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Sperm hyperactivation is described as a fast whip movement of the flagellum, an irregular trajectory, and an asymmetrically flagellum bend. This motility pattern is achieved during the passage of the sperm along the female genital tract. It helps the spermatozoa to cross through different viscous ambient fluids to finally reach the oocyte. Important signaling proteins are located in the sperm head and flagellum, and they all play an important role in the cascade that controls the sperm hyperactivation. The presence of HCO

Introduction Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. Materials and methods We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Results Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Conclusion Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.

Background: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with first presentation of symptoms, followed by a later ‘inflammatory’ phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease.Methods: Trial design: Phase IIA randomised, double-blind, 2 x 2 design, placebo-controlled, interventional trial.Randomisation: Participants will be randomised 1:1 by stratification, with the following factors: age (≤ 55 vs > 55 years old), gender, obesity (BMI Discussion: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus (‘viral load’) in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early diseaseTrial registration: Register at Clinical Trials: NCT04918927 dated June 9th, 2021.

The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease.Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial.Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated.Participants and investigators will both be blinded to treatment allocation (double-blind).We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease.ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Objetivo: Evaluar la calidad de vida laboral de las enfermeras egresadas de la Universidad nacional san Luis Gonzaga de Ica, y conocer el predicamento del empleador respecto al desempeno profesional. Material y metodos: Estudio no experimental, exploratorio- descriptivo, transversal. La muestra fue de 86 enfermeras de los Hospitales del MINSA y ESSALUD del departamento de Ica, que se encontraban laborando en los diversos servicios, durante los meses de octubre a diciembre de 2013. Se utilizo el cuestionario CVP-35 con 35 items, para evaluar la calidad de vida laboral, y una ficha con 10 preguntas para analizar el predicamento del empleador. Resultados: La calidad de vida laboral de las enfermeras egresadas es en promedio 5,79, para una escala maxima de 10, y que representa 47,7% regular, 44,2% buena, y 8,1% muy buena calidad de vida laboral. En forma global, el predicamento del empleador, respecto al desempeno de las enfermeras egresadas de la facultad de enfermeria, es de valoracion muy buena (2,46). Conclusiones: La calidad de vida laboral de las enfermeras es regular y el predicamento del empleador es muy buena. Palabras clave: Calidad de vida

Objetivo General: Determinar la historia de la formación de los profesionales en enfermería: en el aspecto académico–socio-político de la facultad de enfermería. Universidad Nacional San Luis Gonzaga de Ica. Perú 1981-2012. Material y métodos: Investigación aplicada descriptiva de corte transversal, con un paradigma cuali-cuantitativo, la población y muestra fueron docentes y egresados de la Facultad. Resultados: La Facultad en sus 25 años de formación Académica en el aspecto demanda para la Entrada: El ingreso/captación de alumnos: Existe Alta demanda de ingreso 2009-I: (ratio: 11,53), 2009-II (8,6%). Para el proceso: Cuenta con 58 docentes; 09 con grado de Doctor, 21 con grado de magister. El promedio de alumnos por asignatura (2009- II, 2010-I, 2010- II y 2011-I) fue 45 por aula. La relación Alumnos/docentes fue 9,34 (2010-II). El promedio de estudiante/profesor en prácticas clínica (2010-I y 2010-II) 5,5. El promedio ponderado fue 15,02, (±1,17). El currículo establecido a inicios del desempeño académico en el año 1981-1999 fue de tipo tradicional. El año 2000-2001 el currículo de la Comisión Reorganizadora (CORE). Desde el año 2002 hasta la actualidad se viene desarrollando el currículo del tipo constructivista. La modalidad de titulación en los últimos años es por sustentación de tesis. En el aspecto social: El promedio de edad de los alumnos fue 21 años (±3,38). El 84,6% proceden del departamento de Ica, 5,4% de Lima, 4,8% de Ayacucho y 2,3% de Huancavelica. El 90% son de sexo femenino, 76% estudiaron en institución educativa estatal. En el aspecto político, impera un órgano de gobierno tipo Consejo de Facultad. Conclusiones: Existen diferencias relevantes entre las preferencias de los diferentes tipos de modalidades de titulación, con un declive en la preferencia respecto a la suficiencia académica, actualización académica y proyecto de inversión, se observa además una estable preferencia por la complementación académica y un notable ascenso en la titulación por modalidad de tesis. En los últimos años son el 100% la obtención de título universitario.

