Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy

AIMS:Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca(2+) homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca(2+) release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. METHODS AND RESULTS:Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca(2+) responses to mechanical stress and 'hypersensitive' excitation-contraction coupling, hallmarks of increased RyR Ca(2+) sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca(2+) load and leak were unchanged in young mdx mice. However, by the age of 4-5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca(2+) signals and corrected changes in ECC, Ca(2+) load, and leak. CONCLUSION:Our findings suggest that increased RyR Ca(2+) sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.

Harmonic Oscillator in a 1D or 2D Cavity with General Perfectly Reflecting Walls

We investigate the simple harmonic oscillator in a 1-d box, and the 2-d isotropic harmonic oscillator problem in a circular cavity with perfectly reflecting boundary conditions. The energy spectrum has been calculated as a function of the self-adjoint extension parameter. For sufficiently negative values of the self-adjoint extension parameter, there are bound states localized at the wall of the box or the cavity that resonate with the standard bound states of the simple harmonic oscillator or the isotropic oscillator. A free particle in a circular cavity has been studied for the sake of comparison. This work represents an application of the recent generalization of the Heisenberg uncertainty relation related to the theory of self-adjoint extensions in a finite volume.

"Deal of the day” platforms: what drives consumer loyalty?

Maintaining a loyal customer base is challenging for “Deal of the Day” (DoD) platforms. DoD providers market and sell deals on products and services, yet it is the merchants who ultimately deliver those to consumers. Low entry and switching costs drive competition in this market. However, research on the determinants of user loyalty in the DoD context is limited. This study uses Grounded Theory and Structural Equation Modeling to explore the phenomenon of DoD platform loyalty. Particularly, monetary benefits, signal-to-noise ratio, perceived risk, and service friendliness during a merchant encounter emerge as powerful determinants of loyalty in this novel context.

Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

What drives adult personality development? A comparison of theoretical perspectives and empirical evidence

Increasing numbers of empirical studies provide compelling evidence that personality traits change across the entire lifespan. What initiates this continuing personality development and how does this development proceed? In this paper, we compare six theoretical perspectives that offer testable predictions about why personality develops the way it does and identify limitations and potentials of these perspectives by reviewing how they hold up against the empirical evidence. While all of these perspectives have received some empirical support, there is only little direct evidence for propositions put forward by the five-factor theory of personality and the theory of genotype→environment effects. In contrast, the neo-socioanalytic theory appears to offer a comprehensive framework that fits the empirical findings and allows the integration of other, more specialized, perspectives that focus on specific aspects of personality development like the role of time, systematic differences between categories of social roles or the active partake of the person himself or herself. We draw conclusions on the likely driving factors for adult personality development and identify avenues for future research.

Sideband-Ratio and Harmonic Response of Sub-Millimeter Wave Mixers measured with a Martin Puplett Interferometer

Heterodyne receivers at millimeter and submillimeter wavelength are widely used for radiometric spectral line observations for atmospheric remote sensing or radio astronomy. The quantitative analysis of such observations requires an accurate knowledge of the mixers's sideband ratio. In addition, its potential sensitivity to spurious harmonics needs to be well understood. In this paper, we discuss a measurement technique for these receiver characteristics, which is based on a scanning Martin Puplett Interferometer used in conjunction with a wide band digital autocorrelation spectrometer for the analysis of the intermediate frequency band. We present measurement results of different double sideband and sideband separating mixers, which were developed for the proposed 340GHz multi-beam limb sounder STEAMR.

Plant diversity drives soil microbial biomass carbon in grasslands irrespective of global environmental change factors

Soil microbial biomass is a key determinant of carbon dynamics in the soil. Several studies have shown that soil microbial biomass significantly increases with plant species diversity, but it remains unclear whether plant species diversity can also stabilize soil microbial biomass in a changing environment. This question is particularly relevant as many global environmental change (GEC) factors, such as drought and nutrient enrichment, have been shown to reduce soil microbial biomass. Experiments with orthogonal manipulations of plant diversity and GEC factors can provide insights whether plant diversity can attenuate such detrimental effects on soil microbial biomass. Here, we present the analysis of 12 different studies with 14 unique orthogonal plant diversity × GEC manipulations in grasslands, where plant diversity and at least one GEC factor (elevated CO2, nutrient enrichment, drought, earthworm presence, or warming) were manipulated. Our results show that higher plant diversity significantly enhances soil microbial biomass with the strongest effects in long-term field experiments. In contrast, GEC factors had inconsistent effects with only drought having a significant negative effect. Importantly, we report consistent non-significant effects for all 14 interactions between plant diversity and GEC factors, which indicates a limited potential of plant diversity to attenuate the effects of GEC factors on soil microbial biomass. We highlight that plant diversity is a major determinant of soil microbial biomass in experimental grasslands that can influence soil carbon dynamics irrespective of GEC.

Root system of singular perturbations of the harmonic oscillator type operators

We analyze perturbations of the harmonic oscillator type operators in a Hilbert space H, i.e. of the self-adjoint operator with simple positive eigenvalues μ k satisfying μ k+1 − μ k ≥ Δ > 0. Perturbations are considered in the sense of quadratic forms. Under a local subordination assumption, the eigenvalues of the perturbed operator become eventually simple and the root system contains a Riesz basis.

Absolute polarity determination of teeth cementum by phase sensitive second harmonic generation microscopy

The absolute sign of local polarity in relation to the biological growth direction has been investigated for teeth cementum using phase sensitive second harmonic generation microscopy (PS-SHGM) and a crystal of 2-cyclooctylamino-5-nitropyridine (COANP) as a nonlinear optic (NLO) reference material. A second harmonic generation (SHG) response was found in two directions of cementum: radial (acellular extrinsic fibers that are oriented more or less perpendicular to the root surface) and circumferential (cellular intrinsic fibers that are oriented more or less parallel to the surface). A mono-polar state was demonstrated for acellular extrinsic cementum. However, along the different parts of cementum in circumferential direction, two corresponding domains were observed featuring an opposite sign of polarity indicative for a bi-polar microscopic state of cellular intrinsic cementum. The phase information showed that the orientation of radial collagen fibrils of cementum is regularly organized with the donor (D) groups pointing to the surface. Circumferential collagen molecules feature orientational disorder and are oriented up and down in random manner showing acceptor or donor groups at the surface of cementum. Considering that the cementum continues to grow in thickness throughout life, we can conclude that the cementum is growing circumferentially in two opposite directions and radially in one direction. A Markov chain type model for polarity formation in the direction of growth predicts D-groups preferably appearing at the fiber front.

Cryptic invasion drives phenotypic changes in central European threespine stickleback

Cryptic invasions are commonly associated with genetic changes of the native species or genetic lineage that the invaders replace. Phenotypic shifts resulting from cryptic invasions are less commonly reported given the relative paucity of historical specimens that document such phenotypic changes. Here, I study such a case in two populations of threespine stickleback from central Europe, comparing contemporary patterns of gene flow with phenotypic changes between historical and contemporary population samples. I find gene flow from an invasive lineage to be associated with significant phenotypic changes, where the degree of phenotypic change corresponds with the level of gene flow that a population receives. These findings underline the utility of combining genetic approaches with phenotypic data to estimate the impact of gene flow in systems where anthropogenic alterations have removed former geographic barriers promoting cryptic invasions.