Automated preclinical detection of mechanical pain hypersensitivity and analgesia

The lack of sensitive and robust behavioral assessments of pain in preclinical models has been a major limitation for both pain research and the development of novel analgesics. Here, we demonstrate a novel data acquisition and analysis platform that provides automated, quantitative, and objective measures of naturalistic rodent behavior in an observer-independent and unbiased fashion. The technology records freely behaving mice, in the dark, over extended periods for continuous acquisition of 2 parallel video data streams: (1) near-infrared frustrated total internal reflection for detecting the degree, force, and timing of surface contact and (2) simultaneous ongoing video graphing of whole-body pose. Using machine vision and machine learning, we automatically extract and quantify behavioral features from these data to reveal moment-by-moment changes that capture the internal pain state of rodents in multiple pain models. We show that these voluntary pain-related behaviors are reversible by analgesics and that analgesia can be automatically and objectively differentiated from sedation. Finally, we used this approach to generate a paw luminance ratio measure that is sensitive in capturing dynamic mechanical hypersensitivity over a period and scalable for highthroughput preclinical analgesic efficacy assessment.United States Department of DefenseDefense Advanced Research Projects Agency (DARPA) HR0011-19-2-0022United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) F31 NS084716-02 R35 NS105076 R01 NS089521 F31 NS108450 R01 NA114202Bertarelli FoundationSimons Collaboration on the Global BrainNIH BRAIN Initiative U19 NS113201 U24 NS109520 R01AT011447Boston Children's Hospital Technology Development FundConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) 229356/2013-

Identification of FAM173B as a protein methyltransferase promoting chronic pain

The authors thank Cilia de Heus for excellent technical support and Rene Scriwanek for the preparation of the electron micrographs for publication (UMCU, Utrecht, the Netherlands). We thank Angela Ho (University of Oslo, Oslo, Norway) for technical assistance.Author Contributions Conceptualization: Hanneke L. D. M. Willemen, Niels EijkelkampChronic pain is a debilitating problem, and insights in the neurobiology of chronic pain are needed for the development of novel pain therapies. A genome-wide association study implicated the 5p15.2 region in chronic widespread pain. This region includes the coding region for FAM173B, a functionally uncharacterized protein. We demonstrate here that FAM173B is a mitochondrial lysine methyltransferase that promotes chronic pain. Knockdown and sensory neuron overexpression strategies showed that FAM173B is involved in persistent inflammatory and neuropathic pain via a pathway dependent on its methyltransferase activity. FAM173B methyltransferase activity in sensory neurons hyperpolarized mitochondria and promoted macrophage/microglia activation through a reactive oxygen species±dependent pathway. In summary, we uncover a role for methyltransferase activity of FAM173B in the neurobiology of pain. These results also highlight FAM173B methyltransferase activity as a potential therapeutic target to treat debilitating chronic pain conditions.EMBO http://www.embo.org/funding- awards/fellowships/short-term-fellowships (No grant number available) received by HW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Boehringer Ingelheim Travel Grant https://www.bifonds.de/fellowships-grants/travel- grants.html (No grant number available) received by HW. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Utrecht University Life Science Seed Grant https://www.uu.nl/en/ research/life-sciences/research/seed-grants (No grant number available) received by NE. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Raman Spectroscopy and DFT calculations for the Electronic Structure Characterization of Conjugated Polymers

