Immediate-early transcriptional response to insulin receptor stimulation.

Insulin binding to the insulin receptor triggers intracellular signaling cascades involving the activation of protein and lipid kinases. As a result, multiple biological functions of the cells are changed. Here, we analyzed the regulation and signaling cascades leading to insulin-induced activation of the stimulus-responsive transcription factors. For the analyses, we used chromatin-embedded reporter genes having a cellular nucleosomal organisation, and fibroblasts expressing human insulin receptors (HIRcB cells). The results show that stimulation of the insulin receptor induced the expression of the transcription factor Egr-1. Attenuation of Egr-1 promoter activation was observed following expression of a dominant-negative mutant of the ternary complex factor Elk-1. These data were corroborated by experiments showing that insulin receptor stimulation increased the transcriptional activation potential of Elk-1. In addition, the transcriptional activity of AP-1 was significantly elevated in insulin-stimulated HIRcB cells. Expression of the dominant-negative mutant of Elk-1 reduced insulin-induced activation of AP-1, indicating that Elk-1 controls both serum response element and AP-1-regulated transcription. Moreover, we show that stimulation of the insulin receptor activates cyclic AMP response element (CRE)-controlled transcription, involving the transcription factor CREB. Insulin-induced transcription of Elk-1 and CREB-controlled reporter genes was attenuated by overexpression of MAP kinase phosphatase-1 or a constitutively active mutant of calcineurin A, indicating that both phosphatases are part of a negative feedback loop for reducing insulin-mediated gene transcription. Finally, we show that expression of the adenoviral protein E1A selectively reduced CRE-mediated transcription following stimulation of the insulin receptor. These data indicate that insulin-regulated transcription of CRE-containing genes is under epigenetic control.

Cryoballoon pulmonary vein isolation-mediated rise of sinus rate in patients with paroxysmal atrial fibrillation.

BACKGROUND: Modulation of the cardiac autonomic nervous system by pulmonary vein isolation (PVI) influences the sinoatrial nodal rate. Little is known about the causes, maintenance and prognostic value of this phenomenon. We set out to explore the effects of cryoballoon PVI (cryo-PVI) on sinus rate and its significance for clinical outcome. METHODS AND RESULTS: We evaluated 110 patients with paroxysmal atrial fibrillation (AF), who underwent PVI using a second-generation 28 mm cryoballoon by pre-, peri- and postprocedural heart rate acquisition and analysis of clinical outcome. Ninety-one patients could be included in postinterventional follow-up, indicating that cryo-PVI resulted in a significant rise of sinus rate by 16.5% (+ 9.8 ± 0.9 beats/min, p < 0.001) 1 day post procedure compared to preprocedural acquisition. This effect was more pronounced in patients with initial sinus bradycardia (< 60 beats/min.) compared to patients with faster heart rate. Increase of rate was primarily driven by ablation of the right superior pulmonary vein and for a subset of patients, in whom this could be assessed, persisted ≥ 1 year after the procedure. AF recurrence was neither predicted by the magnitude of the initial rate, nor by the extent of rate change, but postprocedural sinus bradycardia was associated with higher recurrence of AF in the year post PVI. CONCLUSIONS: Cryo-PVI causes a significant rise of sinus rate that is more pronounced in subjects with previous sinus bradycardia. Patient follow-up indicates persistence of this effect and suggests an increased risk of AF recurrence in patients with postprocedural bradycardia.

Aseismic mid-crustal magma reservoir at Cleveland Volcano imaged through novel receiver function analyses.

Processes related to eruptions at arc volcanoes are linked by structures that transect the entire crust. Imaging the mid- to lower-crustal portions (here, ~5-15 km and >15 km respectively) of these magmatic systems where intermediate storage may occur has been a longstanding challenge. Tomography, local seismic source studies, geodetic, and geochemical constraints, are typically most sensitive to shallow (<5 km) storage and/or have insufficient resolution at these depths. Geophysical methods are even further limited at frequently-erupting volcanoes where well-developed trans-crustal magmatic systems are likely to exist, due to a lack of deep seismicity. Here we show direct evidence for mid-crustal magma storage beneath the frequently erupting Cleveland volcano, Alaska, using a novel application of seismic receiver functions. We use P-s scattered waves from the Moho as virtual sources to investigate S-wave velocities between the Moho and the surface. Our forward modeling approach allows us to provide direct constraints on the geometry of low velocity regions beneath volcanoes despite having a comparatively sparse seismic network. Our results show clear evidence of mid-crustal magma storage beneath the depths of located volcanic seismicity. Future work using similar approaches will enable an unprecedented comparative examination of magmatic systems beneath sparsely instrumented volcanoes globally.

The role of ridges in the formation and longevity of flat slabs.

Flat-slab subduction occurs when the descending plate becomes horizontal at some depth before resuming its descent into the mantle. It is often proposed as a mechanism for the uplifting of deep crustal rocks ('thick-skinned' deformation) far from plate boundaries, and for causing unusual patterns of volcanism, as far back as the Proterozoic eon. For example, the formation of the expansive Rocky Mountains and the subsequent voluminous volcanism across much of the western USA has been attributed to a broad region of flat-slab subduction beneath North America that occurred during the Laramide orogeny (80-55 million years ago). Here we study the largest modern flat slab, located in Peru, to better understand the processes controlling the formation and extent of flat slabs. We present new data that indicate that the subducting Nazca Ridge is necessary for the development and continued support of the horizontal plate at a depth of about 90 kilometres. By combining constraints from Rayleigh wave phase velocities with improved earthquake locations, we find that the flat slab is shallowest along the ridge, while to the northwest of the ridge, the slab is sagging, tearing, and re-initiating normal subduction. On the basis of our observations, we propose a conceptual model for the temporal evolution of the Peruvian flat slab in which the flat slab forms because of the combined effects of trench retreat along the Peruvian plate boundary, suction, and ridge subduction. We find that while the ridge is necessary but not sufficient for the formation of the flat slab, its removal is sufficient for the flat slab to fail. This provides new constraints on our understanding of the processes controlling the beginning and end of the Laramide orogeny and other putative episodes of flat-slab subduction.