Telomere-driven diseases and telomere-targeting therapies

Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models.Research in the Blasco laboratory is funded by the Spanish Ministry of Economy and Competitiveness and Fondo Europeo de Desarrollo Regional project RET OS (grant SAF2013-45111-R), the European Research Council project TEL STEM CELL (grant ERC-2008-AdG/232854), and Fondacion Botin.S

La paz de la mano de los derechos humanos

Este proyecto fue realizado por los estudiantes Brayan Gutiérrez, Jhonatan Martínez y Paula Rodríguez de octavo semestre de la facultad de educación del programa Licenciatura en Lengua Castellana e Inglés, con la intención de orientar a los infantes sobre la relación existente entre El Tratado de Paz firmado con la antigua guerrilla de las FARC y los Derechos Humanos.Lo que se buscó principalmente con la elaboración de este proyecto de investigación fue que los niños pudieran entender de una manera lúdica y dinámica, qué era exactamente El Tratado de Paz. Se resumió lo mayor posible el documento y se plasmó la información a través de actividades y talleres donde se tuviera que relacionar el Tratado con los Derechos Humanos implícitos en él. Para llevar a cabo la orientación se escogió a niños de tercero primaria del Colegio Integrado Nuevo Mundo, debido a que ellos son el renacer y futuro de nuestra sociedad, además, los infantes aún están a tiempo de poder cambiar aquella Colombia violenta de los últimos años.Resumen. -- Marco Teórico. -- Metodología. -- Análisis de resultados. -- Conclusiones. -- Propuesta. -- Bibliografía. -

Efflorescence of alkali-activated cements (geopolymers) and the impacts on material structures : a critical analysis

Even with the rapid development of the alkali-activated cement (AAC) technology in the past few years, some phenomena still needs to be better understood, that may alter the durability of the material. In many industrial uses and laboratory researches the formation of the salts on the surface alkali-activated type cements was observed, which was identified as efflorescence. This occurs due to the presence of an alkali transported in contact with the humidity and CO2 environment. It may present externally from the formation of salts on the surface and internally with the carbonation of the alkalis in capillary pores. The effects of efflorescence on the material in use, as well as all factors that can influence its formation are not yet fully understood or reported. The search for papers was conducted using the search words efflorescence and geopolymer/alkali-activated, combined in the electronic data base. Due to the limited quantity of papers published related to efflorescence in geopolymers, the review was complemented using papers that discuss this behavior in Portland cement (PC) and based on the main properties that can influence the formation of efflorescence. In this paper, to understand the nature of efflorescence, upon which proper methods of minimizing of this issue can be based, the following aspects are discussed and re-examined: (1) the development of efflorescence’s in PC concrete, (2) the role of alkalis in AACs, (3) efflorescence in AACs, and (4) effect from a physical and microstructural point of view of efflorescence’s on the ACCs. This paper highlights that the nature of the pore structure and the design parameters (such as alkali concentration, presence of soluble silicates, and water content in the activator) are the two most important factors that control efflorescence rate and changes inmechanical behavior. However, the stability of the alkalis and their relationship with the formed gel, which are determining factors in the formation of efflorescence, remain not completely understood. In the same way, the effect of efflorescence in tensile strength and shrinkage needs to be evaluated

Efecto de los parámetros cinéticos de escalamiento del cultivo de Haematococcus pluvialis en fotobiorreactores para producir astaxantina

Haematococcus pluvialis is a microalga of biotechnological interest due to its ability to produce astaxanthin, a carotenoid that is used as a pigment and a bioactive compound. It has applications in the pharmaceutical, cosmetic, nutraceutical, food, and aquaculture industries. This carotenoid is obtained when the microalgae is subjected to stress conditions such as light intensity, light color, nutrient deficiency, and salinity, and involves the use of photobioreactors (PBR). For this reason, this article is intended to show the type of PBR that has been used in its scaling and the related kinetic parameters that influence the performance of the process. PBRs facilitate the adjustment and control of the cultivation conditions, both in the green phase and in the red phase. Likewise, the use of the kinetic scaling parameters allows evaluating the process, thus, establishing the conditions that must be adjusted, to improve the cultivation of the microalgae and obtaining astaxanthin. The kinetic scaling parameters reviewed were biomass (cel/mL), biomass productivity (g/Lday), specific growth rate (µ/day), doubling time (day), astaxanthin content (mg/g) and its productivity. Thus, the technological feasibility of photobioreactors for the scaling of microalgae to produce astaxanthin is demonstrated. The most commonly used PBRs are tubular and cylindrical because they have a greater illumination surface and efficiency in light distribution, and because they report higher astaxanthin productivity; its downside may be the costs for their cleaning.El Haematococcus pluvialis es una microalga de interés biotecnológico por su capacidad para producir astaxantina, un carotenoide que tiene uso como pigmento y compuesto bioactivo, con aplicación en la industria farmacéutica, cosmética, nutracéutica, alimenticia y la acuacultura. Este carotenoide se obtiene cuando la microalga es sometida a condiciones de estrés como intensidad de luz, color de luz, deficiencia de nutrientes y salinidad, e involucra el uso de fotobiorreactores (fbr). Por esto, este artículo busca conocer el tipo de fbr que se ha utilizado en su escalamiento y los parámetros cinéticos relacionados que influyen en el rendimiento del proceso. Los fbr facilitan el ajuste y control de las condiciones de cultivo, tanto en la fase verde como en la fase roja; de igual manera, el uso de los parámetros cinéticos de escalamiento permiten evaluar el proceso y así establecer las condiciones que deben ajustarse, para mejorar el cultivo de la microalga y la obtención de astaxantina. Los parámetros cinéticos de escalamiento revisados fueron la biomasa (cel./mL), la productividad de biomasa (g/Ldía), la velocidad específica de crecimiento (µ/día), el tiempo de duplicación (día), el contenido de astaxantina (mg/g) y su productividad. Se demuestra así la factibilidad tecnológica de los fotobiorreactores para el escalamiento de la microalga para producir astaxantina. Los fbr más usados son los de forma tubular y cilíndrica por tener una superficie mayor de iluminación y eficiencia en la distribución de la luz, y por reportar mayor productividad de astaxantina; su desventaja pueden ser los costos de limpieza

Leptin Inhibits Angiotensin II-Induced Intracellular Calcium Increase and Vasoconstriction in the Rat Aorta

Besides its role in body weight control leptin may also act as a vasoactive hormone. This study was designed to investigate whether leptin modifies angiotensin II (ANG II)-induced vascular responses. The expression of functional leptin receptors (OB-Rb) was detected in vascular smooth muscle cells (VSMCs) from adult Wistar rats by RT-PCR. Immunocytochemistry and Western blot analysis further showed the expression of OB-R protein in VSMCs. The ANG II (10(-7) mol/liter)-induced increase in intracellular Ca(2+) was blocked (P < 0.01) by leptin (10(-8) mol/liter). Moreover, in calcium-free buffer leptin was able to inhibit 65% of the ANG II-induced calcium release from intracellular stores. In endothelium-denuded aortic rings from adult Wistar rats no effect of leptin on basal tension was observed. However, the ANG II-induced isometric contraction was reduced (P < 0.05) by leptin (10(-8) mol/liter). The experiments were also performed in age- and sex-matched Zucker rats, in which no effect of leptin on ANG II-induced calcium increase and vasoconstriction was observed. It is concluded that leptin blocks the vasoconstrictor action of ANG II and inhibits the ANG II-induced increase in intracellular Ca(2+) in VSMCs through OB-Rb. These findings provide new insight into the physiological effects of leptin on blood pressure regulation

Modulation of telomere protection by the PI3K/AKT pathway

Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability. Patient-derived breast cancer PDX mouse models that effectively respond to a PI3Kα specific inhibitor, BYL719, show decreased TRF1 levels and increased DNA damage. These findings functionally connect two of the major pathways for cancer and aging, telomeres and the PI3K pathway, and pinpoint PI3K and AKT as novel targets for chemical modulation of telomere protection.We are indebted to D. Megias for microscopy analysis, to D. Calvo for protein purification as well as to J. Muñoz and F. García for LC/MS/MS analysis. The research was funded by project SAF2013-45111-R of Societal Changes Program of the Spanish Ministry of Economics and Competitiveness (MINECO) co-financed through the European Fund of Regional Development (FEDER), Fundación Botín, Banco Santander (Santander Universities Global Division) and Worldwide Cancer Research (WCR 16-1177).S

Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats

Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.We are indebted to D Megias for microscopy analysis, to J Mun˜ oz and F Garcı´a for hydroxiproline analysis as well as to CNIO Histopathological Unit. The research was funded by project SAF2013- 45111-R of Societal Changes Programme of the Spanish Ministry of Economics and Competitiveness (MINECO) co-financed through the European Fund of Regional Development (FEDER), Fundacio´n Botı´n and Banco Santander (Santander Universities Global Division) and Roche Extending the Innova- tion Network Program (EIN) Academia Partnering Programme.S

Influence of the use of accelerating admixture based on calcium nitrate in the performance of fly ash blended Portland cement mortars

A construção civil tende a exigir a otimização dos processos, com prazos de entrega reduzidos. Logo, tornase necessária a busca por alternativas que forneçam as propriedades necessárias ao concreto em períodos de tempo mais curtos. O objetivo deste trabalho é avaliar a influência de um aditivo acelerador de resistência baseado em nitrato de cálcio na resistência à compressão e em propriedades físicas de argamassas de cimento Portland, com diferentes teores de cinza volante (CV), visando analisar se a incorporação do aditivo compensaria a baixa contribuição desta adição nas resistências nas primeiras idades. Foram realizados ensaios de calorimetria isotérmica, absorção de água por capilaridade, índice de consistência e resistência à compressão em misturas com teores de aditivo de 0%, 0,33%, 0,66% e 1,00%. No que se refere ao tempo de pega final, nas amostras sem CV, o aditivo reduziu este período. Nas amostras com 40% e 60% de CV, verificou-se um aumento deste tempo. Para as resistências à compressão de 1 dia, o teor de aditivo que gerou os maiores valores foi de 1,00% para as argamassas com 0% e 40% CV, não existindo diferenças estatisticamente significativas para os sistemas com 60%. Já em idades superiores, o aditivo ocasionou reduções na resistência das amostras sem CV e aumentos proporcionais ao teor de aditivo nas amostras com 40% e 60% de CV. Constatou-se que as argamassas com aditivo e sem adição de CV apresentaram uma redução no índice de absorção por capilaridade. Já para as amostras com 40% e 60% de CV os menores índices de absorção foram obtidos nos traços sem aditivo. Portanto, é possível concluir que o aditivo avaliado nesta pesquisa acelerou as reações de hidratação, gerando um aumento nas resistências em idades iniciais, mas com um acréscimo insuficiente para compensar a queda de resistência pela incorporação de CV na composição das amostras. Levando em consideração as diferentes propriedades avaliadas, observou-se não ser possível estabelecer um teor ótimo de aditivo para cada teor de CV estabelecido. Sendo necessário avaliar qual propriedade é de maior interesse ao usuário.Civil construction tends to require the optimization of processes with reduced times. Therefore, it is necessary to search for alternatives that provide the required properties to the concrete, in shorter periods of time. The objective of this work is to evaluate the influence of a calcium nitrate based accelerator admixture on the properties of Portland cement mortars with different fly ash (FA) contents, in order to analyze the effect in the incorporation of the admixture, mainly if the accelerator is able to compensate the low strength contribution of the FA at early ages. Tests were carried out using isothermal calorimetry, water absorption by capillarity, consistency index and compressive strength in mixtures with admixture contents of 0%, 0,33%, 0,66% and 1,00%. Regarding setting time results, as excepted the admixture accelerated the final setting time. By the other hand, in the samples with 40% and 60% of FA, an increase of the final setting time was verified. For the 1-day compressive strengths, the admixture content that have generated the highest values was 1.00% for mortars with 0% and 40% FA. At higher ages, the admixtures led to reduce the compressive strength values of the samples without FA. On the other hand, in the samples with 40% and 60% of FA with the use of the accelerator higher compressive strength were identified. It was verified that the mortars with admixture and without addition of FA showed a reduction in the absorption index by capillarity. For the samples with 40% and 60% of FA, the lower absorption index was obtained in the samples without admixture. Therefore, it is possible to conclude that the admixture evaluated in this research accelerated the hydration reactions, generating an increase in the compressive strength at early ages, but with an insufficient increase to compensate the lower reactivity of the FA. Taking into account the different properties evaluated, it was not possible to establish an optimum admixture content for each FA content. It is necessary to evaluate which property is of greater interest to the user

Effect of gypsum on the early hydration of cubic and Na-doped orthorhombic tricalcium aluminate

The tricalcium aluminate (C3A) and sulfate content in cement influence the hydration chemistry, setting time and rheology of cement paste, mortar and concrete. Here, in situ experiments are performed to better understand the effect of gypsum on the early hydration of cubic (cub-)C3A and Na-doped orthorhombic (orth-)C3A. The isothermal calorimetry data show that the solid-phase assemblage produced by the hydration of C3A is greatly modified as a function of its crystal structure type and gypsum content, the latter of which induces non-linear changes in the heat release rate. These data are consistent with the in situ X-ray diffraction results, which show that a higher gypsum content accelerates the consumption of orth-C3A and the subsequent precipitation of ettringite, which is contrary to the cub-C3A system where gypsum retarded the hydration rate. These in situ results provide new insight into the relationship between the chemistry and early-age properties of cub- and orth-C3A hydration and corroborate the reported ex situ findings of these systems