Flash presentationIn the last three decades, there has been a broad academic and industrial interest in conjugated polymers as semiconducting materials for organic electronics. Their applications in polymer light-emitting diodes (PLEDs), polymer solar cells (PSCs), and organic field-effect transistors (OFETs) offer opportunities for the resolution of energy issues as well as the development of display and information technologies1. Conjugated polymers provide several advantages including low cost, light weight, good flexibility, as well as solubility which make them readily processed and easily printed, removing the conventional photolithography for patterning2. A large library of polymer semiconductors have been synthesized and investigated with different building blocks, such as acenes or thiophene and derivatives, which have been employed to design new materials according to individual demands for specific applications. To design ideal conjugated polymers for specific applications, some general principles should be taken into account, including (i) side chains (ii) molecular weights, (iii) band gap and HOMO and LUMO energy levels, and (iv) suited morphology.3-6 The aim of this study is to elucidate the impact that substitution exerts on the molecular and electronic structure of π-conjugated polymers with outstanding performances in organic electronic devices. Different configurations of the π-conjugated backbones are analyzed: (i) donor-acceptor configuration, (ii) 1D lineal or 2D branched conjugated backbones, and (iii) encapsulated polymers (see Figure 1). Our combined vibrational spectroscopy and DFT study shows that small changes in the substitution pattern and in the molecular configuration have a strong impact on the electronic characteristics of these polymers. We hope this study can advance useful structure-property relationships of conjugated polymers and guide the design of new materials for organic electronic applications.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Conjugated Polymers for Organic Electronics: Structural and Electronic Characteristics

The use of organic materials to design electronic devices has actually presented a broad interest for because they constitute an ecological and suitable resource for our current "electronic world". These materials provide several advantages (low cost, light weight, good flexibility and solubility to be easily printed) that cannot be afforded with silicium. They can also potentially interact with biological systems, something impossible with inorganic devices. Between these materials we can include small molecules, polymers, fullerenes, nanotubes, graphene, other carbon-based molecular structures and hybrid materials. Actually these materials are being used to build electronic structures into electronic devices, like organic light-emitting diodes (OLEDs), organic solar cells (OSCs), and organic field-effect transistors (OFETs), constituting and already commercial reality. Some of them are used on a widespread basis1, and are the focus of some recent researches in molecules2,3 and polymers4-6 suitable for these purposes. In this study we analyze the electronic and molecular characteristics of some different π-conjugated structures in order to evaluate their potential as semiconducting materials for organic electronics. For this purpose we focus on the study of conjugated polymers with different backbones configurations: (i) donor-acceptor configuration, (ii) 1D lineal or 2D branched conjugated backbones, and (iii) encapsulated polymers. To achieve this goal, we use a combined experimental and theoretical approach that includes electronic spectroscopies (i.e., absorption, emission and microsecond transient absorption), vibrational Raman spectroscopy and DFT calculations. These structural modifications are found to provoke a strong impact on the HOMO and LUMO levels and the molecular morphology, and, consequently, on their suitability as semiconductors in organic electronic applications.References 1. S. R. Forrest, M. E. Thompson. Chem. Rev., 2007, 107, 923 2. R. C. González-Cano, G. Saini, J. Jacob, J. T. López Navarrete, J. Casado and M. C. Ruiz Delgado. Chem. Eur. J. 2013, 19, 17165 3. J. L. Zafra, R. C. González-Cano, M. C. Ruiz Delgado, Z. Sun, Y. Li, J. T. López Navarrete, J. Wu and J. Casado. J. Chem. Phys. , 2014, 140, 054706 4. M. Goll, A. Ruff, E. Muks, F. Goerigk, B. Omiecienski, I. Ruff, R. C. González-Cano, J. T. López Navarrete, M. C. Ruiz Delgado, S. Ludwigs. Beilstein J. Org. Chem., 2015, 11, 335. 5. D. Herrero-Carvajal, A. de la Peña, R. C. González-Cano, C. Seoane, J. T. López Navarrete, J. L. Segura, J. Casado, M. C. Ruiz Delgado, J. Phys. Chem. C, 2014, 118, 9899. 6. M. Scheuble, Y. M. Gross, D. Trefz, M. Brinkmann, J. T. López Navarrete, M. C. Ruiz Delgado, and S. Ludwigs, Macromolecules, 2015, 48, 7049.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Flexibilidad y rigidez en oligotiofenos y derivados de oligoacenos: aspectos estructurales

