Urocortins improve dystrophic skeletal muscle structure and function through both PKA- and Epac-dependent pathways.

In Duchenne muscular dystrophy, the absence of dystrophin causes progressive muscle wasting and premature death. Excessive calcium influx is thought to initiate the pathogenic cascade, resulting in muscle cell death. Urocortins (Ucns) have protected muscle in several experimental paradigms. Herein, we demonstrate that daily s.c. injections of either Ucn 1 or Ucn 2 to 3-week-old dystrophic mdx(5Cv) mice for 2 weeks increased skeletal muscle mass and normalized plasma creatine kinase activity. Histological examination showed that Ucns remarkably reduced necrosis in the diaphragm and slow- and fast-twitch muscles. Ucns improved muscle resistance to mechanical stress provoked by repetitive tetanizations. Ucn 2 treatment resulted in faster kinetics of contraction and relaxation and a rightward shift of the force-frequency curve, suggesting improved calcium homeostasis. Ucn 2 decreased calcium influx into freshly isolated dystrophic muscles. Pharmacological manipulation demonstrated that the mechanism involved the corticotropin-releasing factor type 2 receptor, cAMP elevation, and activation of both protein kinase A and the cAMP-binding protein Epac. Moreover, both STIM1, the calcium sensor that initiates the assembly of store-operated channels, and the calcium-independent phospholipase A(2) that activates these channels were reduced in dystrophic muscle by Ucn 2. Altogether, our results demonstrate the high potency of Ucns for improving dystrophic muscle structure and function, suggesting that these peptides may be considered for treatment of Duchenne muscular dystrophy.

Feasibility of in vivo 15N MRS detection of hyperpolarized 15N labeled choline in rats.

The increase of total choline in tumors has become an important biomarker in cancer diagnosis. Choline and choline metabolites can be measured in vivo and in vitro using multinuclear MRS. Recent in vivo(13)C MRS studies using labeled substrates enhanced via dynamic nuclear polarization demonstrated the tremendous potential of hyperpolarization for real-time metabolic studies. The present study demonstrates the feasibility of detecting hyperpolarized (15)N labeled choline in vivo in a rat head at 9.4 T. We furthermore report the in vitro (172 +/- 16 s) and in vivo (126 +/- 15 s) longitudinal relaxation times. We conclude that with appropriate infusion protocols it is feasible to detect hyperpolarized (15)N labeled choline in live animals.

Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ).

Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age-related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18-85years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing.

Patterns of positive selection in seven ant genomes.

The evolution of ants is marked by remarkable adaptations that allowed the development of very complex social systems. To identify how ant-specific adaptations are associated with patterns of molecular evolution, we searched for signs of positive selection on amino-acid changes in proteins. We identified 24 functional categories of genes which were enriched for positively selected genes in the ant lineage. We also reanalyzed genome-wide data sets in bees and flies with the same methodology to check whether positive selection was specific to ants or also present in other insects. Notably, genes implicated in immunity were enriched for positively selected genes in the three lineages, ruling out the hypothesis that the evolution of hygienic behaviors in social insects caused a major relaxation of selective pressure on immune genes. Our scan also indicated that genes implicated in neurogenesis and olfaction started to undergo increased positive selection before the evolution of sociality in Hymenoptera. Finally, the comparison between these three lineages allowed us to pinpoint molecular evolution patterns that were specific to the ant lineage. In particular, there was ant-specific recurrent positive selection on genes with mitochondrial functions, suggesting that mitochondrial activity was improved during the evolution of this lineage. This might have been an important step toward the evolution of extreme lifespan that is a hallmark of ants.

Differential responses of newborn pulmonary arteries and veins to atrial and C-type natriuretic peptides.

Atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are important dilators of the pulmonary circulation during the perinatal period. We compared the responses of pulmonary arteries (PA) and veins (PV) of newborn lambs to these peptides. ANP caused a greater relaxation of PA than of PV, and CNP caused a greater relaxation of PV than of PA. RIA showed that ANP induced a greater increase in cGMP content of PA than CNP. In PV, ANP and CNP caused a similar moderate increase in cGMP content. Receptor binding study showed more specific binding sites for ANP than for CNP in PA and more for CNP than for ANP in PV. Relative quantitative RT-PCR for natriuretic peptide receptor A (NPR-A) and B (NPR-B) mRNAs show that, in PA, NPR-A mRNA is more prevalent than NPR-B mRNA, whereas, in PV, NPR-B mRNA is more prevalent than NPR-A mRNA. In conclusion, in the pulmonary circulation, arteries are the major site of action for ANP, and veins are the major site for CNP. Furthermore, the differences in receptor abundance and the involvement of a cGMP-independent mechanism may contribute to the heterogeneous effects of the natriuretic peptides in PA and PV of newborn lambs.

Structural and functional characterization of (110)-oriented epitaxial La2/3Ca1/3MnO3 electrodes and SrTiO3 tunnel barriers

La2/3Ca1/3MnO3 (LCMO) films have been deposited on (110)-oriented SrTiO3 (STO) substrates. X-ray diffraction and high-resolution electron microscopy reveal that the (110) LCMO films are epitaxial and anisotropically in-plane strained, with higher relaxation along the [1¿10] direction than along the [001] direction; x-ray absorption spectroscopy data signaled the existence of a single intermediate Mn3+/4+ 3d-state at the film surface. Their magnetic properties are compared to those of (001) LCMO films grown simultaneously on (001) STO substrates It is found that (110) LCMO films present a higher Curie temperature (TC) and a weaker decay of magnetization when approaching TC than their (001) LCMO counterparts. These improved films have been subsequently covered by nanometric STO layers. Conducting atomic-force experiments have shown that STO layers, as thin as 0.8 nm, grown on top of the (110) LCMO electrode, display good insulating properties. We will show that the electric conductance across (110) STO layers, exponentially depending on the barrier thickness, is tunnel-like. The barrier height in STO (110) is found to be similar to that of STO (001). These results show that the (110) LCMO electrodes can be better electrodes than (001) LCMO for magnetic tunnel junctions, and that (110) STO are suitable insulating barriers.

Cationic Diffusion in La2/3Ca1/3MnO3 Thin Films Grown on LaAlO3 (001) Substrates.

Microstructural features of La2/3Ca1/3MnO3 layers of various thicknesses grown on top of 001 LaAlO3 substrates are studied by using transmission electron microscopy and electron energy loss spectroscopy. Films are of high microstructural quality but exhibit some structural relaxation and mosaicity both when increasing thickness or after annealing processes. The existence of a cationic segregation process of La atoms toward free surface has been detected, as well as a Mn oxidation state variation through layer thickness. La diffusion would lead to a Mn valence change and, in turn, to reduced magnetization.

Analysis of the near-intrinsic and extrinsic photocapacitance due to the EL2 level in boron implanted GaAs

A detailed analysis of the photocapacitance signal at the near‐band and extrinsic energetic ranges in Schottky barriers obtained on horizontal Bridgman GaAs wafers, which were implanted with boron at different doses and annealed at several temperatures, has been carried out by using the optical isothermal transient spectroscopy, OITS. The optical cross sections have been determined as well as the quenching efficiency of the EL2 level which has been found to be independent of the annealing temperature. Moreover, the quenching relaxation presents two significant features: (i) a strong increase of the quenching efficiency from 1.35 eV on and (ii) a diminution of the quenching transient amplitude in relation with that shown by the fundamental EL2 level. In order to explain this behavior, different cases are discussed assuming the presence of several energy levels, the existence of an optical recuperation, or the association of the EL2 trap with two levels located, respectively, at Ev+0.45 eV and Ec−0.75 eV. The theoretical simulation, taking into account these two last cases, is in agreement with the experimental photocapacitance data at low temperature, as well as at room temperature where the EL2 filling phototransient shows an anomalous behavior. Moreover, unlike the previous data reported for the EL2 electron optical cross section, the values found using our experimental technique are in agreement with the behavior deduced from the theoretical calculation. The utilization of the OITS method has also allowed the determination of another level, whose faster optical contribution is often added to that of the EL2 level when the DLOS or standard photocapacitance is used.

Anomalous crossover between thermal and shot noise in macroscopic diffusive conductors

We predict the existence of an anomalous crossover between thermal and shot noise in macroscopic diffusive conductors. We first show that, besides thermal noise, these systems may also exhibit shot noise due to fluctuations of the total number of carriers in the system. Then we show that at increasing currents the crossover between the two noise behaviors is anomalous, in the sense that the low-frequency current spectral density displays a region with a superlinear dependence on the current up to a cubic law. The anomaly is due to the nontrivial coupling in the presence of the long-range Coulomb interaction among the three time scales relevant to the phenomenon, namely, diffusion, transit, and dielectric relaxation time.

Size effects in the magneto-optical response of Co nanoparticles

A study of the magneto-optical (MO) spectral response of Co nanoparticles embedded in MgO as a function of their size and concentration in the spectral range from 1.4 to 4.3 eV is presented. The nanoparticle layers were obtained by sputtering at different deposition temperatures. Transmission electron microscopy measurements show that the nanoparticles have a complex structure which consists of a crystalline core having a hexagonal close-packed structure and an amorphous crust. Using an effective-medium approximation we have obtained the MO constants of the Co nanoparticles. These MO constants are different from those of continuous Co layers and depend on the size of the crystalline core. We associate these changes with the size effect of the intraband contribution to the MO constants, related to a reduction of the relaxation time of the electrons into the nanoparticles.

Shot noise in linear macroscopic resistors

We report on direct experimental evidence of shot noise in a linear macroscopic resistor. The origin of the shot noise comes from the fluctuation of the total number of charge carriers inside the resistor associated with their diffusive motion under the condition that the dielectric relaxation time becomes longer than the dynamic transit time. The present results show that neither potential barriers nor the absence of inelastic scattering are necessary to observe shot noise in electronic devices.

Effects of prior hydrogenation on the structure and properties of thermally nanocrystallized silicon layers

Nanocrystalline silicon layers have been obtained by thermal annealing of films sputtered in various hydrogen partial pressures. The as-deposited and crystallized films were investigated by infrared, Raman, x-ray diffraction, electron microscopy, and optical absorption techniques. The obtained data show evidence of a close correlation between the microstructure and properties of the processed material, and the hydrogen content in the as-grown deposit. The minimum stress deduced from Raman was found to correspond to the widest band gap and to a maximum hydrogen content in the basic unannealed sample. Such a structure relaxation seems to originate from the so-called "chemical annealing" thought to be due to Si-H2 species, as identified by infrared spectroscopy. The variation of the band gap has been interpreted in terms of the changes in the band tails associated with the disorder which would be induced by stress. Finally, the layers originally deposited with the highest hydrogen pressure show a lowest stress-which does not correlate with the hydrogen content and the optical band gap¿and some texturing. These features are likely related to the presence in these layers of a significant crystalline fraction already before annealing.

Resting-state temporal synchronization networks emerge from connectivity topology and heterogeneity.

Spatial patterns of coherent activity across different brain areas have been identified during the resting-state fluctuations of the brain. However, recent studies indicate that resting-state activity is not stationary, but shows complex temporal dynamics. We were interested in the spatiotemporal dynamics of the phase interactions among resting-state fMRI BOLD signals from human subjects. We found that the global phase synchrony of the BOLD signals evolves on a characteristic ultra-slow (<0.01Hz) time scale, and that its temporal variations reflect the transient formation and dissolution of multiple communities of synchronized brain regions. Synchronized communities reoccurred intermittently in time and across scanning sessions. We found that the synchronization communities relate to previously defined functional networks known to be engaged in sensory-motor or cognitive function, called resting-state networks (RSNs), including the default mode network, the somato-motor network, the visual network, the auditory network, the cognitive control networks, the self-referential network, and combinations of these and other RSNs. We studied the mechanism originating the observed spatiotemporal synchronization dynamics by using a network model of phase oscillators connected through the brain's anatomical connectivity estimated using diffusion imaging human data. The model consistently approximates the temporal and spatial synchronization patterns of the empirical data, and reveals that multiple clusters that transiently synchronize and desynchronize emerge from the complex topology of anatomical connections, provided that oscillators are heterogeneous.

Glucose is arrhythmogenic in the anoxic-reoxygenated embryonic chick heart.

Unlike in adult heart, embryonic myocardium works at low PO2 and depends preferentially on glucose. Therefore, activity of the embryonic heart during anoxia and reoxygenation should be particularly affected by changes in glucose availability. Hearts excised from 4-d-old chick embryos were submitted in vitro to strictly controlled anoxia-reoxygenation transitions at glucose concentrations varying from 0 to 20 mmol/L. Spontaneous and regular heart contractions were detected optically as movements of the ventricle wall and instantaneous heart rate, amplitude of contraction, and velocities of contraction and relaxation were determined. Anoxia induced transient tachycardia and rapidly depressed contractile activity, whereas reoxygenation provoked a temporary and complete cardioplegia (oxygen paradox). In the presence of glucose, atrial rhythm became irregular during anoxia and chaotic-periodic during reoxygenation. The incidence of these arrhythmias depended on duration of anoxia, and no ventricular ectopic beats were observed. Removal of glucose or blockade of glycolysis suppressed arrhythmias. These results show similarities but also differences with respect to the adult heart. Indeed, glucose 1) delayed and anoxic contractile failure, shortened the reoxygenation-induced cardiac arrest, and improved the recovery of contractile activity; 2) attenuated stunning at 20 mmol/L but worsened it at 8 mmol/L; and 3) paradoxically, was arrhythmogenic during anoxia and reoxygenation, especially when present at the physiologic concentration of 8 mmol/L. The last named phenomenon seems to be characteristic of the young embryonic heart, and our findings underscore that fluctuations of glycolytic activity may play a role in the reactivity of the embryonic myocardium to anoxiareoxygenation transitions.

Reduced atrial emptying after orthotopic heart transplantation masquerading as restrictive transmitral Doppler flow pattern?

BACKGROUND: An elevated early (E) to late (A) diastolic filling velocities ratio, typically seen in advanced diastolic dysfunction, has also been observed after cardioversion of atrial fibrillation as a consequence of the depressed left atrial (LA) contractility. We hypothesized that the impaired LA contractile function demonstrated after orthotopic cardiac transplantation (OCT) could also lead to this "pseudorestrictive" pattern. METHOD: E/A ratio related to the tissue Doppler early mitral annular velocity (Ea) as preload-independent index of LV relaxation was evaluated in all consecutive OCT patients between 2005 and 2007. RESULTS: The study population comprised 48 patients 97 ± 77 months after OCT. Thirty-two patients (67%) had an E/A ratio > 2. LV systolic function and myocardial relaxation assessed by the Ea velocity were similar compared to patients with normal ratio (61 ± 6% vs. 60 ± 12%, P = 0.854 and 15 ± 4 cm/s vs. 14 ± 3 cm/s, r = 0.15, P = 0.323, respectively). On the other hand, the proportion of the recipient and donor LA cuffs as estimated by the recipient/global LA area ratio and the LA emptying fraction significantly correlated with the E/A ratio (r = 0.40, P = 0.005 and r =-0.33, P = 0.022, respectively). CONCLUSION: Our study shows that there is a high prevalence of elevated E/A ratio after standard OCT which seems mainly related to reduced LA contractility. Recognition of this "pseudorestrictive" pattern may avoid misdiagnosis of diastolic dysfunction.