Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (<28 °C) and cooling compounds (menthol, icilin) and are implicated in sensing unpleasant cold stimuli as well as in mammalian thermoregulation. Overexpression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to describe current known modulators for this ion channel because both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery fieldWe thank Gregorio Fernández-Ballester for the figure of the TRPM8 homology model. Funding from the Ministry of Economy and Competitiveness (BFU 2012-39092-C02; SAF2015-66275-C2-R) and the Generalitat Valenciana (PROMETEO II/2014/011).Peer reviewe

Loot boxes in Spanish adolescents and young adults: Relationship with internet gaming disorder and online gambling disorder

[EN] In recent years, the video game industry has introduced the possibility of buying virtual random goods (e.g., loot boxes) in electronic games using money through microtransactions, which are becoming more widespread and potentially akin to gambling. Although previous research has linked loot boxes with problematic gaming and gambling behaviors, there are very few studies that relate them to the clinical indicators of these problems. The overall goal of this study is to ascertain the prevalence of loot box purchasing behavior and its association with Internet Gaming Disorder (IGD) and Online Gambling Disorder (OGD). A secondary objective is to develop and analyze the psychometric properties of the Problematic Use of Loot Boxes Questionnaire (PU-LB). A crosssectional study was conducted among 6633 participants (4236 males, 63.9%, and 4123 minors, 62.2%) with an average age of 16.73 +/- 3.40 in a range of 11-30 years. The Spanish versions of the Internet Gaming Disorder Scale-Short Form (IGDS9-SF) and the Online Gambling Disorder Questionnaire (OGD-Q) were used. A total of 2013 (30.4%) participants reported purchasing a loot box in the last 12 months (28.9% among minors). A person who had purchased a loot box in the last 12 months had a prevalence rate (PR) of 3.66 [95% CI 2.66, 5.05] of presenting an IGD, and a PR = 4.85 [IC 95% 2.58, 9.12] of presenting an OGD. The PU-LB exhibited adequate reliability and validity indicators and was positively and significantly related to loot box expenditure, IGDS9-SF, and OGD-Q scores. The results are further discussed, and practical implications and future lines of research proposed.This study has been funded by the Ministry of Science and Innovation [RTI2018-094212-B-I00: (CIBER-AACC)] and by the International University of La Rioja in its Own Research Plan [Grupo Ciberpsicologia triennium 2017-2020 and biennium 2020-2022]. Open Access funding provided by University of Basque Country UPV/EHU

Assessment of DNA Damage by Comet Assay in Buccal Epithelial Cells: Problems, Achievement, Perspectives

DNA damage risk assessment in comet assay by the use of buccal mucosa cells has great advantages in comparison with other cell type sample due to more safely, easier, cheaper, and non-invasive method for in vivo studies. According to the OECD Guidelines, the in vivo mammalian alkaline comet assay is well-established and validated method for measuring DNA strand breaks in single eukaryotic cells. Considering exposure to xenobiotics and endogenous damage inductors, buccal mucosa cells are the first to be in direct contact after exposure and this makes them an ideal biomatrices in evaluation of the level of individual genotoxicity to several compounds already mentioned. Their clinical diagnostic applicability confers a potential use in patients across time. However, the number of publications referring to the human buccal comet assay is low in the last two decades. This low growing interest may be explained by several factors, including its relative technical problems. Different procedures have been used in collecting and processing the samples. In order to have widespread acceptance and credibility in human population studies, the comet assay in buccal cells requires standardization of the protocol, of parameters analyzed, and a better knowledge of critical features affecting the assay outcomes, including the definition of the values of spontaneous DNA damage. There is a need for further collaborative work as in the HUMN (micronucleus assay on lymphocytes) and HUMNxL (micronucleus assay on buccal cells) collaborative projects. The creation of a network of laboratories will allow more focused validation studies, including the design of a classic, historic, prospective cohort study in order to explore the link between measures of genetic instability in the buccal mucosa and the risk of cancer and other chronic-degenerative diseases. One such network connection will start in 2016 as a COST project under the name “hCOMET—The comet assay as a human biomonitoring tool” launched by Prof. Andrew Collins

