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To optimize enhanced oil recovery techniques it is essential to know the spatial propagation of the injected fluids in the subsurface. We investigate the applicability of controlled-source electromagnetic (CSEM) methods to monitor fluid movement in a German oilfield (Bockstedt). Injected brines have much lower electrical resistivity than oil within the reservoir. 3D modelling suggests CSEM is sensitive to resistivity changes at reservoir depths, but only if sensors/transmitters are positioned closer to the reservoir, e.g. using observation wells. In particular, the vertical electric field component in shallow boreholes and/or use of alternative source configurations consisting of combinations of vertical and horizontal dipoles are promising. In spring 2014, a borehole CSEM survey (4 transmitters, 25 MT stations) was conducted across the oil field using a new horizontal-vertical source. The current was injected via the steel-casing of a 1.3 km deep abandoned oil-well. Redeployment tests of transmitters demonstrate high repeatability of CSEM measurements. First comparison of recordings from conventional and the new borehole transmitters indicate differing current distribution in the subsurface. Results of the new source configuration are in general agreement with predictions by numerical simulations.

To reduce saturation effects in the arterial input function (AIF) estimation of quantitative myocardial first-pass saturation recovery perfusion imaging by employing a model-based reconstruction.Imaging was performed with a saturation recovery prepared radial FLASH sequence. A model-based reconstruction was applied for reconstruction. By exploiting prior knowledge about the relaxation process, an image series with different saturation recovery times was reconstructed. By evaluating images with an effective saturation time of approximately 3 ms, saturation effects in the AIF determination were reduced. In a volunteer study, this approach was compared with a standard prebolus technique.In comparison to the low-dose injection of a prebolus acquisition, saturation effects were further reduced in the AIFs determined using the model-based approach. These effects, which were clearly visible for all six volunteers, were reflected in a statistically significant difference of up to 20% in the absolute perfusion values.The application of model-based reconstruction algorithms in quantitative myocardial perfusion imaging promises a significant improvement of the AIF determination. In addition to greatly reducing saturation effects that occur even for the prebolus methods, only a single bolus has to be applied. Magn Reson Med 76:880-887, 2016. © 2015 Wiley Periodicals, Inc.

Brine was a scientific joint-project implemented to accompany a prospective CO2 storage site in Eastern Brandenburg, Germany. In this context, we investigated if pore pressure elevation in a CO2 storage reservoir can result in shallow freshwater salinization involving the conceptual design of a geophysical early warning system. Furthermore, assessments of a potential synergetic geothermal heat recovery from the CO2 storage reservoir and hydro-mechanical integrity were carried out. The project results demonstrate that potential freshwater salinization is strongly depending on the presence and characteristics of geological weakness zones. The integrated geophysical early warning system allows for reliable monitoring of these potential leakage pathways at different spatial and time scales.

Main objective is to support reservoir monitoring in an EOR production scheme. Enhanced oil recovery calls for efficient monitoring of hydrocarbon saturation changes. In the onshore Bockstedt oil field there exists a substantial difference in resistivity at reservoir level: for initial oil saturation it exceeds 100 Ohmm reducing to 0.6 Ohmm once fully displaced by formation brine. Applicability of the controlled-source electromagnetic method to monitor such resistivity changes is investigated. Targets are Lower Cretaceous shallow marine clastics at approximately 1200 m depth. Finite difference forward modelling shows CSEM is sensitive to expected resistivity changes, but the effect is difficult to resolve with surface measurements only. Resolution increases significantly if sensors or transmitters are placed in observation wells closer to the reservoir. Behaviour of the vertical electric component (Ez) in shallow boreholes and/or use of complex source configrations look rather promising. In 2014, a borehole-to-surface CSEM configuration was deployed successfully across the Bockstedt oil field, whereby the current was injected via the metal casing of an abandoned production well. The set-up also allowed conventional magnetotelluric (MT) data acquisition when the transmitter is turned off at night. CSEM response functions are of good quality with high repeatability. Recordings from conventional and new borehole transmitters indicate different current distributions in the subsurface. Results of the tested source configuration are in agreement with predictions by numerical simulations. Preliminary 3D inversion is consistent with previous numeric simulations. A timelapse CSEM survey is scheduled for 2015, inclusive drilling of a shallow observation well for Ez component monitoring with a new borehole sensor. In parallel, a timelapse workflow for 3D CSEM inversion is developed.

The acronym EMERALD was supposed to stand for ElectroMagnetic Equipment, Raw data And Locations Database. What survived over the years was the EMERALD processing, a set of computer programs to analyse MT time series data, and the EMERALD file format for storing MT data. This document describes the EMERALD file format and how to use it with the C++, C and FORTRAN programming languages. Interface functions also exist for Matlab and Powershell but they are not described here. EMERALD data files typically come in pairs of two files with the same name but differing file name extensions, sometimes called RAW and XTR files. XTR (extract) files are plain ASCII files, which can be read and modified with text editors. RAW files or more generally, EMERALD ‐type data files are in most cases binary and used to store all kind of magnetotelluric (MT) data such as time series, cross‐ and auto spectra and calibration data. The EMERALD ‐type data files store any number of channels of data in matrix form, but do not contain any description of the data. This information is stored in the according XTR file. In 2015 the original XTR files were replaced by a modernized version based on the Extensible Markup Language (XML). The new files have the extension .XTRX.

