全文获取类型
收费全文 | 280篇 |
免费 | 36篇 |
出版年
2021年 | 2篇 |
2020年 | 2篇 |
2019年 | 3篇 |
2018年 | 2篇 |
2017年 | 8篇 |
2016年 | 7篇 |
2015年 | 7篇 |
2014年 | 10篇 |
2013年 | 12篇 |
2012年 | 15篇 |
2011年 | 14篇 |
2010年 | 9篇 |
2009年 | 12篇 |
2008年 | 12篇 |
2007年 | 12篇 |
2006年 | 11篇 |
2005年 | 8篇 |
2004年 | 12篇 |
2003年 | 12篇 |
2002年 | 11篇 |
2001年 | 6篇 |
2000年 | 12篇 |
1999年 | 8篇 |
1998年 | 14篇 |
1997年 | 10篇 |
1996年 | 6篇 |
1995年 | 4篇 |
1994年 | 7篇 |
1993年 | 2篇 |
1992年 | 7篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1981年 | 4篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 4篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1971年 | 3篇 |
1969年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有316条查询结果,搜索用时 78 毫秒
51.
Negative supercoiling of DNA by gyrase is inhibited in Salmonella enterica serovar Typhimurium during adaptation to acid stress
下载免费PDF全文
![点击此处可从《Molecular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Aoife M. Colgan Heather J. Quinn Stefani C. Kary Lesley A. Mitchenall Anthony Maxwell Andrew D.S. Cameron Charles J. Dorman 《Molecular microbiology》2018,107(6):734-746
DNA in intracellular Salmonella enterica serovar Typhimurium relaxes during growth in the acidified (pH 4–5) macrophage vacuole and DNA relaxation correlates with the upregulation of Salmonella genes involved in adaptation to the macrophage environment. Bacterial ATP levels did not increase during adaptation to acid pH unless the bacterium was deficient in MgtC, a cytoplasmic‐membrane‐located inhibitor of proton‐driven F1F0 ATP synthase activity. Inhibiting ATP binding by DNA gyrase and topo IV with novobiocin enhanced the effect of low pH on DNA relaxation. Bacteria expressing novobiocin‐resistant (NovR) derivatives of gyrase or topo IV also exhibited DNA relaxation at acid pH, although further relaxation with novobiocin was not seen in the strain with NovR gyrase. Thus, inhibition of the negative supercoiling activity of gyrase was the primary cause of enhanced DNA relaxation in drug‐treated bacteria. The Salmonella cytosol reaches pH 5–6 in response to an external pH of 4–5: the ATP‐dependent DNA supercoiling activity of purified gyrase was progressively inhibited by lowering the pH in this range, as was the ATP‐dependent DNA relaxation activity of topo IV. We propose that DNA relaxation in Salmonella within macrophage is due to acid‐mediated impairment of the negative supercoiling activity of gyrase. 相似文献
52.
In vivo sequence diversity of the protease of human immunodeficiency virus type 1: presence of protease inhibitor-resistant variants in untreated subjects. 总被引:17,自引:6,他引:11
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
W J Lech G Wang Y L Yang Y Chee K Dorman D McCrae L C Lazzeroni J W Erickson J S Sinsheimer A H Kaplan 《Journal of virology》1996,70(3):2038-2043
We have evaluated the sequence diversity of the protease human immunodeficiency virus type 1 in vivo. Our analysis of 246 protease coding domain sequences obtained from 12 subjects indicates that amino acid substitutions predicted to give rise to protease inhibitor resistance may be present in patients who have not received protease inhibitors. In addition, we demonstrated that amino acid residues directly involved in enzyme-substrate interactions may be varied in infected individuals. Several of these substitutions occurred in combination either more or less frequently than would be expected if their appearance was independent, suggesting that one substitution may compensate for the effects of another. Taken together, our analysis indicates that the human immunodeficiency virus type 1 protease has flexibility sufficient to vary critical subsites in vivo, thereby retaining enzyme function and viral pathogenicity. 相似文献
53.
54.
55.
56.
ALS/FTD‐associated FUS activates GSK‐3β to disrupt the VAPB–PTPIP51 interaction and ER–mitochondria associations
下载免费PDF全文
![点击此处可从《EMBO reports》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Patricia Gomez‐Suaga Jacqueline C Mitchell Dawn HW Lau Emma H Gray Rosa M Sancho Gema Vizcay‐Barrena Kurt J De Vos Christopher E Shaw Diane P Hanger Wendy Noble Christopher CJ Miller 《EMBO reports》2016,17(9):1326-1342
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD. 相似文献
57.
An overlap between osmotic and anaerobic stress responses: a potential role for DNA supercoiling in the coordinate regulation of gene expression 总被引:44,自引:13,他引:31
The regulation of several genes in response to osmotic and anaerobic stress has been examined. We have demonstrated a clear overlap between these two regulatory signals. Thus, the osmotically induced proU and ompC genes require anaerobic growth for optimum induction while the anaerobically induced tppB gene is also regulated by osmolarity. Furthermore, normal expression of tppB and ompC requires the positive regulatory protein OmpR, yet this requirement can be partially, or even fully, overcome by altering the growth conditions. Finally, the pleiotropic, anaerobic regulatory locus, oxrC, is also shown to affect expression of the osmotically regulated proU gene. The oxrC mutation is shown to affect the level of negative supercoiling of plasmid DNA and its effects on gene expression can be explained as secondary consequences of altered DNA topology. We suggest that there is a class of 'stress-regulated' genes that are regulated by a common mechanism in response to different environmental signals. Furthermore, our data are consistent with the notion that this regulatory overlap is mediated by changes in DNA supercoiling in response to these environmental stresses. 相似文献
58.
DNA supercoiling in Escherichia coli: topA mutations can be suppressed by DNA amplifications involving the tolC locus 总被引:9,自引:0,他引:9
The level of DNA supercoiling is crucial for many cellular processes, including gene expression, and is determined, primarily, by the opposing actions of two enzymes: topoisomerase I and DNA gyrase. Escherichia coli strains lacking topoisomerase I (topA mutants) normally fail to grow in the absence of compensatory mutations which are presumed to relax DNA. We have found that, in media of low osmolarity, topA mutants are viable in the absence of any compensatory mutation, consistent with the view that decreased extracellular osmolarity causes a relaxation of cellular DNA. At higher osmolarity most compensatory mutations, as expected, are in the gyrA and gyrB genes. The only other locus at which compensatory mutations arise, designated toc, is shown to involve the amplification of a region of chromosomal DNA which includes the tolC gene. However, amplification of tolC alone is insufficient to explain the phenotypes of toc mutants. tolC insertion mutations alter the distribution of plasmid topoisomers in vivo. This effect is probably indirect, possibly a result of altered membrane structure and an alteration in the cell's osmotic barrier. As tolC is a highly pleiotropic locus, affecting the expression of many genes, it is possible that some of the TolC phenotypes are a direct result of this topological change. The possible relationship between toc and tolC mutations, and the means by which tolC mutations might affect DNA supercoiling, are discussed. 相似文献
59.
The yeast secretory pathway is perturbed by mutations in PMR1, a member of a Ca2+ ATPase family 总被引:44,自引:0,他引:44
H K Rudolph A Antebi G R Fink C M Buckley T E Dorman J LeVitre L S Davidow J I Mao D T Moir 《Cell》1989,58(1):133-145
The genes for two new P-type ATPases, PMR1 and PMR2, have been identified in yeast. A comparison of the deduced sequences of the PMR proteins with other known ion pumps showed that both proteins are very similar to Ca2+ ATPases. PMR1 is identical to SSC1, a gene previously identified by its effect on secretion of some foreign proteins from yeast. Proteins secreted from pmr1 mutants lack the outer chain glycosylation that normally results from passage through the Golgi. Loss of PMR1 function suppresses the lethality of ypt1-1, a mutation that blocks the secretion pathway. These data suggest that PMR1 functions as a Ca2+ pump affecting transit through the secretory pathway. 相似文献
60.
The bibenzimidazol derivative 33258 Hoechst can be used to distinguish microfluorometrically between mouse and human nuclei in heterokaryons. This affords a quick and accurate alternative to autoradiography in the analysis of such heterokaryons. The 33258 Hoechst fluorescence patterns can be converted after irradiation to a Giemsa rendition of the differential staining. 相似文献