全文获取类型
收费全文 | 865篇 |
免费 | 43篇 |
专业分类
908篇 |
出版年
2023年 | 8篇 |
2022年 | 29篇 |
2021年 | 40篇 |
2020年 | 17篇 |
2019年 | 24篇 |
2018年 | 29篇 |
2017年 | 21篇 |
2016年 | 44篇 |
2015年 | 43篇 |
2014年 | 49篇 |
2013年 | 41篇 |
2012年 | 66篇 |
2011年 | 68篇 |
2010年 | 39篇 |
2009年 | 33篇 |
2008年 | 43篇 |
2007年 | 49篇 |
2006年 | 41篇 |
2005年 | 34篇 |
2004年 | 21篇 |
2003年 | 20篇 |
2002年 | 27篇 |
2001年 | 13篇 |
2000年 | 2篇 |
1999年 | 6篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1995年 | 6篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 9篇 |
1989年 | 2篇 |
1988年 | 9篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 8篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1976年 | 2篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1953年 | 3篇 |
排序方式: 共有908条查询结果,搜索用时 15 毫秒
21.
22.
Teija Parkkari Raisa Haavikko Tuomo Laitinen Dina Navia-Paldanius Roosa Rytilahti Miia Vaara Marko Lehtonen Sami Alakurtti Jari Yli-Kauhaluoma Tapio Nevalainen Juha R. Savinainen Jarmo T. Laitinen 《PloS one》2014,9(5)
Background
α/β-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design.Methodology/Principal Findings
Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors.Conclusions/Significance
We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors. 相似文献23.
The history of green fluorescent protein (GFP) as a marker is less than 10 years old, but it has already made a major impact on many areas of natural sciences, especially on cell biology and histochemistry. GFP can be detected in living cells without selection or staining and it can be fused to other proteins to yield fluorescent chimeras. The potential of GFP has also been recognised by gene therapy researchers and various GFP-tagged therapeutic proteins have been constructed. These chimeric proteins have been used to determine the expression level, site and time course of the therapeutic gene, or the correlation between gene transfer rate and therapeutic outcome. This review summarises the status of the applications of GFP fusions in gene therapy research. 相似文献
24.
Daniela C. Granato Mariana R. Zanetti Rebeca Kawahara Sami Yokoo Romênia R. Domingues Annelize Z. Arag?o Michelle Agostini Marcelo F. Carazzolle Ramon O. Vidal Isadora L. Flores Johanna Korvala Nilva K. Cervigne Alan R. S. Silva Ricardo D. Coletta Edgard Graner Nicholas E. Sherman Adriana F. Paes Leme 《PloS one》2014,9(5)
Understanding the molecular mechanisms of oral carcinogenesis will yield important advances in diagnostics, prognostics, effective treatment, and outcome of oral cancer. Hence, in this study we have investigated the proteomic and peptidomic profiles by combining an orthotopic murine model of oral squamous cell carcinoma (OSCC), mass spectrometry-based proteomics and biological network analysis. Our results indicated the up-regulation of proteins involved in actin cytoskeleton organization and cell-cell junction assembly events and their expression was validated in human OSCC tissues. In addition, the functional relevance of talin-1 in OSCC adhesion, migration and invasion was demonstrated. Taken together, this study identified specific processes deregulated in oral cancer and provided novel refined OSCC-targeting molecules. 相似文献
25.
26.
Cystic echinococcosis (CE) caused by Echinococcus granulosus is a major public health problem worldwide, including Turkey. The aim of the current study was to identify the strains and to estimate the potential risk factors of E. granulosus in operated pediatric cases in eastern Turkey. Ten pediatric patients (7 boys and 3 girls) living in rural areas, with ages ranging from 3 to 15 years old and various clinical histories, were included in this study. Eight patients had only liver hydatid cyst, while 1 patient had liver and lung hydatid cyst and the other liver, lung, and spleen, together. There were 2 ruptured liver cysts. After surgery, during follow-up, no increase was observed in hemagglutination levels, there were no mortalities, and there was no evidence of recurrence at 2 years post operation in all patients. Molecular analysis was performed on hydatid cyst samples obtained from the 10 pediatric cases. According to mt-12S rRNA PCR results, all cases were found to be G1/G3 cluster of E. granulosus sensu stricto. 相似文献
27.
