Applications of the CRISPR–Cas9 system in cancer biology

The prokaryotic type II CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated 9) system is rapidly revolutionizing the field of genetic engineering, allowing researchers to alter the genomes of a large range of organisms with relative ease. Experimental approaches based on this versatile technology have the potential to transform the field of cancer genetics. Here, we review current approaches for functional studies of cancer genes that are based on CRISPR-Cas, with emphasis on their applicability for the development of next-generation models of human cancer

Understanding complex predictive models with ghost variables

The version of record of this article, first published in Test, is available online at Publisher’s website: http://dx.doi.org/10.1007/s11749-022-00826-xFramed in the literature on Interpretable Machine Learning, we propose a new procedure to assign a measure of relevance to each explanatory variable in a complex predictive model. We assume that we have a training set to fit the model and a test set to check its out-of-sample performance. We propose to measure the individual relevance of each variable by comparing the predictions of the model in the test set with those obtained when the variable of interest is substituted (in the test set) by its ghost variable, defined as the prediction of this variable by using the rest of explanatory variables. In linear models it is shown that, on the one hand, the proposed measure gives similar results to leave-one-covariate-out (loco, with a lowest computational cost) and outperforms random permutations, and on the other hand, it is strongly related to the usual F-statistic measuring the significance of a variable. In nonlinear predictive models (as neural networks or random forests) the proposed measure shows the relevance of the variables in an efficient way, as shown by a simulation study comparing ghost variables with other alternative methods (including loco and random permutations, and also knockoff variables and estimated conditional distributions). Finally, we study the joint relevance of the variables by defining the relevance matrix as the covariance matrix of the vectors of effects on predictions when using every ghost variable. Our proposal is illustrated with simulated examples and the analysis of a large real data set.Peer ReviewedPostprint (author's final draft

Rediseño de distribución en planta para reducir el costo de movimiento de materiales en la Empresa de Calzado Paola Della Flores

El presente trabajo de investigación, tiene como finalidad proponer un rediseño de la distribución de instalaciones, que permita reducir el costo del movimiento de materiales en el proceso productivo de la empresa fábrica de calzado “Paola della Flores”. La realización de este proyecto, empieza a partir del estudio y análisis de todo el proceso de fabricación, partiendo de la observación de cada una de sus estaciones de trabajo, identificando oportunidades que permitan la realización de nuestro propósito: reducir los costos generados por las distancias recorridas por materiales. A partir de la información recolectada, se evaluó el sistema de trabajo en el departamento de producción, haciendo uso de los procedimientos y teorías de la Distribución de planta – SLP. El presente estudio, tiene como propósito conocer las distancias y el costo actual de recorrido para efectuar las operaciones y el número actual de cargas interdepartamentales; de esta manera proponer un rediseño de planta que reduzca la congestión del material en proceso. Se detalla una serie de técnicas e instrumentos de recolección de datos empleadas, además de los formatos de matriz “desde-hasta”, diagramas de flujos de procesos, diagrama de operaciones del proceso, diagrama de relaciones y formatos del diagrama de recorrido y distancias. La eficacia de la propuesta, se demostrará a partir de la comparación de los resultados del total del costo de recorrido actual, y el valor final del costo por recorrido en la propuesta basada en la ingeniería de métodos.The present research work has the purpose of proposing a design of the distribution of facilities, which allows to reduce the cost of the travel of materials in the production process of the footwear factory ""Paola della Flores"". The realization of this project begins with the study and analysis of the entire manufacturing process, based on the observation of each of its workstations, identifying opportunities that allow us to achieve our goal: to reduce costs generated by distances Covered by materials. From the information collected, the work system was evaluated in the production department, making use of the procedures and theories of the workshop - type distribution. The present study aims to know the distances and the current cost of travel to carry out the operations and the current number of interdepartmental loads; In this way to propose a plant design that reduces the congestion of the material in process. It details a series of data collection techniques and instruments used, in addition to the ""from-to"" matrix formats, process flow diagrams, process operations diagram, relationship diagram and path diagram formats and distances. The effectiveness of the proposal will be demonstrated by comparing the results of the total cost of the current route and the final value of the cost per route in the proposal based on the method engineering.Tesi

Enhancing a de novo enzyme activity by computationally-focused ultra-low-throughput screening

Directed evolution has revolutionized protein engineering. Still, enzyme optimization by random library screening remains sluggish, in large part due to futile probing of mutations that are catalytically neutral and/or impair stability and folding. FuncLib is a novel approach which uses phylogenetic analysis and Rosetta design to rank enzyme variants with multiple mutations, on the basis of predicted stability. Here, we use it to target the active site region of a minimalist-designed, de novo Kemp eliminase. The similarity between the Michaelis complex and transition state for the enzymatic reaction makes this system particularly challenging to optimize. Yet, experimental screening of a small number of active-site variants at the top of the predicted stability ranking leads to catalytic efficiencies and turnover numbers ( 2 104 M 1 s 1 and 102 s 1) for this anthropogenic reaction that compare favorably to those of modern natural enzymes. This result illustrates the promise of FuncLib as a powerful tool with which to speed up directed evolution, even on scaffolds that were not originally evolved for those functions, by guiding screening to regions of the sequence space that encode stable and catalytically diverse enzymes. Empirical valence bond calculations reproduce the experimental activation energies for the optimized eliminases to within 2 kcal mol 1 and indicate that the enhanced activity is linked to better geometric preorganization of the active site. This raises the possibility of further enhancing the stabilityguidance of FuncLib by computational predictions of catalytic activity, as a generalized approach for computational enzyme designKnut and Alice Wallenberg Foundation (Wallenberg Academy Fellowship) 2018.0140Human Frontier Science Program RGP0041/2017FEDER Funds/Spanish Ministry of Science, Innovation and Universities BIO2015-66426-R RTI2018-097142-B-100FEDER/Junta de Andalucia - Consejeria de Economia y Conocimiento E.FQM.113.UGR18Swedish National Infrastructure for computing (SNAC) 2018/2-3 2019/2-

