β-Adrenergic Receptor-PI3K Signaling Crosstalk in Mouse Heart: Elucidation of Immediate Downstream Signaling Cascades

Sustained β-adrenergic receptors (βAR) activation leads to cardiac hypertrophy and prevents left ventricular (LV) atrophy during LV unloading. The immediate signaling pathways downstream from βAR stimulation, however, have not been well investigated. The current study was to examine the early cardiac signaling mechanism(s) following βAR stimulation. In adult C57BL/6 mice, acute βAR stimulation induced significant increases in PI3K activity and activation of Akt and ERK1/2 in the heart, but not in lungs or livers. In contrast, the same treatment did not elicit these changes in β1/β2AR double knockout mice. We further showed the specificity of β2AR in this crosstalk as treatment with formoterol, a β2AR-selective agonist, but not dobutamine, a predominantly β1AR agonist, activated cardiac Akt and ERK1/2. Acute βAR stimulation also significantly increased the phosphorylation of mTOR (the mammalian target of rapamycin), P70S6K, ribosomal protein S6, GSK-3α/β (glycogen synthase kinase-3α/β), and FOXO1/3a (the forkhead box family of transcription factors 1 and 3a). Moreover, acute βAR stimulation time-dependently decreased the mRNA levels of the muscle-specific E3 ligases atrogin-1 and muscle ring finger protein-1 (MuRF1) in mouse heart. Our results indicate that acute βAR stimulation in vivo affects multiple cardiac signaling cascades, including the PI3K signaling pathway, ERK1/2, atrogin-1 and MuRF1. These data 1) provide convincing evidence for the crosstalk between βAR and PI3K signaling pathways; 2) confirm the β2AR specificity in this crosstalk in vivo; and 3) identify novel signaling factors involved in cardiac hypertrophy and LV unloading. Understanding of the intricate interplay between β2AR activation and these signaling cascades should provide critical clues to the pathogenesis of cardiac hypertrophy and enable identification of targets for early clinical interaction of cardiac lesions

DNA metabarcoding unveils multiscale trophic variation in a widespread coastal opportunist

A thorough understanding of ecological networks relies on comprehensive information on trophic relationships among species. Since unpicking the diet of many organisms is unattainable using traditional morphology‐based approaches, the application of high‐throughput sequencing methods represents a rapid and powerful way forward. Here, we assessed the application of DNA metabarcoding with nearly universal primers for the mitochondrial marker cytochrome c oxidase I in defining the trophic ecology of adult brown shrimp, Crangon crangon, in six European estuaries. The exact trophic role of this abundant and widespread coastal benthic species is somewhat controversial, while information on geographical variation remains scant. Results revealed a highly opportunistic behaviour. Shrimp stomach contents contained hundreds of taxa (>1,000 molecular operational taxonomic units), of which 291 were identified as distinct species, belonging to 35 phyla. Only twenty ascertained species had a mean relative abundance of more than 0.5%. Predominant species included other abundant coastal and estuarine taxa, including the shore crab Carcinus maenas and the amphipod Corophium volutator. Jacobs’ selectivity index estimates based on DNA extracted from both shrimp stomachs and sediment samples were used to assess the shrimp's trophic niche indicating a generalist diet, dominated by crustaceans, polychaetes and fish. Spatial variation in diet composition, at regional and local scales, confirmed the highly flexible nature of this trophic opportunist. Furthermore, the detection of a prevalent, possibly endoparasitic fungus (Purpureocillium lilacinum) in the shrimp's stomach demonstrates the wide range of questions that can be addressed using metabarcoding, towards a more robust reconstruction of ecological networks