Secreted protein, acidic, and rich in cysteine (SPARC) is thought to regulate cell matrix interaction during wound repair. We hypothesized that SPARC might promote migration via integrin-dependent mechanisms. The present study was designed to clarify the contribution of SPARC in the wound healing process after myocardial infarction (MI). Adult mice received a specific alpha(v) integrin inhibitor or vehicle through osmotic mini pumps. Mice of each group were either sham-operated or MI was induced. SPARC expression was investigated 2 days, 7 days, and 1 month after the surgical procedure. For migration assays, a modified Boyden chamber assay was used. A transient increase of SPARC levels was observed, starting at day 2 (2.55+/-0.21), day 7 (3.72+/-0.28), and 1 month (1.9+/-0.16) after MI. After 2 months, SPARC expression dropped back to normal levels compared to sham-operated hearts. Immunofluorescence analysis showed an increase of SPARC in the infarcted area 2 days after MI, a strong increase in the scar area 7 days after MI, and only low levels in the scar area 2 months after MI. Integrin alpha(v) inhibition abolished the up-regulation of SPARC. In vitro migration assays demonstrated that fibronectin-stimulated haptotaxis of fibroblasts was modulated by SPARC. This study provides evidence that SPARC is significantly up-regulated in the infarcted region after MI. This up-regulation is dependent on alpha(v) integrins. As SPARC is found to regulate fibroblast migration, it appears to play an important role in the injured myocardium with regard to healing and scar formation.

SUMMARY Magnetotelluric (MT) response function estimates can be severely disturbed by the effects of cultural noise. Methods to isolate and remove these disturbances are typically based on time-series editing, robust statistics, remote reference processing, or some combination of the above. Robust remote reference processing can improve the data quality at a local site, but only if synchronous recordings of at least one additional site are available and if electromagnetic noise between these sites is uncorrelated. If these prerequisites are not met, we suggest an alternative approach for noise removal, based on a combination of frequency domain editing with subsequent single site robust processing. The data pre-selection relies on a thorough visual inspection of a variety of statistical parameters such as spectral power densities, coherences, the distribution of response functions and their errors, etc. Extreme outliers and particularly noisy data segments are excluded from further data processing by setting threshold values for individual parameters. Examples from Namibia and Jordan illustrate that this scheme can improve data quality significantly. However, the examples also suggest that it is not possible to establish generally valid rules for selection as they depend strongly on the local noise conditions. High coherence, for example, can indicate a good signal-to-noise ratio or strongly correlated noise. However, we found that strong polarization of the magnetic field channels and the distribution of response function errors are two important parameters for noise detection.

Background— Calcineurin (CnA) is important in the regulation of myocardial hypertrophy. We demonstrated that targeted proteolysis of the CnA autoinhibitory domain under pathological myocardial workload leads to increased CnA activity in human myocardium. Here, we investigated the proteolytic mechanism leading to activation of CnA. Methods and Results— In patients with diseased myocardium, we found strong nuclear translocation of CnA. In contrast, in normal human myocardium, there was a cytosolic distribution of CnA. Stimulation of rat cardiomyocytes with angiotensin (Ang) II increased calpain activity significantly (433±11%; P P P P =NS; n=6) after removal of Ang II. Ang II stimulation of cardiomyocytes also translocated CnA into the nucleus as demonstrated by immunohistochemical staining and transfection assays with GFP-tagged CnA. Calpain inhibition and therefore suppression of calpain-mediated proteolysis of CnA enabled CnA exit from the nucleus. Conclusions— Ang II stimulation of cardiomyocytes increased calpain activity, leading to proteolysis of the autoinhibitory domain of CnA. This causes an increase in CnA activity and results in nuclear translocation of CnA. Loss of the autoinhibitory domain renders CnA constitutively nuclear and active, even after removal of the hypertrophic stimulus.

Influenza is a common disease in the population. Influenza vaccination is performed routinely and is usually well tolerated. Minor local or systemic side effects like fever and myalgia are described. Rarely there are more severe adverse events. Systemic vasculitis has been reported in some cases. In this case we report on a female patient with secondary vasculitis and myocardial infarction after influenza vaccination. The patient received cortisol and recovered. The literature about influenza vaccination, its side effects and recommendations about vaccination in patients with coronary artery disease is reviewed.

Magnetotelluric (MT) observations at some sites in the vicinity of the Waterberg Fault/Omaruru Lineament (WF/OL), a major tectono-stratigraphic zone boundary in the Central Zone of the Damara Belt, show evidence for strong three-dimensional (3D) effects. We observe very high skew values, phases over 90°, and a strong correlation of parallel components of the electric and magnetic fields at long periods. Because of the dense site spacing and good spatial coverage, we can positively attribute these effects to local geology and are able to resolve structural detail within the WF/OL. Mapping LaTorraca’s electric characteristic vectors in form of ellipses proved particularly useful in identifying key elements of the conductivity structure for subsequent modelling. 3D and 2D anisotropic modelling can reproduce most of the observed 3D effects. The conductivity anomalies revealed in the area are: (i) a conductive ring structure in the shallow crust along the northern part of the profile; (ii) an anisotropic region in the upper crust with high conductivity parallel to the WF/OL; (iii) anisotropy in the lower crust with a different but undetermined strike direction; and (iv) a shallow elongated conductor sub-normal to the WF/OL. Modelling studies further suggest that the (anisotropic) fault zone is approximately 10 km wide and may reach down to a depth of 14 km or more.

The Namibian margin is dominated by the late Proterozoic to early Cambrian fold belts of the Damara Orogen, which wrap around and separate the Congo and Kalahari Cratons. This mosaic of relatively ‘soft’ fold belts and ‘hard’ cratons apparently controlled the path for the opening of the South Atlantic in the early Cretaceous. The continents split along the coast-parallel fold belts of the Damara Orogen while the inland fold belt (Damara Belt) was effected by extension and widespread igneous intrusion but never developed to the rift stage. This paper is concerned with the interpretation of magnetotelluric (MT) data along a 200 km NW–SE profile across the Damara Belt in NW Namibia. The regional, two-dimensional electrical resistivity model and the induction vector data exhibit three distinctive zones: (i) a generally very resistive upper crust which is typical for the granites and metasediments of the Damara Belt, (ii) two subvertical conductors in upper to mid-crustal levels which correlate with major tectonic zone boundaries and (iii) a highly conductive middle to lower crust in the southern part of the profile. The geometry of the conductive structures could reflect a regional shear system in which upper crustal listric faults pass into a detachment zone in the middle crust. We interpret the high electrical conductivity in terms of graphite (or other forms of mineralization) enrichment along the shear planes. This zone of crustal weakness may have originated in Pre-Damara times and had probably experienced several episodes of crustal reactivation before the intrusion of basaltic dike swarms during the Cretaceous rifting and magmatism associated with the opening of the South Atlantic.

