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The present invention provides an electric vehicle charging controller. The charging controller comprises a first interface connectable to an electric vehicle charge source for receiving a charging current, a second interface connectable to an electric vehicle for providing the charging current to a battery management system in the electric vehicle to charge a battery therein, a first communication unit for receiving a charging message via a communication network, and a control unit for controlling a charging current provided from the charge source to the electric vehicle, the controlling at least in part being performed in response to a first information associated with a charging message received by the first communication unit

Moderne Hochdruckforschung entwickelt sich rasant zu einer der vielfältigstens und überraschensten Disziplinen der Festkörperphysik. Unter Benutzung von Diamantstempelzellen können Drücke erreicht werden, die den Bedingungen im Inneren unserer Erde ähneln. Eine Anwendung von Kernmagnetischen Resonanzexperimenten (NMR) in Diamantstempelzellen galt jedoch fur lange Zeit als unmöglich. In der vorliegenden Arbeit wird ein neuartiger Ansatz weiterentwickelt, der Radiofrequenz-(RF)-Mikrospulen benutzt, die direkt zwischen den Diamantstempeln platziert werden, und somit zu einer signififikanten Sensitivitatssteigerung führen. Es ist gelungen, Hochdruckzellen zu entwickeln, die fur die speziellen Anforderungen der NMR zugeschnitten sind. Des Weiteren konnte eine nicht metallische, nicht magnetische Dichtung entwickelt werden, die zudem zu einer signififikanten Stabilisierung des Probenvolumens führt. Eine breit angelegte Analyse der Leistungsfähigkeit dieser neuartigen NMR-Hochdruckprobenköpfe zeigt deren Leistungsfähigkeit mit sehr hohen Empfifindlichkeiten sowie einer exzellenten RF Anregung und Zeitauflösung. Drei Anwendungsbeispiele, die das Potenzial dieses Ansatzes in dieser Arbeit unterstreichen, werden vorgestellt. Bei Drücken von bis zu 4 GPa werden die elektronischen und dynamischen Eigenschaften von elementarem Gallium untersucht. Unter höheren Drücken ist es gelungen, einen druckinduzierten Isolator-Metall-Übergang in dem ternaren Chalkogenid AgInTe2 zu beobachten. Schlussendlich ist es gelungen, die strukturellen und elektronischen Eigenschaften von Rubin bei Drücken von bis zu 30.5 GPa zu untersuchen, was einer Verdreifachung des bisher zugänglichen experimentellen Druckbereiches entspricht und die NMR fur moderne Hochdruckanwendungen möglich macht.

The aim of this work is to provide a historical reconstruction of the interconnections between Carnap’s Aufbau, Kuhn’s model of theory change, and the structuralist view of scientific theories. I will discuss how the structuralist view takes its motivations from Carnap’s early work, especially from the Aufbau. Carnap’s idea of purely structural definite descriptions exposed in the Aufbau can be seen analogous with the goal of the structuralist view of representing our knowledge about scientific theories structurally. Such Carnapian purely structural definite descriptions of our knowledge guarantee the objectivity and intersubjectivity of our claims. In the same way, structuralist philosophy of science aims to provide objective and ontologically neutral descriptions of the logical structure of our scientific theories. As a further step, I will also discuss how the development of the structuralist view is strongly motivated by Kuhn’s conception of theory change.

International audience; Phase velocities derived from ambient-noise cross-correlation are compared with phase velocities calculated from cross-correlations of waveform recordings of teleseismic earthquakes whose epicentres are approximately on the station–station great circle. The comparison is conducted both for Rayleigh and Love waves using over 1000 station pairs in central Europe. We describe in detail our signal-processing method which allows for automated processing of large amounts of data. Ambient-noise data are collected in the 5–80 s period range, whereas teleseismic data are available between about 8 and 250 s, resulting in a broad common period range between 8 and 80 s. At intermediate periods around 30 s and for shorter interstation distances, phase velocities measured from ambient noise are on average between 0.5 per cent and 1.5 per cent lower than those observed via the earthquake-based method. This discrepancy is small compared to typical phase-velocity heterogeneities (10 per cent peak-to-peak or more) observed in this period range.We nevertheless conduct a suite of synthetic tests to evaluate whether known biases in ambient-noise cross-correlation measurements could account for this discrepancy; we specifically evaluate the effects of heterogeneities in source distribution, of azimuthal anisotropy in surface-wave velocity and of the presence of near-field, rather than far-field only, sources of seismic noise. We find that these effects can be quite important comparing individual station pairs. The systematic discrepancy is presumably due to a combination of factors, related to differences in sensitivity of earthquake versus noise data to lateral heterogeneity. The data sets from both methods are used to create some preliminary tomographic maps that are characterized by velocity heterogeneities of similar amplitude and pattern, confirming the overall agreement between the two measurement methods.

T-cell responses towards tuberculin (purified protein derivative; PPD) or the Mycobacterium tuberculosis-specific antigens early secretory antigenic target (ESAT)-6 and culture filtrate protein-10 are indicative of prior contact with mycobacterial antigens. In this study, we investigated the exceptional case of a 75-yr-old patient who devoted more than one-third of his CD4 T-cells against PPD and ESAT-6. Antigen-specific T-cells were characterised using flow cytometric intracellular cytokine staining, ELISPOT assay, proliferation assays, and T-cell receptor spectratyping. T-cell frequencies were far above those found in age-matched controls (median 0.33%, range 0.05-6.32%) and remained at high levels for >2 yrs. The patient initially presented with haemoptysis, but active tuberculosis was ruled out by repeated analysis of sputum and bronchoalveolar lavage fluid. Skin testing was negative and haemoptyses did not have a M. tuberculosis-related aetiology. Phenotypical and functional properties of specific T-cells were consistent with a terminally differentiated effector-memory phenotype with capacity to produce interferon-γ, interleukin-2 and tumour necrosis factor-α. Epitope mapping showed that the CD4 T-cells were directed against a single peptide from ESAT-6 (amino acid 5-20) that was presented in context of HLA-DR. T-cell receptor Vβ-spectratyping and sequencing of specific CD4 T-cells revealed a prominent peak fraction of monoclonal origin. In conclusion, similar to monoclonal gammopathies of undetermined significance, this may represent the first T-cell counterpart with known specificity against M. tuberculosis.

