全文获取类型
收费全文 | 1449篇 |
免费 | 107篇 |
出版年
2024年 | 3篇 |
2023年 | 12篇 |
2022年 | 34篇 |
2021年 | 67篇 |
2020年 | 32篇 |
2019年 | 44篇 |
2018年 | 58篇 |
2017年 | 45篇 |
2016年 | 60篇 |
2015年 | 92篇 |
2014年 | 85篇 |
2013年 | 100篇 |
2012年 | 143篇 |
2011年 | 131篇 |
2010年 | 61篇 |
2009年 | 71篇 |
2008年 | 80篇 |
2007年 | 76篇 |
2006年 | 62篇 |
2005年 | 70篇 |
2004年 | 65篇 |
2003年 | 33篇 |
2002年 | 41篇 |
2001年 | 12篇 |
2000年 | 5篇 |
1999年 | 9篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 9篇 |
1995年 | 4篇 |
1994年 | 9篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1977年 | 1篇 |
1971年 | 2篇 |
1969年 | 1篇 |
1968年 | 2篇 |
1967年 | 1篇 |
1966年 | 1篇 |
排序方式: 共有1556条查询结果,搜索用时 15 毫秒
861.
Three of the most frequent antitubercular agents employed against Mycobacterium tuberculosis are: Rifampicin, Isoniazid and
Pyrazinamide. It has been proven that the use of these antitubercular agents together, shortens the treatment period from
12–18 months to 6 months [1]. In this work we use a new Density Functional Theory chemistry model called CHIH-DFT (Chihuahua-Heterocycles-Density Functional
Theory) that reflects the mixture of Hartree Fock exchange and DFT exchange, according to a mixing parameter based on empirical
rules suited for heterocyclic systems. This new chemistry model was used to calculate the molecular structure of these antitubercular
compounds, as well as their infrared, UV spectra, chemical reactivity and electronic properties. The UV and infrared spectra
were obtained by experimental techniques. The calculated molecular structure, UV and IR spectra values from CHIH-DFT were
compared with experimentally obtained values and theoretical studies. These results are in good agreement with experimental
and theoretical studies. We also predicted using the relative electrophilicity and relative nucleophilicity concepts as defined
by Roy et al. [2] the chemical active sites for the three antitubercular compounds as well as their electronegativity, ionization potential,
electron affinity, hardness, dipole moment, EHOMO-ELUMO gap energy, etc.
相似文献
862.
Upwelling is known to affect the ecology and life history of temperate nearshore organisms, and these effects are thought to be mediated by changes in temperature and food supply. However, little information is available for tropical systems. To understand how changes in the intensity of upwelling might impact marine invertebrates, we tested how factorial combinations of temperature, salinity, and phytoplankton availability affected growth and reproduction of a common intertidal snail, Crepidula cf. marginalis. We used temperatures typical of nonupwelling (29°C), moderate (26°C) and severe (23°C) upwelling, salinities typical of nonupwelling (30 ppt) and upwelling (34 ppt) and a good diet (Isochrysis) and a better diet (Isochrysis and Tetraselmis) as a proxy for increased productivity during upwelling. Overall, temperature and diet had consistent effects on body size, with better food and lower temperatures promoting larger size, as well as promoting shorter time to first reproduction. Diet had the largest effects on clutch size, with clutch size increasing with better diet. Temperature had the largest effect on offspring size and the frequency of discarded broods; offspring size decreased with increasing temperature and the frequency of discarded broods also decreased with increasing temperatures. We found no significant 3rd order interactions and few significant strong 2nd order interactions, which have often been found in similar experimental studies using stressful treatments. For this tropical slipper limpet, the effect of higher food and cooler temperatures during upwelling appears to be positive, promoting higher growth rates, larger clutch sizes, and larger offspring size suggesting that both factors likely play an important role underlying reproductive responses to upwelling. Climatic changes, like El Niño, which suppress upwelling in the Bay of Panama, appear likely to negatively impact this species. 相似文献
863.
Francesca Fiegna Thomas Scheuerl Alejandra Moreno-Letelier Thomas Bell Timothy G. Barraclough 《Proceedings. Biological sciences / The Royal Society》2015,282(1815)
Species interactions can play a major role in shaping evolution in new environments. In theory, species interactions can either stimulate evolution by promoting coevolution or inhibit evolution by constraining ecological opportunity. The relative strength of these effects should vary as species richness increases, and yet there has been little evidence for evolution of component species in communities. We evolved bacterial microcosms containing between 1 and 12 species in three different environments. Growth rates and yields of isolates that evolved in communities were lower than those that evolved in monocultures, consistent with recent theory that competition constrains species to specialize on narrower sets of resources. This effect saturated or reversed at higher levels of richness, consistent with theory that directional effects of species interactions should weaken in more diverse communities. Species varied considerably, however, in their responses to both environment and richness levels. Mechanistic models and experiments are now needed to understand and predict joint evolutionary dynamics of species in diverse communities. 相似文献
864.
Guelaug Katrín Hákonardóttir Pablo López-Ceballos Alejandra Donají Herrera-Reyes Raibatak Das Daniel Coombs Guy Tanentzapf 《Molecular biology of the cell》2015,26(22):4149-4162
Cell adhesion to the extracellular matrix (ECM) allows cells to form and maintain three-dimensional tissue architecture. Cell–ECM adhesions are stabilized upon exposure to mechanical force. In this study, we used quantitative imaging and mathematical modeling to gain mechanistic insight into how integrin-based adhesions respond to increased and decreased mechanical forces. A critical means of regulating integrin-based adhesion is provided by modulating the turnover of integrin and its adhesion complex (integrin adhesion complex [IAC]). The turnover of the IAC component Talin, a known mechanosensor, was analyzed using fluorescence recovery after photobleaching. Experiments were carried out in live, intact flies in genetic backgrounds that increased or decreased the force applied on sites of adhesion. This analysis showed that when force is elevated, the rate of assembly of new adhesions increases such that cell–ECM adhesion is stabilized. Moreover, under conditions of decreased force, the overall rate of turnover, but not the proportion of adhesion complex components undergoing turnover, increases. Using point mutations, we identify the key functional domains of Talin that mediate its response to force. Finally, by fitting a mathematical model to the data, we uncover the mechanisms that mediate the stabilization of ECM-based adhesion during development. 相似文献
865.
866.
María-José Lorenzo Inés Moret Benjamín Sarria Enrique Cases Julio Cortijo Raúl Méndez Jose Molina Alejandra Gimeno Rosario Menéndez 《Respiratory research》2015,16(1)
Background
In community-acquired pneumonia host inflammatory response against the causative microorganism is necessary for infection resolution. However an excessive response can have deleterious effects. In addition to antimicrobial effects, macrolide antibiotics are known to possess immunomodulatory properties.We aimed to evaluate inflammatory cytokine profiles – both locally (bronchoalveolar lavage) and systemically (blood) – in community-acquired pneumonia admitted patients after at least 72 hours of antibiotic treatment (with and without macrolide containing regimens) and requiring bronchoscopic examination for inadequate response due to infection progression and/or lack of clinical stability.Methods
A prospective study was performed on 52 admitted patients who developed an inadequate response after 72 hours of antibiotic treatment - non-responders community-acquired pneumonia - (blood and bronchoalveolar lavage), and two control groups: 1) community-acquired pneumonia control (blood) and 2) non-infection control (blood and bronchoalveolar lavage). Cytokine profiles (interleukin (IL)-6, IL-8, IL-10), tumour necrosis factor α and clinical outcomes were assessed.Results
Non–responders patients treated with macrolide containing regimens showed significantly lower levels of IL-6 and TNF-α in bronchoalveolar lavage fluid and lower IL-8 and IL-10 in blood than those patients treated with non-macrolide regimens. Clinical outcomes showed that patients treated with macrolide regimens required fewer days to reach clinical stability (p < 0.01) and shorter hospitalization periods (p < 0.01).Conclusions
After 72 hours of antibiotic effect, patients who received macrolide containing regimens exhibited lower inflammatory cytokine levels in pulmonary and systemic compartments along with faster stabilization of infectious parameters. 相似文献867.
Kirsten M Ellegaard Daniel Tamarit Emelie Javelind Tobias C Olofsson Siv GE Andersson Alejandra Vásquez 《BMC genomics》2015,16(1)
Background
In the honeybee Apis mellifera, the bacterial gut community is consistently colonized by eight distinct phylotypes of bacteria. Managed bee colonies are of considerable economic interest and it is therefore important to elucidate the diversity and role of this microbiota in the honeybee. In this study, we have sequenced the genomes of eleven strains of lactobacilli and bifidobacteria isolated from the honey crop of the honeybee A. mellifera.Results
Single gene phylogenies confirmed that the isolated strains represent the diversity of lactobacilli and bifidobacteria in the gut, as previously identified by 16S rRNA gene sequencing. Core genome phylogenies of the lactobacilli and bifidobacteria further indicated extensive divergence between strains classified as the same phylotype. Phylotype-specific protein families included unique surface proteins. Within phylotypes, we found a remarkably high level of gene content diversity. Carbohydrate metabolism and transport functions contributed up to 45% of the accessory genes, with some genomes having a higher content of genes encoding phosphotransferase systems for the uptake of carbohydrates than any previously sequenced genome. These genes were often located in highly variable genomic segments that also contained genes for enzymes involved in the degradation and modification of sugar residues. Strain-specific gene clusters for the biosynthesis of exopolysaccharides were identified in two phylotypes. The dynamics of these segments contrasted with low recombination frequencies and conserved gene order structures for the core genes. Hits for CRISPR spacers were almost exclusively found within phylotypes, suggesting that the phylotypes are associated with distinct phage populations.Conclusions
The honeybee gut microbiota has been described as consisting of a modest number of phylotypes; however, the genomes sequenced in the current study demonstrated a very high level of gene content diversity within all three described phylotypes of lactobacilli and bifidobacteria, particularly in terms of metabolic functions and surface structures, where many features were strain-specific. Together, these results indicate niche differentiation within phylotypes, suggesting that the honeybee gut microbiota is more complex than previously thought.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1476-6) contains supplementary material, which is available to authorized users. 相似文献868.
869.
Mendez-Bolaina Enrique; Sanchez-Gonzalez Javier; Ramirez-Sanchez Israel; Ocharan-Hernandez Esther; Nunez-Sanchez Marisol; Meaney-Mendiolea Eduardo; Meaney Alejandra; Asbun-Bojalil Juan; Miliar-Garcia Angel; Olivares-Corichi Ivonne; Ceballos-Reyes Guillermo 《American journal of physiology. Cell physiology》2007,293(6):C1953
Caveolae are identifiable plasma membrane invaginations. The main structural proteins of caveolae are the caveolins. There are three caveolins expressed in mammals, designated Cav-1, Cav-2, and Cav-3. It has been postulated that Cav-1 acts as a scaffold protein for signaling proteins; these include ion channels, enzymes, and other ligand receptors like membrane-associated estrogen receptor (ER) or ERβ. Caveolae-associated membrane proteins are involved in regulating some of the rapid estrogenic effects of 17β-estradiol. One important system related to the activity of ER and caveolae is the renin-angiotensin system. Angiotensin II (ANG II) has numerous actions in vascular smooth muscle, including modulation of vasomotor tone, cell growth, apoptosis, phosphatidylinositol 3-kinase (PI3K)/Akt activation, and others. Many proteins associated with caveolae are in close relation with the scaffolding domain of Cav-1 (82–101 amino acid residues). It has been proposed that this peptide may acts as a kinase inhibitor. Therefore, to explore the ability of Cav-1 scaffolding peptide (CSP-1) to regulate ANG II function and analyze the relationship between ER and ANG II type 1 and 2 (AT1 and AT2) receptors, we decided to study the effects of CSP-1 on ANG II-induced intracellular Ca2+ kinetics and the effect of 17β-estradiol on this modulation using human smooth muscle cells in culture, intracellular Ca2+ concentration measurements, immuno- and double-immunocytochemistry confocal analysis of receptor expression, immunoblot analysis, and immunocoprecipitation assays to demonstrate coexpression. We hypothesized that CSP-1 inhibits ANG II-mediated increases in intracellular Ca2+ concentrations by interfering with intracellular signaling including the PI3K/Akt pathway. We also hypothesize that AT2 receptors associate with Cav-1. Our results show that there is a close association of AT1, AT2, and ER with Cav-1 in human arterial smooth muscle cells in culture. CSP-1 inhibits ANG II-induced intracellular signaling. estrogen receptors; angiotensin type 1 and 2 receptors; phosphatidylinositol 3-kinase; intracellular signaling; tissue culture; angiotensin receptors 相似文献
870.
Romina A. Gisonno Tomas Masson Nahuel A. Ramella Exequiel E. Barrera Víctor Romanowski M. Alejandra Tricerri 《Proteins》2022,90(1):258-269
Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural consequences introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA-I. We combined evolutionary studies, in silico mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation-prone regions (APRs) present in apoA-I. Sequence analysis demonstrated that among the four amyloidogenic regions described for human apoA-I, only two (APR1 and APR4) are evolutionary conserved across different species of Sarcopterygii. Moreover, stability analysis carried out with the FoldX engine showed that APR1 contributes to the marginal stability of apoA-I. Structural properties of full-length apoA-I models suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Compared to silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of amyloid mutations showed evidence of a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the alpha-helix bundle with the concomitant exposure of APR1 to the solvent, suggesting an insight into the early steps involved in its aggregation. Our findings highlight APR1 as a relevant component for apoA-I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of this region. 相似文献