Background — In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. Methods and Results — We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. Conclusions — Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.

Background: Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders. Methods and Results: We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions. However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression. We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.

Introduction: E193, a human mutation in the transcription cofactor Eyes absent 4 (EYA4) causes hearing impairment followed by terminal heart failure, defining an important role for Eya4 in maintaining normal cardiac function. METHODS AND RESULTS: First, in-vitro experiments show that overexpression of Eya4 and the mutant isoform alter the expression of p27kip1 on both, transcript and protein levels. Next, we generated transgenic mice with cardiomyocyte-specific Eya4 or E193 overexpression to elucidate the in vivo function of Eya4 upon cardiac physiology. Luciferase and CHIP assays revealed that Eya4 and E193 bind to and regulate p27 expression in a contradictory manner, as already seen in vitro. Activity and phoshorylation of the downstream molecules CK2α and HDAC2 were significantly elevated in Eya4 mice, whereas they were significantly reduced in E193 animals compared to WT littermates. MRI and hemodynamic analysis indicate that a constitutive overexpression of Eya4 results in the age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 overexpressing animals develop onset of dilative cardiomyopathy as seen in human patients carrying the E193 mutation. Morphometric analysis proved ventricular hypertrophy or dilation of the LV associated with a thinning of the myocardial wall, interstitial fibrosis of myocardial tissue and alterations in cell size. Re-activation of fetal genes also occured in both TG models, characteristic for cardiac disease. Both cardiac phenotypes were aggravated upon pressure overload. Finally, we identified a new human heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein. Conclusion: Our results implicate that Eya4 plays a critical role in regulating normal cardiac physiology and function via Six1/p27/CK2α/HDAC2 and that an imbalance within the Eya4/Six1 transcriptional complex leads to an age dependent onset of cardiomyopthy and heart failure.

Magnetic resonance imaging (MRI) has long been regarded a general contraindication in patients with cardiovascular implanted electronic devices such as cardiac pacemakers or cardioverter defibrillators (ICDs) due to the risk of severe complications and even deaths caused by interactions of the magnetic resonance (MR) surrounding and the electric devices. Over the last decade, a better understanding of the underlying mechanisms responsible for such potentially life-threatening complications as well as technical advances have allowed an increasing number of pacemaker and ICD patients to safely undergo MRI. This review lists the key findings from basic research and clinical trials over the last 20 years, and discusses the impact on current day clinical practice. With ‘MR-conditional’ devices being the new standard of care, MRI in pacemaker and ICD patients has been adopted to clinical routine today. However, specific precautions and specifications of these devices should be carefully followed if possible, to avoid patient risks which might appear with new MR technology and further increasing indications and patient numbers.

ModEM is a modular system of computer codes for inversion of EM geophysical data developed over the past decade at Oregon State University. A stable version of the code tailored to inversion of 3D magnetotelluric data has been made freely available for academic research. The modularity of the code also makes ModEM an ideal test bed for exploring new developments in inversion search algorithms. Here we discuss implementation of, and results from, several inversion algorithms for 3D EM problems (both MT and CSEM) recently developed using the ModEM system. These include hybrid schemes which make the Occam inversion approach more practical for 3D problems, multi-transmitter schemes which make better use of the multiplicity of gradient components computed for independent transmitters, and weighting schemes in joint EM inversion.

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a truncating mutation in Eya4, E193, causes hearing impairment followed by terminal heart failure suggesting Eya4 is a regulator in cardiac physiology. Methods and Results: Transgene- or adenovirus mediated overexpression of Eya4 or E193 altered the expression of p27kip1, a critical mediator of cardiac hypertrophy in adult cardiomyocytes. Luciferase reporter and EMSA assays revealed that Eya4 directly binds to and suppresses p27kip1 promoter activity, while E193 exerts an opposing effect, respectively. Activity and phosphorylation of downstream molecules were significantly altered in Eya4 and E193 transgenic (TG) mice in a contradictory manner. Cardiac phenotypes evolved in both TG models already under basal conditions. Eya4 TG hearts developed hypertrophy as judged by increases in heart weight and cross-sectional cell surfaces and re-activation of fetal genes as well as fibrosis. E193 TG animals showed onset of DCM along with wall thinning, ventricular dilation, fibrosis and slightly compromised cardiac function. These two distinct cardiac phenotypes were even more aggravated upon pressure overload or Angiotensin II infusion. Finally, we just recently identified a new mutation in Eya4, E215, which also causes hearing impairment and heart failure. Conclusion: Our data indicate that Eya4, in a physical complex with Six1, plays a critical role in regulating normal cardiac function via p27/CK2-α/HDAC2 and allude that mutations within the Exa4/Six1 transcriptional complex interfere with this newly established signalling pathway, finally leading to age-related onset of cardiomyopathy. Clinical Perspective: Gaining a better understanding of this disease mechanism could help identify new treatment options for heart failure patients.

