increased endothelin 1 mediated vasoconstrictor tone in human obesity effects of gut hormones

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome

Naposomes: a new class of peptide-derivatized, target-selectivemultimodal nanoparticles for imaging and therapeutic applications

Modified supramolecular aggregates for selective delivery of contrast agents and/or drugs are examined with a focus on a new class of peptide-derivatized nanoparticles: naposomes. These nanoparticles are based on the co‑aggregation of two different amphiphilic monomers that give aggregates of different shapes and sizes (micelles, vesicles and liposomes) with diameters ranging between 10 and 300 nm. Structural properties and in vitro and in vivo behaviors are discussed. For the high relaxitivity values (12–19 mM-1s-1) and to detect for the presence of a surface exposed peptide, the new peptide-derived supramolecular aggregates are very promising candidates as targetselective MRI contrast agents. The efficiency of surface-exposed peptides in homing these nanovectors to a specific target introduces promising new opportunities for the development of diagnostic and therapeutic agents with high specificity toward the biological target and reduced toxic side effects on nontarget organs

Forward precision medicine: Micelles for active targeting driven by peptides

Precision medicine is based on innovative administration methods of active principles. Drug delivery on tissue of interest allows improving the therapeutic index and reducing the side effects. Active targeting by means of drug-encapsulated micelles decorated with targeting bioactive moieties represents a new frontier. Between the bioactive moieties, peptides, for their versatility, easy synthesis and immunogenicity, can be selected to direct a drug toward a considerable number of molecular targets overexpressed on both cancer vasculature and cancer cells. Moreover, short peptide sequences can facilitate cellular intake. This review focuses on micelles achieved by self-assembling or mixing peptide-grafted surfactants or peptide-decorated amphiphilic copolymers. Nanovectors loaded with hydrophobic or hydrophilic cytotoxic drugs or with gene silence sequences and externally functionalized with natural or synthetic peptides are described based on their formulation and in vitro and in vivo behaviors

Supramolecular aggregates containing lipophilic Gd(III) complexes as contrast agents in MRI

Magnetic resonance imaging (MRI) contrast agents based on paramagnetic gadolinium complexes are widely used in biomedical research and diagnosis. Their application is intended to improve efficacy of MRI providing physiological information along with the impressive anatomical detail already obtained by images without contrast. The classical gadolinium complexes currently used for MRI contrast enhancement are all lowmolecularweightcompounds that rapidly equilibrate between the intra and extravascular spaces after intravenous administration. In order to obtain gadolinium-based agents with different pharmacokinetic properties, supramolecular aggregates such as micelles and liposomes have been recently proposed. Micelles and liposomes, obtained by the aggregation of lipophilic gadolinium complexes are here described, with the aim to correlate their structural and relaxometric properties.We report on the state of the art in the development of supramolecular aggregates obtained by self-assembly of lipophilic gadolinium complexes and aggregates in which lipophilic gadolinium complexes are assembled with surfactants. Moreover aggregates derivatized with bioactive molecules, such as peptides and antibodies, acting as target selective MRI contrast agents are described

Defect Dynamics for Spiral Chaos in Rayleigh-Benard Convection

A theory of the novel spiral chaos state recently observed in Rayleigh-Benard convection is proposed in terms of the importance of invasive defects i.e defects that through their intrinsic dynamics expand to take over the system. The motion of the spiral defects is shown to be dominated by wave vector frustration, rather than a rotational motion driven by a vertical vorticity field. This leads to a continuum of spiral frequencies, and a spiral may rotate in either sense depending on the wave vector of its local environment. Results of extensive numerical work on equations modelling the convection system provide some confirmation of these ideas.Comment: Revtex (15 pages) with 4 encoded Postscript figures appende

Fast Reinforcement Learning with Large Action Sets Using Error-Correcting Output Codes for MDP Factorization

International audienceThe use of Reinforcement Learning in real-world scenarios is strongly limited by issues of scale. Most RL learning algorithms are unable to deal with problems composed of hundreds or sometimes even dozens of possible actions, and therefore cannot be applied to many real-world problems. We consider the RL problem in the supervised classification framework where the optimal policy is obtained through a multiclass classifier, the set of classes being the set of actions of the problem. We introduce error-correcting output codes (ECOCs) in this setting and propose two new methods for reducing complexity when using rollouts-based approaches. The first method consists in using an ECOC-based classifier as the multiclass classifier, reducing the learning complexity from O(A2) to O(Alog(A)) . We then propose a novel method that profits from the ECOC's coding dictionary to split the initial MDP into O(log(A)) separate two-action MDPs. This second method reduces learning complexity even further, from O(A2) to O(log(A)) , thus rendering problems with large action sets tractable. We finish by experimentally demonstrating the advantages of our approach on a set of benchmark problems, both in speed and performance

Target-Selective Drug Delivery through Liposomes Labeled with Oligobranched Neurotensin Peptides.

The structure and the in vitro behavior of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a branched moiety containing four copies of the 8-13 neurotensin (NT) peptide is reported. The new functionalized liposomes, DOPC-NT(4) Lys(C(18) )(2) , are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT(4) Lys(C(18) )(2) , which contains a lysine scaffold derivatized with a lipophilic moiety and a tetrabranched hydrophilic peptide, NT8-13, a neurotensin peptide fragment well known for its ability to mimic the neurotensin peptide in receptor binding ability. Dynamic light scattering measurements indicate a value for the hydrodynamic radius (RH) of 88.3±4.4 nm. The selective internalization and cytotoxicity of DOPC-NT(4) Lys(C(18) )(2) liposomes containing Doxo, as compared to pure DOPC liposomes, were tested in HT29 human colon adenocarcinoma and TE671 human rhabdomyosarcoma cells, both of which express neurotensin receptors. Peptide-functionalized liposomes show a clear advantage in comparison to pure DOPC liposomes with regard to drug internalization in both HT29 and TE671 tumor cells: FACS analysis indicates an increase in fluorescence signal of the NT(4) -liposomes, compared to the DOPC pure analogues, in both cell lines; cytotoxicity of DOPC-NT(4) Lys(C(18) )(2) -Doxo liposomes is increased four-fold with respect to DOPC-Doxo liposomes in both HT29 and TE671 cell lines. These effects could to be ascribed to the higher rate of internalization for DOPC-NT(4) Lys(C(18) )(2) -Doxo liposomes, due to stronger binding driven by a lower dissociation constant of the NT(4) -liposomes that bind the membrane onto a specific protein, in contrast to DOPC liposomes, which approach the plasma membrane unselectively