Papel de las isoformas del factor de transcripción tcfl5 en procesos tumorales de cáncer de colon, pluripotencia y desarrollo

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 25-07-2019Esta tesis tiene embargado el acceso al texto completo hasta el 25-01-2021Los factores de transcripción son proteínas clave en el control de la expresión génica y tienen un papel importante en diversos procesos celulares. La desregulación de estas proteínas está asociado a numerosos procesos patológicos entre los que se encuentra el cáncer. El cáncer es la principal causa de muerte en países desarrollados, siendo el de colon el segundo en incidencia y mortalidad. Este tipo de cáncer es resultado de la alta proliferación de las células epiteliales de la mucosa del colon y sus glándulas, considerandose uno de los más peligrosos por su alta capacidad metastásica y la adquisición de quimioresistencia. Transcription Factor Like 5 (TCFL5) es un factor de transcripción poco estudiado implicado principalmente en espermatogénesis, sistema inmune y cáncer. Se ha descrito la presencia de dos isoformas: TCFL5 y CHA. Sin embargo, pocos estudios discriminan entre estas. En este trabajo hemos descrito que TCFL5 es un gen con múltiples isoformas tanto en humanos como en ratón. Nuestros resultados muestran la importancia de la expresión de estas isoformas en cáncer de colon, ya que la deleción completa de las isoformas reduce drásticamente las propiedades tumorales de las células, principalmente de la formación de MCTS y del crecimiento tumoral in vivo. TCFL5 y CHA presentaron una regulación recíproca y su sobreexpresión específica mostró funciones diferentes en la célula ejerciendo CHA un papel más protumoral que TCFL5. Además, la expresión TCFL5/CHA es fundamental para la actividad NFKB2 regulando la expresión de genes antiapoptóticos como BCL2. TCFL5/CHA controla también la expresión de los marcadores de pluripotencia SOX2, NANOG y KLF4. Por último, TCFL5 se encuentra expresado en el desarrollo embrionario temprano de ratón durante el periodo de preimplantación y juega un papel en la diferenciación de células embrionarias a precursores de la línea germinal reprimiendo la expresión de genes de pluripotencia y controlando la de genes importantes en la diferenciación. En conjunto, este trabajo pone de manifiesto la importancia de TCFL5 en el desarrollo de cáncer de colon y procesos de pluripotencia y diferenciación. Además, plantea un complejo modelo de regulación de su expresión donde el ratio de expresión determina el fenotipo final de la célula.Transcription factors are key proteins in the gene expression control. They have an important role in several cellular processes and their dysregulation is associated to many pathological processes such as cancer. Cancer is the first cause of death in developed countries and specifically colorectal cancer has the second highest incidence and mortality. This cancer is a consequence of increased proliferation of epithelium and its glands. Because of its metastatic and chemoresistance capacity it is one of the most dangerous cancer. Transcription Factor Like 5 (TCFL5) is a poorly studied transcription factor implicated in spermatogenesis, immune system and cancer. Two isoforms for this gene have been found: TCFL5 and CHA. However, few studies discriminated them. In this work we have described multiple isoforms for TCFL5 in humans and mice. Our results showed the relevance of these isoforms expression in colorectal cancer. Complete deletion of the isoforms drastically decreased cell tumoral properties, mainly the in vivo tumoral growth and multicellular tumor spheroids (MCTS) formation. TCFL5 and CHA showed a reciprocal regulation and its specific overexpression presented different functions: CHA had more pro-tumoral effects than TCFL5. Moreover, TCFL5/CHA over-expression was important for the NFKB2 activity regulating anti-apoptotic genes as BCL2. These isoforms also controlled pluripotency markers expression such as SOX2, NANOG and KLF4. Finally, TCFL5 was expressed in mouse early embryonic development during preimplantation stages. It also had a role in the embryonic stem cells differentiation to primordial germinal cells repressing the pluripotency genes expression and controlling differentiation genes. Colectively, TCFL5 is an important gene in the colorectal cancer development, pluripotency and differentiation processes. In addition, this work shows a complex regulation model where the ratio of expression determines the cellular phenotype.Este trabajo ha sido financiado por la ayuda a Proyecto de Investigación “Prostanoides y Receptores Tipo Toll como Mediadores Clave y Potenciales Dianas Terapéuticas Enfermedades Inflamatorias Crónicas” (SAF2013-42850-R) otorgado por el Ministerio de Economía y Competitividad

Wind powered water pump

Diseñar una pequeña y simple turbina eólica para bombear agua en un país en vías de desarrollo. Tiene que ser transportable y capaz de tomar agua de un pozo de 10 metros de profundidad hasta un tanque de 2 metros de altura (unos 12 metros en total)

Sintonía fina de la política monetaria mexicana entre objetivos e instrumentos durante la crisis 2007-2009