Electromagnetic (EM) methods are routinely applied to image the subsurface from shallow to regional structures. EM methods differ in their sensitivities towards resistive and conductive structures as well as in their exploration depths. Joint 3D inversion of multiple EM data result in significantly better resolution of subsurface structures than the individual inversions. Proper weighting between different EM data is essential, however. We present a recently developed weighting algorithm to combine magnetotelluric (MT), controlled source EM (CSEM) and DC-geoelectric (DC) data. It is known that MT data are mostly sensible to regional conductive structures, whereas, CSEM and DC data are suitable to recover more shallow and resistive structures. Our new scheme is based on weighting individual components of the total data gradient after each model update. Norms of each data residual are used to assess how much weight individual components of the total gradient must have to achieve an equal contribution of all data in the inverse model. A numerically efficient way to search for appropriate weighting factors could be established by applying a bi-diagonalization to the sensitivity matrix. Thereby, the original inverse problem can be projected onto a smaller dimension in which the search of weighting factors is numerically cheap.

Combining different electromagnetic (EM) methods in joint inversion approaches can enhance the overall resolution power. Every method is associated with a particular sensitivity pattern. By assembling complementary patterns, subsurface imaging becomes more complete and reliable. We describe different paths to obtain multi-EM inversions. First, a joint inversion approach using finite difference forward operators is outlined that formulates the problem of minimizing the objective function using different weights for each individual method. Then we address a sequential approach using finite element methods on unstructured grids to cycle through the different EM methods iteratively. Both methods are based on a traditional parametrization using piecewise constant model parameters which may be inefficient when describing the usually rather coarse models. Therefore, we investigate wavelet-based model representations as an alternative.

In an Enhanced Oil Recovery (EOR) pilot project Wintershall Holding GmbH, Kassel, is testing their newly developed biopolymer Schizophyllan in one of their oil fields. Mixture with the highly saline formation water results in a polymer solution with much lower electrical resistivity than the displaced oil within the reservoir. To advance and optimize EOR techniques it is essential to know the spatial propagation and distribution of the injected fluids in the subsurface. At GFZ Potsdam, we investigate the applicability of the CSEM method to monitor the distribution of the polymers solution. Based on a 26-site MT survey across the oil-field and calibration with resistivity well-logs, we constructed a 3D resistivity model of the reservoir region for 3D CSEM forward simulations; main focus of the study was to test the sensitivity of various source-receiver configurations. 3D modelling results suggest that CSEM is sensitive to resistivity changes at reservoir depths, but the effect is difficult to resolve with surface measurements only. Resolution potential increases significantly, however, if sensors/transmitters can be placed in observation wells closer to the reservoir. In particular, observation of vertical electric fields in shallow boreholes and/or use of novel source configurations consisting of vertical and horizontal dipoles appear promising.

The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca\(^{2+}\) component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na\(^{+}\) and Ca\(^{2+}\) influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca\(^{2+}\) influx which has been regarded as ideal Ca\(^{2+}\) source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation. Functional properties of TRPC4 are also based on the expression of the TRPC4 splice variants TRPC4α and TRPC4β. Aim of the present study was to analyze cytosolic Ca\(^{2+}\) signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4α or TRPC4β. The analysis of Ca\(^{2+}\) transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4α and TRPC4β affected Ca\(^{2+}\) cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca\(^{2+}\) transient amplitude at baseline and TRPC4β increasing the Ca\(^{2+}\) peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4β (Ad-C4β) also responded with a sustained Ca\(^{2+}\) influx when treated with Ang II under non-pacing conditions. Consistent with the Ca\(^{2+}\) data, NRCs infected with TRPC4α (Ad-C4α) showed an elevated calcineurin/NFAT activity and a baseline hypertrophic phenotype but did not further develop hypertrophy during chronic Ang II/phenylephrine stimulation. Down-regulation of endogenous TRPC4α reversed these effects, resulting in less hypertrophy of NRCs at baseline but a markedly increased hypertrophic enlargement after chronic agonist stimulation. Ad-C4β NRCs did not exhibit baseline calcineurin/NFAT activity or hypertrophy but responded with an increased calcineurin/NFAT activity after GPCR stimulation. However, this effect was not translated into an increased propensity towards hypertrophy but rather less hypertrophy during GPCR stimulation. Further analyses revealed that, although hypertrophy was preserved in Ad-C4α NRCs and even attenuated in Ad-C4β NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4α and TRPC4β differentially affect Ca\(^{2+}\) signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation.

The basic helix-loop-helix transcription factors eHAND and dHAND are involved in developmental cardiac growth and differentiation. We investigated HAND gene expression in the normal and in the hypertrophied right and left ventricle of patients with tetralogy of Fallot (ToF) and hypertrophic obstructive cardiomyopathy (HOCM). HAND mRNA was constitutively expressed in the hypertrophied heart and increased in the hypertrophic tissue of both patient groups. HAND genes had a complementary left-right cardiac asymmetry of expression with dHAND predominantly in the right and eHAND in the left ventricle. The two cardiac bHLH factors have the ability to form heterodimers with the ubiquitous bHLH protein E12, subsequently recognizing E-boxes in the promoter region of target genes like ALC-1. We found a highly significant positive correlation between HAND and ALC-1 mRNA. The total ALC-1 protein level in ToF was smaller than in HOCM, although ALC-1 mRNA as well as HAND mRNA levels were significantly higher. ToF patients expressed around four times more ALC-1 mRNA for similar amounts of ALC-1 than HOCM patients. Suggesting disturbed ALC-1 translation in ToF, we found ALC-1 antisense mRNA expression in the hypertrophied, but not in the normal, ventricles. The higher the antisense/sense ALC-1 mRNA ratio, the lower ALC-1 protein was expressed. J. Cell. Biochem. 74:551–561, 1999. © 1999 Wiley-Liss, Inc.

