspar Arindam Mitra Shreenal Patel Kanchan Rao Robert Chiesa Persis Amrolia Kimberly Gilmour Gul Ahsan Mary Slatter Andrew R. Gennery Robert F. Wynn Paul Veys Waseem Qasim 《Cytotherapy》2018,20(6):830-838
Background
Adenovirus (ADV) reactivation can cause significant morbidity and mortality in children after allogeneic stem cell transplantation. Antiviral drugs can control viremia, but viral clearance requires recovery of cell-mediated immunity.Method
This study was an open-label phase 1/2 study to investigate the feasibility of generating donor-derived ADV-specific T cells (Cytovir ADV, Cell Medica) and to assess the safety of pre-emptive administration of ADV-specific T cells in high-risk pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT) to treat adenoviremia. Primary safety endpoints included graft-versus-host disease (GvHD), and secondary endpoints determined antiviral responses and use of antiviral drugs.Results
Between January 2013 and May 2016, 92 donors were enrolled for the production of ADV T cells at three centers in the United Kingdom (UK), and 83 products were generated from 72 mobilized peripheral blood harvests and 20 steady-state whole blood donations. Eight children received Cytovir ADV T cells after standard therapy and all resolved ADV viremia between 15 and 127 days later. ADV-specific T cells were detectable using enzyme-linked immunospot assay (ELISpot) in the peripheral blood of all patients analyzed. Serious adverse events included Grade II GvHD, Astrovirus encephalitis and pancreatitis.Conclusion
The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy. 相似文献53.
54.
W. H. Wynn 《BMJ (Clinical research ed.)》1915,1(2828):458-461
55.
56.
Structure of the catalytic domain of human polo-like kinase 1 总被引:2,自引:0,他引:2
Kothe M Kohls D Low S Coli R Cheng AC Jacques SL Johnson TL Lewis C Loh C Nonomiya J Sheils AL Verdries KA Wynn TA Kuhn C Ding YH 《Biochemistry》2007,46(20):5960-5971
Polo-like kinase 1 (Plk1) is an attractive target for the development of anticancer agents due to its importance in regulating cell-cycle progression. Overexpression of Plk1 has been detected in a variety of cancers, and expression levels often correlate with poor prognosis. Despite high interest in Plk1-targeted therapeutics, there is currently no structure publicly available to guide structure-based drug design of specific inhibitors. We determined the crystal structures of the T210V mutant of the kinase domain of human Plk1 complexed with the nonhydrolyzable ATP analogue adenylylimidodiphosphate (AMPPNP) or the pyrrolo-pyrazole inhibitor PHA-680626 at 2.4 and 2.1 A resolution, respectively. Plk1 adopts the typical kinase domain fold and crystallized in a conformation resembling the active state of other kinases. Comparison of the kinetic parameters determined for the (unphosphorylated) wild-type enzyme, as well as the T210V and T210D mutants, shows that the mutations primarily affect the kcat of the reaction, with little change in the apparent Km for the protein or nucleotide substrates (kcat = 0.0094, 0.0376, and 0.0049 s-1 and Km(ATP) = 3.2, 4.0, and 3.0 microM for WT, T210D, and T210V, respectively). The structure highlights features of the active site that can be exploited to obtain Plk1-specific inhibitors with selectivity over other kinases and Plk isoforms. These include the presence of a phenylalanine at the bottom of the ATP pocket, combined with a cysteine (as opposed to the more commonly found leucine) in the roof of the binding site, a pocket created by Leu132 in the hinge region, and a cluster of positively charged residues in the solvent-exposed area outside of the adenine pocket adjacent to the hinge region. 相似文献
57.
We examined whether the effects of elevated CO2 on growth of 1-year old Populus deltoides saplings was a function of the assimilation responses of particular leaf developmental stages. Saplings were grown for 100 days
at ambient (approximately 350 ppm) and elevated (ambient + 200 ppm) CO2 in forced-air greenhouses. Biomass, biomass distribution, growth rates, and leaf initiation and expansion rates were unaffected
by elevated CO2. Leaf nitrogen (N), the leaf C:N ratio, and leaf lignin concentrations were also unaffected. Carbon gain was significantly
greater in expanding leaves of saplings grown at elevated compared to ambient CO2. The Rubisco content in expanding leaves was not affected by CO2 concentration. Carbon gain and Rubisco content were significantly lower in fully expanded leaves of saplings grown at elevated
compared to ambient CO2, indicating CO2-induced down-regulation in fully expanded leaves. Elevated CO2 likely had no overall effect on biomass accumulation due to the more rapid decline in carbon gain as leaves matured in saplings
grown at elevated compared to ambient CO2. This decline in carbon gain has been documented in other species and shown to be related to a balance between sink/source
balance and acclimation. Our data suggest that variation in growth responses to elevated CO2 can result from differences in leaf assimilation responses in expanding versus expanded leaves as they develop under elevated
CO2.
Received: 28 September 1998 / Accepted: 23 June 1999 相似文献
58.
A study of bacterial surface oligosaccharides were investigated among
different strains of Neisseria gonorrhoeae to correlate structural features
essential for binding to the MAb 2C7. This epitope is widely expressed and
conserved in gonococcal isolates, characteristics essential to an effective
candidate vaccine antigen. Sample lipooligosaccharides (LOS), was prepared
by a modification of the hot phenol-water method from which de-O-acetylated
LOS and oligosaccharide (OS) components were analyzed by ES-MS-CID-MS and
ES-MSnin a triple quadrupole and an ion trap mass spectrometer,
respectively. Previously documented natural heterogeneity was apparent from
both LOS and OS preparations which was admixed with fragments induced by
hydrazine and mild acid treatment. Natural heterogeneity was limited to
phosphorylation and antenni extensions to the alpha-chain. Mild acid
hydrolysis to release OS also hydrolyzed the beta(1-->6) glycosidic
linkage of lipid A. OS structures were determined by collisional and
resonance excitation combined with MS and multistep MSn which provided
sequence information from both neutral loss, and nonreducing terminal
fragments. A comparison of OS structures, with earlier knowledge of MAb
binding, enzyme treatment, and partial acid hydrolysis indicates a generic
overlapping domain for 2C7 binding. Reoccurring structural features include
a Hepalpha(1-->3)Hepbeta(1-->5)KDO trisaccharide core branched on the
nonreducing terminus (Hep-2) with an alpha(1-->2) linked GlcNAc
(gamma-chain), and an alpha-linked lactose (beta-chain) residue. From the
central heptose (Hep-1), a beta(1-->4) linked lactose (alpha-chain),
moiety is required although extensions to this residue appear unnecessary.
相似文献
59.
Douty B Wayland B Ala PJ Bower MJ Pruitt J Bostrom L Wei M Klabe R Gonneville L Wynn R Burn TC Liu PC Combs AP Yue EW 《Bioorganic & medicinal chemistry letters》2008,18(1):66-71
The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme. 相似文献
60.
Summary In many scientific problems the purpose of the comparison of two regression models, which describe the relationship between a same response variable and several same covariates for two different groups, is to demonstrate that one model is no higher than the other by a negligible amount, or to demonstrate that the models have only negligible differences and so they can be regarded as describing practically the same relationship between the response variable and the covariates. In this article, methods based on one‐sided pointwise confidence bands are proposed for assessing the nonsuperiority of one model to the other and for assessing the equivalence of two regression models. Examples from QT/QTc study and from drug stability study are used to illustrate the methods. 相似文献