This paper carries out an exploration of how the Mexican Bank Central conducted its monetary policy during the crisis 2007-2009 based on the analytical framework of the neoclassical macroeconomics. It is shown that in that period it was followed a countercyclical policy to reduce the crisis adverse effect on economic activity. To accomplish the above, Central Bank used a fine-tuning strategy between objectives and instruments. We estimate a Structural Vector Autoregressions model (SVAR), which allows us to show empirical evidence that Mexican monetary authority reacted in the short term with a countercyclical policy to stimulate economic activity through of a monetary expansion accompanied by a slow reaction of the general price level; while in the long term the dynamics of the general price level increased the interest rate due to an augment in agents’ inflation expectations, thereby the economic activity was negatively affected

Sintonía fina de la política monetaria mexicana entre objetivos e instrumentos durante la crisis 2007-2009

This paper carries out an exploration of how the Mexican Bank Central conducted its monetary policy during the crisis 2007-2009 based on the analytical framework of the neoclassical macroeconomics. It is shown that in that period it was followed a countercyclical policy to reduce the crisis adverse effect on economic activity. To accomplish the above, Central Bank used a fine-tuning strategy between objectives and instruments. We estimate a Structural Vector Autoregressions model (SVAR), which allows us to show empirical evidence that Mexican monetary authority reacted in the short term with a countercyclical policy to stimulate economic activity through of a monetary expansion accompanied by a slow reaction of the general price level; while in the long term the dynamics of the general price level increased the interest rate due to an augment in agents’ inflation expectations, thereby the economic activity was negatively affected

Phytotherapy in pregnancy and lactation: benefit or risk? Review of the literature

INTRODUCCIÓN: Durante el embarazo el organismo de la mujer sufre cambios temporales con aparición de estructuras orgánicas nuevas como la placenta. Cualquier sustancia, natural o sintética, que pueda producir una alteración de los procesos fisiológicos propios de esta etapa están contraindicados. OBJETIVO: Dar a conocer los productos de origen vegetal utilizados habitualmente en el embarazo y la lactancia y evaluar su eficacia y seguridad. MATERIAL Y MÉTODOS: Revisión integradora de la literatura en las bases de datos Cochrane Library, Cinahl, Medline, Cuiden, Cuidatge, Bireme, Enfispo y buscadores de la red. Tras la lectura de los artículos, se realizó una valoración crítica, síntesis e interpretación para llegar a conclusiones de todos los estudios seleccionados. RESULTADOS: El uso de plantas medicinales en el embarazo es habitual, encontrándose el jengibre y la equinácea entre las más utilizadas. En cuanto a la etapa del embarazo de mayor consumo, se identifica el primer trimestre. El mayor porcentaje de las gestantes utiliza las plantas sin indicación médica. En cuanto a la eficacia: la equinácea es eficaz para el resfriado común e infecciones vaginales, el arándano rojo para la infección urinaria, la raíz de jengibre y la ipecacuana tienen acción antiemética, la hierba de San Juan es eficaz en la depresión postparto, la valeriana para combatir el nerviosismo y el aceite de onagra para inducir el parto. El nivel de seguridad varía según la planta por lo que se recomienda un control por parte del profesional sanitario. DISCUSIÓN Y CONCLUSIONES: De forma general las mujeres no están educadas en cuanto a la influencia que ejerce el estilo de vida en las primeras células embrionarias. El uso de productos fitoterápicos puede ser eficaz para ayudar a solucionar muchos de los problemas del embarazo pero es necesario ver la relación riesgo-efectividad. Por eso, antes, durante y después del embarazo o lactancia materna las mujeres que desean tomar preparados herbarios, deben consultar con su matrona u otro profesional sanitario bien informado al respecto, porque muchos de los efectos de las plantas sobre los fetos y la leche materna son desconocidos.INTRODUCTION: During pregnancy, women´s body suffers from temporary changes with new organic structures such as placenta. Any subtance, natural or sintetic which may alter physiological proceses on this own state are contraindicated. OBJECTIVE: Dara know the plant products commonly used in pregnancy and lactation and assess their effectiveness and safety. MATERIAL AND METHODS: Integrative review of literature in the databases Cochrane Library, CINAHL, Medline, Cuiden, Cuidatge, Medicine , ENFISPO and Web searches. After reading the articles, critical appraisal, synthesis and interpretation was performed to reach conclusions of all selected studies. RESULTS: The use of medicinal plants during pregnancy is frequent, being ginger and echinace some of the most used ones. Regarding the stage of pregnancy with higher consumption, it is the first term. The highest percentage of pregnant women use plants without any medical advices. As for effectiveness: Echinacea is effective for the common cold and vaginal infections, cranberry for urinary infection, ginger root and ipecac have antiemetic action, St. John's wort is effective in postpartum depression, valerian to combat nervousness and evening primrose oil to induce labor. The security level varies depending on the plant so a control by the health care professional is recommended. DISCUSION AND CONCLUSIONS: Generally, women are not aware of the influence of their life style on the first embryonic cells. The use of herbal products can be effective in helping to solve many of the problems of pregnancy but you need to see the risk-effectiveness. Because of that, previously, during an after pregnancy or breastfeeding, those women who want to take herbalist products, should first consult a midwife or another medical professional who is well-informed about it, because many of the effect of plants on fetus and breastmilk are still unknown