Lectura de pseudopalabras en árabe y español

El objetivo de este estudio consiste en analizar las diferencias entre la lectura de palabras en alumnos ecuatorianos y argelinos en Educación Primaria. La muestra está formada por un grupo de 128 alumnos de una escuela de Ecuador y por otro grupo de 113 alumnos de una escuela de Argel, pertenecientes a una clase social media y sin necesidades educativas especiales. Los participantes fueron evaluados en lectura de pseudopalabras en primero y segundo curso de Educación Primaria. Las palabras utilizadas en español fueron adaptadas al árabe, teniendo en cuenta la longitud y frecuencia de cada una de ellas en esta lengua. Se llevó a cabo un diseño factorial mixto 2x2, donde el factor intersujeto fue el tipo de lengua según la consistencia ortográfica (transparente y opaca) y el factor intrasujeto el nivel educativo (primero y segundo curso de educación primaria). Los resultados del ANOVA de medidas repetidas en un factor muestran efectos significativos de ambos factores (tipo de lengua y nivel educativo) y de su interacción. Se encontró mejor precisión lectora de pseudopalabras en los niños de lengua árabe en ambos niveles educativos, un aumento de la lectura de pseudopalabras entre los dos cursos en las dos lenguas, siendo más intenso en español, y una menor diferencia en lectura de pseudopalabras entre lenguas en segundo curso. Estos resultados van en la línea de aquellos estudios que defienden las diferencias en la adquisición de la lectura en lenguas de distinta consistencia, pero no concuerdan con aquellos que apuntan que las lenguas opacas son más tardías. Se resalta la necesidad de analizar las diferencias en otras edades más tempranas y en otras medidas lectoras, controlando el grado de consistencia lingüística.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Laccase gene silencing negatively effects growth and development in Pleurotus ostreatus

42-51In this study we describe the effects of Pleurotus ostreatus transformants that have been silenced for laccase genes. Using the RNAi strategy, transformants with different levels of phenotypic alteration were obtained with respect to their oxidation capacity of 2,6-dimethoxyphenol (DMP). The analysis of laccase activity on DMP allowed us to select transformants with severe, medium and light phenotypic alteration in comparison to the PoB strain. The measurements of the average growth rate of the transformants with severe phenotypic alteration suggested that laccase expression could play a role in the vegetative growth of P. ostreatus. It was observed that both in solid and liquid cultures, PoB and the transformants express mRNA for lacc10, although the transformants with medium and severe phenotypic alteration present a decrease in intensity, especially in solid culture. This suggests that the product of this gene is responsible for the development of the mycelium and probably participates in the production of biomass in solid culture and also could be related to the decrease in the intensity of the constant isoenzyme observed in both culture systems

Structural stabilization of botulinum neurotoxins by tyrosine phosphorylation

AbstractTyrosine phosphorylation of botulinum neurotoxins augments their proteolytic activity and thermal stability, suggesting a substantial modification of the global protein conformation. We used Fourier-transform infrared (FTIR) spectroscopy to study changes of secondary structure and thermostability of tyrosine phosphorylated botulinum neurotoxins A (BoNT A) and E (BoNT E). Changes in the conformationally-sensitive amide I band upon phosphorylation indicated an increase of the α-helical content with a concomitant decrease of less ordered structures such as turns and random coils, and without changes in β-sheet content. These changes in secondary structure were accompanied by an increase in the residual amide II absorbance band remaining upon H-D exchange, consistent with a tighter packing of the phosphorylated proteins. FTIR and differential scanning calorimetry (DSC) analyses of the denaturation process show that phosphorylated neurotoxins denature at temperatures higher than those required by non-phosphorylated species. These findings indicate that tyrosine phosphorylation induced a transition to higher order and that the more compact structure presumably imparts to the phosphorylated neurotoxins the higher catalytic activity and thermostability

Generation of Molecular Diversity from Amino Acids. A Source for the Discovery of New TRP Channel Modulators

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.Ion channels are central and challenging targets in medicinal chemistry but, because of the scarce structural knowledge, rational approaches to ion channel modulators are still rare. Moreover, the multimodal activation of some channels, like TRPs, complicates still more the scenario for rational discovery programs. Due to these facts, most strategies directed to identify ion channel modulators rely on the screening of peptide and small-molecule libraries. In this context, we have been involved in the development of synthetic pathways for the generation of diverse, chiral, highly functionalized linear and heterocyclic scaffolds from amino acids, and in the production of discrete libraries from them. The screening of these libraries on different TRP channels has allowed the discovery of some innovative hits that have progressed to hit-to-lead optimization programs. This communication will deal with the synthesis, structural characterization, and biological evaluation of a collection of β,γ–diaminoester derivatives that display significant activity at TRPV1, TRPM8 and TRPA1 channels. Compound RGM04-7, a selective.Supported by MICINN grants: Consolider-Ingenio 2010 (CSD2008-00005 and CSD2006-00015), SAF2009-09323 and BFU2009-08346, and the Generalitat Valenciana (PROMETEO/2010/046)

