Interplay between R513 methylation and S516 phosphorylation of the cardiac voltage-gated sodium channel

Arginine methylation is a novel post-translational modification within the voltage-gated ion channel superfamily, including the cardiac sodium channel, Naᵥ1.5. We show that Naᵥ1.5 R513 methylation decreases S516 phosphorylation rate by 4 orders of magnitude, the first evidence of protein kinase A inhibition by arginine methylation. Reciprocally, S516 phosphorylation blocks R513 methylation. Naᵥ1.5 p.G514C, associated to cardiac conduction disease, abrogates R513 methylation, while leaving S516 phosphorylation rate unchanged. This is the first report of methylation–phosphorylation cross-talk of a cardiac ion channel

Electron delocalization and aromaticity in low-lying excited states of archetypal organic compounds

Aromaticity is a property usually linked to the ground state of stable molecules. Although it is well-known that certain excited states are unquestionably aromatic, the aromaticity of excited states remains rather unexplored. To move one step forward in the comprehension of aromaticity in excited states, in this work we analyze the electron delocalization and aromaticity of a series of low-lying excited states of cyclobutadiene, benzene, and cyclooctatetraene with different multiplicities at the CASSCF level by means of electron delocalization measures. While our results are in agreement with Baird's rule for the aromaticity of the lowest-lying triplet excited state in annulenes having 4n pi-electrons, they do not support Soncini and Fowler's generalization of Baird's rule pointing out that the lowest-lying quintet state of benzene and septet state of cyclooctatetraene are not aromatic

Exploring the validity of the Glidewell-Lloyd extension of Clar's pi-sextet rule: assessment from polycyclic conjugated hydrocarbons

The Clar pi-sextet rule was formulated as a tool to qualitatively assign the local aromatic character of six-membered rings in benzenoid species. This simple rule has been widely validated both experimentally and theoretically. In 1984, Glidewell and Lloyd reported an extension of this rule to polycyclic conjugated hydrocarbons having rings with any even number of carbon atoms in their structure. In this work, we assess the validity of the Glidewell-Lloyd extension in 69 polycyclic conjugated hydrocarbons composed of different combinations of four-, six-, and eight-membered rings. Our results support the validity of this extension with some exceptions that are discussed. Finally, a minor modification to the rule is proposed

Protein-directed crystalline 2D fullerene assemblies

Water soluble 2D crystalline monolayers of fullerenes grow on planar assemblies of engineered consensus tetratricopeptide repeat proteins. Designed fullerene-coordinating tyrosine clamps on the protein introduce specific fullerene binding sites, which facilitate fullerene nucleation. Through reciprocal interactions between the components, the hybrid material assembles into two-dimensional 2 nm thick structures with crystalline order, that conduct photo-generated charges. Thus, the protein-fullerene hybrid material is a demonstration of the developments toward functional materials with protein-based precision control of functional elements

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration

p38γ is essential for cell cycle progression and liver tumorigenesis

The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)–cyclin protein complex1. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycle. p38γ shares high sequence homology, inhibition sensitivity and substrate specificity with CDK family members. In mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma tumour suppressor protein at known CDK target residues. Lack of p38γ or treatment with the p38γ inhibitor pirfenidone protects against the chemically induced formation of liver tumours. Furthermore, biopsies of human hepatocellular carcinoma show high expression of p38γ, suggesting that p38γ could be a therapeutic target in the treatment of this disease

Analysis of chemical bonding and aromaticity from electronic delocalization descriptors