The adult rodent heart adapts to increased work load by reexpression of its fetal genes, for example, beta-myosin heavy chain (MHC), in order to improve contractile function. However, the human ventricle regulates contractility by expression of atrial essential myosin light chain (ALC-1) rather than beta-MHC. We evaluated the impact of both mechanisms in patients with hypertrophic cardiomyopathy. MHC isoform expression was quantified at the mRNA and protein levels by reverse transcriptase polymerase chain reaction and immunoblotting, respectively. Although alpha-MHC mRNA was detected in control and hypertrophied human ventricular tissue, alpha-MHC protein was not observed. Similarly, we investigated the expression of ALC-1 by two-dimensional polyacrylamide gel electrophoresis and the clinical and hemodynamic parameters of the patients with hypertrophic cardiomyopathy. We found a significant positive correlation between ALC-1 protein expression and dP/dtmax in the hypertrophied human ventricle in vivo. Correlations between dP/dtmax and expression of protein for the ryanodine receptor and L-type Ca2+ channel were excluded. Our data suggest that reexpression of ALC-1 improves the contractile state of the adult human heart. We propose that two evolutionarily divergent compensatory mechanisms for increased work demand exist in the mammalian heart: MHC regulation in rodents and essential MLC regulation, of cardiac contractility, in humans.

Robust estimates of magnetotelluric and geomagnetic response functions are determined using the coherency and expected uniformity of the magnetic source field as quality criteria. The method is applied on data sets of three simultaneously recording sites. For the data acquisition we used a new generation of geophysical equipment (S.P.A.M. MkIII), which comprises novel concepts of parallel computing and networked, digital data transmission. The data-processing results show that the amount of noise on the horizontal components of the magnetic field varies considerably in time, between sites and over the frequency range. The removal of such contaminated data beforehand is essential for most data-processing schemes, as the magnetic channels are usually assumed to be free of noise. The standard remote reference method is aimed at reducing bias in response function estimates. However, this does not necessarily improve their precision as our results clearly show. With our method, on the other hand, we can filter out source field irregularities, thereby providing suitable working conditions for the robust algorithm, and eventually obtain considerably improved results. Contrary to previous concepts, we suggest rejecting as much data as feasible in order to concentrate on the remaining parts of high-quality observations.

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

Background Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. Methods Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. Results Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n

Background: Surgical procedures in small animal models of heart disease, such as artificial ligation of the coronary arteries for experimental myocardial infarction, can evoke alterations in cardiac morphology and function. Such alterations might induce artificial early or long term effects in vivo that might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies in small animal models of heart disease. Methods: Female Wistar rats were matched for weight and distributed to sham left coronary artery ligation or untreated control. Cardiac parameters were then investigated in vivo by high-field MRI over time after the surgical procedure, determining left and right ventricular morphology and function. Additionally, the time course of several metabolic and inflammatory blood parameters was determined. Results: Rats after sham surgery showed a lower body weight for up to 8 weeks after the intervention compared to healthy controls. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p Conclusion: There is a small distinct impact of cardio-thoracic surgical procedures on the global integrity of the organism, which in the long term also includes circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective studies and transferring the findings to conditions in patients.

Chagas disease and its causative agent Trypanosoma cruzi are endemic in almost all countries in South and Middle America. Currently, there are more than 10 million affected people. It is the most common reason for heart failure and a frequent cause of intestinal problems in Latin America. The phenotype of the Chagas cardiomyopathy is varying. Dilative cardiomyopathy, often accompanied by an apical aneurysm is the most common finding in the end stage heart failure, but rhythm disorders like conduction blocks, ventricular or supraventricular forms of tachycardia or repolarization changes occur as well, mainly in the early stages. Migration of infected people leads to a distribution from the endemic countries to North America and Europe. Although more than 500,000 people of Latin American origin are currently living in Europe, Chagas disease is not considered as a public health problem, yet. Cases of transmission via blood donation, organ transplantation or from mother-to-child are reported for several European countries but there is no database for Germany. Current epidemiological data are mostly available from regional surveys from other countries or are extrapolated. Hence, there is a large variation in the estimated numbers on the incidence of Chagas. Robust and reliable data are lacking. This review gives an overview on the currently available data and calls for a German Chagas surveillance.

For a long time the root mean square (RMS) error has been used in the EM community: - to characterize data fit for a particular model; - as a criterion to compare several models obtained from inversion. The RMS error appears to be a natural choice since we usually tackle inverse problems in a least-squares sense. Over the years, RMS became a customary criterion and gained ultimate significance. However, on the hunt for low RMS values, one often needs to introduce subjectivity by arbitrarily adjusting error floors or masking “bad” data without referring to the assumptions behind RMS. In this contribution, we revisit basic assumptions behind RMS, demonstrate its deficiency and propose alternative ways, which may provide more insight into our data and allow a more comprehensive assessment of the quality of the modelling result/resistivity model.

For 3-D inversion of controlled-source electromagnetic (CSEM) data, increasing availability of high-performance computers enables us to apply inversion techniques that are theoretically favourable, yet have previously been considered to be computationally too demanding. We present a newly developed parallel distributed 3-D inversion algorithm for interpreting CSEM data in the frequency domain. Our scheme is based on a direct forward solver and uses Gauss–Newton minimization with explicit formation of the Jacobian. This combination is advantageous, because Gauss–Newton minimization converges rapidly, limiting the number of expensive forward modelling cycles. Explicit calculation of the Jacobian allows us to (i) precondition the Gauss–Newton system, which further accelerates convergence, (ii) determine suitable regularization parameters by comparing matrix norms of data- and model-dependent terms in the objective function and (iii) thoroughly analyse data sensitivities and interdependencies. We show that explicit Jacobian formation in combination with direct solvers is likely to require less memory than combinations of direct solvers and implicit Jacobian usage for many moderate-scale CSEM surveys. We demonstrate the excellent convergence properties of the new inversion scheme for several synthetic models. We compare model updates determined by solving either a system of normal equations or, alternatively, a linear least-squares system. We assess the behaviour of three different stabilizing functionals in the framework of our inversion scheme, and demonstrate that implicit regularization resulting from incomplete iterative solution of the model update equations helps stabilize the inversion. We show inversions of models with up to two million unknowns in the forward solution, which clearly demonstrates applicability of our approach to real-world problems., Geophysical Journal International, 193 (3), ISSN:0956-540X, ISSN:1365-246X

[1] Long-term monitoring of geoelectromagnetic fields, recorded with a network of nine stations covering an area of approximately 25,000 km2at low geomagnetic latitudes in northern Chile, reveals systematic and seasonally modulated variations of geomagnetic field properties. The observed seasonal variation affects almost exclusively the east-west magnetic field component for periods between 100 and 3000 s. The ground-based measurements of magnetic and electric fields show statistically significant coherences with the interplanetary electric field derived from solar wind and interplanetary magnetic field data of the Advanced Composition Explorer satellite. The interplanetary electric field (IEF) penetrates the polar ionosphere from where it propagates toward equatorial latitudes by waveguide transmission, with ionosphere and solid Earth acting as conducting boundaries. Signal coherence between IEF and ground data peaks at periods of approximately 90 min and up to the four harmonics. Coherence values reach 0.4 at these periods and depend on the electromagnetic field component. They vary with season and local time. Transfer functions computed between IEF and ground-based electric and magnetic fields show local maxima at similar periods (90 min and harmonics). The coupling between the east-west magnetic field component and the IEF shows significant seasonal variability, much larger than the other electromagnetic field components. We conclude that the IEF drives primarily a global circuit of Pedersen currents in the ionosphere. Resulting time-varying magnetic fields induce electric currents in the ground. Related ground-based magnetic (primarily north-south) and electric (primarily east-west) signals vary coherently at all local times and seasons. Conversely, magnetic signals caused by the IEF-driven Hall currents depend much on local time and season. We show for the first time that these ionospheric Hall currents cause no induction in the ground, but they generate magnetic signatures that are confined to the waveguide between ionosphere and Earth's surface.

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a mutation in Eya4 (E193) leads to late-onset familial dilated cardiomyopathy and heart failure. A precise role for Eya4 in the myocardium has not yet been identified. It appears to regulate the cyclin dependent kinase inhibitor p27 kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in induced cardiac hypertrophy. Methods and results: We generated transgenic mice with cardiac-specific overexpression of HA-tagged Eya4 or E193 to elucidate the function of these proteins in the development of heart failure in vivo . These and wildtype littermates were challenged with angiotensin II (ATII) or subjected to transaortic constriction (TAC). Magnetic resonance imaging to visualize cardiac structures in detail showed that in response to sustained ATII stimulation and TAC, Eya4 mice exhibited a phenotype with significantly increased parameters of hypertrophy compared to WT and E193 overexpressing animals as judged by increases in heart weight and LV free wall diameter, cross-sectional cell surface areas and fibrosis. MRI also showed mild cardiac hypertrophy in Eya4 transgenic mice already under baseline conditions in an age dependent fashion. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression and resulted in increased levels of phosphorylated histone deacetylase 2 (HDAC2). E193 overexpression induced age dependent wall thinning and ventricular dilation under baseline conditions with no obvious structural or functional defects. ATII or TAC induced significant changes in HW/BW ratio, IVS, fibrosis, hemodynamic and cell size measurements, albeit to a lesser extent than seen with Eya4 mice. p27 expression and pHDAC2 levels were only slightly altered. Conclusion: In summary, we have demonstrated a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27, which leads to phosphorylation and activation of HDAC2 and results in the development of cardiac hypertrophy.

Background: Recent evidence demonstrates that not only NFAT, but also calcineurin is translocated into the nucleus upon hypertrophic stimulation. Previously it was also demonstrated that calpain-mediated degradation caused a constitutive active calcineurin. We hypothesised that nuclear calcineurin is an intranuclear Ca 2+ sensor hypertrophied myocardium and that inhibition of nuclear translocation of calcineurin is a therapeutic strategy to prevent hypertrophy. Methods: Employing a transgene mouse model with conditional calpastatin overexpression (”tet-off”, resulting in calpain inhibition), different adenoviral calcineurin mutants and confocal microscopy in isolated adult cardiac myocytes we investigated calcineurin translocation and nuclear Ca 2+ transients. Assessment of cardiac function if transgenic animals was performed by 7T MRI. Results: We could demonstrate that chronic Ang II stimulation of mice caused calpain-mediated degradation of calcineurin resulting in a constitutive active calcineurin with nuclear translocation. The constitutive active calcineurin in the nucleus escaped further degradation by the UPS and sustained an ongoing hypertrophic response, even after removal of Ang II. Inhibition of nuclear translocation of activated calcineurin by a small inhibitory peptide prevented myocardial hypertrophy in vivo. Transgenic inhibition of calpain activity by calpastatin overexpression prevented proteolysis of calcineurin and allowed for relocation of calcineurin from the nucleus back to the cytosol and regression hypertrophy after removal of Ang II. We were also able to demonstrate that Ang II increases nuclear Ca 2+ transients via InsP3 receptors and that calcineurin is able to act as nuclear Ca 2+ sensor detecting local Ca 2+ release from the nuclear envelope via InsP3R. Nuclear calcineurin mutants that are defective for Ca 2+ activation failed to activate NFAT dependent transcription. Conclusion: This provides an explanation how Ca 2+ and calcineurin can regulate transcription in cardiomyocytes in response to neurohumoral signals apart from Ca 2+ changes in contraction regulation.

