全文获取类型
收费全文 | 842篇 |
免费 | 70篇 |
出版年
2023年 | 6篇 |
2022年 | 11篇 |
2021年 | 13篇 |
2020年 | 10篇 |
2019年 | 14篇 |
2018年 | 15篇 |
2017年 | 12篇 |
2016年 | 26篇 |
2015年 | 42篇 |
2014年 | 44篇 |
2013年 | 68篇 |
2012年 | 59篇 |
2011年 | 62篇 |
2010年 | 55篇 |
2009年 | 28篇 |
2008年 | 58篇 |
2007年 | 46篇 |
2006年 | 43篇 |
2005年 | 36篇 |
2004年 | 39篇 |
2003年 | 40篇 |
2002年 | 40篇 |
2001年 | 8篇 |
2000年 | 10篇 |
1999年 | 9篇 |
1998年 | 19篇 |
1997年 | 9篇 |
1996年 | 6篇 |
1995年 | 11篇 |
1994年 | 8篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1978年 | 3篇 |
1975年 | 3篇 |
1971年 | 2篇 |
1965年 | 2篇 |
1951年 | 1篇 |
1949年 | 1篇 |
排序方式: 共有912条查询结果,搜索用时 15 毫秒
31.
32.
Lise Pascale Alejandro López González Audrey Di Giorgio Marc Gaysinski Jordi Teixido Closa Roger Estrada Tejedor 《Journal of biomolecular structure & dynamics》2016,34(11):2327-2338
A series of pentameric “Polyamide Amino Acids” (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships. 相似文献
33.
Estefania Ugarte‐Berzal Erik Martens Lise Boon Jennifer Vandooren Daniel Blockmans Paul Proost Ghislain Opdenakker 《Journal of cellular and molecular medicine》2019,23(1):576-585
Gelatin zymography analysis is a sensitive method and commonly used to characterize and quantify the presence of the gelatinases (MMP‐2 and MMP‐9) in biological samples. In human plasma samples from healthy controls and systemic lupus erythematosus (SLE) patients, we observed a gelatinolytic molecule at 80 kDa, suggestive for activated human MMP‐9. However, by developing and using the EDTA/gelatin zymography method and after purification of the 80 kDa entity, we proved that this molecule was the C1s subunit of the complement system. The zymolytic capacity of C1s was validated and found to be enhanced, in the absence of calcium and in the presence of EDTA. Our findings indicate that for correct identification of gelatinolytic proteins in complex biological samples the use of EDTA/gelatin zymography for enzyme development is advised. In addition, by quantification of EDTA/gelatin zymography analysis and ELISA, we observed that the levels of C1s were higher in plasma and immune complexes of SLE patients than of healthy individuals. Therefore, our data imply that C1s may become a marker for the diagnosis of SLE. 相似文献
34.
Anne-Marie Lundsgaard Jacob B. Holm Kim A. Sjøberg Kirstine N. Bojsen-Møller Lene S. Myrmel Even Fjære Benjamin A.H. Jensen Trine S. Nicolaisen Janne R. Hingst Sine L. Hansen Sophia Doll Philip E. Geyer Atul S. Deshmukh Jens J. Holst Lise Madsen Karsten Kristiansen Jørgen F.P. Wojtaszewski Erik A. Richter Bente Kiens 《Cell metabolism》2019,29(1):50-63.e4
35.
Although the cyclic nucleotide-modulated potassium channel from Mesorhizobium loti, MlotiK1, is easily studied using a 86Rb+ flux assay, its comparatively low activity raises serious concerns about the integrity of the purified protein. We investigated the pathway of uptake using a multi-pronged approach. First, we probed the conduction pathway using quaternary ammonium compounds known to block conduction in eukaryotic K+ channels. Second, we examined the effect of chemical modification of putative pore-lining residues. Our results are consistent with ions traversing MlotiK1 along a conduction pathway like that of the eukaryotic channels, but at a much slower rate. 相似文献
36.
Organelle genomics has become an increasingly important research field, with applications in molecular modeling, phylogeny, taxonomy, population genetics and biodiversity. Typically, research projects involve the determination and comparative analysis of complete mitochondrial and plastid genome sequences, either from closely related species or from a taxonomically broad range of organisms. Here, we describe two alternative organelle genome sequencing protocols. The "random genome sequencing" protocol is suited for the large majority of organelle genomes irrespective of their size. It involves DNA fragmentation by shearing (nebulization) and blunt-end cloning of the resulting fragments into pUC or BlueScript-type vectors. This protocol excels in randomness of clone libraries as well as in time and cost-effectiveness. The "long-PCR-based genome sequencing" protocol is specifically adapted for DNAs of low purity and quantity, and is particularly effective for small organelle genomes. Library construction by either protocol can be completed within 1 week. 相似文献
37.
