A functional equation with polynomial solutions and application to Neural Networks

We construct and discuss a functional equation with contraction property. The solutions are real univariate polynomials. The series solving the natural fixed point iterations have immediate interpretation in terms of Neural Networks with recursive properties and controlled accuracy

Accuracy of Neural Networks for Surrogate Modelling of the Sag of Hanging Cables

The creation of surrogate models is a classical problem in Machine Learning. The present paper is a case study of training a surrogate model for a real-life engineering problem: the computation of the sag of a cable hanging between two pylons. Neural networks have been trained using samples of the solution for several physical parameters. A parametric study of the role of three hyperparameters (the number of training samples, the size of the network and the initialization of gradient descent) is presented

A functional equation with polynomial solutions and application to Neural Networks

We construct and discuss a functional equation with contraction property. The solutions are real univariate polynomials. The series solving the natural fixed point iterations have immediate interpretation in terms of Neural Networks with recursive properties and controlled accuracy

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery

<b>BACKGROUND AND PURPOSE</b> Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems. <br></br> <b>EXPERIMENTAL APPROACH</b> Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)2 receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over-express recombinant CB2 receptor. <br></br> <b>KEY RESULTS</b> Anandamide and S1P induced relaxation of the rat CA. CB2 receptor antagonists attenuated anandamide-induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P3. Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide-mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P3, specifically within the vascular endothelium, was required for anandamide-mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB2 receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB2 receptor was also observed in HEK293 cells over-expressing the CB2 receptor. <br></br> <b>CONCLUSIONS AND IMPLICATIONS</b> In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P3. In addition, we report that S1P may exert some of its effects via a CB2 receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P3 to induce vascular relaxation

Reconstrucción petrológica del sistema de alimentación del volcán Ubinas y sus implicaciones para la evaluación de la amenaza

La evaluación de la amenaza volcánica se basa en gran medida en la reconstrucción de la historia eruptiva de los volcanes activos o susceptibles de reactivarse, con el fin de identificar los diferentes tipos de dinamismos eruptivos, así como la frecuencia y la magnitud de sus erupciones susceptibles de ocurrir en cada volcán. En el caso del volcán Ubinas (Perú), los estudios vulcanológicos llevados a cabo en los últimos años (Thouret et al., 2005; Rivera, 2010) han permitido establecer varios escenarios eruptivos que comprenden erupciones pequeñas de tipo vulcaniano (VEI = 2, Volcanic Explosivity Index); erupciones vulcanianas a subplinianas de tamaño moderado (VEI 2-3); y grandes erupciones plinianas altamente explosivas (VEI = 4). Sin embargo, uno de los mayores retos de la vulcanología es identificar cual de los escenarios eruptivos previamente definidos se materializará en caso de una erupción futura. En este trabajo se describen las características petrológicas de los productos eruptivos emitidos durante los últimos miles de años por el volcán Ubinas, con el fin de identificar los procesos magmáticos y las condiciones físicas (P-T) pre-eruptivas asociadas con los diferentes tipos de erupciones de este volcán. Este trabajo permitirá de identificar las características petrológicas propias de cada tipo de erupción y de esta manera tratar de definir los patrones de comportamiento futuro del volcán

Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility

Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod

Fingolimod is a sphingosine-1-phosphate (S1P) analogue that has been used in clinical trials as a systemic immunomodulatory therapy for multiple sclerosis. Fingolimod readily accesses the central nervous system, raising the issue of its direct effects on neural cells. We assessed the effects of active fingolimod on dissociated cultures of mature, myelin-producing oligodendrocytes (OLGs) derived from adult human brain. Human OLGs express S1P receptor transcripts in relative abundance of S1P5>S1P3>S1P1, with undetectable levels of S1P4. Low doses of fingolimod (100 pmol/L to 1 nmol/L) induced initial membrane elaboration (2 days), subsequent retraction (4 days), and recurrence of extension with prolonged treatment (8 days). Higher doses (10 nmol/L to 1 μmol/L) caused the opposite modulation of membrane dynamics. Retraction was rescued by co-treatment with the S1P3/S1P5 pathway antagonist, suramin, and was associated with RhoA-mediated cytoskeletal signaling. Membrane elaboration was mimicked using the S1P1 agonist SEW2871. Fingolimod rescued human OLGs from serum and glucose deprivation-induced apoptosis, which was reversed with suramin co-treatment and mimicked using an S1P5 agonist. High doses of fingolimod induced an initial down-regulation of S1P5 mRNA levels relative to control (4 hours), subsequent up-regulation (2 days), and recurrent down-regulation (8 days). S1P1 mRNA levels were inversely regulated compared with S1P5. These results indicate that fingolimod modulates maturity- and species-specific OLG membrane dynamics and survival responses that are directly relevant for myelin integrity

Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis

Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington’s disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development

Mouse Sphingosine Kinase 1a Is Negatively Regulated through Conventional PKC-Dependent Phosphorylation at S373 Residue

Sphingosine kinase is a lipid kinase that converts sphingosine into sphingosine-1-phosphate, an important signaling molecule with intracellular and extracellular functions. Although diverse extracellular stimuli influence cellular sphingosine kinase activity, the molecular mechanisms underlying its regulation remain to be clarified. In this study, we investigated the phosphorylation-dependent regulation of mouse sphingosine kinase (mSK) isoforms 1 and 2. mSK1a was robustly phosphorylated in response to extracellular stimuli such as phorbol ester, whereas mSK2 exhibited a high basal level of phosphorylation in quiescent cells regardless of agonist stimulation. Interestingly, phorbol ester-induced phosphorylation of mSK1a correlated with suppression of its activity. Chemical inhibition of conventional PKCs (cPKCs) abolished mSK1a phosphorylation, while overexpression of PKC alpha, a cPKC isoform, potentiated the phosphorylation, in response to phorbol ester. Furthermore, an in vitro kinase assay showed that PKC alpha directly phosphorylated mSK1a. In addition, phosphopeptide mapping analysis determined that the S373 residue of mSK1a was the only site phosphorylated by cPKC. Interestingly, alanine substitution of S373 made mSK1a refractory to the inhibitory effect of phorbol esters, whereas glutamate substitution of the same residue resulted in a significant reduction in mSK1a activity, suggesting the significant role of this phosphorylation event. Taken together, we propose that mSK1a is negatively regulated through cPKC-dependent phosphorylation at S373 residueopen

Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness