全文获取类型
收费全文 | 401篇 |
免费 | 36篇 |
专业分类
437篇 |
出版年
2021年 | 3篇 |
2019年 | 4篇 |
2017年 | 3篇 |
2016年 | 6篇 |
2015年 | 11篇 |
2014年 | 16篇 |
2013年 | 12篇 |
2012年 | 12篇 |
2011年 | 22篇 |
2010年 | 20篇 |
2009年 | 16篇 |
2008年 | 10篇 |
2007年 | 11篇 |
2006年 | 5篇 |
2005年 | 8篇 |
2004年 | 9篇 |
2003年 | 10篇 |
2002年 | 8篇 |
2001年 | 14篇 |
2000年 | 18篇 |
1999年 | 21篇 |
1998年 | 7篇 |
1997年 | 5篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 9篇 |
1992年 | 10篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 7篇 |
1988年 | 10篇 |
1987年 | 10篇 |
1986年 | 8篇 |
1985年 | 6篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1979年 | 5篇 |
1978年 | 7篇 |
1977年 | 8篇 |
1976年 | 4篇 |
1972年 | 3篇 |
1970年 | 4篇 |
1969年 | 4篇 |
1964年 | 2篇 |
1961年 | 2篇 |
1902年 | 2篇 |
1897年 | 4篇 |
排序方式: 共有437条查询结果,搜索用时 15 毫秒
41.
João Neres Mark L. Brewer Laura Ratier Horacio Botti Alejandro Buschiazzo Philip N. Edwards Paul N. Mortenson Michael H. Charlton Pedro M. Alzari Alberto C. Frasch Richard A. Bryce Kenneth T. Douglas 《Bioorganic & medicinal chemistry letters》2009,19(3):589-596
trans-Sialidase from Trypanosoma cruzi (TcTS) has emerged as a potential drug target for treatment of Chagas disease. Here, we report the results of virtual screening for the discovery of novel TcTS inhibitors, which targeted both the sialic acid and sialic acid acceptor sites of this enzyme. A library prepared from the Evotec database of commercially available compounds was screened using the molecular docking program GOLD, following the application of drug-likeness filters. Twenty-three compounds selected from the top-scoring ligands were purchased and assayed using a fluorimetric assay. Novel inhibitor scaffolds, with IC50 values in the submillimolar range were discovered. The 3-benzothiazol-2-yl-4-phenyl-but-3-enoic acid scaffold was studied in more detail, and TcTS inhibition was confirmed by an alternative sialic acid transfer assay. Attempts to obtain crystal structures of these compounds with TcTS proved unsuccessful but provided evidence of ligand binding at the active site. 相似文献
42.
David Reby Benjamin D. Charlton Yann Locatelli Karen McComb 《Proceedings. Biological sciences / The Royal Society》2010,277(1695):2747-2753
Across vertebrates, the observation that lower-pitched vocalizations are typically associated with larger and/or higher quality males has lead to the widespread belief that inter- and intra-sexual selection will produce male calls with low fundamental frequencies (F0). Here we investigated the response of oestrous red deer hinds to playback of re-synthesized male roars characterized by either higher than average or lower than average F0. We found that hinds prefer higher rather than lower ‘pitched’ roars, providing, to our knowledge, the first evidence of such a bias in nonhuman mammals. Our findings can be interpreted in relation to previous observations that the minimum F0 of roars is positively correlated with male reproductive success in free-ranging red deer stags, and that across Cervids the F0 of male mating calls shows extreme variability. Females showing preferences for higher-pitched roars might derive genetic benefits through more competitive male offspring. Our results emphasize the need for further investigations of female preferences in mammals in order to better understand the extreme variation of F0 values observed in male sexual calls. 相似文献
43.
A method is described for preparing undisturbed cell cultures for both scanning and transmission electron microscopy. Cells were propagated on polycarbonate membranes with pores of 0.2 micrometer or less. Cultured cells together with their supports were prepared for both scanning electron microscopy and transmission electron microscopy using routine methods. For transmission electron microscopy a rapid schedule of infiltration and polymerization was used. The method described in this report yielded good results and it allowed the fine structure of cultured cells to be viewed in situ by both scanning electron microscopy and transmission electron microscopy. 相似文献
44.
45.