SUMMARY We present an algorithm for automated S-phase arrival time determination of local, regional and teleseismic events based on autoregressive (AR) prediction of the waveform. The waveforms of the horizontal components are predicted using a scalar AR model for multicomponent recordings. The AR coefficients are estimated in a short moving window using a least-squares approach minimizing the forward prediction error. Synthetic tests with single-component data show that the least-squares approach yields similar or even better results than the Yule–Walker and Burg’s algorithms. We discuss the choice of the AR model and show that the corresponding prediction error of the AR model, applied to both horizontal components, is sufficient to detect instantaneous changes in amplitude, frequency, phase and polarization. The rms prediction error of both horizontal components defines the characteristic function, to which an algorithm for the estimation of the arrival time is applied. The proposed algorithm also accounts for automatic quality assessment of the estimated S-onset times. Four quality criteria are used to define the weight of the automatically estimated S-arrival time. They are based on two different estimations of the slope of the characteristic function and on two signal-to-noise ratios (SNRs). The proposed algorithm is applied to a large data set recorded by a dense regional seismic network in the southern Aegean. The data set contains recordings of local and regional crustal as well as intermediate deep earthquakes. The reliability and the robustness of the picking algorithm is tested by comparing more than 2600 manual S readings, serving as reference picks, with the corresponding automatically derived S-onset times. We find an average deviation from the reference picks of 0.5 s ± 0.8 s. If only excellent automatic picks are considered, the average difference from the reference picks is reduced to −0.057 s ± 0.12 s. The proposed automatic quality weighting scheme yields similar weights for the individual S onsets as the ones set by the analysts. The presented algorithm works reliably and robust even when applied to a data set with heterogeneous SNRs. Furthermore, the proposed method may be suitable for the implementation in an earthquake early-warning system as additional, accurate S-wave arrival time estimates stabilize the location, especially the determination of the event depth.

Intravenous iron preparations are key components in the management of anaemia of various etiologies. These iron-carbohydrate complexes permit safe systemic delivery of iron, whilst protecting from the potential toxic effects of over-saturation. This in turn permits efficient haematopoiesis following erythropoietin administration. Since the rate of release of iron is dependent upon the structure of this iron-carbohydrate complex, it is essential to ensure that an intravenous iron preparation is well characterized and its properties documented. This report describes physicochemical and toxicological studies into a new iron sucrose generic preparation, "Iron Sucrose Azad (ISA)", using the original iron sucrose product as reference. It could be demonstrated that the specifications and physicochemical characteristics of ISA reflect those of the reference product. Furthermore, in a rat model previously shown to identify possible toxicological effects of "unsimilar" iron sucrose preparations, ISA was found to have the same properties as the reference product, with both being well tolerated.

Introduction: The role of elevated homocysteine in primary and secondary Raynaud phenomenon (RP) and in patients with atherosclerosis has been reported controversially. In secondary RP due to connective tissue disease specific alterations of nailfold capillaries might be present. An association between these microvascular changes and homocysteine has been suggested. Aim: The aim of this study was to determine whether homocysteine level differs between patients with primary and secondary RP and to test the hypothesis that homocysteine or other cardiovascular risk factors are associated with specific features of microangiopathy in secondary RP. Patients and Methods: Eighty-one consecutive patients with RP referred for vascular assessment were studied by nailfold capillaroscopy. Homocysteine, C-reactive protein and cholesterol were measured and other cardiovascular risk factors and comorbidities assessed. Results: Homocysteine, C-reactive-protein and cholesterol levels did not differ between patients with primary (n=60) and secondary RP (n=21). Likewise, no differences in the prevalence of cardiovascular risk factors and comorbidities were found. In secondary RP no correlation was found between microvascular involvement and homocysteine or C-reactive protein. Conclusion: Plasma homocysteine is not different in patients with either primary or secondary RP and is therefore not a marker for the distinction of these diseases. The extent of microvascular involvement in secondary RP does not correlate with plasma homocysteine.

An unresolved question in the bioenergetics of methanogenic archaea is how the generation of proton-motive and sodium-motive forces during methane production is used to synthesize ATP by the membrane-bound A(1)A(o)-ATP synthase, with both proton- and sodium-coupled enzymes being reported in methanogens. To address this question, we investigated the biochemical characteristics of the A(1)A(o)-ATP synthase (MbbrA(1)A(o)) of Methanobrevibacter ruminantium M1, a predominant methanogen in the rumen. Growth of M. ruminantium M1 was inhibited by protonophores and sodium ionophores, demonstrating that both ion gradients were essential for growth. To study the role of these ions in ATP synthesis, the ahaHIKECFABD operon encoding the MbbrA(1)A(o) was expressed in Escherichia coli strain DK8 (Δatp) and purified yielding a 9-subunit protein with an SDS-stable c oligomer. Analysis of the c subunit amino acid sequence revealed that it consisted of four transmembrane helices, and each hairpin displayed a complete Na(+)-binding signature made up of identical amino acid residues. The purified MbbrA(1)A(o) was stimulated by sodium ions, and Na(+) provided pH-dependent protection against inhibition by dicyclohexylcarbodiimide but not tributyltin chloride. ATP synthesis in inverted membrane vesicles lacking sodium ions was driven by a membrane potential that was sensitive to cyanide m-chlorophenylhydrazone but not to monensin. ATP synthesis could not be driven by a chemical gradient of sodium ions unless a membrane potential was imposed. ATP synthesis under these conditions was sensitive to monensin but not cyanide m-chlorophenylhydrazone. These data suggest that the M. ruminantium M1 A(1)A(o)-ATP synthase exhibits all the properties of a sodium-coupled enzyme, but it is also able to use protons to drive ATP synthesis under conditions that favor proton coupling, such as low pH and low levels of sodium ions.