Hypermethylated 14-3-3-σ and ESR1 gene promoters in serum as candidate biomarkers for the diagnosis and treatment efficacy of breast cancer metastasis

9 páginas, 5 figuras, 2 tablas.-- et al.[Methods]: We studied two cohorts of patients: 77 patients treated for breast cancer with no signs of disease, and 34 patients with metastatic breast cancer. DNA was obtained from serum samples, and promoter methylation status was determined by using DNA bisulfite modification and quantitative methylation-specific PCR. [Results]: Serum levels of methylated gene promoter 14-3-3-σ significantly differed between Control and Metastatic Breast Cancer groups (P < 0.001), and between Disease-Free and Metastatic Breast Cancer groups (P < 0.001). The ratio of the 14-3-3-σ level before the first chemotherapy cycle to the level just before administration of the second chemotherapy cycle was defined as the Biomarker Response Ratio [BRR]. We calculated BRR values for the "continuous decline" and "rise-and-fall" groups. Subsequent ROC analysis showed a sensitivity of 75% (95% CI: 47.6 - 86.7) and a specificity of 66.7% (95% CI: 41.0 - 86.7) to discriminate between the groups for a cut-off level of BRR = 2.39. The area under the ROC curve (Z = 0.804 ± 0.074) indicates that this test is a good approach to post-treatment prognosis. [Conclusions]: The relationship of 14-3-3-σ with breast cancer metastasis and progression found in this study suggests a possible application of 14-3-3-σ as a biomarker to screen for metastasis and to follow up patients treated for metastatic breast cancer, monitoring their disease status and treatment response.This study was supported by a grant from the Ministerio de Ciencia e Innovación: SAF 2004-00889; JL Linares is supported by the Junta de Andalucía (P06-CTS-1385).Peer reviewe

Weather Projections and Dynamical Downscaling for the Republic of Panama: Evaluation of Implementation Methods via GPGPU Acceleration

Climate change could have a critical impact on the Republic of Panama where a major segment of the economy is dependent on the operation of the Panama Canal. New capabilities to do targeted research around climate change impacts on Panama is therefore being established. This includes anew GPU-cluster infrastructure called Iberogun, based around 2 DGX1 servers (each running 16 NVIDIA Tesla P100 GPUs). This infrastructure will be used to evaluate potential climate models and models of extreme weather events. In this review we therefore present an evaluation of the GPGPU (General Purpose Graphic Processing Unit, here abbreviated GPU) implementation methods for the study of weather projections and dynamical downscaling in the Republic of Panama. Different methods are discussed, including: domain-specific languages (DSLs), directive-based porting methods, granularity optimization methods, and memory layout transforming methods. One of these approaches that has yielded interesting previous results is further discussed, a directive-based code transformation method called ‘Hybrid Fortran’ that permits a high-performance GPU port for arranged lattice Fortran codes. Finally, we suggest a method akin to previous investigations related to climate change done for the Republic of Panama, but with acceleration via GPU capabilities.We acknowledge a scientific fund from Sistema Nacional de Investigación de Panamá (SNI) and Projects: FID- 2016-275 and EIE-2018-16 of Convocatorias públicas of Secretaria Nacional de Ciencia y Tecnología e Innovación (SENACYT). We acknowledge funds and support from JSPS Grant-in-Aid for Specially Promoted Research 16H06291. We acknowledge Theme C of the TOUGOU program granted by the Japanese Ministry of Education, Culture, Sports, Science and Technology. The authors thank the Universidad Tecnológica de Panamá their extensive support, and for the use of their CIHH-group HPC-Cluster-Iberogun. Also acknowledge to NVIDIA Corporation with the donation of the Titan Xp GPU used for this research

Inactivation of the waterborne marine pathogen Vibrio alginolyticus by photo-chemical processes driven by UV-A, UV-B, or UV-C LED combined with H2O2 or HSO5.

