全文获取类型
收费全文 | 685篇 |
免费 | 33篇 |
国内免费 | 1篇 |
出版年
2023年 | 6篇 |
2022年 | 8篇 |
2021年 | 22篇 |
2020年 | 8篇 |
2019年 | 17篇 |
2018年 | 25篇 |
2017年 | 17篇 |
2016年 | 27篇 |
2015年 | 42篇 |
2014年 | 47篇 |
2013年 | 50篇 |
2012年 | 61篇 |
2011年 | 48篇 |
2010年 | 35篇 |
2009年 | 29篇 |
2008年 | 44篇 |
2007年 | 49篇 |
2006年 | 39篇 |
2005年 | 29篇 |
2004年 | 23篇 |
2003年 | 28篇 |
2002年 | 21篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 6篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1982年 | 1篇 |
排序方式: 共有719条查询结果,搜索用时 15 毫秒
41.
Abstract: We have reported the production of monoclonal antibody 4C5, which recognizes a cell surface antigen, the 4C5 antigen, involved in granule cell migration processes. In the present study, we investigated in a more precise manner the role of the 4C5 antigen in the different types of granule cell migrations that take place during cerebellar development. When cerebellar explant cultures derived from 10-day-old rats were performed for 2 days in the presence of monoclonal antibody 4C5, vertical granule cell migration, occurring in the presence of glia, was not significantly inhibited. In contrast, when monoclonal antibody 4C5 was included in the medium of microexplant cultures derived from 4-day-old mice and maintained for 4 days in vitro, granule cell migrations that occurred both parallel and perpendicular to the neurite bundles that were free of glia were inhibited. Moreover, a stronger inhibitory effect of the antibody was observed on migration perpendicular to the neurite bundles compared with the parallel type of migration. Our results indicate that the 4C5 antigen differentially affects the different developmental stages and types of granule cell migration during rodent cerebellar development. 相似文献
42.
Anja Irmisch Eleni Ampatzidou Ken'ichi Mizuno Matthew J O'Connell Johanne M Murray 《The EMBO journal》2009,28(2):144-155
The Smc5/6 structural maintenance of chromosomes complex is required for efficient homologous recombination (HR). Defects in Smc5/6 result in chromosome mis‐segregation and fragmentation. By characterising two Schizosaccharomyces pombe smc6 mutants, we define two separate functions for Smc5/6 in HR. The first represents the previously described defect in processing recombination‐dependent DNA intermediates when replication forks collapse, which leads to increased rDNA recombination. The second novel function defines Smc5/6 as a positive regulator of recombination in the rDNA and correlates mechanistically with a requirement to load RPA and Rad52 onto chromatin genome‐wide when replication forks are stably stalled by nucleotide depletion. Rad52 is required for all HR repair, but Rad52 loading in response to replication fork stalling is unexpected and does not correlate with damage‐induced foci. We propose that Smc5/6 is required to maintain stalled forks in a stable recombination‐competent conformation primed for replication restart. 相似文献
43.
44.
George Pentheroudakis Georgia Raptou Vassiliki Kotoula Ralph M. Wirtz Eleni Vrettou Vasilios Karavasilis Georgia Gourgioti Chryssa Gakou Konstantinos N. Syrigos Evangelos Bournakis Grigorios Rallis Ioannis Varthalitis Eleni Galani Georgios Lazaridis George Papaxoinis Dimitrios Pectasides Gerasimos Aravantinos Thomas Makatsoris Konstantine T. Kalogeras George Fountzilas 《PloS one》2015,10(5)
Background
Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study.Patients and Methods
Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa.Results
Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC.Conclusions
In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression.Trial Registration
ANZCTR.org.au ACTRN12610000509066 相似文献45.
Thomas C. Darton Christoph J. Blohmke Eleni Giannoulatou Claire S. Waddington Claire Jones Pamela Sturges Craig Webster Hal Drakesmith Andrew J. Pollard Andrew E. Armitage 《PLoS neglected tropical diseases》2015,9(9)
BackgroundIron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge.Conclusions/SignificanceWe demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi. 相似文献
46.
Dimitrios Konstantinidis Filipa Pereira EvaMaria Geissen Kristina Grkovska Eleni Kafkia Paula Jouhten Yongkyu Kim Saravanan Devendran Michael Zimmermann Kiran Raosaheb Patil 《Molecular systems biology》2021,17(8)
Adaptive laboratory evolution has proven highly effective for obtaining microorganisms with enhanced capabilities. Yet, this method is inherently restricted to the traits that are positively linked to cell fitness, such as nutrient utilization. Here, we introduce coevolution of obligatory mutualistic communities for improving secretion of fitness‐costly metabolites through natural selection. In this strategy, metabolic cross‐feeding connects secretion of the target metabolite, despite its cost to the secretor, to the survival and proliferation of the entire community. We thus co‐evolved wild‐type lactic acid bacteria and engineered auxotrophic Saccharomyces cerevisiae in a synthetic growth medium leading to bacterial isolates with enhanced secretion of two B‐group vitamins, viz., riboflavin and folate. The increased production was specific to the targeted vitamin, and evident also in milk, a more complex nutrient environment that naturally contains vitamins. Genomic, proteomic and metabolomic analyses of the evolved lactic acid bacteria, in combination with flux balance analysis, showed altered metabolic regulation towards increased supply of the vitamin precursors. Together, our findings demonstrate how microbial metabolism adapts to mutualistic lifestyle through enhanced metabolite exchange. 相似文献
47.
Ana Flávia Azevedo Carvalho Maurício Boscolo Roberto da Silva Henrique Ferreira Eleni Gomes 《Journal of microbiology (Seoul, Korea)》2010,48(4):452-459
An α-glucosidase enzyme produced by the fungus Thermoascus aurantiacus CBMAI 756 was purified by ultra filtration, ammonium sulphate precipitation, and chromatography using Q Sepharose, Sephacryl
S-200, and Superose 12 columns. The apparent molecular mass of the enzyme was 83 kDa as determined in gel electrophoresis.
Maximum activity was observed at pH 4.5 at 70°C. Enzyme showed stability stable in the pH range of 3.0–9.0 and lost 40% of
its initial activity at the temperatures of 40, 50, and 60°C. In the presence of ions Na+, Ba2+, Co2+, Ni2+, Mg2+, Mn2+, Al3+, Zn2+, Ca2+ this enzyme maintained 90–105% of its maximum activity and was inhibited by Cr3+, Ag+, and Hg2+. The enzyme showed a transglycosylation property, by the release of oligosaccharides after 3 h of incubation with maltose,
and specificity for short maltooligosaccharides and α-PNPG. The Km measured for the α-glucosidase was 0.07 μM, with a Vmax of 318.0 μmol/min/mg. 相似文献
48.
Demetrios Tzimopoulos Anastasia.-C. Varvogli Maria Gdaniec Eleni Nikolakaki Pericles D. Akrivos 《Journal of inorganic biochemistry》2010,104(4):423-8167
The synthesis and study of trimethyl-, tributyl- and triphenyltin esters of the 3- and 4-aminobenzoic acids are reported. The triorganotin derivatives are characterized by elemental analyses, FT-IR and solution 1H and 13C NMR spectra. The structure of the trimethyltin 4-aminobenzoate is solved by X-ray diffraction and proves to be polymeric in nature with bridging carboxylates and trigonal bipyramidal tin(IV) environment. However, all the compounds become monomeric in solution with a tetrahedral tin coordination environment in chloroform and trigonal bipyramidal in DMSO due to coordination of the solvent as the NMR spectra have revealed. The compounds exhibit variable cytotoxic activity when tested against Κ562 myelogenous leukaemia, HeLa cervical cancer and HepG2 hepatocellular carcinoma cell lines, with the butyl derivatives being the more effective and the methyl ones the less. Interestingly, their antibacterial action was significantly lower when tested against Escherichia coli, while not appreciable direct interaction with DNA has been observed. The above observations account for a mode of action that may be related to their potential interaction with cell membranes and the subsequent inhibition of various signaling processes. 相似文献
49.
Efthimiadou EK Psomas G Sanakis Y Katsaros N Karaliota A 《Journal of inorganic biochemistry》2007,101(3):525-535
Nine new metal complexes of the quinolone antibacterial agent N-propyl-norfloxacin, pr-norfloxacin, with VO(2+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Zn(2+), MoO(2)(2+), Cd(2+) and UO(2)(2+) have been prepared and characterized with physicochemical and spectroscopic techniques while molecular mechanics calculations for Fe(3+), VO(2+) and MoO(2)(2+) complexes have been performed. In all complexes, pr-norfloxacin acts as a bidentate deprotonated ligand bound to the metal through the pyridone and one carboxylate oxygen atoms. All complexes are six-coordinate with slightly distorted octahedral geometry. For the complex VO(N-propyl-norfloxacinato)(2)(H(2)O) the axial position, trans to the vanadyl oxygen, is occupied by one pyridone oxygen atom. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA resulting to a B-->A DNA transition. The antimicrobial activity of the complexes has been tested on three different microorganisms. The complexes show equal or decreased biological activity in comparison to the free pr-norfloxacin except UO(2)(pr-norf)(2) which shows better inhibition against S. aureus. 相似文献
50.
Eleni K. Efthimiadou Nikos Katsaros Alexandra Karaliota George Psomas 《Inorganica chimica acta》2007,360(15):4093-4102
The neutral mononuclear copper(II) complexes with the quinolone antibacterial drugs, pipemidic acid and N-propyl-norfloxacin, in the presence or absence of nitrogen-donor heterocyclic ligands, 2,2′-bipyridine, 1,10-phenanthroline or 2,2′-dipyridylamine, have been prepared and characterized spectroscopically. The interaction of copper(II) with the deprotonated quinolone ligand leads to the formation of the neutral mononuclear complexes of the type [Cu(quinolone)2(H2O)] (1)–(2) while the presence of the N-donor ligand leads to the formation of the neutral mononuclear complexes of the type [Cu(quinolone)(N-donor)Cl] (3)–(8). In all the complexes, copper(II) is pentacoordinate having a distorted square pyramidal geometry. The electron paramagnetic resonance spectra of 1 and 2 are typical of mononuclear Cu(II) complexes, while for the mixed-ligands complexes 3–8 a mixture of dimeric and monomeric species is indicated. The interaction of the complexes with calf-thymus DNA has been investigated with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA by the intercalative mode. The antimicrobial activity of the complexes has been tested on three different microorganisms. All the complexes show an increased biological activity in comparison to the corresponding free quinolone ligand. 相似文献