The aim of this study was to investigate the efficacy of idebenone on neurological function as assessed by ICARS and FARS neurological rating scales in pediatric Friedreich's ataxia (FRDA) patients. Sixty-eight pediatric patients were enrolled in an open-label extension study (IONIA-E) where patients received idebenone (Catena(®), 150 mg film-coated tablets) at a weight-adjusted dose of 1,350/2,250 mg/day for 12 months after patients had completed a double-blind, randomized, placebo-controlled study (IONIA) receiving either idebenone at a weight-adjusted dose of 450/900 or 1,350/2,250 mg/day or placebo for 6 months. Changes in ICARS and FARS total scores and subscores were recorded for the 12-month IONIA-E study and for the 18-month combined IONIA and IONIA-E study period. Data analyzed by a mixed-model repeated-measures ANCOVA relative to baseline resulted in least square means for the change in ICARS for the IONIA-E study of +0.98 points (SEM 0.73; p = 0.180), indicating a trend for worsening. However, combined with the IONIA study the change was -1.03 ± 0.68 points (p = 0.132), indicating a trend for improvement in neurological function over the 18-month period. Importantly, patients who received idebenone 1,350/2,250 mg/day over this period significantly improved in neurological function (change in ICARS: -3.02 ± 1.22, p = 0.014). The improvement in neurological function over time was best seen when the posture and stance subscore was excluded from the analysis. Comparable data were obtained with the FARS. The findings of the open-label IONIA-E study combined with the double-blind IONIA study indicate that idebenone at a dose of 1,350/2,250 mg/day may offer a therapeutic benefit to pediatric FRDA patients by stabilizing the overall neurological function and improving fine motor skills and speech.

SUMMARY Seismic surface wave measurements offer tight constraints on shear wave speed values within the lithosphere and asthenosphere. It is still a matter of debate, however, how accurately and under what conditions surface waves can resolve the depth and thickness of the lithosphere–asthenosphere boundary (LAB). We investigate the sensitivity of Rayleigh waves to LAB properties and find that if the LAB is associated with a 2–3 per cent shear speed reduction at a depth less than 100 km, then 10–20 km variations in its depth translate into phase-velocity changes of up to 1 per cent. Variations in the thickness of the LAB from zero to a few tens of kilometres cause much smaller phase-velocity changes (∼0.1 per cent), although the signal of the LAB-thickness variations is enhanced by a distinct frequency-dependent pattern of phase-velocity increases and decreases. For LAB depths increasing beyond 100 km, larger absolute variations in the LAB depth and thickness are needed to generate response of the same amplitude in phase velocities. We introduce a grid-search inversion of phase-velocity curves for the LAB depth and thickness, defining them as the middle and the width, respectively, of a depth interval with a linear shear-speed decrease in it. The inversion comprises dense sampling of the LAB depthLAB thickness parameter plane and non-linear, gradient-search inversions at every point; it accountsforanytrade-offsoftheLABparameterswithshearspeedvariationsaboveandbelow the LAB. Inversions of phase-velocity curves for the LAB depth and thickness show that the two parameters have uncorrelated uncertainties, with the LAB depth constrained better than the LAB thickness. Random errors in phase-velocity measurements have a limited effect on LAB-depth measurements, causing errors of only a few kilometres. Measurements of the LAB thickness are less robust and are not possible in the presence of large (∼1 per cent) random errors. Substantial systematic biases in the measurements (errors that persist over broad period ranges of tens of seconds) can affect both LAB-depth and LAB-thickness estimates; phasevelocity curves with such biases are not suitable for inversions for LAB properties. Resolving the LAB, however, in particular the LAB depth, should already be possible with some of the accurate, broad-band, phase-velocity measurements available today. Applying our method to phase-velocity data measured in Phanerozoic west-central Germany, we find best-fitting LAB depths in the 60–80 km range (the LAB depth always understood to be the middle of the shear-speed reduction depth range), with minimum misfits achieved near the 70-km LAB depth. Beneath the Archean Guyana Shield, we determine a 140–175 km LAB-depth range, with a 160 km best-fitting (mid-)LAB depth.

The ATP synthase of the alkaliphile Bacillus pseudofirmus OF4 has a tridecameric c-subunit rotor ring. Each c-subunit has an AxAxAxA motif near the center of the inner helix, where neutralophilic bacteria generally have a GxGxGxG motif. Here, we studied the impact of four single and six multiple Ala-to-Gly chromosomal mutations in the A16xAxAxA22 motif on the capacity for nonfermentative growth and, for most of the mutants, on ATP synthesis by ADP- and P(i)-loaded membrane vesicles at pH 7.5 and 10.5. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analyses of the holo-ATP synthases were used to probe stability of the mutant c-rotors and mobility properties of the c-rotors as well as the monomeric c-subunits that are released from them by trichloroacetic acid treatment. Mutants containing an Ala16-to-Gly mutation exhibited the most severe functional defects. Via SDS-PAGE, most of the mutant c-monomers exhibited increased mobility relative to the wild-type (WT) c-subunit, but among the intact c-rings, only Ala16-to-Gly mutants exhibited significantly increased mobility relative to that of the WT c-ring. The hypothesis that these c-rings have a decreased c-subunit stoichiometry is still untested, but the functional impact of an Ala16-to-Gly mutation clearly depended upon additional Ala-to-Gly mutation(s) and their positions. The A16/20G double mutant exhibited a larger functional deficit than both the A16G and A16/18G mutants. Most of the mutant c-rings showed in vitro instability relative to that of the WT c-ring. However, the functional deficits of mutants did not correlate well with the extent of c-ring stability loss, so this property is unlikely to be a major factor in vivo.

Based on the spherical cavity expansion (SCE) problem, Cudmani and Osinov (Can Geotech J 38:622–638, 2001), Osinov and Cudmani (Int J Numer Anal Method Geomech 25:473–495, 2001) developed a semi-empirical method of interpretation of CPT for coarse-grained soils (sand, gravel) using a hypoplastic constitutive model. Using a material-independent shape factor, the cone penetration resistance was related to the limit pressure required to expand a spherical cavity. The shape factor was observed to be a function of the soil state only, in particular the pressure-dependent relative density. This paper presents an analogous interpretation technique for CPT in fine-grained soils using the shape factor concept, Cavity Expansion approach, and a hypoplastic constitutive model. Relations for the shape factor and the limit pressure have been proposed based on the parameters affecting these quantities. A validation of the proposed interpretation technique with experimental results has also been performed.

While it is widely acknowledged that the ubiquitin– proteasome system plays an important role in transcription, little is known concerning the mechanistic basis, in particular the spatial organization of proteasome-dependent proteolysis at the transcription site. Here, we show that proteasomal activity and tetraubiquitinated proteins concentrate to nucleoplasmic microenvironments in the euchromatin. Such proteolytic domains are immobile and distinctly positioned in relation to transcriptional processes. Analysis of gene arrays and early genes in Caenorhabditis elegans embryos reveals that proteasomes and proteasomal activity are distantly located relative to transcriptionally active genes. In contrast, transcriptional inhibition generally induces local overlap of proteolytic microdomains with components of the transcription machinery and degradation of RNA polymerase II. The results establish that spatial organization of proteasomal activity differs with respect to distinct phases of the transcription cycle in at least some genes, and thus might contribute to the plasticity of gene expression in response to environmental stimuli.