En esta Tesis doctoral se estudian sistemas caracterizados estructuralmente por: i) un esqueleto oligomérico o polimérico basado en anillos de tiofeno flexible debido a la inclusión de anillos y cadenas de tiofeno a modo de ramificaciones; ii) un sistema central rígido, planarizado gracias a la fusión de anillos (tipo aceno) o a la formación de puentes de carbono (oligo parafenilenos vinilenos). Estos sistemas se estudian en profundidad con el fin de elucidar el efecto de la libertad conformacional/imposición de rigidez sobre la estructura molecular y electrónica de las mismas haciendo uso de una amplia variedad de técnicas experimentales y cálculos teóricos

Upconversion and Optical Nanothermometry in LaGdO3: Er3+ Nanocrystals in the RT-900 K Range

This work has been supported by the Spanish Ministerio de Economía, Industria y Competitividad (Projects Nos. MAT2015-69508-P and PGC2018-101464-B-I00), the European Research Council (Ref. NCLas H2020-EU829161), and BSH Electrodomésticos España, S.A

Analyses of Genetic Diversity in the Endangered “Berrenda” Spanish Cattle Breeds Using Pedigree Data

Pedigree analyses of two endangered cattle breeds were performed in order to study the structure and the genetic variability in their populations. Pedigree data were analyzed from 12,057 individuals belonging to the “Berrenda en Negro” cattle breed (BN) and 20,389 individuals belonging to the “Berrenda en Colorado” cattle breed (BC) that were born between 1983 and 2020. BN and BC reference populations (RP) were set up by 2300 and 3988 animals, respectively. The generation interval in BN and BC reference populations was equal to 6.50 and 6.92 years, respectively. The pedigree completeness level was 82.76% in BN and 79.57% in BC. The inbreeding rates were 4.5% in BN and 3.4% in BC, respectively. The relationship among animals when they were born in different herds was 1.8% in BN and 5% in BC; these values increased to 8.5% and 7.7%, respectively when comparing animals that were born in the same herd. The effective number of founding herds was 23.9 in BN and 60.9 in BC. Number of ancestors needed to explain 50% of genes pool in the whole population was 50 and 101, in BN and in BC, respectively. The effective population size based on co-ancestries was 92.28 in BN and 169.92 in BC. The genetic variability has been maintained in both populations over time and the results of this study suggest that measures to promote the conservation of the genetic variability in these two breeds would go through for the exchange of breeding animals among farms and for monitoring the genetic contributions before implementing any selective action

Caracterización Electrónica y Molecular de Materiales Orgánicos Conjugados: Estudio Experimental y Teórico

Actualmente, existe una alternativa ecológica plausible al uso de silicio en materiales para dispositivos electrónicos: los materiales orgánicos policonjugados. Éstos presentan una serie de ventajas frente a los materiales inorgánicos: bajo coste de producción, ligereza, flexibilidad, disponibilidad para ser impresos y posibilidad de interaccionar con material biológico. Dichos materiales pueden ser desde moléculas discretas a polímeros, pasando por estructuras más complejas (fullereno, nanotubos, grafeno…). Se utilizan en dispositivos electrónicos como diodos emisores de luz orgánicos (OLEDs), células solares orgánicas (OSCs) y transistores orgánicos de efecto campo (OFETs), formando parte de la actualidad tecnológica comercial. Se presentan en diferentes soportes [1], y han sido objeto de estudio distintas estructuras moleculares [2,3] y poliméricas [4-6]. En el presente trabajo se analizan las estructuras electrónicas y moleculares de diferentes materiales π-conjugados y las modificaciones que en éstos se pueden ejercer, pudiendo así estudiar su capacidad como potencial material semiconductor en este tipo de aplicaciones. Para ello, se han llevado a cabo de forma paralela una serie de experimentos, incluyendo la espectroscopía Raman, en comparación con cálculos químico-cuánticos en DFT, obteniendo de este modo una visión completa del comportamiento electrónico observado en diferentes modelos moleculares y poliméricos. Referencias [1] S. R. Forrest, M. E. Thompson. Chem Rev. 2007, 107, 923. [2] R. C. González-Cano, G. Saini, J. Jacob, J. T. López Navarrete, J. Casado and M. C. Ruiz Delgado. Chem. Eur. J. 2013, 19, 17165. [3] J. L. Zafra, R. C. González-Cano, M. C. Ruiz Delgado, Z. Sun, Y. Li, J. T. López Navarrete, J. Wu and J. Casado, J. Chem. Phys., 2014, 140, 054706. [4] M. Goll, A. Ruff, E. Muks, F. Goerigk, B. Omiecienski, I. Ruff, R. C. González-Cano, J. T. López Navarrete, M. C. Ruiz Delgado, S. Ludwigs, Beilstein J. Org. Chem. 2015, 11, 335. [5] D. Herrero-Carvajal, A. de la Peña, R. C. González-Cano, C. Seoane, J. T. López Navarrete, J. L. Segura, J. Casado, M. C. Ruiz Delgado, J. Phys. Chem. C, 2014, 118, 9899. [6] M. Scheuble, Y. M. Gross, D. Trefz, M. Brinkmann, J. T. López Navarrete, M. C. Ruiz Delgado, and S. Ludwigs, Macromolecules, 2015, 48, 7049.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Cálculos DFT en materiales orgánicos conjugados: importancia en el análisis de los datos experimentales