Photon generation by laser-Compton scattering at the KEK-ATF

We performed a photon generation experiment by laser-Compton scattering at the KEK-ATF, aiming to develop a Compton based polarized positron source for linear colliders. In the experiment, laser pulses with a 357 MHz repetition rate were accumulated and their power was enhanced by up to 250 times in the Fabry-Perot optical resonant cavity. We succeeded in synchronizing the laser pulses and colliding them with the 1.3 GeV electron beam in the ATF ring while maintaining the laser pulse accumulation in the cavity. As a result, we observed 26.0 +/- 0.1 photons per electron-laser pulse crossing, which corresponds to a yield of 10^8 photons in a second.Comment: 3 pages, 5 figures, Preprint submitted to TIPP09 Proceedings in NIM

The proton spin sum rule chiral bag prediction, an update

We reevaluate a quark model prediction using the new QCD evolution function calculated to the 3 loop order and conclude that this model compares favorably with the new experimental results.Comment: 10 pages, 2 figures available by request, give fax numbe

X-ray Time Lags in TeV Blazars

We use Monte Carlo/Fokker-Planck simulations to study the X-ray time lags. Our results show that soft lags will be observed as long as the decay of the flare is dominated by radiative cooling, even when acceleration and cooling timescales are similar. Hard lags can be produced in presence of a competitive achromatic particle energy loss mechanism if the acceleration process operates on a timescale such that particles are slowly moved towards higher energy while the flare evolves. In this type of scenario, the {\gamma} -ray/X-ray quadratic relation is also reproduced.Comment: 4 pages, 6 figures, Proceeding of `Multiwavelength Variability of Blazars', Guangzhou, Chin

Direct Sensing of Endothelial Oxidants by Vascular Endothelial Growth Factor Receptor-2 and c-Src

BACKGROUND: ADPH oxidase-derived reactive oxygen species (ROS) play important roles in redox homeostasis and signal transduction in endothelial cells (ECs). We previously demonstrated that c-Src plays a key role in VEGF-induced, ROS-dependent selective activation of PI3K-Akt but not PLCγ-1-ERK1/2 signaling pathways. The aim of the present study was to understand how VEGFR-2-c-Src signaling axis 'senses' NADPH oxidase-derived ROS levels and couples VEGF activation of c-Src to the redox state of ECs. METHODOLOGY/PRINCIPAL FINDINGS: Using biotinylated probe that detects oxidation of cysteine thiol (cys-OH) in intracellular proteins, we demonstrate that VEGF induced oxidative modification in c-Src and VEGFR-2, and that reduction in ROS levels using siRNA against p47(phox) subunit of Rac1-dependent NADPH oxidase inhibited this phenomenon. Co-immunoprecipitation studies using human coronary artery ECs (HCAEC) showed that VEGF-induced ROS-dependent interaction between VEGFR-2 and c-Src correlated with their thiol oxidation status. Immunofluorescence studies using antibodies against internalized VEGFR-2 and c-Src demonstrated that VEGF-induced subcellular co-localization of these tyrosine kinases were also dependent on NADPH oxidsase-derived ROS. CONCLUSION/SIGNIFICANCE: These results demonstrate that VEGF induces cysteine oxidation in VEGFR-2 and c-Src in an NADPH oxidase-derived ROS-dependent manner, suggesting that VEGFR-2 and c-Src can 'sense' redox levels in ECs. The data also suggest that thiol oxidation status of VEGFR-2 and c-Src correlates with their ability to physically interact with each other and c-Src activation. Taken together, these findings suggest that prior to activating downstream c-Src-PI3K-Akt signaling pathway, VEGFR-2-c-Src axis requires an NADPH oxidase-derived ROS threshold in ECs

Restricted feedback control of one-dimensional maps

Dynamical control of biological systems is often restricted by the practical constraint of unidirectional parameter perturbations. We show that such a restriction introduces surprising complexity to the stability of one-dimensional map systems and can actually improve controllability. We present experimental cardiac control results that support these analyses. Finally, we develop new control algorithms that exploit the structure of the restricted-control stability zones to automatically adapt the control feedback parameter and thereby achieve improved robustness to noise and drifting system parameters.Comment: 29 pages, 9 embedded figure