Continental lithosphere can undergo pervasive internal deformation, often distributed over broad zones near plate boundaries. However, because of the paucity of observational constraints on three-dimensional movement at depth, patterns of flow within the lithosphere remain uncertain. Endmember models for lithospheric flow invoke deformation localized on faults or deep shear zones or, alternatively, diffuse, viscous-fluid-like flow. Here we determine seismic Rayleigh-wave anisotropy in the crust and mantle of the Aegean region, an archetypal example of continental deformation. Our data reveal a complex, depth-dependent flow pattern within the extending lithosphere. Beneath the northern Aegean Sea, fast shear wave propagation is in a North-South direction within the mantle lithosphere, parallel to the extensional component of the current strain rate field. In the south-central Aegean, where deformation is weak at present, anisotropic fabric in the lower crust runs parallel to the direction of palaeo-extension in the Miocene. The close match of orientations of regional-scale anisotropic fabric and the directions of extension during the last significant episodes of deformation implies that at least a large part of the extension in the Aegean has been taken up by distributed viscous flow in the lower crust and lithospheric mantle.

Early mortality in Duchenne muscular dystrophy (DMD) is related to cardiac and respiratory complications. A phase IIa doubleblind randomized placebo-controlled clinical trial was conducted to investigate the tolerability and efficacy of idebenone therapy in children with DMD. Twenty-one DMD patients (aged 8–16 years) were randomly assigned to daily treatment with 450 mg idebenone (Catena )( n = 13) or placebo (n = 8) for 12 months. All subjects completed the study and idebenone was safe and well tolerated. Idebenone treatment resulted in a trend (p = 0.067) to increase peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. A significant respiratory treatment effect on peak expiratory flow was observed (p = 0.039 for PEF and p = 0.042 for PEF percent predicted). Limitations of this study were the small sample size, and a skewed age distribution between treatment groups. Data from this study provided the basis for the planning of a confirmatory study. 2011 Elsevier B.V. All rights reserved.

Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin ('mini-agrin') or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.

The microscopic mechanism of coupled c-ring rotation and ion translocation in F(1)F(o)-ATP synthases is unknown. Here we present conclusive evidence supporting the notion that the ability of c-rings to rotate within the F(o) complex derives from the interplay between the ion-binding sites and their nonhomogenous microenvironment. This evidence rests on three atomic structures of the c(15) rotor from crystals grown at low pH, soaked at high pH and, after N,N'-dicyclohexylcarbodiimide (DCCD) modification, resolved at 1.8, 3.0 and 2.2 Å, respectively. Alongside a quantitative DCCD-labeling assay and free-energy molecular dynamics calculations, these data demonstrate how the thermodynamic stability of the so-called proton-locked state is maximized by the lipid membrane. By contrast, a hydrophilic environment at the a-subunit-c-ring interface appears to unlock the binding-site conformation and promotes proton exchange with the surrounding solution. Rotation thus occurs as c-subunits stochastically alternate between these environments, directionally biased by the electrochemical transmembrane gradient.

The functional mechanism of the F1Fo ATP synthase, like many membrane transporters and pumps, entails a conformational cycle that is coupled to the movement of H+ or Na+ ions across its transmembrane domain, down an electrochemical gradient. This coupling is an efficient means of energy transduction and regulation, provided that ion binding to the membrane domain, known as Fo, is appropriately selective. In this study we set out to establish the structural and energetic basis for the ion-binding selectivity of the membrane-embedded Fo rotors of two representative ATP synthases. First, we use a biochemical approach to demonstrate the inherent binding selectivity of these rotors, that is, independently from the rest of the enzyme. We then use atomically detailed computer simulations of wild-type and mutagenized rotors to calculate and rationalize their selectivity, on the basis of the structure, dynamics and coordination chemistry of the binding sites. We conclude that H+ selectivity is most likely a robust property of all Fo rotors, arising from the prominent presence of a conserved carboxylic acid and its intrinsic chemical propensity for protonation, as well as from the structural plasticity of the binding sites. In H+-coupled rotors, the incorporation of hydrophobic side chains to the binding sites enhances this inherent H+ selectivity. Size restriction may also favor H+ over Na+, but increasing size alone does not confer Na+ selectivity. Rather, the degree to which Fo rotors may exhibit Na+ coupling relies on the presence of a sufficient number of suitable coordinating side chains and/or structural water molecules. These ligands accomplish a shift in the relative binding energetics, which under some physiological conditions may be sufficient to provide Na+ dependence.

The seismic coupling and the spatiotemporal distribution of seismicity on the presumed rupture surface of the 365 A.D. M w 8.3±0.2 Crete event at the shallow plate contact of the Hellenic subduction zone (HSZ) southwest of Crete is investigated. The maximum cumulative average seismic slip ( U seis ) on the rupture surface is estimated for different time periods using historic and instrumental seismicity catalogs and utilizing a formula that incorporates empirical relations linking rupture area and average slip of an event to its moment magnitude ( M w ). Events above the completeness magnitude of the catalog are incorporated by summation while events below are taken account of by integrating over the extrapolated frequency–magnitude distribution using a truncated Gutenberg–Richter relation. Estimates of U seis for the time intervals 0–1999, 1500–1999, and 1964–2006 using historic and instrumental catalogs suggest a considerable seismic slip deficit when compared with the total slip expected from the temporal extrapolation of geodetic measurements. This suggests a recent weakly coupled plate contact and a total slip predominantly accommodated aseismically despite the 365 A.D. event. High seismic activity up to magnitudes of about M w 6 is found accompanying the aseismic slip at the plate contact. Investigations of the seismicity distribution hint at a spatial variability of the seismic energy release in the western forearc of the HSZ. Activity in the proximity of the 365 A.D. epicenter is observed to be an order of magnitude larger than toward the northwest between Crete and Peloponnese. This spatiotemporal variability of the seismic energy release and seismic coupling suggests that subregions of the plate contact undergo alternating periods of locking followed by intermediate magnitude events and aseismic sliding. Thus, the behavior of significant portions of the plate contact southwest of Crete may be described as conditionally stable.

3rd Joint German/UK Bioenergetics Conference co-organized by the Biochemical Society and Max Planck Institute of Biophysics; 10–13 April 2013; Schloss Rauischholzhausen, Ebsdorfergrund, Germany

Over the last 25 years mining-induced seismicity in the Ruhr area has continuously been monitored by the Ruhr-University Bochum. About 1,000 seismic events with local magnitudes between 0.7 ≤ ML ≤ 3.3 are located every year. For example, 1,336 events were located in 2006. General characteristics of induced seismicity in the entire Ruhr area are spatial and temporal correlation with mining activity and a nearly constant energy release per unit time. This suggests that induced stresses are released rapidly by many small events. The magnitude–frequency distribution follows a Gutenberg–Richter relation which is a result from combining distributions of single longwalls that themselves show large variability. A high b-value of about 2 was found indicating a lack of large magnitude events. Local analyses of single longwalls indicate that various factors such as local geology and mine layout lead to significant differences in seismicity. Stress redistribution acts very locally since differences on a small scale of some hundreds of meters are observed. A regional relation between seismic moment M0 and local magnitude ML was derived. The magnitude–frequency distribution of a single longwall in Hamm was studied in detail and shows a maximum at ML = 1.4 corresponding to an estimated characteristic source area of about 2,200 m2. Sandstone layers in the hanging or foot wall of the active longwall might fail in these characteristic events. Source mechanisms can mostly be explained by shear failure of two different types above and below the longwall. Fault plane solutions of typical events are consistent with steeply dipping fracture planes parallel to the longwall face and nearly vertical dislocation in direction towards the goaf. We also derive an empirical relation for the decay of ground velocity with epicenter distance and compare maximum observed ground velocity to local magnitude. This is of considerable public interest because about 30 events larger than ML ≥ 1.2 are felt each month by people living in the mining regions. Our relations, for example, indicate that an event in Hamm with a peak ground velocity of 6 mm/s which corresponds to a local magnitude ML between 1.7 and 2.3 is likely to be felt within about 2.3 km radius from the event.

The crystal structure of the c-ring from the proton-coupled F1Fo ATP synthase from Spirulina platensis is shown at 2.1-A resolution. The ring includes 15 membrane-embedded c subunits forming an hourglass-shaped assembly. The structure demonstrates that proton translocation across the membrane entails protonation of a conserved glutamate located near the membrane center in the c subunit outer helix. The proton is locked in this site by a precise hydrogen bond network reminiscent of that in Na+-dependent ATP synthases. However, the structure suggests that the different coordination chemistry of the bound proton and the smaller curvature of the outer helix drastically enhance the selectivity of the H+ site against other cations, including H3O+. We propose a model for proton translocation whereby the c subunits remain in this proton-locked state when facing the membrane lipid. Proton exchange would occur in a more hydrophilic and electrostatically distinct environment upon contact with the a subunit interface.

Laminin alpha2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.

X-linked dyskeratosis congenita (DC) is a rare bone marrow failure syndrome caused by mostly missense mutations in the pseudouridine synthase NAP57 (dyskerin/Cbf5). As part of H/ACA ribonucleoproteins (RNPs), NAP57 is important for the biogenesis of ribosomes, spliceosomal small nuclear RNPs, microRNAs and the telomerase RNP. DC mutations concentrate in the N- and C-termini of NAP57 but not in its central catalytic domain raising questions as to their impact. We demonstrate that the N- and C-termini together form the binding surface for the H/ACA RNP assembly factor SHQ1 and that DC mutations modulate the interaction between the two proteins. Pinpointing impaired interaction between NAP57 and SHQ1 as a potential molecular basis for X-linked DC has implications for therapeutic approaches, e.g. by targeting the NAP57–SHQ1 interface with small molecules.

Assembly of H/ACA RNPs in yeast is aided by at least two accessory factors, Naf1p and Shq1p. Although the function of Naf1p and its human ortholog NAF1 has been delineated in detail, that of Shq1p and its putative human ortholog SHQ1 remains obscure. We demonstrate that SHQ1 indeed functions in the biogenesis of human H/ACA RNPs and we dissect its mechanism of action. Like NAF1, SHQ1 binds the major H/ACA core protein and pseudouridine synthase NAP57 (aka dyskerin) but precedes the assembly role of NAF1 at nascent H/ACA RNAs because the interaction of SHQ1 with NAP57 in vivo and in vitro precludes that of NAF1 and of the other H/ACA core proteins that are present at the sites of H/ACA RNA transcription. The N-terminal heat shock protein 20-like CS domain of SHQ1 is dispensable for NAP57 binding. Consistent with its role as an assembly factor, SHQ1 localizes to the nucleoplasm and is excluded from nucleoli and Cajal bodies, the sites of mature H/ACA RNPs. In an in vitro assembly system of functional H/ACA RNPs that is dependent on NAF1, excess recombinant SHQ1 interferes with assembly. Importantly, knockdown of cellular SHQ1 prevents accumulation of a newly synthesized H/ACA reporter RNA and generally reduces the levels of endogenous H/ACA RNAs including telomerase RNA. In summary, the sequential action of SHQ1 and NAF1 is required for functional assembly of H/ACA RNPs in vivo and in vitro. This step-wise process could serve as an efficient means of quality control during H/ACA RNP assembly.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease that affects boys and leads to early death. In the quest for new treatments that improve the quality of life and in the search for a possible definitive cure, the use of animal models plays undoubtedly an important role. Therefore, a number of different mammalian models for DMD have been described. Much knowledge on the molecular mechanisms underlying the disease has arisen from studies in these animals. However, the use of different models does not often allow a direct comparison of results obtained in preclinical trials and therefore hinders a straightforward translational research. In the frame of "TREAT-NMD", a European Network of Excellence addressing the fragmentation in the assessment and treatment of neuromuscular diseases, we compare here the currently used mammalian animal models for DMD with the aim of selecting and recommending the most appropriate ones for preclinical efficacy testing of new therapeutic strategies.

