Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach

In this work, we analyze the structure–activity relationships (SAR) of epigenetic inhibitors (lysine mimetics) against lysine methyltransferase (G9a or EHMT2) using a combined activity landscape, molecular docking and molecular dynamics approach. The study was based on a set of 251 G9a inhibitors with reported experimental activity. The activity landscape analysis rapidly led to the identifcation of activity clifs, scafolds hops and other active an inactive molecules with distinct SAR. Structure-based analysis of activity clifs, scafold hops and other selected active and inactive G9a inhibitors by means of docking followed by molecular dynamics simulations led to the identifcation of interactions with key residues involved in activity against G9a, for instance with ASP 1083, LEU 1086, ASP 1088, TYR 1154 and PHE 1158. The outcome of this work is expected to further advance the development of G9a inhibitors

Lipid Metabolism Alterations in a Rat Model of Chronic and Intergenerational Exposure to Arsenic

Chronic exposure to arsenic (As), whether directly through the consumption of contaminated drinking water or indirectly through the daily intake of As-contaminated food, is a health threat for more than 150 million people worldwide. Epidemiological studies found an association between chronic consumption of As and several pathologies, the most common being cancer-related disorders. However, As consumption has also been associated with metabolic disorders that could lead to diverse pathologies, suchas type 2 diabetes mellitus, nonalcoholic fatty liver disease, and obesity. Here, we used ultra-performance liquid chromatography (UPLC) coupled to electrospray ionization/quadrupole time-of-flight mass spectrometry (ESI-QToF) to assess the effect of chronic intergenerational As exposure on the lipid metabolism profiles of serum from 4-month-old Wistar rats exposed to As prenatally and also during early life in drinking water (3 ppm). Significant differences in the levels of certain identified lyso-phospholipids, phosphatidylcholines, and triglycerides were found between the exposed rats and the control groups, as well as between the sexes. Significantly increased lipid oxidation determined by the malondialdehyde (MDA) method was found in exposed rats compared with controls. Chronic intergenerational As exposure alters the rat lipidome, increases lipid oxidation, and dysregulates metabolic pathways, the factors associated with the chronic inflammation present in different diseases associated with chronic exposure to As (i.e., keratosis, Bowen’s disease, and kidney, liver, bladder, and lung cancer)

A Multi-Stage CTLE Design and Optimization for PCI Express Gen6.0 Link Equalization

The continuously increasing bandwidth demand from new applications has led to the development of the new peripheral component interconnect express (PCIe) Gen6, reaching data rates of 64 giga-transfers per second (GT/s) and adopting the pulse amplitude modulation 4-level (PAM4) signaling scheme. While PAM4 solves the bandwidth requirements, it brings new challenges for the physical channel design. PAM4 is more susceptible to errors due to various noise sources caused by reduced voltage (and timing) ranges, yielding a higher bit error rate (BER). It also introduces new challenges in slicers, transition jitter, and equalizers, making of equalization (EQ) a critical process for PAM4 signaling. In this paper, we propose a multi-stage continuous-time linear equalizer (CTLE) with high-band, mid-band, and low-band frequency boost stages to deal with highly lossy channels. Given the complexity of EQ of multi-level signals, optimization techniques are used, including an efficient optimization of the transmitter finite impulse response (FIR) filter and the receiver CTLE tuning.ITESO, A.C

OPTIMIZACIÓN DE REFUERZO DE COSTILLA EN CAJAS PLANAS PLÁSTICAS MOLDEADAS POR INYECCIÓN

ResumenEn este trabajo se presenta el diseño y optimización de una caja reforzada con costillas inyectada en polioximetileno. Utilizando un diseño experimental de Taguchi L27-35, se definió un perfil que permite evaluar el efecto de la geometría de las costillas en la deformación. La modelación de la inyección en Moldflow Adviser permitió establecer la geometría óptima para la inyección de una pieza con mínima deformación y mínima tendencia al rechupe. Se diseñó y fabricó un molde instrumentado en base a la geometría óptima y la geometría con mayor tendencia a presentar defectos. La deformación y rechupe de las partes inyectadas fueron medidos con un equipo de análisis dimensional de imágenes, mostrando que los datos obtenidos de la modelación con respecto a los medidos tienen un error del 2% para la deformación, 6% para los rechupes y 5% para la profundidad media de rechupe, siendo estos resultados satisfactorios.Palabra(s) Clave: costillas, deformación, inyección de plásticos, molde de inyección, rechupes. OPTIMIZATION OF RIB REINFORCEMENT IN INJECTION MOLDED PLASTIC FLAT BOXES AbstractIn this paper, the design and optimization of a plastic box reinforced with ribs and injected with polyoxymethylene are presented. Using a Taguchi design of experiments, a geometric profile was defined. This profile allow us to evaluate the effect of the ribs geometry on the deformation of the component. Moldflow Adviser was used to simulate the injection molding process in order to establish the optimum geometry for obtaining products with minimum deformation and sink marks. Based on the optimum geometry, and also on the one that maximized deformation, injection molding cavities were design and manufactured. The deformation and sink marks of the injected components were measured and compared with simulation results. Excellent agreement was found with 2% of error for deformation results, 6% for sink marks, and 5% for sink marks depth.Keywords: deformation, injection mold, plastics injection molding, ribs, sink marks

Alcancías BRED en escuelas primarias para incentivar las donaciones económicas

En el presente reporte se desarrolla el contenido de la realización del proyecto de implementación de alcancías en escuelas primarias para incentivar las donaciones económicas en la ONG de BRED, un banco de ropa, calzado y enseres domésticos ubicado en Guadalajara, Jalisco. Se retoma el proyecto a partir de los resultados obtenidos en el periodo de primavera 2022, por otros compañeros del Observatorio de Servicios e Innovación, quienes entregaron un prototipo de alcancías hecho en opalina y una propuesta para llevarlas a las escuelas primarias en tres modalidades distintas (personal, grupal y escolar). Se validó y rediseñó el prototipo de alcancías para incentivar las donaciones económicas para BRED, y el enfoque va para las escuelas primarias. El rediseño surge a partir del cuestionamiento y revisión de materiales y el proceso de implementación en las escuelas. Se pretende implementarlo y conseguir un prototipo de un producto duradero y eficiente, y, además, que motive la participación para aumentar el sustento económico de la ONG.Se llevó a cabo el proceso de Design Thinking para la generación y validación de ideas. El proyecto abarca la definición del diseño con sus características y la explicación detallada de la implementación para la participación de escuelas primarias, incluso de pruebas piloto con niños en particular, sin embargo, aún queda por resolver el tema de hacer pruebas en un escenario real y la fabricación de la versión final de las alcancías. Por otro lado, se desarrollaron los proyectos de la rúbrica de servicios para validar y poder aplicarlas en las ONG con la finalidad de que sigan en mejora continua sin la necesidad de tener consultoría directa, partiendo de la propuesta de preguntas y áreas a evaluar, y también se trabajó en el proyecto de redes sociales y podcast del Observatorio para difundir el material generado y dar a conocer las actividades dentro del mismo.ITESO, A.C

Determinación de Mercurio, Cadmio, Plomo y Arsénico en ríos de la zona minera de la subcuenca del Río Titihuapa, Cabañas, El Salvador, C.A.

The sub-basin of the Titihuapa River in the department of Cabañas houses part of the Tertiary volcanism of El Salvador in that region, and therefore has an abundance of minerals. The mining activity that developed since the end of the 19th century, made this area appear as one of the most favorable for the exploitation of gold and silver in El Salvador. However, this mining prosperity could have led to the metallic contamination of a good part of the Titihuapa river basin. The methodology used included taking sediment samples at sites located at the confluence points of the tributary rivers to the Titihuapa sub-basin, which were protected and transported to the laboratory for their respective analysis using atomic absorption techniques, graphite furnace method. and flame generator method. The Slight Effects Level (NEL) of the Guide for the Evaluation of Sediments, of the Department of Environmental Protection of New Jersey, 1998 was used as a parameter. The concentrations of Hg, Cd and Pb are below the values of the NEL. As concentrations, most of them exceed the NEL which is 6.0 µg / g.La subcuenca del río Titihuapa en el departamento de Cabañas alberga parte del vulcanismo Terciario de El Salvador en esa región, y por ende posee una abundancia de minerales. La actividad minera que se desarrolló desde finales del siglo XIX, hizo figurar a esta zona como una de las más propicias para la explotación de oro y plata en El Salvador. Sin embargo, esta prosperidad minera, pudo haber propiciado la contaminación metálica de buena parte de la cuenca del río Titihuapa. La metodología empleada incluyó la toma de muestras de sedimentos en sitios ubicados en los puntos de confluencia de los ríos tributarios a la subcuenca Titihuapa, las cuales fueron resguardadas y transportadas al laboratorio para su respectivo análisis mediante técnicas de absorción atómica, método de horno de grafito y método de generador de flama. Se usó como parámetro el Nivel de Efectos Leves (NEL) de la Guía Para la Evaluación de Sedimentos, del departamento de Protección Ambiental de New Jersey, 1998. Las concentraciones de Hg, Cd y Pb están por debajo de los valores de la NEL. Las concentraciones de As, la mayoría sobrepasa el NEL que es de 6.0 μg/g

Effects of lng Mutations on LngA Expression, Processing, and CS21 Assembly in Enterotoxigenic Escherichia coli E9034A

Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity in children under 5 years of age in low- and middle-income countries and a leading cause of traveler's diarrhea worldwide. The ability of ETEC to colonize the intestinal epithelium is mediated by fimbrial adhesins, such as CS21 (Longus). This adhesin is a type IVb pilus involved in adherence to intestinal cells in vitro and bacterial self-aggregation. Fourteen open reading frames have been proposed to be involved in CS21 assembly, hitherto only the lngA and lngB genes, coding for the major (LngA) and minor (LngB) structural subunit, have been characterized. In this study, we investigated the role of the LngA, LngB, LngC, LngD, LngH, and LngP proteins in the assembly of CS21 in ETEC strain E9034A. The deletion of the lngA, lngB, lngC, lngD, lngH, or lngP genes, abolished CS21 assembly in ETEC strain E9034A and adherence to HT-29 cells was reduced 90%, compared to wild-type strain. Subcellular localization prediction of CS21 proteins was similar to other well-known type IV pili homologues. We showed that LngP is the prepilin peptidase of LngA, and that ETEC strain E9034A has another peptidase capable of processing LngA, although with less efficiency. Additionally, we present immuno-electron microscopy imagens to show that the LngB protein could be localized at the tip of CS21, and probably helps to control CS21 length. In conclusion, our results demonstrate that the LngA, LngB, LngC, LngD, LngH, and LngP proteins are essential for CS21 assembly, as well as for bacterial aggregation and adherence to HT-29 cells