28.
Jukka Bisi Tuija Liukkonen Sakari Mykrä Mari Pohja-Mykrä Sami Kurki 《European Journal of Wildlife Research》2010,56(5):771-779
This article focuses on the roots of the Finnish wolf conflict by using stakeholder evaluations of the wolf as a tool. The
recent growth of the wolf population has highlighted stakeholders’ contradictory objectives and revealed a conflict between
the two main stakeholders, conservationists and hunters, in wolf management. The question of hunting emerges as the core of
the conflict. The negative evaluation of the wolf by hunters reflects a competitive situation, which is typical of the historical
development of wolf management in Finland. In areas with the most abundant wolf populations, hunters view the wolf most negatively.
This study clearly demonstrates that the Finnish wolf conflict is rooted in the values of modern society and carries a long
historical, practical and ecological background in which humans and wolves compete over resources, mainly the moose. The conflict
between hunters and conservationists in wolf management is connected to the appreciation of moose as game and stems from competition
between humans and wolves over their prey and the historical presence or absence of the wolf. 相似文献
29.
Aspergillus niger broth culture on wheat bran was assessed for olive wastewater (OW) hydrolysis in order to release hydroxytyrosol (HT). The enzyme profiles of this culture broth gave essentially (IU/L): 3000 β-glucosidase and 100 esterase. Hydrolysis activity of A. niger enzyme preparation was evaluated by using three substrates: raw OW, phenolic fraction extracted from OW by ethyl acetate and its corresponding exhausted fraction. Large amounts of free simple phenolics were released from exhausted fraction and raw OW after enzymatic treatment. HPLC analyses show that HT was the main phenolic compound. One step of ethyl acetate extraction of hydrolysed OW allowed the recovery of 0.8 g of HT per litre of OW. The antioxidant activity of extracts from OW and exhausted fraction, measured by DPPH method, was drastically enhanced after hydrolysis treatment. This study demonstrates that hydrolysed OW is a potential source of bioactive phenolic compounds with promising applications in food and pharmaceutical industries. 相似文献
30.
Model‐based integration of observed and expert‐based information for assessing the geographic and environmental distribution of freshwater species 下载免费PDF全文
Freshwater ecosystems harbor specialized and vulnerable biodiversity, and the prediction of potential impacts of freshwater biodiversity to environmental change requires knowledge of the geographic and environmental distribution of taxa. To date, however, such quantitative information about freshwater species distributions remains limited. Major impediments include heterogeneity in available species occurrence data, varying detectability of species in their aquatic environment, scarcity of contiguous freshwater‐specific predictors, and methods that support addressing these issues in a single framework. Here we demonstrate the use of a hierarchical Bayesian modeling (HBM) framework that combines disparate species occurrence information with newly‐developed 1 km freshwater‐specific predictors, to account for imperfect species detection and make fine‐grain (1 km) estimates of distributions in freshwater organisms. The approach integrates a Bernoulli suitability and a Binomial observability process into a hierarchical zero‐inflated Binomial model. The suitability process includes point presence observations, records of site visits, 1 km environmental predictors and expert‐derived species range maps integrated with a distance‐decay function along the within‐stream distance as covariates. The observability process uses repeated observations to estimate a probability of observation given that the species was present. The HBM accounts for the spatial autocorrelation in species habitat suitability projections using an intrinsic Gaussian conditional autoregressive model. We used this framework for three fish species native to different regions and habitats in North America. Model comparison shows that HBMs significantly outperformed non‐spatial GLMs in terms of AUC and TSS scores, and that expert information when appropriately included in the model can provide an important refinement. Such ancillary species information and an integrative, hierarchical Bayesian modeling framework can therefore be used to advance fine‐grain habitat suitability predictions and range size estimates in the freshwater realm. Our approach is extendable in terms of data availability and generality and can be used on other freshwater organisms and regions. 相似文献