The microbiota-gut-brain axis:Neurobehavioral correlates, health and sociality

Recent data suggest that the human body is not such a neatly self-sufficient island after all. It is more like a super-complex ecosystem containing trillions of bacteria and other microorganisms that inhabit all our surfaces; skin, mouth, sexual organs, and specially intestines. It has recently become evident that such microbiota, specifically within the gut, can greatly influence many physiological parameters, including cognitive functions, such as learning, memory and decision making processes. Human microbiota is a diverse and dynamic ecosystem, which has evolved in a mutualistic relationship with its host. Ontogenetically, it is vertically inoculated from the mother during birth, established during the first year of life and during lifespan, horizontally transferred among relatives, mates or close community members. This micro-ecosystem serves the host by protecting it against pathogens, metabolizing complex lipids and polysaccharides that otherwise would be inaccessible nutrients, neutralizing drugs and carcinogens, modulating intestinal motility, and making visceral perception possible. It is now evident that the bidirectional signaling between the gastrointestinal tract and the brain, mainly through the vagus nerve, the so called “microbiota–gut–vagus–brain axis,” is vital for maintaining homeostasis and it may be also involved in the etiology of several metabolic and mental dysfunctions/disorders. Here we review evidence on the ability of the gut microbiota to communicate with the brain and thus modulate behavior, and also elaborate on the ethological and cultural strategies of human and non-human primates to select, transfer and eliminate microorganisms for selecting the commensal profile

DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit a-calcitonin gene-related peptide (a-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of a-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt a-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit a-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target. © 202

Optimization of the efficiency in an induction machine drive by algorithm based on the interior point method