En este artículo se presenta el diseño de una maquina mezcladora de 1000 kg automatizada para el proceso de producción del alimento balanceado Engorde Hermelinda en la empresa Nutriaves SAC con el fin de mejorar la productividad de la maquinaria en su fase de mezclado y la calidad de los productos producidos. La investigación es de carácter no experimental y la metodología aplicada es cuantitativa. Para su elaboración, se utilizaron las fórmulas de volumen del cilindro y del tronco de cono que permitieron el cálculo de las dimensiones de su estructura, a su vez, se realizaron conversiones de unidades para obtener los tiempos de vaciado de cada uno de los ingredientes transportados mediante el sistema de tuberías que llenan al equipo. Asimismo, el circuito eléctrico con PLC S7-1212 y su programación se desarrolló con el programa CADE SIMU que también permitió comprobar el cumplimiento de todos los procedimientos que se desea que haga mediante su simulación. Finalmente, se concluyó que la productividad mejoro en un 50%, ya que aumento de 6.19 tn/h a 12.37 tn/h y, del mismo modo, se optimizo con la calidad debido a la consistencia y precisión de la automatización implementada que elimina por completo el error humano.

Tryptophan hydroxylase-type 2 (Tph2) is the first rate-limiting step in the biosynthesis of serotonin (5-HT) in the brain. The ophthalmic administration (Op-Ad) is a non-invasive method that allows delivering genetic vehicles through the eye and reaches the brain. Here, the murine Tph2 gene was cloned in a non-viral vector (pIRES-hrGFP-1a), generating pIRES-hrGFP-1a-Tph2, plus the FLAG-tag. Recombinant Tph2-FLAG was detected and tested in vitro and in vivo, where 25 μg of pIRES-hrGFP-1a-Tph2-FLAG was Op-Ad to mice. The construct was capable of expressing and producing the recombinant Tph2-FLAG in vitro and in vivo. The in vivo assays showed that the construct efficiently crossed the Hemato-Ocular Barrier and the Blood–Brain Barrier, reached brain cells, passed the optical nerves, and transcribed mRNA-Tph2-FLAG in different brain areas. The recombinant Tph2-FLAG was observed in amygdala and brainstem, mainly in raphe dorsal and medial. Relative Tph2 expression of threefold over basal level was recorded three days after Op-Ad. These results demonstrated that pIRES-hrGFP-Tph2-FLAG, administrated through the eyes was capable of reaching the brain, transcribing, and translating Tph2. In conclusion, this study showed the feasibility of delivering therapeutic genes, such as the Tph2, the first enzyme, rate-limiting step in the 5-HT biosynthesis.

En la presente investigación se ha diseñado y llevado a cabo un prototipo que cumple la función de elaborar los siguientes cocteles: margarita y piña colada con el controlador LOGO! para la discoteca 360° ubicada en la ciudad de Managua-Nicaragua. Para elaborar el proyecto se realizó una investigación descriptiva con enfoque mixto, el cual permite obtener resultados cualitativos y cuantitativos acerca de la problemática que se presenta en el establecimiento, esto permitió llevar a cabo un diagnóstico en el cual se confirmó que existe la necesidad de reducir el tiempo de la mezcla de los cocteles, para beneficiar al bartender y evitar que exista una perdida innecesaria de la materia prima. Para contrarrestar la problemática y aportar una ayuda al avance tecnológico en este tipo de áreas (discotecas o bares) se diseñó un sistema semiautomático, con la capacidad de realizar mezclas de bebidas en un menor tiempo y sin desperdiciar la materia prima, beneficiando así al local en términos generales, es decir para los trabajadores y clientela, particularmente al bartender. Así mismo se creó el prototipo para demostrar la funcionalidad del sistema, el cual posee características propias en la forma de preparación de los cocteles, es un gran beneficio para la Discoteca 360° y otros lugares que brinden el servicio de coctelería, esto debido a que en Nicaragua no se ha implementado este tipo de tecnología para dichos locales

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects, therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 &plusmn, 9.9 &mu, M) and trypomastigote (IC50 = 166.21 &plusmn, 14.5 &mu, M and 185.1 &plusmn, 8.5 &mu, M on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

Breast cancer is the second cause of cancer death in women and the large majority of those deaths are due to drug resistance and/or recurrence. The cancer stem cell (CSC) model suggests that tumor stem-like cells play key roles in resistance and recurrence in breast cancer patients. Thus, CSCs have been pointed as targets for new anti-cancer therapies. CD49f is an integrin subunit that participates in the CSC-niche interaction. Knock-down of CD49f in breast cancer cells impairs mammosphere formation in vitro and tumorigenesis in vivo, suggesting that this protein is needed for maintenance of stemness. Aiming to target breast CSC, we used consensus docking to select potential CD49f antagonists from a collection of 13,000+ drugs with previous clinical evaluations. Seven compounds with the lowest consensus Z score were selected for in vitro biological validation. Cell adhesion assays showed that four of the selected drugs (5193, 1382, 7631, and 12723) decrease the binding of CD49f+ MDA-MB-231 breast cancer cells to laminin, suggesting that those compounds antagonize the receptor. Mammosphere formation assays showed that compounds 5193, 1382, and 12723 limit the clonogenic capability of CD49f+ breast cancer cells in vitro. Compound 5193 was highly toxic in 2D cell viability assays. On the other hand, the clonogenic impairment produced by compounds 1382 and 12723 is independent of bulk cell line cytotoxicity, suggesting a direct impact on the CSC pool. The analyses of the effect of these drugs on the expression of breast CSC markers and CD49f-activated pathways are on their way. Thus, we have identified some drugs that might be repurposed to target breast CSC. Since the pharmacokinetics and toxicology of those drugs is known, they could easily be ready for clinical trials. We demonstrated that in silico screening is useful to identify antagonists of receptors with relevant roles in breast CSC biology. This work was supported by CONACYT 221105, PAPIIT-UNAM IN228616, and Red temática de células troncales y medicina regenerativa. Citation Format: Velasco-Velázquez M, Velázquez-Quesada I, Aguirre-Alvarado C, Guerrero-Rodríguez S, Ruiz-Moreno A, Ramirez-Salinas G, Segura-Cabrera A, Pérez-Tapia M. Selection of presumed CD49f antagonists and their biological evaluation in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-09.

Polyamines are ubiquitous polycationic compounds that are highly charged at physiological pH. While passing through the epididymis, sperm lose their capacity to synthesize the polyamines and, upon ejaculation, again come into contact with the polyamines contained in the seminal fluid, unleashing physiological events that improve sperm motility and capacitation. In the present work, we hypothesize about the influence of polyamines, namely, spermine, spermidine, and putrescine, on the activity of sperm channels, evaluating the intracellular concentrations of chloride [Cl&minus, ]i, calcium [Ca2+]i, sodium [Na+]i, potassium [K+]i, the membrane Vm, and pHi. The aim of this is to identify the possible regulatory mechanisms mediated by the polyamines on sperm-specific channels under capacitation and non-capacitation conditions. The results showed that the presence of polyamines did not directly influence the activity of calcium and chloride channels. However, the results suggested an interaction of polyamines with sodium and potassium channels, which may contribute to the membrane Vm during capacitation. In addition, alkalization of the pHi revealed the possible activation of sperm-specific Na+/H+ exchangers (NHEs) by the increased levels of cyclic AMP (cAMP), which were produced by soluble adenylate cyclase (sAC) and interact with the polyamines, evidence that is supported by in silico analysis.

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 μM) and trypomastigote (IC50 = 166.21 ± 14.5 μM and 185.1 ± 8.5 μM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs.

Materia: Derecho Civil (Familia) Nº de Expediente: N° 00096-2009. Materia: Derecho Penal Nº de Expediente: N° 1743-2005 El expediente versa sobre la denuncia interpuesta por A. A. A., en contra de B. B. B. B. por la supuesta violación sexual a su menor hija, la menor de 13 años de edad de iniciales C. C. C.

CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24− cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists.

The present study evaluates the possible antifertility effect of aqueous crude extract (OBACE) of Echeveria gibbiflora, a plant that belongs to the crassulaceae family, used in traditional Mexican medicine as a vaginal post coital rinse to prevent pregnancy and shown to have an immobilization/agglutination effect on sperm of different mammal species. We evaluated the effect of OBACE on functional parameters of mouse sperm, such as viability, capacitation, and acrosome reaction. In addition, due to the high concentrations of calcium bis-(hydrogen-1-malate) hexahydrate [Ca (C4H5O5)2•6H2O] present in this plant extract, we evaluated its effect on Ca(2+) influx in mouse sperm under capacitating conditions. Moreover, we determined the acute toxicity of OBACE and its in vivo effect in mouse sperm motility administering a single daily dose of 50 and 100 mg/kg during seven days, intraperitoneally. The sperm viability was not affected by the presence of different concentrations of OBACE, however, the capacitation and acrosome reaction suffered a significant decrease in a concentration-dependent manner, coinciding with the reduction of Ca(2+) influx. Furthermore, OBACE displayed an LD50 of 3,784.42 mg/kg and can be classified as a low toxic substance. Also, in vivo OBACE showed an inhibition of total and progressive motility on mouse sperm alongside a significant decrease of motility kinematic parameters and IVF rates. The results confirm the antifertility effect of this plant used in Mexican folk medicine. Further study on OBACE as a possible contraceptive treatment is warranted because of its activity and low in vivo toxicity.ALH: lateral amplitude; AP: acid phosphatase; BCF: beat frequency; BSA: bovine serum albumine; CTC: chlortetracycline; FDA: fluorescein diacetate; Fura-2 AM: fura-2-acetoxymethyl ester; HIV: human immunodeficiency virus; IVF: in vitro fertilization; OBACE: aqueous crude extract of Echeveria gibbiflora; PI: propidum iodide; SN: supernatant; VAP: average path velocity; VCL: track speed; VSL: straight line velocity.