Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Inhibidor de MNK1; OncologíaInhibidor de MNK1; OncologiaMNK1 inhibitor; OncologyTargeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.This work was supported by the Instituto de Salud Carlos III (PI17/02247), (PI20/01687), and CIBERONC (CB16/12/00363). S.R.y.C. acknowledges support from the Generalitat de Catalunya (2017-9015-385045). E. Bou-Petit thanks the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2017 FI_B2 00139) and the European Social Funds for her predoctoral fellowship

Selección De Personal Para El Banco Del Llano S.A

N/AEl proyecto se centra en mejorar la selección de personal en el Banco del Llano S.A., un banco en Colombia orientado hacia la atención al cliente y la expansión nacional. Enfrenta desafíos en el mercado laboral, como la brecha de habilidades y la diversidad cultural. Se inicia con una introducción sobre la importancia de la selección de personal en un entorno competitivo, abordando sesgos y discriminación respaldados por investigaciones. Se justifica el proyecto citando expertos en recursos humanos, enfatizando la relevancia estratégica de mejorar los procesos de selección. Se busca identificar fortalezas y debilidades en el proceso de selección del banco, con el argumento de que una selección efectiva no solo beneficia comercialmente a la entidad, sino que también tiene un impacto social positivo mediante la generación de empleo y el fortalecimiento organizativo. Los objetivos incluyen optimizar el proceso de selección con un modelo eficaz que promueva la diversidad, utilizar pruebas y evaluaciones para identificar candidatos adecuados, y explorar la evolución de la gestión humana, enfocándose en el talento como ventaja competitiva. Se mencionan detalles legales que respaldan el proceso de selección, como la Ley de Protección de Datos Personales y leyes que garantizan la igualdad de oportunidades y la protección contra la discriminación. La metodología de investigación es mixta, combinando enfoques cualitativos y cuantitativos, y se describe la población objetivo, el tamaño de la muestra y las técnicas de análisis de datos. Los resultados resaltan la necesidad de innovación, especialmente la incorporación de inteligencia artificial para reducir sesgos. Se hacen recomendaciones, como adoptar tecnologías emergentes, desarrollar programas de formación innovadores y estrategias para la diversidad e inclusión, y monitorear las tendencias laborales.The project focuses on improving staff selection at Banco del Llano S.A., a bank in Colombia oriented towards customer service and national expansion. It faces challenges in the labour market, such as skills gap and cultural diversity. It begins with an introduction on the importance of staff selection in a competitive environment, addressing biases and discrimination supported by research. The project is justified by quoting human resources experts, emphasizing the strategic relevance of improving selection processes. It seeks to identify strengths and weaknesses in the selection process of the bank, arguing that an effective selection not only benefits the entity commercially, but also has a positive social impact through employment generation and organizational strengthening. Objectives include optimizing the selection process with an effective model that promotes diversity, using tests and evaluations to identify suitable candidates, and exploring the evolution of human management, focusing on talent as a competitive advantage. Legal details supporting the selection process are mentioned, such as the Personal Data Protection Act and laws guaranteeing equal opportunities and protection against discrimination. The research methodology is mixed, combining qualitative and quantitative approaches, and describes the target population, sample size and data analysis techniques. The results highlight the need for innovation, especially the incorporation of artificial intelligence to reduce biases. Recommendations are made, such as adopting emerging technologies, developing innovative training programs and strategies for diversity and inclusion, and monitoring work trends

La pregunta como elemento estratégico de la evaluación del pensamiento reflexivo en el aula universitaria

Propósito: El presente estudio de investigación tuvo como objetivo general determinar dimensiones y criterios que sirvan de referentes para la elaboración de preguntas en pruebas escritas, con el fin de favorecer el pensamiento reflexivo en el aula universitaria. Método: El método utilizado fue la investigación proyectiva en la cual se realizó un diagnóstico, análisis y una propuesta de intervención En las fases de diagnóstico y análisis, se escogieron las pruebas escritas de las asignaturas de inglés, francés y física de tres universidades colombianas. Se diseñaron y aplicaron dos (2) instrumentos: con el Instrumento #2, se valoró el pensamiento reflexivo en las respuestas a nuevas preguntas elaboradas por el grupo de investigación, como parte de la fase con la aplicación del Instrumento #1, en el que se realizó un diagnóstico del nivel de pensamiento reflexivo que se encontraba en las preguntas de pruebas escritas.Purpose: This research study aimed to determine overall dimensions and criteria that serve as reference for the development of questions in written tests, in order to encourage reflective thinking in the university classroom. Method: The method used was the projective research in which a diagnosis, analysis and intervention proposals was made. In diagnosis and analysis phases, written tests in English, French and physics subjects of three Colombian universities were chosen. Two (2) instruments were designed and implemented: with the implementation of the Instrument # 1 a diagnosis of reflective thinking level that was favored through written test questions was made. With the Instrument # 2 was assessed reflective thinking in responses to new questions developed by the research group as part of the projective phase.Magíster en EducaciónMaestrí

Structural and vibrational study of pseudocubic CdIn2Se4 under compression

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry C, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jp5077565We report a comprehensive experimental and theoretical study of the structural and vibrational properties of a-CdIn2Se4 under compression. Angle-dispersive synchrotron X-ray diffraction and Raman spectroscopy evidence that this ordered-vacancy compound with pseudocubic structure undergoes a phase transition (7 GPa) toward a disordered rocksalt structure as observed in many other ordered-vacancy compounds. The equation of state and the pressure dependence of the Raman-active modes of this semiconductor have been determined and compared both to ab initio total energy and lattice dynamics calculations and to related compounds. Interestingly, on decreasing pressure, at similar to 2 GPa, CdIn2Se4 transforms into a spinel structure which, according to calculations, is energetically competitive with the initial pseudocubic phase. The phase behavior of this compound under compression and the structural and compressibility trends in AB(2)Se(4) selenides are discussed.This study was supported by the Spanish government MEC under Grant Nos: MAT2013-46649-C4-3-P, MAT2013-46649-C4-2-P, MAT2010-21270-C04-03/04, and CTQ2009-14596-C02-01, by MALTA Consolider Ingenio 2010 Project (CSD2007-00045) and by Generalitat Valenciana (GVA-ACOMP-2013-1012). A.M. and P.R-H. acknowledge computing time provided by Red Espanola de Supercomputacion (RES) and MALTA-Cluster, and also to S. Munoz-Rodriguez for providing a data-parsing application. J.A.S. acknowledges Juan de la Cierva fellowship program for financial support.Santamaría Pérez, D.; Gomis, O.; Pereira, ALJ.; Vilaplana Cerda, RI.; Popescu, C.; Sans Tresserras, JÁ.; Manjón Herrera, FJ.... (2014). Structural and vibrational study of pseudocubic CdIn2Se4 under compression. Journal of Physical Chemistry C. 118(46):26987-26999. https://doi.org/10.1021/jp5077565S26987269991184

Pathway-Specific Utilization of Synaptic Zinc in the Macaque Ventral Visual Cortical Areas

Synaptic zinc is an activity-related neuromodulator, enriched in hippocampal mossy fibers and a subset of glutamatergic cortical projections, exclusive of thalamocortical or corticothalamic. Some degree of pathway specificity in the utilization of synaptic zinc has been reported in rodents. Here, we use focal injections of the retrograde tracer sodium selenite to identify zinc-positive (Zn+) projection neurons in the monkey ventral visual pathway. After injections in V1, V4, and TEO areas, neurons were detected preferentially in several feedback pathways but, unusually, were restricted to deeper layers without involvement of layers 2 or 3. Temporal injections resulted in more extensive labeling of both feedback and intratemporal association pathways. The Zn+ neurons had a broader laminar distribution, similar to results from standard retrograde tracers. After anterograde tracer injection in area posterior TE, electron microscopic analysis substantiated that a proportion of feedback synapses was colabeled with zinc. Nearby injections, Zn+ intrinsic neurons concentrated in layer 2, but in temporal areas were also abundant in layer 6. These results indicate considerable pathway and laminar specificity as to which cortical neurons use synaptic zinc. Given the hypothesized roles of synaptic zinc, this is likely to result in distinct synaptic properties, possibly including differential synaptic plasticity within or across projections

Synaptic Reorganization in the Adult Rat's Ventral Cochlear Nucleus following Its Total Sensory Deafferentation

Ablation of a cochlea causes total sensory deafferentation of the cochlear nucleus in the brainstem, providing a model to investigate nervous degeneration and formation of new synaptic contacts in the adult brain. In a quantitative electron microscopical study on the plasticity of the central auditory system of the Wistar rat, we first determined what fraction of the total number of synaptic contact zones (SCZs) in the anteroventral cochlear nucleus (AVCN) is attributable to primary sensory innervation and how many synapses remain after total unilateral cochlear ablation. Second, we attempted to identify the potential for a deafferentation-dependent synaptogenesis. SCZs were ultrastructurally identified before and after deafferentation in tissue treated for ethanolic phosphotungstic acid (EPTA) staining. This was combined with pre-embedding immunocytochemistry for gephyrin identifying inhibitory SCZs, the growth-associated protein GAP-43, glutamate, and choline acetyltransferase. A stereological analysis of EPTA stained sections revealed 1.11±0.09 (S.E.M.)×109 SCZs per mm3 of AVCN tissue. Within 7 days of deafferentation, this number was down by 46%. Excitatory and inhibitory synapses were differentially affected on the side of deafferentation. Excitatory synapses were quickly reduced and then began to increase in number again, necessarily being complemented from sources other than cochlear neurons, while inhibitory synapses were reduced more slowly and continuously. The result was a transient rise of the relative fraction of inhibitory synapses with a decline below original levels thereafter. Synaptogenesis was inferred by the emergence of morphologically immature SCZs that were consistently associated with GAP-43 immunoreactivity. SCZs of this type were estimated to make up a fraction of close to 30% of the total synaptic population present by ten weeks after sensory deafferentation. In conclusion, there appears to be a substantial potential for network reorganization and synaptogenesis in the auditory brainstem after loss of hearing, even in the adult brain

Relationships between Gene Expression and Brain Wiring in the Adult Rodent Brain

We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain “connectome” from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS