The Drosophila Gap Gene Network Is Composed of Two Parallel Toggle Switches

Drosophila “gap” genes provide the first response to maternal gradients in the early fly embryo. Gap genes are expressed in a series of broad bands across the embryo during first hours of development. The gene network controlling the gap gene expression patterns includes inputs from maternal gradients and mutual repression between the gap genes themselves. In this study we propose a modular design for the gap gene network, involving two relatively independent network domains. The core of each network domain includes a toggle switch corresponding to a pair of mutually repressive gap genes, operated in space by maternal inputs. The toggle switches present in the gap network are evocative of the phage lambda switch, but they are operated positionally (in space) by the maternal gradients, so the synthesis rates for the competing components change along the embryo anterior-posterior axis. Dynamic model, constructed based on the proposed principle, with elements of fractional site occupancy, required 5–7 parameters to fit quantitative spatial expression data for gap gradients. The identified model solutions (parameter combinations) reproduced major dynamic features of the gap gradient system and explained gap expression in a variety of segmentation mutants

Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Drosophila Development

Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6–0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision

Bypass surgery or stenting for left main coronary artery disease in patients with diabetes

Background The randomized EXCEL (Evaluation of XIENCE versus Coronary Arteryandnbsp;Bypass Surgeryandnbsp;for Effectiveness of Left Main Revascularization) trial reported a similar rate of the 3-year composite primary endpoint ofandnbsp;death,andnbsp;myocardial infarctionandnbsp;(MI), orandnbsp;strokeandnbsp;in patients with left mainandnbsp;coronary artery diseaseandnbsp;(LMCAD) and site-assessed low or intermediateandnbsp;SYNTAX scoresandnbsp;treated withandnbsp;percutaneous coronary interventionandnbsp;(PCI) and coronary artery bypass grafting (CABG). Whether these results are consistent in high-riskandnbsp;patients with diabetes, who have fared relatively better with CABG in most prior trials, is unknown. Objectives In this pre-specifiedandnbsp;subgroup analysisandnbsp;from the EXCEL trial, the authors sought to examine the effect ofandnbsp;diabetesandnbsp;in patients with LMCAD treated with PCI versus CABG. Methods Patients (Nandnbsp;=andnbsp;1,905) with LMCAD and site-assessed low or intermediate CAD complexity (SYNTAX scoresandnbsp;andle;32) were randomized 1:1 to PCI with everolimus-elutingandnbsp;stentsandnbsp;versus CABG, stratified by the presence ofandnbsp;diabetes. The primary endpoint was the rate of a composite of all-causeandnbsp;death,andnbsp;stroke, or MI at 3 years. Outcomes were examined in patients with (nandnbsp;=andnbsp;554) and without (nandnbsp;=andnbsp;1,350) diabetes. Results The 3-year composite primary endpoint was significantly higher in diabetic compared with nondiabetic patients (20.0% vs. 12.9%; pandnbsp;andlt; 0.001). The rate of the 3-year primary endpoint was similar after treatment with PCI and CABG in diabetic patients (20.7% vs. 19.3%, respectively;andnbsp;hazard ratio: 1.03; 95%andnbsp;confidence interval: 0.71 to 1.50; pandnbsp;=andnbsp;0.87) and nondiabetic patients (12.9% vs. 12.9%, respectively;andnbsp;hazard ratio: 0.98; 95% confidence interval: 0.73 to 1.32; pandnbsp;=andnbsp;0.89). All-cause death at 3 years occurred in 13.6% of PCI and 9.0% of CABG patients (pandnbsp;=andnbsp;0.046), although no significant interaction was present between diabetes status and treatment for all-cause death (pandnbsp;=andnbsp;0.22) or other endpoints, including the 3-year primary endpoint (pandnbsp;=andnbsp;0.82) or the major secondary endpoints of death, MI, or stroke at 30andnbsp;days (pandnbsp;=andnbsp;0.61) or death, MI, stroke, or ischemia-driven revascularization at 3 years (pandnbsp;=andnbsp;0.65). Conclusions In the EXCEL trial, the relative 30-day and 3-year outcomes of PCI with everolimus-eluting stents versus CABG were consistent in diabetic and nondiabetic patients with LMCAD and site-assessed low or intermediateandnbsp;SYNTAX scores.(Evaluation of XIENCE versusandnbsp;Coronary Artery Bypassandnbsp;Surgery for Effectiveness of Left Mainandnbsp;Revascularizationandnbsp;[EXCEL];andnbsp;NCT01205776)</p

Everolimus-eluting stents or bypass surgery for left main coronary artery disease.

Background Patients with obstructive left main coronary artery disease are usually treated with coronary-artery bypass grafting (CABG). Randomized trials have suggested that drug-eluting stents may be an acceptable alternative to CABG in selected patients with left main coronary disease. Methods We randomly assigned 1905 eligible patients with left main coronary artery disease of low or intermediate anatomical complexity to undergo either percutaneous coronary intervention (PCI) with fluoropolymer-based cobalt–chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). Anatomic complexity was assessed at the sites and defined by a Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score of 32 or lower (the SYNTAX score reflects a comprehensive angiographic assessment of the coronary vasculature, with 0 as the lowest score and higher scores [no upper limit] indicating more complex coronary anatomy). The primary end point was the rate of a composite of death from any cause, stroke, or myocardial infarction at 3 years, and the trial was powered for noninferiority testing of the primary end point (noninferiority margin, 4.2 percentage points). Major secondary end points included the rate of a composite of death from any cause, stroke, or myocardial infarction at 30 days and the rate of a composite of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years. Event rates were based on Kaplan–Meier estimates in time-to-first-event analyses. Results At 3 years, a primary end-point event had occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P = 0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval, 0.79 to 1.26; P = 0.98 for superiority). The secondary end-point event of death, stroke, or myocardial infarction at 30 days occurred in 4.9% of the patients in the PCI group and in 7.9% in the CABG group (P&lt;0.001 for noninferiority, P = 0.008 for superiority). The secondary end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years occurred in 23.1% of the patients in the PCI group and in 19.1% in the CABG group (P = 0.01 for noninferiority, P = 0.10 for superiority). Conclusions In patients with left main coronary artery disease and low or intermediate SYNTAX scores by site assessment, PCI with everolimus-eluting stents was noninferior to CABG with respect to the rate of the composite end point of death, stroke, or myocardial infarction at 3 years.</p

Contrasting patterns in the vertical distribution of decapod crustaceans throughout ontogeny

In marine ecosystems, the most significant migration observed in terms of biomass distribution is the one connected with the vertical movements in the water column. In the present study, the vertical profiles of the mesopelagic shrimps Gennadas elegans, Eusergestes arcticus, Sergia robusta, and the epipelagic Parasergestes vigilax in the Balearic Sea (western Mediterranean), during the stratified (summer) and non-stratified (autumn) hydrographic conditions, were investigated through their ontogeny, from the larval to adult stages. The mesopelagic adults were observed to move down to the deeper layers during the night more than during the daylight hours. Most larvae aggregated within the limits of the upper water column. The P. vigilax larvae were collected only during the stratified period. The first two larval stages vertical distribution indicates that the mesopelagic crustacean spawning could occur at greater depths. During the non-stratified period, the larvae of the mesopelagic species tended to remain at about 500 m depth at night, rising towards the upper layers at sunrise. Vertical patterns are discussed, as strategies associated with predator–prey trade-offs. To our knowledge, the present study is the first such attempt to jointly analyze the vertical migrations of the developmental stages of the pelagic shrimps in the Mediterranean SeaVersión del editor1,78