Actualmente, y cada vez con mayor intensidad, los materiales orgánicos policonjugados se están erigiendo como la alternativa ecológica real al uso de silicio en materiales para dispositivos electrónicos. Este hecho se debe principalmente a una serie de ventajas que presentan frente a los materiales inorgánicos tradicionales, tales como bajo coste de producción, ligereza, flexibilidad, disponibilidad para ser impresos y posibilidad de interacción con material biológico. Éstos pueden estar constituidos por diferentes estructuras, desde moléculas discretas a polímeros, pasando por macromoléculas de mayor complejidad (fullereno, nanotubos, grafeno…). Hoy en día es posible encontrarlos integrados en dispositivos electrónicos como diodos emisores de luz orgánicos (OLEDs), células solares orgánicas (OSCs) y transistores orgánicos de efecto campo (OFETs) y presentados en diferentes soportes1, constituyendo de este modo parte fundamental de la actualidad tecnológica comercial. Dado su impacto, son uno de los principales objetos de estudio, ya sea como estructuras moleculares2,3 o poliméricas4-6. En el trabajo desarrollado se analizan las estructuras electrónicas y moleculares de diferentes materiales π-conjugados, las modificaciones que se pueden ejercer en los mismos y las propiedades exclusivas derivadas de éstas, pudiendo, de este modo, determinar su capacidad como potencial material semiconductor en aplicaciones optoelectrónicas. Para ello se han llevado a cabo una serie de experimentos (espectroscopía Raman y espectroscopía electrónica de absorción) cuyo resultado ha sido analizado en profundidad utilizando cálculos químico-cuánticos en DFT como herramienta analítica. Gracias, por tanto, a los cálculos realizados, es posible obtener una visión completa del comportamiento electrónico observado en diferentes modelos moleculares y poliméricos, así como esclarecer la causa que genera ciertos comportamientos inéditos hasta el momento en este tipo de materiales.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Materiales conjugados en electrónica orgánica: aspectos electrónicos y estructurales

En nuestro actual “mundo electrónico” existe un creciente interés en el diseño y fabricación de dispositivos electrónicos orgánicos, con propiedades ecológicas y de alta calidad. A diferencia de aquéllos basados en el silicio, se caracterizan por tener un bajo coste, ser ligeros, flexibles, solubles, imprimibles y con posibilidad de interacción con sistemas biológicos. Aparte de ser una realidad comercial reciente (OLEDs, OFETs, células solares orgánicas), nuevas moléculas1,2 y polímeros3-5 constituyen un objeto de investigación actual. En la presente comunicación se detalla el estudio de las características electrónicas y moleculares de diversas estructuras π-conjugadas (moleculares y poliméricas), para evaluar su potencial como semiconductores en diversos materiales electrónicos orgánicos.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech