Design, Synthesis, Pharmacological Evaluation and Vascular Effects of Delphinidin Analogues

BACKGROUND: Among polyphenolic compounds suggested to prevent cardiovascular diseases (CVDs) and to explain the "French paradox", the anthocyanidin delphinidin (Dp) has been reported to support at least partly the vascular beneficial effects of dietary polyphenolic compounds including those from fruits and related products as red wine. It has also been highlighted that Dp interacts directly with the active site of estrogen receptor α (ERα), leading to activation of endothelial NO synthase (eNOS) pathway thus contributing to the prevention of endothelial dysfunction in mice aorta. However, anthocyanidins have very low bioavailability and despite a well described in vitro efficacy, the very high hydrophilicity and physicochemical instability of Dp might explain the lack of in vivo reported effects. OBJECTIVE: The aim of this study was to identify new Dp analogues with increased lipophilicity and vasorelaxation potential by a chemical modulation of its structure and to characterize the signaling pathway notably in relation with ERα signaling and nitric oxide (NO) production. METHOD: OCH3-substituted delphinidin analogues were obtained through the coupling of the corresponding acetophenones with substituted benzaldehydes. Prediction of resorption of the flavylium derivatives was performed with the calculated logP and induction of vasorelaxation was performed by myography on WT and ERαKO mice thoracic aorta rings and compared to Dp. NO production was evaluated in vitro on human primary endothelial cells. RESULTS: Eight Dp analogues were synthesized including four new flavylium derivatives. Two compounds (9 and 11) showed a strong increase of vasorelaxation potential and a theoretically increased bioavailability compared to Dp. Interestingly, 9 and 11 induced increased O2 - or NO endothelial production respectively and revealed a novel NO-dependent ERα-independent relaxation compared to Dp. We suggested that this mechanism may be at least in part supported by the inhibition of vascular cyclic nucleotide phosphodiesterase (PDEs). CONCLUSION: The current study demonstrated that pharmacomodulation of the Dp backbone by replacement of OH groups by OCH3 groups of the A and B rings led to the identification and characterization of two compounds (9 and 11) with enhanced physio-chemical properties that could be associated to higher permeability capability and pharmacological activity for the prevention of CVDs compared to Dp

Multiphoton radiative recombination of electron assisted by laser field

In the presence of an intensive laser field the radiative recombination of the continuum electron into an atomic bound state generally is accompanied by absorption or emission of several laser quanta. The spectrum of emitted photons represents an equidistant pattern with the spacing equal to the laser frequency. The distribution of intensities in this spectrum is studied employing the Keldysh-type approximation, i.e. neglecting interaction of the impact electron with the atomic core in the initial continuum state. Within the adiabatic approximation the scale of emitted photon frequencies is subdivided into classically allowed and classically forbidden domains. The highest intensities correspond to emission frequencies close to the edges of classically allowed domain. The total cross section of electron recombination summed over all emitted photon channels exhibits negligible dependence on the laser field intensity.Comment: 14 pages, 5 figures (Figs.2-5 have "a" and "b" parts), Phys.Rev.A accepted for publication. Fig.2b is presented correctl

Pupillary Light Reflexes are Associated with Autonomic Dysfunction in Bolivian Diabetics But Not Chagas Disease Patients

Autonomic dysfunction is common in Chagas disease and diabetes. Patients with either condition complicated by cardiac autonomic dysfunction face increased mortality, but no clinical predictors of autonomic dysfunction exist. Pupillary light reflexes (PLRs) may identify such patients early, allowing for intensified treatment. To evaluate the significance of PLRs, adults were recruited from the outpatient endocrine, cardiology, and surgical clinics at a Bolivian teaching hospital. After testing for Chagas disease and diabetes, participants completed conventional autonomic testing (CAT) evaluating their cardiovascular responses to Valsalva, deep breathing, and orthostatic changes. PLRs were measured using specially designed goggles, then CAT and PLRs were compared as measures of autonomic dysfunction. This study analyzed 163 adults, including 96 with Chagas disease, 35 patients with diabetes, and 32 controls. PLRs were not significantly different between Chagas disease patients and controls. Patients with diabetes had longer latency to onset of pupil constriction, slower maximum constriction velocities, and smaller orthostatic ratios than nonpatients with diabetes. PLRs correlated poorly with CAT results. A PLR-based clinical risk score demonstrated a 2.27-fold increased likelihood of diabetes complicated by autonomic dysfunction compared with the combination of blood tests, CAT, and PLRs (sensitivity 87.9%, specificity 61.3%). PLRs represent a promising tool for evaluating subclinical neuropathy in patients with diabetes without symptomatic autonomic dysfunction. Pupillometry does not have a role in the evaluation of Chagas disease patients

Ecological-economic sustainability of the Baltic cod fisheries under ocean warming and acidification

Human-induced climate change such as ocean warming and acidification, threatens marine ecosystems and associated fisheries. In the Western Baltic cod stock socio-ecological links are particularly important, with many relying on cod for their livelihoods. A series of recent experiments revealed that cod populations are negatively affected by climate change, but an ecological-economic assessment of the combined effects, and advice on optimal adaptive management are still missing. For Western Baltic cod, the increase in larval mortality due to ocean acidification has experimentally been quantified. Time-series analysis allows calculating the temperature effect on recruitment. Here, we include both processes in a stock-recruitment relationship, which is part of an ecological-economic optimization model. The goal was to quantify the effects of climate change on the triple bottom line (ecological, economic, social) of the Western Baltic cod fishery. Ocean warming has an overall negative effect on cod recruitment in the Baltic. Optimal management would react by lowering fishing mortality with increasing temperature, to create a buffer against climate change impacts. The negative effects cannot be fully compensated, but even at 3 °C warming above the 2014 level, a reduced but viable fishery would be possible. However, when accounting for combined effects of ocean warming and acidification, even optimal fisheries management cannot adapt to changes beyond a warming of +1.5° above the current level. Our results highlight the need for multi-factorial climate change research, in order to provide the best available, most realistic, and precautionary advice for conservation of exploited species as well as their connected socio-economic systems

Economic Activity of Firms and Asset Prices

In this review we survey the recent research on the fundamental determinants of stock returns. These studies explore how firms' systematic risk and their investment and production decisions are jointly determined in equilibrium. Models with production provide insights into several types of empirical patterns, including (a) the correlations between firms' economic characteristics and their risk premia, (b) the comovement of stock returns among firms with similar characteristics, and (c) the joint dynamics of asset returns and macroeconomic quantities. Moreover, by explicitly relating firms' stock returns and cash flows to fundamental shocks, models with production connect the analysis of financial markets with the research on the origins of macroeconomic fluctuations

Hydrocarbon-bearing sulphate-polymetallic deposits at the Colipilli area, Neuquén Basin, Argentina: Implications in the petroleum system modeling

This work deals with the hydrocarbon-bearing barite-polymetallic mineralizations of the Colipilli area, located in the western sector of the Agrio Fold and Thrust Belt (Neuqu´en Basin, Argentina). The mineralizations consist of bed- and vein-type deposits mainly composed of barite (barite96.99%–celestine2.93%) with minor amounts of Feoxyhydroxides and sulfides. The bed-type deposits have zebra texture and are emplaced along the contact between Late Cretaceous–Paleocene igneous rocks (Naunauco Group) and their Early Cretaceous sedimentary host rocks (e.g., Huitrín Formation). In contrast, the vein-type deposits have breccia texture and are crosscutting the Mulichinco, Agrio and Huitrín formations or the andesitic/dioritic stocks and sills of the Naunauco Group. Different types and families of primary fluid inclusions (FI) were identified in the barite crystals. Fluorescence techniques with UV incident light and Raman spectroscopy allowed FI from completely aqueous to completely organic, including all the intermediate terms, to be identified. The organic FI have blue fluorescence and contain liquid hydrocarbons. The blue fluorescence is correlated with medium to high API gravity values (ca. 40◦), indicating the presence of light hydrocarbons of advanced maturity related with the window for the generation of liquid/gaseous hydrocarbons. Microthermometry studies carried out on aqueous FI revealed that vein-type deposits formed at higher temperatures and salinities (249.7 ◦C and 0.5–9.3 wt % NaCl equivalent) than bed-type deposits (162.2 ◦C and 0.2–7.2 wt % NaCl equivalent). The heat influx provided by the Late Cretaceous– Paleocene magmatism promoted the circulation of inorganic and organic fluids of connate origin and the leaching of metallic and non-metallic elements from the sedimentary pile. During its crystallization, barite trapped fluids with variable hydrocarbon contents. The thermal anomaly associated with the magmatic activity could also have contributed with the maturation of the nearby source rocks and to the development of an atypical petroleum system.Instituto de Recursos Minerale