4 research outputs found

    Identification of Genome Targets of the DET1 Complex in Higher Plants

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    Light provides a major source of information from the environment during plant growth and development. Light-regulated gene expression is partly controlled by the phytochrome photoreceptors, which once activated, are imported into the nucleus where they bind and activate transcription factors such as PIF3. Coupled with this, the degradation of positively acting intermediates such as the transcription factor HY5 by COP1 and other ubiquitin ligases acts to repress photomorphogenesis in darkness. Another negative regulator of photomorphogenesis is DET1 (De-Etiolated 1), which forms part of a nuclear-localised complex with the plant homolog of UV- Damaged DNA Binding protein 1 (DDB1) and the E2 ubiquitin-ligase activating protein COP10 (Constitutive Photomorphogenic 10). Previously it was found that DET 1 binds chromatin via a direct interaction with the core histone H2B, suggesting that DET1 may repress light activated genes by interacting directly with their promoters. Here it is shown that DET1 forms part of a CUL4-based ubiquitin ligase complex and is localised to discrete foci throughout the nucleus. Chromatin Immunoprecipitation experiments show that in the dark DET 1 binds to the promoters of the light induced CAB2 and HEMA1 genes, and that this binding is abolished in the light, coincidental with the activation of these genes. DET 1 was also detected at the promoter of the light-repressed POR-A gene when it is in its repressed state as well as the promoter of the developmental^ regulated FT gene, again when this gene is repressed. Based on these data it is proposed that the DET1 complex binds the promoters of light- regulated genes in the dark and directly represses their transcription, either by chromatin remodelling and/or ubiquitin-mediated regulation of the transcriptional apparatus. Light causes the dissociation of the DET 1 complex from these promoters, allowing activation of these genes. DET1 may also play a more general role in genome maintenance during plant development

    Health-status outcomes with invasive or conservative care in coronary disease

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    BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

    Initial invasive or conservative strategy for stable coronary disease

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    BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used
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