One of the main shortcomings of interventional electrophysiology (EP) is its inability to generate sufficient soft tissue contrast for intra-procedural visualization of the myocardium and the surrounding tissue, using conventional imaging techniques. Interventional cardiovascular magnetic resonance imaging (MRI) aims at bringing about significant improvements to the complex and decisive EP interventions far beyond the capabilities of currently available supportive imaging techniques used to surmount the drawbacks of fluoroscopy, as MRI not only allows of precise three-dimensional exposure of the cardiovascular morphology, but also proves to be a promising technique exclusively suitable for direct visualization of arrhythmogenic substrate and therapeutic effects. The major challenge posed by clinical adoption of MR-guided EP interventions is the development of a set-up that overcomes the large number of technical problems caused by the interference of the EP set-up with the MRI environment. Late decisive improvements of an interventional MR-EP setup just recently enabled accomplishment of initial clinical applications in our hospital using this new technique. The figure illustrates the successful treatment of the first patient with arrhythmia after two failed approaches of conventional catheter ablation therapy using catheter ablation under real-time MRI guidance. This patient suffered from congestive heart failure due to pulmonary hypertension with repeated pulmonary embolism resulting in a highly dilated right ventricle (Panel A). His clinical condition dramatically worsened because of atrial flutter, but medical therapy was inefficient and catheter ablation failed to restore sinus rhythm, presumably because of pronounced right ventricular and atrial hypertrophy. The patient was referred to the MRI for real-time MR-guided ablation therapy. The intervention was performed in total in the MR scanner room (1.5 T MRI, Siemens, Germany) without using fluoroscopy. Intra-cardiac catheter guidance and mapping in the right atrium and ventricle with the custom,irrigated catheters (VascoMed/Biotronik, Germany) specially designed for use in the MRI is shown in Panel B and in Supplementary material online, Video S1. Panels C and D illustrate real-time monitoring of lesion formation during the procedure, with T2-weighted imaging used to confirm transmurality of the lesions after ablation (arrow, Panel D). Surface ECG and IEGMs acquired by a Cardio Lab EP console with custom filters during MR-guided mapping, ablation, and after successful completion of isthmus blockade are shown in Panel E. ​. In this patient, catheter ablation under real-time MRI guidance could be successfully carried out as a new technique to treat arrhythmia after two failed approaches of conventional catheter ablation. Combination of advanced imaging techniques for simultaneous tissue and catheter visualization, monitoring of ablation, and assessment of the ablation lesions may be potential advantages over conventional EP in the future. Further technical and procedural improvements are warranted, which would concurrently widen the range of applications and assure patient safety, in order to bring this technique to broader clinical practice. Supplementary material is available at European Heart Journal online. Funding: Funding to pay the Open Access publication charges for this article was provided by Department of Medicine I, University of Wurzburg, Germany.

Nephrogenic Systemic Fibrosis is a rare condition appearing only in patients with severe renal impairment or failure and presents with dermal lesions and involvement of internal organs. Although many cases are mild, an estimated 5 % have a progressive debilitating course. To date, there is no known effective treatment thus stressing the necessity of ample prevention measures. An association with the use of Gadolinium based contrast agents (GBCA) makes Nephrogenic Systemic Fibrosis a potential side effect of contrast enhanced magnetic resonance imaging and offers the opportunity for prevention by limiting use of gadolinium based contrast agents in renal failure patients. In itself toxic, Gadolinium is embedded into chelates that allow its safe use as a contrast agent. One NSF theory is that Gadolinium chelates distribute into the extracellular fluid compartment and set Gadolinium ions free, depending on multiple factors among which the duration of chelates exposure is directly related to the renal function. Major medical societies both in Europe and in North America have developed guidelines for the usage of GBCA. Since the establishment of these guidelines and the increased general awareness of this condition, the occurrence of NSF has been nearly eliminated. Giving an overview over the current knowledge of NSF pathobiochemistry, pathogenesis and treatment options this review focuses on the guidelines of the European Medicines Agency, the European Society of Urogenital Radiology, the FDA and the American College of Radiology from 2008 up to 2011 and the transfer of this knowledge into every day practice.

To evaluate and to compare Parallel Imaging and Compressed Sensing acquisition and reconstruction frameworks based on simultaneous multislice excitation for high resolution contrast-enhanced myocardial first-pass perfusion imaging with extended anatomic coverage.The simultaneous multislice imaging technique MS-CAIPIRINHA facilitates imaging with significantly extended anatomic coverage. For additional resolution improvement, equidistant or random undersampling schemes, associated with corresponding reconstruction frameworks, namely Parallel Imaging and Compressed Sensing can be used. By means of simulations and in vivo measurements, the two approaches were compared in terms of reconstruction accuracy. Comprehensive quality metrics were used, identifying statistical and systematic reconstruction errors.The quality measures applied allow for an objective comparison of the frameworks. Both approaches provide good reconstruction accuracy. While low to moderate noise enhancement is observed for the Parallel Imaging approach, the Compressed Sensing framework is subject to systematic errors and reconstruction induced spatiotemporal blurring.Both techniques allow for perfusion measurements with a resolution of 2.0 × 2.0 mm(2) and coverage of six slices every heartbeat. Being not affected by systematic deviations, the Parallel Imaging approach is considered to be superior for clinical studies.

Background One of the safety concerns when performing electrophysiological (EP) procedures under magnetic resonance (MR) guidance is the risk of passive tissue heating due to the EP catheter being exposed to the radiofrequency (RF) field of the RF transmitting body coil. Ablation procedures that use catheters with irrigated tips are well established therapeutic options for the treatment of cardiac arrhythmias and when used in a modified mode might offer an additional system for suppressing passive catheter heating. Methods A two-step approach was chosen. Firstly, tests on passive catheter heating were performed in a 1.5 T Avanto system (Siemens Healthcare Sector, Erlangen, Germany) using a ASTM Phantom in order to determine a possible maximum temperature rise. Secondly, a phantom was designed for simulation of the interface between blood and the vascular wall. The MR-RF induced temperature rise was simulated by catheter tip heating via a standard ablation generator. Power levels from 1 to 6 W were selected. Ablation duration was 120 s with no tip irrigation during the first 60 s and irrigation at rates from 2 ml/min to 35 ml/min for the remaining 60 s (Biotronik Qiona Pump, Berlin, Germany). The temperature was measured with fluoroscopic sensors (Luxtron, Santa Barbara, CA, USA) at a distance of 0 mm, 2 mm, 4 mm, and 6 mm from the catheter tip. Results A maximum temperature rise of 22.4°C at the catheter tip was documented in the MR scanner. This temperature rise is equivalent to the heating effect of an ablator's power output of 6 W at a contact force of the weight of 90 g (0.883 N). The catheter tip irrigation was able to limit the temperature rise to less than 2°C for the majority of examined power levels, and for all examined power levels the residual temperature rise was less than 8°C. Conclusion Up to a maximum of 22.4°C, the temperature rise at the tissue surface can be entirely suppressed by using the catheter's own irrigation system. The irrigated tip system can be used to increase MR safety of EP catheters by suppressing the effects of unwanted passive catheter heating due to RF exposure from the MR scanner.

The motion of tectonic plates is accommodated at fault zones. One of the unanswered questions about fault zones relates to the role they play in controlling shallow and local hydrology. This study focuses on the Arava/Araba Fault (AF) zone, the southern portion of the Dead Sea Transform (DST) in the Middle East. We combine seismic and electromagnetic methods (EM) to image the geometry and map the petro-physical properties and water occurrence in the top 100 m of this active fault. For three profiles, P-velocity and resistivity images were derived independently. Using a neural network cluster analysis three classes with similar P-velocity and resistivities could then be determined from these images. These classes correspond to spatial domains of specific material and wetness. The first class occurs primarily east of the fault consisting of ‘wet’ sand (dunes) and brecciated sediments, whereas the second class composed of similar material located west of the fault is ‘dry’. The third class lies at depth below ca. 50 m and is composed of highly deformed and weathered Precambrian rocks that constitute the multi-branch fault zone of the AF at this location. The combination of two independent measurements like seismics and EM linked by a stringent mathematical approach has thus shown the potential to delineate the interplay of lithology and water near active faults.

[1] Long-term monitoring of geoelectromagnetic fields, recorded with a network of nine stations covering an area of approximately 25,000 km2at low geomagnetic latitudes in northern Chile, reveals systematic and seasonally modulated variations of geomagnetic field properties. The observed seasonal variation affects almost exclusively the east-west magnetic field component for periods between 100 and 3000 s. The ground-based measurements of magnetic and electric fields show statistically significant coherences with the interplanetary electric field derived from solar wind and interplanetary magnetic field data of the Advanced Composition Explorer satellite. The interplanetary electric field (IEF) penetrates the polar ionosphere from where it propagates toward equatorial latitudes by waveguide transmission, with ionosphere and solid Earth acting as conducting boundaries. Signal coherence between IEF and ground data peaks at periods of approximately 90 min and up to the four harmonics. Coherence values reach 0.4 at these periods and depend on the electromagnetic field component. They vary with season and local time. Transfer functions computed between IEF and ground-based electric and magnetic fields show local maxima at similar periods (90 min and harmonics). The coupling between the east-west magnetic field component and the IEF shows significant seasonal variability, much larger than the other electromagnetic field components. We conclude that the IEF drives primarily a global circuit of Pedersen currents in the ionosphere. Resulting time-varying magnetic fields induce electric currents in the ground. Related ground-based magnetic (primarily north-south) and electric (primarily east-west) signals vary coherently at all local times and seasons. Conversely, magnetic signals caused by the IEF-driven Hall currents depend much on local time and season. We show for the first time that these ionospheric Hall currents cause no induction in the ground, but they generate magnetic signatures that are confined to the waveguide between ionosphere and Earth's surface.

Introduction: We previously identified a mutation in the human transcriptional cofactor Eya4 (E193) as cause of familial dilated cardiomyopathy (DCM) and heart failure. Upon interaction with real transcription factors such as Six family members, Eya4 is recruited to and interacts with target genes. One of the few known Eya-Six targets expressed in the heart is the cyclin-dependent kinase inhibitor p27kip1, which has been shown to inhibit hypertrophic growth in adult cardiomyocytes, is. We therefore hypothesize that Eya4/Six1 regulates targets relevant in normal cardiac function. Methods and results: We examined p27 expression in response to Eya4 in permanent mammalian cell lines. Western blot analysis demonstrated that an overexpression of Eya4 led to a significant downregulation of p27, whereas the overexpression of E193 had no effect on p27 levels. Studies using a p27 promoter fragment including Six1 consensus sites cloned in front of a Luciferase reporter gene proved Eya4 acts as a suppressor of p27 already at the transcriptional level, whereas E193 could not sufficiently inhibit p27 expression. Further transfection and knockdown experiments revealed that under basal conditions an Eya4 overexpression decreased protein synthesis in primary cardiac myocytes. We constructed transgenic mouse models with a constitutive myocardial overexpression of E193 and Eya4 to study the precise role of Eya4 in the heart. First analysis of these animals using magnetic resonance imaging to visualize cardiac structures in detail show that an overexpression of E193 leads to an age related onset of DCM as seen in an increase in LVEDV, whereas Eya4 overexpressing mice show no signs of heart disease. Conclusion: In summary, we identified a mutation in Eya4 to cause DCM. We now provide evidence that the Eya4/Six1 signalling cascade is also relevant in more common forms of acquired heart disease. Eya4/Six1 seems to regulate the expression of p27kip1, an important inhibitor of the development of hypertrophy in postmitotic cardiomyocytes. Studies using E193 overexpressing mice support our hypothesis whereas tempering the Eya4/Six1 signalling cascade disturbs cardiac physiology.