Daniel Berry Johanna E. Takach Christopher L. Schardl Nikki D. Charlton Barry Scott Carolyn A. Young 《Applied and environmental microbiology》2015,81(8):2797-2807
Peramine is an insect-feeding deterrent produced by Epichloë species in symbiotic association with C3 grasses. The perA gene responsible for peramine synthesis encodes a two-module nonribosomal peptide synthetase. Alleles of perA are found in most Epichloë species; however, peramine is not produced by many perA-containing Epichloë isolates. The genetic basis of these peramine-negative chemotypes is often unknown. Using PCR and DNA sequencing, we analyzed the perA genes from 72 Epichloë isolates and identified causative mutations of perA null alleles. We found nonfunctional perA-ΔR* alleles, which contain a transposon-associated deletion of the perA region encoding the C-terminal reductase domain, are widespread within the Epichloë genus and represent a prevalent mutation found in nonhybrid species. Disparate phylogenies of adjacent A2 and T2 domains indicated that the deletion of the reductase domain (R*) likely occurred once and early in the evolution of the genus, and subsequently there have been several recombinations between those domains. A number of novel point, deletion, and insertion mutations responsible for abolishing peramine production in full-length perA alleles were also identified. The regions encoding the first and second adenylation domains (A1 and A2, respectively) were common sites for such mutations. Using this information, a method was developed to predict peramine chemotypes by combining PCR product size polymorphism analysis with sequencing of the perA adenylation domains. 相似文献
46.
Mohammed Jamshad Jack Charlton Yu-Pin Lin Sarah?J. Routledge Zharain Bawa Timothy?J. Knowles Michael Overduin Niek Dekker Tim?R. Dafforn Roslyn?M. Bill David?R. Poyner Mark Wheatley 《Bioscience reports》2015,35(2)
G-protein coupled receptors (GPCRs) constitute the largest class of membrane proteins and are a major drug target. A serious obstacle to studying GPCR structure/function characteristics is the requirement to extract the receptors from their native environment in the plasma membrane, coupled with the inherent instability of GPCRs in the detergents required for their solubilization. In the present study, we report the first solubilization and purification of a functional GPCR [human adenosine A2A receptor (A2AR)], in the total absence of detergent at any stage, by exploiting spontaneous encapsulation by styrene maleic acid (SMA) co-polymer direct from the membrane into a nanoscale SMA lipid particle (SMALP). Furthermore, the A2AR–SMALP, generated from yeast (Pichia pastoris) or mammalian cells, exhibited increased thermostability (∼5°C) compared with detergent [DDM (n-dodecyl-β-D-maltopyranoside)]-solubilized A2AR controls. The A2AR–SMALP was also stable when stored for prolonged periods at 4°C and was resistant to multiple freeze-thaw cycles, in marked contrast with the detergent-solubilized receptor. These properties establish the potential for using GPCR–SMALP in receptor-based drug discovery assays. Moreover, in contrast with nanodiscs stabilized by scaffold proteins, the non-proteinaceous nature of the SMA polymer allowed unobscured biophysical characterization of the embedded receptor. Consequently, CD spectroscopy was used to relate changes in secondary structure to loss of ligand binding ([3H]ZM241385) capability. SMALP-solubilization of GPCRs, retaining the annular lipid environment, will enable a wide range of therapeutic targets to be prepared in native-like state to aid drug discovery and understanding of GPCR molecular mechanisms. 相似文献
47.
Reaper PM Griffiths MR Long JM Charrier JD Maccormick S Charlton PA Golec JM Pollard JR 《Nature chemical biology》2011,7(7):428-430
Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs. 相似文献
48.
Background
MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective ‘window’ to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism.Methods
We recruited 91 children aged 7–16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates.Results
Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles.Conclusions
Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to “social brain” dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a “fossil record” of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism. 相似文献49.
Yu‐Kuang Liao Maël Brossard Dan‐Hua Hsieh Tzu‐Neng Lin Martin D. B. Charlton Shun‐Jen Cheng Chyong‐Hua Chen Ji‐Lin Shen Lung‐Teng Cheng Tung‐Po Hsieh Fang‐I Lai Shou‐Yi Kuo Hao‐Chung Kuo Pavlos G. Savvidis Pavlos G. Lagoudakis 《Liver Transplantation》2015,5(2)
A novel scheme for hybridizing inkjet‐printed thin film Cu(In,Ga)Se2 (CIGS) solar cells with self‐assembled clusters of nanocrystal quantum dots (NQDs), which provides a 10.9% relative enhancement of the photon conversion efficiency (PCE), is demonstrated. A non‐uniform layer of NQD aggregates is deposited between the transparent conductive oxide and a CdS/CIGS p‐n junction using low cost pulsed‐spray deposition. Hybridization significantly improves the external quantum efficiency of the hybrid devices in the absorption range of the NQDs and in the red to near‐IR parts of the spectrum. The low wavelength response enhancement is found to be induced by luminescent down‐shifting (LDS) from the NQD layer, while the increase at longer wavelengths is attributed to internal scattering from NQD aggregates. LDS is demonstrated using time‐resolved spectroscopy, and the morphology of the NQD layer is investigated in fluorescence microscopy and cross‐sectional transmission electron microscopy. The influence of the NQD dose on the PCE of the hybrid devices is investigated and an optimum value is obtained. The low costs and limited material consumptions associated with pulsed‐spray deposition make these flexible hybrid devices promising candidates to help push thin‐film photovoltaic technology towards grid parity. 相似文献
50.