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.

"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.

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.

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.

What drives European beech (Fagus sylvatica L.) mortality after forest fires of varying severity?

Predicting the timing and amount of tree mortality after a forest fire is of paramount importance for post-fire management decisions, such as salvage logging or reforestation. Such knowledge is particularly needed in mountainous regions where forest stands often serve as protection against natural hazards (e.g., snow avalanches, rockfalls, landslides). In this paper, we focus on the drivers and timing of mortality in fire-injured beech trees (Fagus sylvatica L.) in mountain regions. We studied beech forests in the southwestern European Alps, which burned between 1970 and 2012. The results show that beech trees, which lack fire-resistance traits, experience increased mortality within the first two decades post-fire with a timing and amount strongly related to the burn severity. Beech mortality is fast and ubiquitous in high severity sites, whereas small- (DBH <12 cm) and intermediate-diameter (DBH 12–36 cm) trees face a higher risk to die in moderate-severity sites. Large-diameter trees mostly survive, representing a crucial ecological legacy for beech regeneration. Mortality remains low and at a level similar to unburnt beech forests for low burn severity sites. Beech trees diameter, the presence of fungal infestation and elevation are the most significant drivers of mortality. The risk of beech to die increases toward higher elevation and is higher for small-diameter than for large-diameter trees. In case of secondary fungi infestation beech faces generally a higher risk to die. Interestingly, fungi that initiate post-fire tree mortality differ from fungi occurring after mechanical injury. From a management point of view, the insights about the controls of post-fire mortality provided by this study should help in planning post-fire silvicultural measures in montane beech forests.

HACCP Drives Safe Seafood

Seafood is part of a healthy diet, but how can you be sure that the seafood on your plate has not become contaminated somewhere between the boat and your home? HACCP training helps seafood processors and handlers meet FDA regulations to control potential hazards along the way.

Fibulin-2 stabilizes tumor extracellular matrix and drives malignant progression of lung adenocarcinoma

The ECM of epithelial carcinomas undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How tumors maintain ECM integrity in the face of dynamic biophysical forces is still largely unclear. This study addresses these deficiencies using mouse models of human lung adenocarcinoma. Spontaneous lung tumors were marked by disorganized basement membranes, dense collagen networks, and increased tissue stiffness. Metastasis-prone lung adenocarcinoma cells secreted fibulin-2 (Fbln2), a matrix glycoprotein involved in ECM supra-molecular assembly. Fibulin-2 depletion in tumor cells decreased the intra-tumoral abundance of matrix metalloproteinases and reduced collagen cross-linking and tumor compressive properties resulting in inhibited tumor growth and metastasis. Fbln2 deposition within intra-tumoral fibrotic bands was a predictor of poor clinical outcome in patients. Collectively, these findings support a feed-forward model in which tumor cells secrete matrix-stabilizing factors required for the assembly of ECM that preferentially favors malignant progression. To our knowledge, this is the first evidence that tumor cells directly regulate the integrity of their surrounding matrix through the secretion of matrix-stabilizing factors such as fibulin-2. These findings open a new avenue of research into matrix assembly molecules as potential therapeutic targets in cancer patients.

Saturating light and not increased carbon dioxide under ocean acidification drives photosynthesis and growth in Ulva rigida (Chlorophyta)

Carbon physiology of a genetically identified Ulva rigida was investigated under different CO2(aq) and light levels. The study was designed to answer whether (1) light or exogenous inorganic carbon (Ci) pool is driving growth; and (2) elevated CO2(aq) concentration under ocean acidification (OA) will downregulate CAext-mediated inline image dehydration and alter the stable carbon isotope (delta13C) signatures toward more CO2 use to support higher growth rate. At pHT 9.0 where CO2(aq) is <1 ?mol/L, inhibition of the known inline image use mechanisms, that is, direct inline image uptake through the AE port and CAext-mediated inline image dehydration decreased net photosynthesis (NPS) by only 56-83%, leaving the carbon uptake mechanism for the remaining 17-44% of the NPS unaccounted. An in silico search for carbon-concentrating mechanism elements in expressed sequence tag libraries of Ulva found putative light-dependent inline image transporters to which the remaining NPS can be attributed. The shift in delta13C signatures from -22 per mil toward -10 per mil under saturating light but not under elevated CO2(aq) suggest preference and substantial inline image use to support photosynthesis and growth. U. rigida is Ci saturated, and growth was primarily controlled by light. Therefore, increased levels of CO2(aq) predicted for the future will not, in isolation, stimulate Ulva blooms.

Performance optimization in switched reluctance motor drives

In this paper, switched reluctance motors (SRM) are proposed as an alternative for electric power assisted steering (EPAS) applications. A prototype machine has been developed as very attractive design for a steering electric motor, both from a cost and size perspective. A fourphase 8/6 SRM drive is designed for a rack type EPAS which should provide a maximum force of 10 kN. Two-dimension finite element analysis is used to validate the design.