The volcanic center of Santorini Island is the most active volcano of the southern Aegean volcanic arc. Α dense seismic array consisting of fourteen portable broadband seismological stations has been deployed in order to monitor and study the seismo-volcanic activity at the broader area of the Santorini volcanic center between March 2003 and September 2003. Additional recordings from a neighbouring larger scale temporary network (CYCNET) were also used for the relocation of more than 240 earthquakes recorded by both arrays. A double-difference relocation technique was used, in order to obtain optimal focal parameters for the best-constrained earthquakes. The results indicate that the seismic activity of the Santorini volcanic center is strongly associated with the tectonic regime of the broader Southern Aegean Sea area as well as with the volcanic processes. The main cluster of the epicenters is located at the Coloumbo Reef, a submarine volcano of the volcanic system of Santorini Islands. A smaller cluster of events is located near the Anydros Islet, aligned in a NE–SW direction, running almost along the main tectonic feature of the area under study, the Santorini–Amorgos Fault Zone. In contrast, the main Santorini Island caldera is characterized by the almost complete absence of seismicity. This contrast is in very good agreement with recent volcanological and marine studies, with the Coloumbo volcanic center showing an intense high-temperature hydrothermal activity, in comparison to the corresponding low-level activity of the Santorini caldera. The high-resolution hypocentral relocations present a clear view of the volcanic submarine structure at the Coloumbo Reef, showing that the main seismic activity is located within a very narrow vertical column, mainly at depths between 6 and 9 km. The focal mechanisms of the best-located events show that the cluster at the Coloumbo Reef is associated with the “Kameni–Coloumbo Fracture Zone”, which corresponds to the western termination of the major ENE–WSW Santorini–Amorgos Fault Zone. Stress–tensor inversion of the available fault plane solutions from Coloumbo Reef, as well as existing neotectonic fault information from NE Santorini (Coloumbo peninsula), suggests that the NE Santorini–Coloumbo faults belong to a single rupture system, with a ~ 30° rotation of the local stress field with respect to the NNW–SSE regional extension field of the southern Aegean Sea. The observed change of the fault plane solutions shows that local conditions at the Coloumbo submarine volcano area control the observed faulting pattern.

Seismic events, i.e., fractures in rock that radiate detectable seismic waves, are a worldwide phenomena associated with mining and reservoir exploitation. Longwall mining in German coal mines often causes seismic events, which can be felt at surface where they can lead to a considerable annoyance of residents and sometimes even lead to minor damages of buildings and infrastructure. Strong seismic events are in a large part responsible for a more and more decreasing community acceptance of mining. The mines therefore have to investigate the local conditions, which cause the generation of seismic events, to find ways of avoiding strong mining induced seismic events. This paper describes the research on mining-induced seismicity around a specific active longwall at 1100 m depth under several previously mined longwall panels. Seismic events are recorded by a local network featuring 15 surface and six subsurface stations. Location and fault plane solutions show the occurrence of at least three different event types, which are characterized by distinct modes of failure. Underground core drilling and an extensive rock testing program are used to build up a rock mechanical model featuring a multi-layer strata for use with numerical analyses. The numerical model is able to explain the different failure mechanisms as fault activation, remnant pillar punching and beam failure. The use of rock mass classification, rock mass strength criteria and in situ stresses together with 2D and 3D numerical analyses facilitates the evaluation of the results from seismology approaches, and makes future analysis of longwall-related seismic events possible.

A large-size creeping natural slope was simulated with the Finite Element (FE) method, using a visco-hypoplastic material model, which describes the mechanical behaviour of cohesive soils, allowing for viscous effects (i.e. creep, relaxation and rate-dependence of stiffness). First, the required material parameters were determined by means of standard geotechnical laboratory tests using representative soil samples taken from the slope. Then a FE mesh of a slope section was constructed and boundary conditions were established. The slope movements were simulated and compared with inclinometer measurements, which were available for a period of 16 years. The calculation results are in good agreement with the observed velocities. A parameter study was carried out in order to assess the influence of slope angle, initial void ratio, material parameters as well as their spatial distribution.

OBJECTIVE: Fabry disease is a rare X-linked disorder caused by deficiency of alpha-galactosidase A. The metabolic defect results in the progressive accumulation of globotriaosylceramide within vascular cells leading to renal, cardiac and cerebrovascular manifestations. The aim of this study was to evaluate nailfold capillaroscopy as a non-invasive diagnostic tool in Fabry disease and to characterize morphological and functional changes of the capillaries in vivo. METHODS: Twenty-five consecutive patients with Fabry disease (17 males) without enzyme-replacement therapy had been studied by fluorescence nailfold capillaroscopy. Macrocirculation of digital arteries was tested by digital pulse volume recording and patients had been asked about the presence of Raynaud phenomenon. RESULTS: Significant more bushy capillaries and clusters were present in Fabry patients (72%) compared to healthy controls (10%). No avascular fields had been seen, and in only one patient atypical architecture and in another one a giant capillary was present. Enhanced natrium-fluorescein diffusion into the pericapillary area has been observed in three male patients. Six patients (one female) reported Raynaud phenomenon of all fingers. CONCLUSIONS: In Fabry disease morphological and functional microangiopathy of nailfold capillaries is present. Furthermore, these new findings might explain, at least in part, the unusual high frequency of Raynaud phenomenon in Fabry patients, which has not been described so far. Our data suggest that capillaroscopy might be used as an additional non-invasive diagnostic tool for Fabry disease.

In order to eradicate vagrancy in Switzerland, between 1926 and 1973 children of Yenish origin were systematically taken from their parents and placed with foster families, in homes and institutions. With the support of the authorities and under the auspices of the renowned Pro Juventute foundation, the campaign was carried out by the so-called Hilfswerk fur die Kinder der Landstrasse ('Relief Organisation for the Children of the open road'). This campaign is nowadays seen as one of the darkest chapters in recent Swiss history, but is little-known outside Switzerland.Firstly the 'Children of the open road' campaign is described: the aims and the methods, the accomplishment and the institutional network, the extent and the consequences. In addition, due to exceptional access to the files of the Hilfswerk, new findings can be presented. Secondly, the political and ideological context is shown. It is demonstrated that the 'Children of the open road' campaign was only the rigorous continuation of an assimilat...

Mass spectrometry of large macromolecules is still a methodological challenge. We here report on the application of the recently developed LILBID (laser induced liquid bead ion desorption) mass spectrometry by which the biomolecules dissolved in microdroplets are desorbed/ablated by a mid-IR laser into vacuum. Two modes of desorption are possible: an ultrasoft mode at low laser intensity in which a macromolecule is desorbed as integral complex into vacuum and a harsher mode at higher intensity, by which it is dissociated into its covalent subunits. With this method we studied the soluble core polymerase II and a membrane-embedded F 1 F o -ATP synthase, solubilized by detergent. For both complexes the complete complex in different charge state is observed at ultrasoft conditions. At elevated laser intensities all 10 subunits could be assigned for the core Pol II. In the case of the ATP synthase under equal conditions all eight subunits appear in the mass spectrum, assigned by a correspondence of the expected theoretical masses of the subunits and the observed ones. In addition the method requires only sample volumes of microliter at micromolar concentration and is tolerant to detergents. Therefore it is a low consumptive method well adapted for the mass analysis of biomolecules of low availability such as membrane molecules.

Evolution of continental lithosphere during orogenies and the following periods of relative stability is poorly understood, largely because of the lack of relevant observational constraints. Measurements of seismic anisotropy provide such constraints, but due to limitations in the resolving power of available data sets and, more generally, of various data types, detailed mapping of lithospheric anisotropy has remained elusive. Here we apply surface-wave array analysis to data from the East-central U.S. and determine the layering of azimuthal anisotropy beneath the Grenville–Appalachian orogen in the entire lithosphere–asthenosphere depth range. Combined measurements of Rayleigh-wave phase velocities along 60 interstation paths constrain phase-velocity maps with statistically significant anisotropy. Distinct anisotropy patterns in three different period ranges point to the existence of three distinct layers beneath the orogen, with different anisotropic fabric within each. We invert phase-velocity maps and, alternatively, pairs of selected measured dispersion curves for anisotropic shear-velocity structure. The results confirm that three anisotropic layers with different fabric within each are present, two in the lithosphere (30–70 km; 70–150 km depths) and another in the asthenosphere beneath (> 150 km). Directions of fast wave propagation in the upper lithosphere are parallel to the Grenville and Appalachian fronts, suggesting that the region-scale anisotropy pattern reflects the pervasive deformation of the lower crust and uppermost mantle during the continental collisions. The fast-propagation azimuth within the lower lithosphere is different, parallel to the NNW direction of North America's motion after the orogeny (~ 160–125 Ma). This suggests that the lithosphere, 70-km thick by the end of the Appalachian orogeny, gradually thickened to the present 150-km while inheriting the fabric from the sheared asthenosphere below, as the plate moved NNW. Below 150 km, the fast-propagation direction is parallel to the present plate motion, indicating fabric due to recent asthenospheric flow. Anisotropy in narrower depth ranges beneath the region has been sampled previously. Published results (from observations of Pn and SKS and waveform tomography) can be accounted for and reconciled by the three-layered model of anisotropy for the lithosphere–asthenosphere depth range constrained in this study. In particular, the anisotropy we detect in the asthenosphere can account for the magnitude of SKS-wave splitting, with the fast wave-propagation directions inferred from SKS and surface-wave data also consistent, both parallel to the current plate motion.

Tectonics of the eastern Mediterranean are strongly influenced by subduction of oceanic lithosphere with slab pull as a prominent driving force. The current distribution of remnants of oceanic lithosphere and the properties of African mantle lithosphere beneath the eastern Mediterranean basin have been a matter of debate. Previous studies variously found continental as well as oceanic lithosphere in this region. A set of 1-D S-wave velocity models is determined in order to characterize the mantle lithosphere in the area between Crete and the Middle East. For seven paths starting from Cyprus and running to Crete, to Anatolia as well as to the Middle East, broad-band average phase velocity curves of the fundamental Rayleigh mode are obtained in the frequency range of about 3 mHz to 90 mHz by a two-station method. In addition, an east–west oriented path crossing southern Anatolia and a path running parallel to the Dead Sea Fault Zone are considered. Phase velocity curves are inverted for path average 1-D S-wave velocity models. Resolution is investigated with the Neighbourhood Algorithm. Comparing the resulting 1-D models, cold oceanic mantle lithosphere showing S-wave velocities above 4.6 km s− 1 can be distinguished from mantle lithosphere with low S-wave velocities. Oceanic lithosphere is found west of Cyprus beneath the Herodotus basin. As indicated by Benioff zones, it is subducting towards northwest in the southeastern Aegean and towards northeast beneath southwestern Anatolia. To the east of Cyprus the mantle lithosphere beneath the easternmost Mediterranean Sea shows low S-wave velocities. No indications for cold oceanic mantle lithosphere are found beneath the Levant basin. In the region of the Dead Sea Fault Zone and the Levant basin the lithosphere–asthenosphere boundary is located at shallow depths of about 60 km to 80 km. The DSFZ is situated in a region of thinned lithosphere underlain by an asthenosphere with anomalous low S-wave velocities. Low S-wave velocities beneath southern Anatolia extend down to at least 150 km depth as expected for a back arc setting. Inferred Moho depths vary for the different paths between 28 km and 41 km.

The interaction between the c(11)ring and the gammaepsilon complex, forming the rotor of the Ilyobacter tartaricus ATP synthase, was probed by surface plasmon resonance spectroscopy and in vitro reconstitution analysis. The results provide, for the first time, a direct and quantitative assessment of the stability of the rotor. The data indicated very tight binding between the c(11)ring and the gammaepsilon complex, with an apparent K(d) value of approximately 7.4nm. The rotor assembly was primarily dependent on the interaction of the cring with the gammasubunit, and binding of the cring to the free epsilon subunit was not observed. Mutagenesis of selected conserved amino acid residues of all three rotor components (cR45, cQ46, gammaE204, gammaF203 and epsilonH38) severely affected rotor assembly. The interaction kinetics between the gammaepsilon complex and c(11)ring mutants suggested that the assembly of the c(11)gammaepsiloncomplex was governed by interactions of low and high affinity. Low-affinity binding was observed between the polar loops of the cring subunits and the bottom part of the gamma subunit. High-affinity interactions, involving the two residues gammaE204 and epsilonH38, stabilized the holo-c(11)gammaepsilon complex. NMR experiments indicated the acquisition of conformational order in otherwise flexible C- and N-terminal regions of the gamma subunit on rotor assembly. The results of this study suggest that docking of the central stalk of the F(1)complex to the rotor ring of F(o) to form tight, but reversible, contacts provides an explanation for the relative ease of dissociation and reconstitution of F(1)F(o)complexes.