Psychometric properties and invariance of an English self-efficacy scale for university students in Peru

"Background: English is a global language used to communicate with members of the international community. Self-efficacy in learning English is an important factor that is influenced by perceived importance, interest, and beliefs about the ability to successfully perform tasks in English. Objective: The aim is to develop and validate a measurement instrument to assess English self-efficacy. Methods: A total of 453 students from different Peruvian universities participated, with ages ranging from 18 to 60 years (M = 23; SD = 6.18). Statistical techniques for latent variables were used and recommendations for educational and psychological tests were followed in its construction. The sample was divided into two groups to perform exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Results: The English Self-Efficacy Scale (ESS-P) is representative and relevant in terms of its item content (Aiken’s V > 0.70). Its internal structure is organized into three first order factors and a second order factor that are consistent with the theoretical proposal and was confirmed through CFA with excellent goodnessof-fit indices (χ2  = 1184.9, gl = 626, CFI = 0.92, TLI = 0.92, RMSEA = 0.06 y SRMR = 0.04). It also has adequate internal consistency in its three factors (Reading α/ω = 0.96), Oral Communication (α/ω = 0.95), and Writing (α/ω = 0.97) and the whole scale (α/ω = 0.98), is invariant with respect to sex, and has a conceptual relationship with variables such as academic self-efficacy and exam anxiety. Conclusion: The ESS-P is a measurement instrument with evidence of validity, factorial invariance, and good reliability of its scores. Therefore, it can be used in future studies in the academic contex

Stage-specific sensitivity to p53 restoration during lung cancer progression

2011 May 25Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1, 2, 3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)American Cancer Society (New England Area Fellow)Leukemia & Lymphoma Society of America (Fellow)Massachusetts Institute of Technology. Undergraduate Research Program (John Reed Fund)Damon Runyon Cancer Research Foundation (Merck Fellow)Genentech, Inc. (Postdoctoral Fellow)Howard Hughes Medical Institut

Estado de México y democracia en los albores del siglo XXI

De acuerdo con su título, este libro, compuesto por seis capítulos y dos anexos, reúne textos relativos a la democracia y al Estado de México, una de las principales entidades federativas de la República Mexicana. La importancia del Estado de México en el contexto nacional es indiscutible: de las 32 entidades que integran el país, es la que tiene más habitantes y electores (el segundo y el tercer lugares en ambos sentidos son ocupados, respectivamente, por el Distrito Federal y Veracruz), en tanto que está en el segundo lugar por el tamaño de su economía (en el primero se ubica el Distrito Federal y en el tercero, Nuevo León)

Influenza A(H5N1) detection in two asymptomatic poultry farm workers in Spain, September to October 2022: suspected environmental contamination

In autumn 2022, the Spanish Influenza National Reference Laboratory (NRL) confirmed the detection of influenza A(H5N1) in samples from two asymptomatic workers linked to an outbreak in a poultry farm in Spain. Nasopharyngeal swabs were taken according to a national screening protocol for exposed workers. Absence of symptoms, low viral load and negative serology in both workers suggested environmental contamination. These findings motivated an update of the early detection strategy specifying timing and sampling conditions in asymptomatic exposed persons.S

Evolución de la calidad de vida relacionada con la salud (CVRS) en niños/as escolares de las ciudades de Córdoba y Bahía Blanca

1 p.El uso del indicador CVRS se incrementa en la clínica y la investigación pediátrica. Su seguimiento permite conocer el sentido y la magnitud de los cambios en cada dimensión de la salud. Objetivo: Describir la evolución de la CVRS en un período de 6 meses en niños/as de 9 a 12 años, de escuelas de Córdoba y Bahía Blanca según sexo y desarrollo puberal (DP).http://www.sap.org.ar/docs/congresos/2013/conarpe/resumenes.pdfFil: Jouglard, Ezequiel Francisco. Universidad Nacional del Sur. Departamento de Ciencias de la Salud; Argentina.Fil: Fueyo Lavin, Julieta. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Salud Pública. Centro de Investigación Epidemiológica y en Servicios de Salud; Argentina.Fil: Mamondi, Verónica. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Salud Pública. Centro de Investigación Epidemiológica y en Servicios de Salud; Argentina.Fil: Rivera, Carolina. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Salud Pública. Centro de Investigación Epidemiológica y en Servicios de Salud; Argentina.Fil: Pogany, Lourdes. Hospital Nacional de Pediatría Garrahan; Argentina.Fil: Sanchez, María Camila. Servicio de Gastroenterología Infantil del Hospital Italiano de Buenos Aires; Argentina.Fil: Prina, Martina. Hospital Nacional de Pediatría Garrahan; Argentina.Fil: Roizen, Mariana. Hospital Nacional de Pediatría Garrahan; Argentina.Fil: Esand, María Eugenia. Universidad Nacional del Sur. Departamento de Ciencias de la Salud; Argentina.Fil: Berra, Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación en Ciencias de la Salud; Argentina.Pediatrí