全文获取类型
收费全文 | 1405篇 |
免费 | 134篇 |
专业分类
1539篇 |
出版年
2024年 | 3篇 |
2023年 | 15篇 |
2022年 | 32篇 |
2021年 | 52篇 |
2020年 | 23篇 |
2019年 | 30篇 |
2018年 | 42篇 |
2017年 | 42篇 |
2016年 | 64篇 |
2015年 | 91篇 |
2014年 | 122篇 |
2013年 | 115篇 |
2012年 | 132篇 |
2011年 | 111篇 |
2010年 | 83篇 |
2009年 | 69篇 |
2008年 | 87篇 |
2007年 | 77篇 |
2006年 | 85篇 |
2005年 | 60篇 |
2004年 | 54篇 |
2003年 | 56篇 |
2002年 | 41篇 |
2001年 | 3篇 |
2000年 | 5篇 |
1999年 | 8篇 |
1998年 | 5篇 |
1997年 | 2篇 |
1996年 | 6篇 |
1995年 | 1篇 |
1994年 | 6篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1989年 | 4篇 |
1988年 | 3篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1975年 | 1篇 |
排序方式: 共有1539条查询结果,搜索用时 10 毫秒
91.
92.
Damien Laporte Fabien Courtout Beno?t Pinson Jim Dompierre Bénédicte Salin Lysiane Brocard Isabelle Sagot 《The Journal of cell biology》2015,210(1):1011-1025
Cells perpetually face the decision to proliferate or to stay quiescent. Here we show that upon quiescence establishment, Schizosaccharomyces pombe cells drastically rearrange both their actin and microtubule (MT) cytoskeletons and lose their polarity. Indeed, while polarity markers are lost from cell extremities, actin patches and cables are reorganized into actin bodies, which are stable actin filament–containing structures. Astonishingly, MTs are also stabilized and rearranged into a novel antiparallel bundle associated with the spindle pole body, named Q-MT bundle. We have identified proteins involved in this process and propose a molecular model for Q-MT bundle formation. Finally and importantly, we reveal that Q-MT bundle elongation is involved in polarity reestablishment upon quiescence exit and thereby the efficient return to the proliferative state. Our work demonstrates that quiescent S. pombe cells assemble specific cytoskeleton structures that improve the swiftness of the transition back to proliferation. 相似文献
93.
Claude Wicker-Thomas Damien Garrido Gwéna?lle Bontonou Laura Napal Nicolas Mazuras Béatrice Denis Thomas Rubin Jean-Philippe Parvy Jacques Montagne 《Journal of lipid research》2015,56(11):2094-2101
In terrestrial insects, cuticular hydrocarbons (CHCs) provide protection from desiccation. Specific CHCs can also act as pheromones, which are important for successful mating. Oenocytes are abdominal cells thought to act as specialized units for CHC biogenesis that consists of long-chain fatty acid (LCFA) synthesis, optional desaturation(s), elongation to very long-chain fatty acids (VLCFAs), and removal of the carboxyl group. By investigating CHC biogenesis in Drosophila melanogaster, we showed that VLCFA synthesis takes place only within the oenocytes. Conversely, several pathways, which may compensate for one another, can feed the oenocyte pool of LCFAs, suggesting that this step is a critical node for regulating CHC synthesis. Importantly, flies deficient in LCFA synthesis sacrificed their triacylglycerol stores while maintaining some CHC production. Moreover, pheromone production was lower in adult flies that emerged from larvae that were fed excess dietary lipids, and their mating success was lower. Further, we showed that pheromone production in the oenocytes depends on lipid metabolism in the fat tissue and that fatty acid transport protein, a bipartite acyl-CoA synthase (ACS)/FA transporter, likely acts through its ACS domain in the oenocyte pathway of CHC biogenesis. Our study highlights the importance of environmental and physiological inputs in regulating LCFA synthesis to eventually control sexual communication in a polyphagous animal. 相似文献
94.
Thomas?Durand Sophie?Jacob Laura?Lebouil Hassen?Douzane Philippe?Lestaevel Amithys?Rahimian Dimitri?Psimaras Lo?c?Feuvret Delphine?Leclercq Bruno?Brochet Radia?Tamarat Fabien?Milliat Marc?Benderitter Nicolas?Vayatis Georges?No?l Khê?Hoang-Xuan Jean-Yves?Delattre Damien?Ricard Marie-Odile?BernierEmail author 《BMC neurology》2015,15(1):261
Background
Radiotherapy is one of the most important treatments of primary and metastatic brain tumors. Unfortunately, it can involve moderate to severe complications among which leukoencephalopathy is very frequent and implies cognitive deficits such as memory, attention and executive dysfunctions. However, the incidence of this complication is not well established and the risk factors and process are poorly understood. The main objective of the study is to improve knowledge on radio-induced leukoencephalopathy based on pluridisciplinar approaches combining cognitive, biologic, imagery and dosimetric investigations.Method/Design
The EpiBrainRad study is a prospective cohort study including newly diagnosed high grade gliomas patients treated by radiotherapy and concomitant-adjuvant temozolomide chemotherapy. Patients are included between their surgery and first day of radio-chemotherapy, and the follow-up lasts for 3 years after treatment. Cognitive functioning assessments, specific blood biomarkers measures and magnetic resonance imagery are performed at different moment during the follow-up, and a specific dosimetric assessment of organs involved in the beam fields is performed. Firstly, leukoencephalopathy incidence rate will be estimated in this population. Secondly, correlations between cognitive impairments and dosimetry, biomarkers ranges and anomalies on imagery will be analyzed in order to better understand the onset and evolution of cognitive decrement associated with radiotherapy. Furthermore, a new cognitive test, quickly and easily performed, will be studied to determine its sensibility to detect leukoencephalopathy decrement.Discussion
With an original multidisciplinary approach, the EpiBrainRad study aims to improve knowledge on radio-induced leukoencephalopathy in order to improve its early diagnosis and prevention. The main challenge is to preserve quality-of-life after cancer treatments which imply to study the incidence of radiation-induced complications and their associated risk factors.Trial Registration
NCT0254417895.
Mitochondria are cellular organelles involved in host-cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS-a crucial adaptor for RIGI-like receptor signalling-as a mitochondria-anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins-such as mitochondrial DNA and formyl peptides-can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling. 相似文献
96.
Patrelle C Ohst T Picard D Pagano A Sourice S Dallay MG Plötner J 《Molecular ecology resources》2011,11(1):200-205
We describe a non‐invasive, PCR‐RFLP‐based method that allows reliable determination of the European water frog species Pelophylax lessonae and Pelophylax ridibundus and the hybrid form Pelophylax esculentus. Maximum‐likelihood analysis of ITS2 sequences revealed two robust monophyletic clades corresponding to water frogs of the P. lessonae and P. ridibundus groups. Three restriction enzymes (KpnI, HaeII, and SmaI) were used to digest three conserved ITS2 domains. Taxonomic identification was unambiguous; the three restriction enzymes gave the same results. A French reference sample was identified using allozyme electrophoresis. Our PCR‐RFLP method confirmed circa 83% of identification of the allozyme method. We conclude that the difference between identifications was caused by introgression. 相似文献
97.
Matar-Merheb R Rhimi M Leydier A Huché F Galián C Desuzinges-Mandon E Ficheux D Flot D Aghajari N Kahn R Di Pietro A Jault JM Coleman AW Falson P 《PloS one》2011,6(3):e18036
Background
Membrane proteins are privileged pharmaceutical targets for which the development of structure-based drug design is challenging. One underlying reason is the fact that detergents do not stabilize membrane domains as efficiently as natural lipids in membranes, often leading to a partial to complete loss of activity/stability during protein extraction and purification and preventing crystallization in an active conformation.Methodology/Principal Findings
Anionic calix[4]arene based detergents (C4Cn, n = 1–12) were designed to structure the membrane domains through hydrophobic interactions and a network of salt bridges with the basic residues found at the cytosol-membrane interface of membrane proteins. These compounds behave as surfactants, forming micelles of 5–24 nm, with the critical micellar concentration (CMC) being as expected sensitive to pH ranging from 0.05 to 1.5 mM. Both by 1H NMR titration and Surface Tension titration experiments, the interaction of these molecules with the basic amino acids was confirmed. They extract membrane proteins from different origins behaving as mild detergents, leading to partial extraction in some cases. They also retain protein functionality, as shown for BmrA (Bacillus multidrug resistance ATP protein), a membrane multidrug-transporting ATPase, which is particularly sensitive to detergent extraction. These new detergents allow BmrA to bind daunorubicin with a Kd of 12 µM, a value similar to that observed after purification using dodecyl maltoside (DDM). They preserve the ATPase activity of BmrA (which resets the protein to its initial state after drug efflux) much more efficiently than SDS (sodium dodecyl sulphate), FC12 (Foscholine 12) or DDM. They also maintain in a functional state the C4Cn-extracted protein upon detergent exchange with FC12. Finally, they promote 3D-crystallization of the membrane protein.Conclusion/Significance
These compounds seem promising to extract in a functional state membrane proteins obeying the positive inside rule. In that context, they may contribute to the membrane protein crystallization field. 相似文献98.
99.
100.
Dubois D Pihet M Clec'h CL Croué A Beguin H Bouchara JP Chabasse D 《Mycopathologia》2005,160(2):117-123
Here we report a case of cutaneous alternariosis in a 74-year-old man treated by corticotherapy for myasthenia, and presenting
with papular, crusted lesions on the left elbow and the right knee. Histological examination of the biopsy specimens showed
fungal hyphae associated with round-shaped cells which were highly suggestive of alternariosis. Mycological culture allowed
the isolation of a dematiaceous fungus which was identified as a member of the Alternaria infectoria species-group. This was
confirmed by PCR amplification and sequencing of the internal transcribed spacer domain of the gene encoding nuclear ribosomal
DNA and of the mitochondrial small subunit ribosomal DNA domain. The fungus was therefore referred to the Scientific Institute
of Public Health where it was identified as Alternaria infectoria, on the basis of its very small 1 or 2-celled conidia often
arranged in long chains and presenting with very long secondary conidiophores. Corticotherapy was stopped and a local antifungal
treatment with ketoconazole was initiated, allowing the stabilisation of the cutaneous lesions within 2 months. 相似文献