Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet\uae model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity

Adjustment of food textural properties for elderly patients

Over the next twenty years the number of people over 60 years will exceed one billion. Changes associated with ageing have an impact on food texture choices for healthy elders and those used therapeutically for people with swallowing difficulties (dysphagia). The ideal “swallow-safe” bolus is moist, cohesive and slippery. A general reduction in muscle strength is seen throughout the ageing oropharyngeal musculature, resulting in a reduced ability to safely and efficiently manage hard or fibrous textured foods. Reduced masticatory ability combined with dental loss further compounds the issue. Dry mouth is commonly associated with old age, making it difficult to propel dry or sticky textures through the pharynx, and increases the likelihood of pharyngeal residue. An age related reduction in laryngopharyngeal sensitivity dampens the ability to detect residue, increasing choking risk. Reduced tongue pressure, increases in pharyngeal transit time, valleculae residue, number of clearing swallows and slower and less efficient oesophageal transit occur with aged swallowing. Food textures that are sticky and adhesive will require increased lingual effort to propel them into and through the pharynx. Taken in combination these factors mean that food textures prescribed to the elderly need to be soft and moist and for fibers to be easily broken. To improve moisture content, additional nutrient dense products (e.g., milk, cream or butter) may be required to artificially moisten the bolus. Careful, individualized attention to diet recommendations will result in a diet that is appealing and also provide a variety of textures that are swallow-safe and nutrient dense. Practical Application: Aged related changes in the oral cavity and the oral, pharyngeal and oesophageal phases of swallowing require special thought to the suitability of food textures for the elderly. Foods that are fibrous, hard or dry may be unsuitable due to difficulties with safe particle size reduction and bolus formation for swallowing. Foods that are sticky and adhesive are also problematic and increase risk for both choking and residue. Food texture properties that are ideally suited for the elderly include those that are soft, moist, and easily reduced with minimal chewing effort. Hard food textures that break down and dissolve easily with minimal chewing should be investigated. Increased aroma and flavor may improve appeal lost through reduced variety in food textures. Diet reviews need to consider both textures that can be safely managed and the nutrient density of those textures

Tarsal Tunnel Syndrome – a narrative review of the literature

International audienceThe effect of the mean effective stress on the elastic properties of unbound granular materials is a well-known experimental result. Power laws between the mean effective stress and the shear modulus G vhmax of three natural sands are established for isotropic stress paths using bender elements. Triaxial test results reveal that such power laws are also suitable for contracting deviatoric stress paths whereas it is no longer the case for dilating deviatoric stress paths. Fabric changes during shearing are therefore highlighted. These observations seem to be a typical feature of the behavior of granular materials

Molecular Modeling Studies of 4,5-Dihydro-1H-pyrazolo[4,3-h] quinazoline Derivatives as Potent CDK2/Cyclin A Inhibitors Using 3D-QSAR and Docking

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r2cv values of 0.747 and 0.518 and r2 values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity

Por un cuerpo del tacto: mirar, tocar, hender el poema Una puesta en diálogo de lecturas a Jean-Luc Nancy y José Watanabe

¿Cómo pensar el cuerpo sin someterlo al régimen del sentido, sin significarlo o hacerlo significar? ¿Cómo hacerle justicia si es evidente que, aquí y ahora, éste es mi cuerpo (Hoc est enim corpus meum)? Jean-Luc Nancy propone llevar la escritura lo más lejos posible, para tocar el cuerpo en el límite del sentido, donde éste se interrumpe. El cuerpo constituye una apertura, es lo abierto de la clausura y lo infinito de lo finito. Entonces se hace necesario abrir una pequeña hendidura en la corteza, tocando su cierre. Y, como indica Nancy: “Puede ser que sólo haya abertura gracias a un tacto o a un toque”. Derrida recupera la clasificación de cinco sentidos y su división en dos categorías: “los sentidos objetivos (tactus, visus, auditus) y los subjetivos (gustus, olfatus)” . Los primeros aportan significativamente al conocimiento, y entre ellos predomina el tacto. Éste es el más importante en la medida en que es el “único sentido de la percepción exterior inmediata” . El tacto funda así los dos sentidos objetivos restantes, la vista y el oído, los cuales deben ser referidos originalmente al tacto para poder “'constituir un conocimiento por la experiencia'” . Nancy conserva la idea de preeminencia del tacto, pero reformula su justificación afirmando que “sería mejor hablar del toque, o destacar el valor verbal de la palabra, como cuando se dice 'el sentir' […]. El tacto forma cuerpo con el sentir o hace de este -de su pluralidad- un cuerpo; no es más que el corpus de los sentidos”Fil: Cichero, Anuar. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Escuela de Letras; Argentina.Otras Filosofía, Étnica y Religió

¿Sumar 1 + 2n + ... + mn para cualquier n? ¡Es fácil!

En este artículo obtenemos en forma directa mediante métodos elementales la suma de las n-ésimas potencias de los primeros m enteros positivos. La deducción se basa enteramente en los conceptos de recursión y prueba por Inducción Completa y parte de una idea simple: disponer la suma 1 + 2n + ... + mn en un arreglo triangular de potencias (n-1)-ésimas. La solución de este problema es bien conocida: las funciones Pn(m) son polinomios de grado n + 1 en la indeterminada m que se expresan en términos de los polinomios y números de Bernoulli. Al obtener los coeficientes de Pn(m) recobramos como subproducto de nuestro trabajo esta importante familia de números racionales. Sin embargo, hay algo nuevo: el cálculo directo de Pn(m) no sólo nos permite ver más de cerca cómo está constituido cada número de Bernoulli Bn, sino que nos facilita la construcción de un eficaz algoritmo de cómputo para obtenerlos hasta cualquier N fijo deseado

Synthesis and biological evaluation of novel (thio)semicarbazone-based benzimidazoles as antiviral agents against human respiratory viruses

Respiratory RNA viruses are responsible for recurrent acute respiratory illnesses that stillrepresent a major medical need. Previously we developed a large variety of benzimidazole derivativesable to inhibit these viruses. Herein, two series of (thio)semicarbazone- and hydrazone-basedbenzimidazoles have been explored, by derivatizing 5-acetyl benzimidazoles previously reported by us,thereby evaluating the influence of the modification on the antiviral activity. Compounds6,8,16and17,bearing the 5-(thio)semicarbazone and 5-hydrazone functionalities in combination with the 2-benzylring on the benzimidazole core structure, acted as dual inhibitors of influenza A virus and humancoronavirus. For respiratory syncytial virus (RSV), activity is limited to the 5-thiosemicarbazone(25) and 5-hydrazone (22) compounds carrying the 2-[(benzotriazol-1/2-yl)methyl]benzimidazolescaffold. These molecules proved to be the most effective antiviral agents, able to reach the potencyprofile of the licensed drug ribavirin. The molecular docking analysis explained the SAR of thesecompounds around their binding mode to the target RSV F protein, revealing the key contacts forfurther assessment. The herein-investigated benzimidazole-based derivatives may represent valuablehit compounds, deserving subsequent structural improvements towards more efficient antiviralagents for the treatment of pathologies caused by these human respiratory viruses

Taller Conozco

Trabajo aplicable al modo un alumno: un laptop. Conozco propone mostrar como generar un juego tipo trivia sobre una lámina didáctica para que funcione en la xo. Comienza analizando a la "lámina didáctica" como una partición en zonas respuesta. Se redactan para estas respuestas, preguntas y textos de ayuda. Al final se re-utiliza el código de Conozco Uruguay, que elige al azar una pregunta entre las definidas, evalúa la respuesta -click del puntero sobre la lámina- y plantea otra pregunta o brinda un texto de ayuda. El Taller propone realizar -en cuatro horas- una actividad a modo de ejemplo. Es prerrequisito manejar editores de texto e imágenes o integrarse en equipos con quien lo haga. Como recurso habrá prontas láminas para temas de geometría. El resultado del taller tendrá licencia GNU GENERAL PUBLIC LICENSE V3

O Pluralismo interacionista da TTM de Karl Popper como uma teoria da mente alternativa [Karl Popper’s TTM interactional pluralism, as a theory concerning the alternative mind]

O problema mais importante deste artigo é: por que o pluralismo interacionista de Popper é uma alternativa para explicar a relação mente-corpo? Defende-se aqui a hipótese de que o pluralismo interacionista se justifica como alternativa em relação às teorias da mente contemporâneas porque propõem uma tentativa de explicação da realidade que envolva a natureza e a existência dos objetos matemáticos e lógicos. Nesse sentido, a estrutura do nosso artigo é a seguinte: 1. Por que as teorias monistas materialistas são insuficientes para explicar relação mente-corpo? 2. Por que as teorias dualistas interacionistas falham em explicar a relação mente-corpo? 3. Por que o pluralismo interacionista de Popper pode ser considerado uma alternativa para o problema mente-corpo

Entendendo o anarquismo metodológico de P. K. Feyerabend

ResumoPor volta de 1975 a filosofia da ciência foi assombrada pela publicação do irreverente livro de P.K. Feyerabend “Contra o Método” (“Against Method”) que ousava defender a tese de que a ciência não progredia amarrada por uma metodologia determinada e nem mesmo era uma atividade humana racional como positivistas e falseacionistas entendiam. O objetivo deste artigo é mostrar quais são as teses de Feyerabend que abalaram a maneira de pensar dos epistemólogos das ciências. Para isso confrontamos as teses de Feyerabend com os positivistas, falseacionistas e com o relativismo pragmático de T. Kuhn. O resultado foi um mergulho no ceticismo. Do dogmatismo de positivistas e falseacionistas para o relativismo de Kuhn e acabando no ceticismo de Feyerabend em respeito a atividade científica