Ultraviolet (UV) radiation is a well-implemented process for water disinfection. The development of emergent UV sources, such as light-emitting diodes (LEDs), has afforded new possibilities for advanced oxidation processes. The emission wavelength is considered to be an important factor for photo-chemical processes in terms of both biological damage and energetic efficiency, as the inactivation mechanisms and mode-of-action may differ according to the wavelength that is applied. In addition, these processes merit exploration for inactivating emerging pathogens, such as marine vibrios, that are important bacteria to control in maritime activities. The main goal of this study was to compare the disinfection efficacy of several UV-LED driven processes with different modes of action. First, the effect of UV-LEDs was assessed at different UV ranges (UV-A, UV-B, or UV-C). Second, the possible enhancement of a combination with hydrogen peroxide (H2O2) or peroxymonosulfate salt (HSO5-) was investigated under two different application strategies, i.e. simultaneous or sequential. The results obtained indicate a high sensitivity of Vibrio alginolyticus to UV radiation, especially under UV-B (kobs=0.24cm2/mJ) and UV-C (kobs=1.47cm2/mJ) irradiation. The highest inactivation rate constants were obtained for UV/HSO5- (kobs (cm2/mJ)=0.0007 (UV-A); 0.39 (UV-B); 1.79 (UV-C)) with respect to UV/H2O2 (kobs (cm2/mJ)=0.0006 (UV-A); 0.26 (UV-B); and 1.54 (UV-C)) processes, however, regrowth was avoided only with UV/H2O2. Additionally, the disinfection enhancement caused by a chemical addition was more evident in the order UV-A>UV-B>UV-C. By applying H2O2 (10mg/L) or HSO5- (2.5mg/L) in a sequential mode before the UV, negligible effects were obtained in comparison with the simultaneous application. Finally, promising electrical energy per order (EEO) values were obtained as follows: UV/HSO5- (EEO (kWh/m3)=1.68 (UV-A); 0.20 (UV-B); 0.04 (UV-C)) and UV/H2O2 (EEO (kWh/m3)=2.15 (UV-A); 0.32 (UV-B); 0.04 (UV-C)), demonstrating the potential of UV-LEDs for disinfection in particular activities such as the aquaculture industry or maritime transport

TCFL5 deficiency impairs the pachytene to diplotene transition during spermatogenesis in the mouse

Spermatogenesis is a complex, multistep process during which spermatogonia give rise to spermatozoa. Transcription Factor Like 5 (TCFL5) is a transcription factor that has been described expressed during spermatogenesis. In order to decipher the role of TCFL5 during in vivo spermatogenesis, we generated two mouse models. Ubiquitous removal of TCFL5 generated by breeding TCFL5fl/fl with SOX2-Cre mice resulted in sterile males being unable to produce spermatozoa due to a dramatic alteration of the testis architecture presenting meiosis arrest and lack of spermatids. SYCP3, SYCP1 and H1T expression analysis showed that TCFL5 deficiency causes alterations during pachytene/diplotene transition resulting in a meiotic arrest in a diplotene-like stage. Even more, TCFL5 deficient pachytene showed alterations in the number of MLH1 foci and the condensation of the sexual body. In addition, tamoxifen-inducible TCFL5 knockout mice showed, besides meiosis phenotype, alterations in the spermatids elongation process resulting in aberrant spermatids. Furthermore, TCFL5 deficiency increased spermatogonia maintenance genes (Dalz, Sox2, and Dmrt1) but also increased meiosis genes (Syce1, Stag3, and Morc2a) suggesting that the synaptonemal complex forms well, but cannot separate and meiosis does not proceed. TCFL5 is able to bind to the promoter of Syce1, Stag3, Dmrt1, and Syce1 suggesting a direct control of their expression. In conclusion, TCFL5 plays an essential role in spermatogenesis progression being indispensable for meiosis resolution and spermatids maturatio

Aligned copper nanowires as a cut-and-paste exclusive electrochemical transducer for free-enzyme highly selective quantification of intracellular hydrogen peroxide in cisplatin-treated cells

The role and reliable quantification of intracellular hydrogen peroxide during cancer therapy constitutes an unexplored and fascinating application. In this work, we report the fabrication of vertically aligned copper nanowires (v-CuNWs) using electrosynthesis on templates, and their application as a cut-and-paste exclusive and flexible electrochemical transducer. This easily adaptable electrodic platform is demonstrated for a fast, simple and free-enzyme selective quantification of intracellular hydrogen peroxide in Cisplatin-treated human renal HK-2 cells. The v-CuNWs sensor was compared with an HRP-enzyme-based biosensor showing excellent correlation and indicates the good selectivity and analytical performance of the v-CuNWs. This sensing approach opens novel avenues for monitoring cell death processes and shows the potential of H2O2 as a cellular damage biomarker, with a clear potency for further developments for in vitro diagnosis and its implication in cancer therapy.Comunidad de MadridMinisterio de Economía y CompetitividadMinisterio de Ciencia e Innovació