SUMMARY The lithospheric structure of the Aegean region is investigated by analysis of Rayleigh-wave fundamental mode dispersion measurements. Isotropic 1-D models for almost 100 two-station ray paths across the region display distinct variations in the Moho depth and crustal S-wave velocities. The descending slab of the subducting African plate can be resolved down to 120 km depth beneath the volcanic arc. Three different regions are distinguished in terms of Moho depth: (1) The forearc, with large crustal thicknesses between 38 and 48 km and an average of 43 km, (2) the northern Aegean, with an average Moho depth of 28 km and (3) the southern Aegean (central volcanic arc, i.e. Cyclades, and Sea of Crete) with an even thinner crust of around 25 km. Lateral variations in structure between 25 and 55 km depth indicate a marked difference between the western and eastern forearc, collocated with pronounced changes in trench and slab geometry as well as published deformation rates. S velocities between 25 and 55 km depth are low everywhere beneath the forearc but increase from the Peleponnesus to Crete. An abrupt change occurs between western and central Crete in terms of the visibility of the Aegean Moho and the seismic structure of the lithospheric mantle wedge: An Aegean mantle wedge with S velocities above 4.4 km s−1 is only observed to the east of central Crete, whereas to the west velocities of less than 4.0 km s−1 occur down to the plate contact. These low velocities above the slab may indicate the presence of a melange of metamorphic rocks at the depths. A low-velocity asthenospheric layer is observed beneath the Sea of Crete and the Cyclades below 40 km depth, between the thinned lithosphere above and the slab below. The observed radial anisotropy in the northern part of the Aegean is likely to be due to preferred orientation of anisotropic minerals within the lower crust, possibly caused by lateral ductile flow associated with recent lithospheric extension.

SUMMARY We explore the Rayleigh-wave phase velocity structure of the east-central US in a broad period range (10‐200 s). Using a recent implementation of the two-stations method, we first measure interstation dispersion curves of Rayleigh-wave phase velocities along 60 paths. We then invert our collection of dispersion curves for isotropic and azimuthally anisotropic (2� and 4� ) phase‐velocity maps. The inversion is performed by a damped, smoothed LSQR, and the output model is parametrized on a triangular grid of knots with a 140 km grid spacing. Using the isotropic component of the phase velocity maps to constrain regional variations in shear velocity and Moho-depth, we observe that over the upper-middle crust depth range (z 1 per cent), and the azimuth of the fast-propagation direction is uniform over the entire region and equal to 54 ◦ . Our results suggest that azimuthal anisotropy beneath the east-central US is vertically distributed in three distinct layers, with a different geodynamic origin for each of them.

The Na+ F1F0 ATP synthase operon of the anaerobic, acetogenic bacterium Acetobacterium woodii is unique because it encodes two types of c subunits, two identical 8 kDa bacterial F0-like c subunits (c2 and c3), with two transmembrane helices, and a 18 kDa eukaryal V0-like (c1) c subunit, with four transmembrane helices but only one binding site. To determine whether both types of rotor subunits are present in the same c ring, we have isolated and studied the composition of the c ring. High-resolution atomic force microscopy of 2D crystals revealed 11 domains, each corresponding to two transmembrane helices. A projection map derived from electron micrographs, calculated to 5 A resolution, revealed that each c ring contains two concentric, slightly staggered, packed rings, each composed of 11 densities, representing 22 transmembrane helices. The inner and outer diameters of the rings, measured at the density borders, are approximately 17 and 50 A. Mass determination by laser-induced liquid beam ion desorption provided evidence that the c rings contain both types of c subunits. The stoichiometry for c2/c3 : c1 was 9 : 1. Furthermore, this stoichiometry was independent of the carbon source of the growth medium. These analyses clearly demonstrate, for the first time, an F0–V0 hybrid motor in an ATP synthase.

The island of Crete is located in the forearc of the Hellenic subduction zone, where the African lithospheric plate is subducting beneath the Eurasian one. The depth of the plate contact as well as the internal structure of the Aegean plate in the area of Crete have been a matter of debate. In this study, seismic constrains obtained by wide-angle seismic, receiver function and surface wave studies are discussed and compared to a 3D density model of the region. The interface between the Aegean continental lithosphere and the African one is located at a depth of about 50 km below Crete. According to seismic studies, the Aegean lithosphere in the area of Crete is characterised by strong lateral, arc–parallel heterogeneity. An about 30 km thick Aegean crust is found in central Crete with a density of about 2850 kg/m 3 for the lower Aegean continental crust and a density of about 3300 kg/m 3 for the mantle wedge between the Aegean crust and the African lithosphere. For the deeper crust in the area of western Crete two alternative models have been proposed by seismic studies. One with an about 35 km thick crust and another one with crustal velocities down to the plate contact. A grid search is performed to test the consistency of these models with gravimetric constraints. For western Crete a model with a thick lower Aegean crust and a density of about 2950 kg/m 3 is favoured. The inferred density of the lower Aegean crust in the area of Crete correlates well with S-wave velocities obtained by surface wave studies. Based on the 3D density model, the weight of the Aegean lithosphere is estimated along an E–W oriented profile in the area of Crete. Low weights are found for the region of western Crete.

Despite the thermodynamic problem imposed on alkaliphilic bacteria of synthesizing adenosine triphosphate (ATP) against a large inverted pH gradient and consequently a low electrochemical proton potential, these bacteria still utilize a proton-coupled F(1)F(o)-ATP synthase to synthesize ATP. One potential solution to this apparent thermodynamic problem would be the operation of a larger oligomeric c ring, which would raise the ion to ATP ratio, thus facilitating the conversion of a low electrochemical potential into a significant phosphorylation potential. To address this hypothesis, we have purified the oligomeric c ring from the thermoalkaliphilic bacterium Bacillus sp. strain TA2.A1 and determined the number of c-subunits using a novel mass spectrometry method, termed 'laser-induced liquid bead ion desorption' (LILBID). This technique allows the mass determination of non-covalently assembled, detergent-solubilized membrane protein complexes, and hence enables an accurate determination of c ring stoichiometries. We show that the Bacillus sp. strain TA2.A1 ATP synthase harbours a tridecameric c ring. The operation of a c ring with 13 subunits renders the thermodynamic problem of ATP synthesis at alkaline pH less severe and may represent a strategy for ATP synthesis at low electrochemical potential.