Jon Nielsen Vibeke Brix Christensen Lise Borgwardt Allan Rasmussen Olga Østrup Mette Skalshøi Kjær 《生物化学与生物物理学报:疾病的分子基础》2019,1865(3):577-586
Pediatric liver disease (PLD) is a major cause of severe morbidity and prolonged hospitalizations in children. Stratifying patients in terms of prognosis remains challenging. The limited knowledge about molecular mechanisms causing and accompanying PLD remains the main obstacle in a search for reliable prognostic biomarkers. A systematic search of MEDLINE via PubMed and Embase via OVID was conducted on studies published between August 2007 and August 2017. Molecular markers with a prognostic potential in terms of survival, need for liver transplantation or disease progression/regression were selected. In general, identified studies were single center smaller case-control studies or case series with a low level of evidence and a high risk of bias. Only 23 studies comprising 898 patients could be included, mostly focusing on biliary atresia, non-alcoholic fatty liver disease, viral hepatitis, and LT; and markers related to morphogenesis and fibrosis. Furthermore, molecular markers in metabolic pathways and inflammation shown to be relevant, however requiring further validation. Hence, further biological and clinical studies are needed to gain greater molecular insight into PLD. 相似文献
38.
Virginie E Desse Cassandra R Blanchette Malika Nadour Paola Perrat Lise Rivollet Anagha Khandekar Claire Y Bnard 《Genetics》2021,218(4)
Whereas remarkable advances have uncovered mechanisms that drive nervous system assembly, the processes responsible for the lifelong maintenance of nervous system architecture remain poorly understood. Subsequent to its establishment during embryogenesis, neuronal architecture is maintained throughout life in the face of the animal’s growth, maturation processes, the addition of new neurons, body movements, and aging. The Caenorhabditis elegans protein SAX-7, homologous to the vertebrate L1 protein family of neural adhesion molecules, is required for maintaining the organization of neuronal ganglia and fascicles after their successful initial embryonic development. To dissect the function of sax-7 in neuronal maintenance, we generated a null allele and sax-7S-isoform-specific alleles. We find that the null sax-7(qv30) is, in some contexts, more severe than previously described mutant alleles and that the loss of sax-7S largely phenocopies the null, consistent with sax-7S being the key isoform in neuronal maintenance. Using a sfGFP::SAX-7S knock-in, we observe sax-7S to be predominantly expressed across the nervous system, from embryogenesis to adulthood. Yet, its role in maintaining neuronal organization is ensured by postdevelopmentally acting SAX-7S, as larval transgenic sax-7S(+) expression alone is sufficient to profoundly rescue the null mutants’ neuronal maintenance defects. Moreover, the majority of the protein SAX-7 appears to be cleaved, and we show that these cleaved SAX-7S fragments together, not individually, can fully support neuronal maintenance. These findings contribute to our understanding of the role of the conserved protein SAX-7/L1CAM in long-term neuronal maintenance and may help decipher processes that go awry in some neurodegenerative conditions. 相似文献
39.
Malte Jochum Lise Thouvenot Olga Ferlian Romy Zeiss Bernhard Klarner Ulrich Pruschitzki Edward A. Johnson Nico Eisenhauer 《Biology letters》2022,18(3)
Declining arthropod communities have recently gained a lot of attention, with climate and land-use change among the most frequently discussed drivers. Here, we focus on a seemingly underrepresented driver of arthropod community decline: biological invasions. For approximately 12 000 years, earthworms have been absent from wide parts of northern North America, but they have been re-introduced with dramatic consequences. Most studies investigating earthworm-invasion impacts focus on the belowground world, resulting in limited knowledge on aboveground-community changes. We present observational data on earthworm, plant and aboveground arthropod communities in 60 plots, distributed across areas with increasing invasion status (low, medium and high) in a Canadian forest. We analysed how earthworm-invasion status and biomass impact aboveground arthropod community abundance, biomass and species richness, and how earthworm impacts cascade across trophic levels. We sampled approximately 13 000 arthropods, dominated by Hemiptera, Diptera, Araneae, Thysanoptera and Hymenoptera. Total arthropod abundance, biomass and species richness declined significantly from areas of low to those with high invasion status, with reductions of 61, 27 and 18%, respectively. Structural equation models suggest that earthworms directly and indirectly impact arthropods across trophic levels. We show that earthworm invasion can alter aboveground multi-trophic arthropod communities and suggest that belowground invasions might be underappreciated drivers of aboveground arthropod decline. 相似文献
40.
Twisted gastrulation (Tsg) is a secreted protein that regulates Bmp signaling in the extracellular space through its direct interaction with Bmp/Dpp and Chordin (Chd)/Short gastrulation (Sog). The ternary complex of Tsg/Chd/Bmp is cleaved by the metalloprotease Tolloid (Tld)/Xolloid (Xld). Studies in Drosophila, Xenopus and zebrafish suggest that Tsg can act both as an anti-Bmp and as a pro-Bmp. We have analyzed Tsg loss-of-function in the mouse. Tsg homozygous mutants are viable but of smaller size and display mild vertebral abnormalities and osteoporosis. We provide evidence that Tsg interacts genetically with Bmp4. When only one copy of Bmp4 is present, a requirement of Tsg for embryonic development is revealed. Tsg-/-;Bmp4+/- compound mutants die at birth and display holoprosencephaly, first branchial arch and eye defects. The results show that Tsg functions to promote Bmp4 signaling during mouse head development. 相似文献