[EN] This work optimizes the efficiency of the squirrel cage type Inverter-Induction Machine (IM) system, using an algorithm based on the Interior Point Method (IPM), where the input variables are the electromagnetic torque and the rotor speed at steady state,and as outputs the optimal efficiency and slip values are obtained. The optimum rotor flux value is calculated, which is used as a reference in the flux control loop, in the direct control vector method of the IM. Simulation results are obtained where the increase in efficiency is observed in low load states. The experimental installation used in the implementation of the vector control with maximum system efficiency is described, and the experimental results obtained are shown. A discussion is carried out on the results and the use of the Interior Point Optimization Method.[ES] En este trabajo se realiza la optimización de la eficiencia del sistema  Inversor-Máquina de Inducción (MI) del tipo jaula de ardilla, utilizando un algoritmo basado en el Método de Punto Interior (MPI), donde las variables de entrada son el par electromagnético y la velocidad del rotor en estado estacionario, y como salidas se obtienen los valores de la eficiencia óptima y del deslizamiento. Se calcula el valor del flujo óptimo del rotor que se utiliza como referencia en el lazo de control del flujo, en el control vectorial método directo de la MI. Se obtienen resultados de simulación donde se observa el incremento de la eficiencia en estados de baja carga. Se describe la instalación experimental usada en la implementación del control vectorial con máxima eficiencia del sistema, y se muestran los resultados experimentales obtenidos. Se realiza una discusión sobre los resultados y la utilización del Método de Optimización de Punto Interior.Instituto Politécnico Nacional (IPN), proyecto multidisciplinario registro número 1995.Pacheco-Montiel, J.; Badaoui, M.; Rodríguez-Rivas, J.; Alvarado-Farías, JM.; Carranza-Castillo, O.; Ortega-González, R. (2021). Optimización de la eficiencia en el accionamiento de una máquina de inducción mediante algoritmo basado en el método de punto interior. Revista Iberoamericana de Automática e Informática industrial. 18(4):336-346. https://doi.org/10.4995/riai.2020.13418OJS336346184Andréasson, N., Evgrafov, A., Patriksson, M, 2020. An Introduction to Continuous Optimization Fundations & Fundamental Algorithms. Dover Publications.Benson, H. Y., Shanno, D. F, 2014. Interior-point methods for nonconvex nonlinear programming: cubic regularization. Comput Optim Appl, 58:323-346. https://doi.org/10.1007/s10589-013-9626-8Borisevich, A., and Schullerus, G, 2016. 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E., Duarte, A. Q, 2014. Technical and Economical Considerations on Super High-Efficiency Three-Phase Motors. IEEE Trans. on Ind. App., vol. 50, no. 2, pp. 1274-1285, March/April. https://doi.org/10.1109/TIA.2013.2272548Eftekhari, S. R., Davari, S. A., Naderi, P., García C., Rodriguez, J, 2020. Robust Loss Minimization for Predictive Direct Torque and Flux Control of an Induction Motor With Electrical Circuit Model. IEEE Trans. on Power Electronics, vol. 35, no. 5, pp. 5417-5426, May. https://doi.org/10.1109/TPEL.2019.2944190Farhat, I. A., El-Hawary, M. E, 2009. Interior point methods application in optimum operational scheduling of electric power systems. IET Generation, Transmission & Distribution, vol. 3, Iss. 11, pp. 1020-1029. https://doi.org/10.1049/iet-gtd.2008.0573IEA International Energy Agency. World Energy Outlook, 2018. IEA, Paris 2018. 01/2020. https://www.iea.org/reports/world-energy-outlook-2018.IEC 60034-30-1, 2014. Efficiency classes of line operated AC motors (IE-code), Edition 1.0.Mallik, S., Mallik, K., Barman, A., Maiti, D., Biswas, S. K., Deb, N. K., Basu, S, 2017. Efficiency and Cost Optimized Design of an Induction Motor Using Generic Algorithm. IEEE Trans. on Ind. Appl., vol. 64, no. 12, pp. 9854-9863, December. https://doi.org/10.1109/TIE.2017.2703687McElveen, R., Melfi, M., McFarland, J, 2019. Improved Characterization of Polyphase Induction Motor Losses: Test Standards Must Be Modified to Improve Efficiency Optimization. IEEE Ind. Appl. Magazine., pp. 61-68, Nov./Dec. https://doi.org/10.1109/MIAS.2018.2875208Rao, N., and Chamund, D, 2014. Calculating Power Losses in an IGBT Module. Application Note. DYNEX Power Control through Innovation.Rathore, A. K., Holtz, J., Boller, T, 2013. Generalized Optimal Pulsewidth Modulation of Multilevel Inverters for Low-Switching-Frequency Control of Medium-Voltage High-Power Industrial AC Drives. IEEE Trans. on Ind. Electronics, vol. 60, no. 10, pp. 4215-4224, Oct. https://doi.org/10.1109/TIE.2012.2217717Seung-Ki, S, 2011. Control of Electric Machine Drive Systems. IEEE Press & Wiley. Printed in the USA.Salomon, C. P., Sant'Ana, W. C., Borges da Silva, L. E., Torres, G. L., Bonaldi, E. L., Olveira, L. E. L., Borges da Silva, J. G, 2015. Induction Motor Efficiency Evaluation Using a New Concept of Stator Resistance. IEEE Trans. on Inst. and Meas., vol. 64, no. 11, pp. 2908-2917, November. https://doi.org/10.1109/TIM.2015.2437632Santos, V. S., Felipe, P. R. V, Sarduy, J. R. G., Lemozy, N. A. L., Jurado, A., Quispe, E. C, 2015. Procedure for Determining Induction Motor Efficiency Working Under Distorted Grid Voltages. IEEE Trans. on Energy Conv., vol. 30, no. 1, pp. 331-339, March. https://doi.org/10.1109/TEC.2014.2335994Shukla, S., and Singh, B, 2017. Solar Powered Sensorless Induction Motor Drive with Improved Efficiency forWater Pumping. IET Power Electronics, vol. 11, issue 3, pp. 1-11, March. https://doi.org/10.1049/iet-pel.2017.0452Stumper, J. F., Dötlinger, A., Kennel, R, 2013. Loss Minimization of Induction Machines in Dynamic Operation. IEEE Trans. on Energy Conv., vol. 28, no. 3, pp. 726-735, September. https://doi.org/10.1109/TEC.2013.2262048Sul, S. K., 2011. Control of Electric Machine Drive Systems. IEEE Press-Wiley & Sons. https://doi.org/10.1002/9780470876541Taheri, A., Rahmati, A., Kaboli, S, 2012. Efficiency Improvement in DTC of Six-Phase Induction Machine by Adaptive Gradient Descent of Flux. IEEE Trans. on Power Electronics, vol. 27, no. 3, pp. 1552-1562, March. https://doi.org/10.1109/TPEL.2011.2163420Vanderbei, R. J., Shanno, D. F, 1999. Interior-point methods for nonconvex nonlinear programming. Computational Optimization and Applications, 13, 31-252. https://doi.org/10.1023/A:1008677427361Vural, A. M, 2015. Interior point-based slack-bus free-power flow solution for balanced islanded microgrids. Int. Trans. Electr. Energ. Syst, 26:968-992. https://doi.org/10.1002/etep.2117Xu, W., Hu, D., Lei, G., Zhu, J, 2019. System-Level Efficiency Optimization of a Linear Induction Motor Drive System. IEEE Trans. on Electrical Machines and Systems, vol. 3, no. 3, pp. 285-291, Sept. https://doi.org/10.30941/CESTEMS.2019.00037Xu, W., Xiao, X., Du, G., Zou, J, 2020. Comprehensive Efficiency Optimization of Linear Induction Motors for Urban Transit. IEEE Trans. on Vehicular Tech., vol. 69, no. 1, pp. 131-139, January. https://doi.org/10.1109/TVT.2019.295395