Interactions between electrons determine the structure and properties of matter from molecules to solids. Therefore, the understanding of the electronic structure of molecules will enable us to extract relevant chemical information. In the first part of this thesis, we focus our attention on the analysis of chemical bonding by means of the Electron Localization Function (ELF) and the Domain-Averaged Fermi Hole analysis (DAFH). In the second part, we assess the performance of some indicators of aromaticity by analyzing their advantages and drawbacks. We propose a series of tests based on well-known aromaticity trends that can be applied to evaluate the aromaticity of current and future indicators of aromaticity in both organic and inorganic species. Moreover, we investigate the nature of electron delocalization in both aromatic and antiaromatic systems in the light of Hückel’s (4n + 2) rule. Finally, we analyze the phenomenon of multiple aromaticity in all-metal clusters.Les interaccions entre electrons determinen l’estructura i propietats de la matèria. Per tant, la comprensió de l’estructura electrònica de les molècules ens permetrà extreure informació química rellevant. En la primera part d’aquesta tesi, centrem la nostra atenció en l’anàlisi de l’enllaç químic per mitjà de la funció de localització electrònica (ELF) i l’anàlisi dels anomenats domain averaged Fermi holes (DAFH). En la segona part, s’avalua el comportament d’alguns indicadors d’aromaticitat analitzant els seus avantatges i inconvenients. Al llarg d’aquesta part, es proposen una sèrie de tests basats en tendències d’aromaticitat conegudes que es poden aplicar per avaluar el comportament dels indicadors actuals en espècies tan orgàniques com inorgàniques. A més a més, s’investiga la naturalesa de la deslocalització d’electrons en sistemes aromàtics i antiaromàtics que segueixen la regla 4n+2 que proposà Hückel. Finalment, analitzem el fenomen de l’aromaticitat múltiple en sistemes metàl•lic

Desenvolupament d'un braçalet mèdic intel·ligent: projecte VITALIS

Aquest treball té com a objectiu principal crear un sistema de monitoratge continu de les constants vitals dels pacients ingressats als hospitals. Aquest rep el nom de projecte VITALS, i es basa en el disseny i implementació d'un braçalet intel·ligent sense fils, de nom Bibo band, encarregat de prendre les constants vitals als pacients ingressats i enviar aquestes dades a un servidor central perquè puguin ser mostrades a través de la plataforma web. El projecte també compta amb un sistema d'alarmes per indicar si les constants dels pacients no són les òptimes i informar així al personal sanitari. Per a la correcta realització de les tasques plantejades, tant aquelles delegades al hardware com les de software, s’han englobat dins del projecte totes les diverses àrees de coneixement que s’han ofert al llarg del grau d'enginyeria de sistemes TIC. Entre aquestes àrees s’hi troben l'electrònica, la informàtica o bé les comunicacions i totes actuen de forma sinèrgica per a oferir als usuaris un servei tangible i eficaç.Este trabajo tiene como objetivo principal crear un sistema de monitorización continuo de las constantes vitales de los pacientes ingresados en los hospitales. Este recibe el nombre de proyecto VITALS, y se basa en el diseño e implementación de un brazalete inteligente sin cables, de nombre Bibo band, encargado de tomar las constantes vitales a los pacientes ingresados y enviar estos datos a un servidor central para que puedan ser mostradas a través de la plataforma web. El proyecto también cuenta con un sistema de alarmas para indicar si las constates de los pacientes no son las óptimas e informar así al personal sanitario. Para la correcta realización de las tareas planteadas, tanto aquellas delegadas al hardware como las de software, se han englobado dentro del proyecto las diversas áreas de conocimiento que se han ofrecido al largo del grado de ingeniería de sistemas TIC. Entre estas áreas se puede encontrar la electrónica, la informática o bien las comunicaciones y todas actúan de forma sinérgica para ofrecer un servicio tangible y eficaz.The main goal of this project is to create a system for continuous monitoring of the vital signs of patients admitted to hospitals. This project, named VITALS, is based upon the design and implementation of a wireless smart bracelet, called Bibo band, which is responsible for analysing the vital signs of hospitalized patients and sending their data to a central server so said signs can be displayed through the web platform of the project. VITALS also has an alarm system which signs if the patient’s constants are not optimal and thus inform health personnel. For the correct performance of the proposed tasks, both those delegated to hardware and software alike, all the various areas of knowledge that has been offered throughout the degree of ICT systems engineering has been included in the project. These areas include electronics, computing and communications, all of which act synergistically to provide users with a tangible and effective service