全文获取类型
收费全文 | 847篇 |
免费 | 95篇 |
出版年
2022年 | 10篇 |
2021年 | 16篇 |
2017年 | 13篇 |
2016年 | 11篇 |
2015年 | 17篇 |
2014年 | 25篇 |
2013年 | 33篇 |
2012年 | 36篇 |
2011年 | 30篇 |
2010年 | 37篇 |
2009年 | 22篇 |
2008年 | 34篇 |
2007年 | 45篇 |
2006年 | 30篇 |
2005年 | 36篇 |
2004年 | 29篇 |
2003年 | 19篇 |
2002年 | 36篇 |
2001年 | 28篇 |
2000年 | 32篇 |
1999年 | 21篇 |
1998年 | 16篇 |
1997年 | 8篇 |
1996年 | 13篇 |
1994年 | 6篇 |
1993年 | 6篇 |
1992年 | 12篇 |
1991年 | 19篇 |
1990年 | 14篇 |
1989年 | 10篇 |
1988年 | 8篇 |
1987年 | 13篇 |
1986年 | 15篇 |
1985年 | 7篇 |
1984年 | 14篇 |
1983年 | 13篇 |
1982年 | 7篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 11篇 |
1978年 | 13篇 |
1977年 | 9篇 |
1974年 | 8篇 |
1973年 | 13篇 |
1972年 | 7篇 |
1971年 | 5篇 |
1970年 | 5篇 |
1969年 | 11篇 |
1967年 | 5篇 |
1963年 | 5篇 |
排序方式: 共有942条查询结果,搜索用时 31 毫秒
61.
Development of protegrins for the treatment and prevention of oral mucositis: structure-activity relationships of synthetic protegrin analogues 总被引:9,自引:0,他引:9
Chen J Falla TJ Liu H Hurst MA Fujii CA Mosca DA Embree JR Loury DJ Radel PA Cheng Chang C Gu L Fiddes JC 《Biopolymers》2000,55(1):88-98
Protegrin antimicrobial peptides possess activity against gram-positive and gram-negative bacteria and yeasts. An extensive structure-activity relationship (SAR) study was conducted on several hundred protegrin analogues to gain understanding of the relationship between the primary and secondary structure of the protegrins and their antimicrobial activities, and to identify a protegrin analogue for clinical development. Native sequence protegrins are cationic, amphiphilic peptides that are characterized by the presence of a beta-sheet structure that is maintained by two disulfide bridges. The presence of the beta-sheet is key to the stability of the protegrin structure; linearized analogues or analogues that have amino acid substitutions that eliminate hydrogen bonding across the beta-sheet have reduced activity, especially in the presence of physiological concentrations of NaCl. Also, maintaining amphiphilicity of the beta-sheet is key; analogues with substitutions of polar amino acids in the hydrophobic face have reduced activity. Analogues with reduced positive charge tend to be less active, an observation that is more marked for gram-negative than gram-positive bacteria, and may implicate binding to lipopolysaccharide as a key mechanistic step in the killing of gram-negative bacteria. A very large number of amino acid substitutions are tolerated by the protegrin structure, implying that overall structural features such as amphiphilicity, charge, and shape are more important to activity than the presence of specific amino acids. This lack of importance of specific stereochemistry is supported by the fact that completely D-amino acid substituted protegrins are fully potent. Based on the SAR studies, and on the microbiological data from an animal model, one protegrin analogue, IB-367, was selected for clinical development as a topical agent to prevent the oral mucositis associated with cancer therapy. 相似文献
62.
NO way back: nitric oxide and programmed cell death in Arabidopsis thaliana suspension cultures 总被引:27,自引:2,他引:25
Clarke A Desikan R Hurst RD Hancock JT Neill SJ 《The Plant journal : for cell and molecular biology》2000,24(5):667-677
Recent research has implicated nitric oxide (NO) in the induction of the hypersensitive response (HR) during plant-pathogen interactions. Here we demonstrate that Arabidopsis suspension cultures generate elevated levels of NO in response to challenge by avirulent bacteria, and, using NO donors, show that these elevated levels of NO are sufficient to induce cell death in Arabidopsis cells independently of reactive oxygen species (ROS). We also provide evidence that NO-induced cell death is a form of programmed cell death (PCD), requiring gene expression, and has a number of characteristics of PCD of mammalian cells: NO induced chromatin condensation and caspase-like activity in Arabidopsis cells, while the caspase-1 inhibitor, Ac-YVAD-CMK, blocked NO-induced cell death. A well-established second messenger mediating NO responses in mammalian cells is cGMP, produced by the enzyme guanylate cyclase. A specific inhibitor of guanylate cyclase blocked NO-induced cell death in Arabidopsis cells, and this inhibition was reversed by the cell-permeable cGMP analogue, 8Br-cGMP, although 8Br-cGMP alone did not induce cell death or potentiate NO-induced cell death. This suggests that cGMP synthesis is required but not sufficient for NO-induced cell death in Arabidopsis. In-gel protein kinase assays showed that NO activates a potential mitogen-activated protein kinase (MAPK), although a specific inhibitor of mammalian MAPK activation, PD98059, which blocked H2O2-induced cell death, did not inhibit the effects of NO. 相似文献
63.
The repeatability of patterns of variation in Ka/Ks and Ks is expected if such patterns are the result of deterministic forces. We have contrasted the molecular evolution of the mammalian insulin-like growth factor type II receptor (Igf2r) in the mouse-rat comparison with that in the human-cow comparison. In so doing, we investigate explanations for both the evolution of genomic imprinting and for Ks variation (and hence putatively for mutation rate evolution). Previous analysis of Igf2r, in the mouse-rat comparison, found Ka/Ks patterns that were suggested to be contrary to those expected under the conflict theory of imprinting. We find that Ka/Ks variation is repeatable and hence confirm these patterns. However, we also find that the molecular evolution of Igf2r signal sequences suggests that positive selection, and hence conflict, may be affecting this region. The variation in Ks across Igf2r is also repeatable. To the best of our knowledge this is the first demonstration of such repeatability. We consider three explanations for the variation in Ks across the gene: (1) that it is the result of mutational biases, (2) that it is the result of selection on the mutation rate, and (3) that it is the product of selection on codon usage. Explanations 2 and 3 predict a Ka-Ks correlation, which is not found. Explanation 3 also predicts a negative correlation between codon bias and Ks, which is also not found. However, in support of explanation 1 we do find that in rodents the rate of silent C --> T mutations at CpG sites does covary with Ks, suggesting that methylation-induced mutational patterns can explain some of the variation in Ks. We find evidence to suggest that this CpG effect is due to both variation in CpG density, and to variation in the frequency with which CpGs mutate. Interestingly, however, a GC4 analysis shows no covariance with Ks, suggesting that to eliminate methyl-associated effects CpG rates themselves must be analyzed. These results suggest that, in contrast to previous studies of intragenic variation, Ks patterns are not simply caused by the same forces responsible for Ka/Ks correlations. 相似文献
64.
Employing a set of 43 othologous mouse and rat genes, Hughes and Yeager (J. Mol. Evol. 45:125–130, 1997) reported (1) no correlation between synonymous and nonsynonymous rates of nucleotide substitution, (2)
a positive correlation between intronic GC contents (GC
i) and intronic substitution rates (K
i), (3) that the average K
i value was very similar to the average K
s value, and (4) that the compositional correlation between the rat and the mouse genes is stronger at the third codon position
(GC3) than at the first and second codon positions (GC12). We have examined the robustness of these results to alterations in substitution rate estimation protocol, alignment protocol,
and statistical procedure. We find that a significant correlation between K
a and K
s is observed either if a rank correlation statistic is used instead of regression analysis, if one outlier is excluded from
the analysis, or if a regression weighted by gene size is employed. The correlation between K
i and GC
i we find to be sensitive to changes in alignment protocol and disappears on the use of weighted means. The finding that K
s and K
i are approximately the same is dependent on the method for estimating K
s values. Finally, the variance around the regression line of rat GC3 versus mouse GC3 we find to be significantly higher than that in GC12. The source of the discrepancy between this and Hughes and Yeager's result is unclear. The variance around the line for GC4 is higher still, as might be expected. Using a methodology that may be considered preferable to that of Hughes and Yeager,
we find that all four of their results are contradicted. More importantly this analysis reinforces the need for caution in
assembling and analyzing data sets, as the degree of sensitivity to what many might consider minor methodological alterations
is unexpected.
Received: 2 February 1998 / Accepted: 23 March 1998 相似文献
65.
Background
Whilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time.Methods
Gastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms.Results
The gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity.Conclusions
Whilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between subjects generally precluded the identification of all but gross variation between treatments. The lack of any differences between treatments in either total small or large intestinal transit times indicates that the solutions administered in the lactulose mannitol test of permeability had no consistent influence on the temporal pattern of absorption. The negatively exponential profile and lack of any peaks in the frequency spectra of cyclic variation in gastric intraluminal pressure that were consistent with reported physiological frequencies of contractile activity profile suggests that the principal source of this variation is stochastic likely resulting from the effects of external events occasioned by normal daily activities on intra-abdominal pressure.Trial Registration
Australian New Zealand Clinical Trials Registry ACTRN12615000596505 相似文献66.
Whilst parthenogenesis has evolved multiple times from sexual invertebrate and vertebrate lineages, the drivers and consequences
of the sex-asex transition remain mostly uncertain. A model by Stouthamer et al. recently published in BMC Evolutionary Biology shows a pathway by which obligate asexuality could be selected for following endosymbiont infection. 相似文献
67.
Adrian Doroszko Thomas S Hurst Dorota Polewicz Jolanta Sawicka Justyna Fert-Bober David H Johnson Grzegorz Sawicki 《Proteome science》2010,8(1):3
Background
Although mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses. 相似文献68.
69.
70.
Isolation of avian paramyxovirus 1 from a patient with a lethal case of pneumonia 总被引:4,自引:0,他引:4 下载免费PDF全文
Goebel SJ Taylor J Barr BC Kiehn TE Castro-Malaspina HR Hedvat CV Rush-Wilson KA Kelly CD Davis SW Samsonoff WA Hurst KR Behr MJ Masters PS 《Journal of virology》2007,81(22):12709-12714
An unknown virus was isolated from a lung biopsy sample and multiple other samples from a patient who developed a lethal case of pneumonia following a peripheral blood stem cell transplant. A random PCR-based molecular screening method was used to identify the infectious agent as avian paramyxovirus 1 (APMV-1; a group encompassing Newcastle disease virus), which is a highly contagious poultry pathogen that has only rarely been found in human infections. Immunohistochemical analysis confirmed the presence of APMV-1 antigen in sloughed alveolar cells in lung tissue from autopsy. Sequence from the human isolate showed that it was most closely related to virulent pigeon strains of APMV-1. This is the most completely documented case of a systemic human infection caused by APMV-1 and is the first report of an association between this virus and a fatal disease in a human. 相似文献