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

Serovar distribution of a DNA sequence involved in the antigenic relationship between Leptospira and equine cornea

BACKGROUND: Horses infected with Leptospira present several clinical disorders, one of them being recurrent uveitis. A common endpoint of equine recurrent uveitis is blindness. Serovar pomona has often been incriminated, although others have also been reported. An antigenic relationship between this bacterium and equine cornea has been described in previous studies. A leptospiral DNA fragment that encodes cross-reacting epitopes was previously cloned and expressed in Escherichia coli. RESULTS: A region of that DNA fragment was subcloned and sequenced. Samples of leptospiral DNA from several sources were analysed by PCR with two primer pairs designed to amplify that region. Reference strains from serovars canicola, icterohaemorrhagiae, pomona, pyrogenes, wolffi, bataviae, sentot, hebdomadis and hardjo rendered products of the expected sizes with both pairs of primers. The specific DNA region was also amplified from isolates from Argentina belonging to serogroups Canicola and Pomona. Both L. biflexa serovar patoc and L. borgpetersenii serovar tarassovi rendered a negative result. CONCLUSIONS: The DNA sequence related to the antigen mimicry with equine cornea was not exclusively found in serovar pomona as it was also detected in several strains of Leptospira belonging to different serovars. The results obtained with L. biflexa serovar patoc strain Patoc I and L. borgpetersenii serovar tarassovi strain Perepelicin suggest that this sequence is not present in these strains, which belong to different genomospecies than those which gave positive results. This is an interesting finding since L. biflexa comprises nonpathogenic strains and serovar tarassovi has not been associated clinically with equine uveitis

Sorción de hidrolizados proteicos en lana tratada con bisulfito sódico: influencia en las propiedades químicas y físico-mecánicas.

La sorción de hidrolizados proteicos en fibras queratinicas provoca una mejora en las propiedades físicas y quimicas de fibras dañadas. En este trabajo se presentan los resultados de las modificaciones de estas propiedades en lana tratada con bisulfito sódico e hidrolizado proteico bien de colágeno o de queratina o de sus respectivos derivados anfifílicos cuaternizados y se comparan con las obtenidas para lana tratada sólo con bisulfito sódico.The sorption of protein hydrolisates in keratin fibres improves the physical and chemical propetties of damaged fibres. This paper describes the results of modifying these properties in wool treated with sodium bisulphite and protein hydrolisate, either of collagen or keratin or their respective amphiphilic quaternaty derivatives. The properties attained are compared to those of wool only treated with sodium bisulphite.La sorption d'hydrolysés sur les fibres kératiniques améliore les propriétés physiques et chimiques des fibres abimées. Ce travail présente les résultats des modifications de ces propriétés sur la laine traitée avec du bisulfite de sodium et d'hydrolisé protéique de collagene, de kératine ou de leurs dérivés quatemisés, comparés aux résultats obtenus sur de la laine traitée avec du bisulfite de sodium seulement.Peer Reviewe

Influencia de la sorción de hidrolizados proteicos cuaternizados en las propiedades químicas de lana oxidada.

La sorción de hidrolizados proteicos anfifílicos de amonio cuaternario en fibras de queratina produce cambios favorables en relación con las propiedades químicas y físicas de fibras queratínicas químicamente dafiadas aportando, además, nuevas cualidades. En este trabajo se presenta un estudio de la sorción de péptidos anfifílicos de amonio cuaternario en fibras de lana tratadas con peróxido de hidrógeno en medio alcalino y se discuten las modificaciones causadas en las propiedades químicas de dichas fibras, tales como solubilidad alcalina y solubilidad urea-bisulfito, y los posibles mecanismos implicados.The sorption of amphiphilic proteic hydrolyzates of quaternary ammonium in keratin fibres produces favourable changes in the chemical and physical fibres of chemically damaged keratin fibres providing new qualities. This paper presents a study about the sorption of amphiphilic peptides of quaternary ammonium in wool fibres treated with hydrogen peroxide in an alkaline medium; the modifications caused in the chemical properties of the fibres, such as alkali solubility and urea-bisulphite and the possible mechanisms involved are discussed.La sorption d'hydrolysés protéiques amphiphiles d'ammonium quaternaire sur des fibres de kératine produit des changements favorables par rapport aux propriétés chimiques et physiques de fibres kératiniques chimiquement affectées apportant en outre de nouvelles qualités. Dans ce travail, on presente une étude de la sortion de peptides amphiphiles d'ammonium quaternaire sur des fibres de laine traitées au peroxyde d'hydrogene en milieu alcalin et on y discute les modifications causées sur les propriétés chimiques desdites fibres, telles que la solubilité alcaline et la solubilité urée-bisulfite, et les possibles mécanismes impliqués.Peer Reviewe

MAKING TECHNOLOGIES WORK IN RURAL COMMUNITIES: THE CASE OF FLATBED DRYER APPROPRIATION IN STO. DOMINGO, NUEVA ECIJA, PHILIPPINES

This paper aimed to explain how rice farmers in Sto. Domingo, Nueva Ecija, Philippines managed to properly appropriate flatbed dryers. It also sought to describe the modes of appropriation offlatbed dryers: adoption, adaptation, and peer/group learning.  Data were gathered through a survey among 131 rice farmers and key informant interviews. Findings revealed that the rice farmers experimented and modified the features of flatbed dryers to better adapt the technology to their needs. The rice farmers have encountered problems in using the technology but have managed to employ adaptation strategies to address these problems which resulted to peer/group learning among them

Estudio del comportamiento friccional de hilos acrílicos y sus mezclas con lana y mohair

En este trabajo se presenta un estudio del comportamiento friccional de hilos acrílicos y de mezclas Acrílico/Lana y Acrílico/Mohair en función del número métrico de los hilos y de las condiciones de trabajo (material de rozamiento, ángulo de deslizamiento y velocidad de desplazamiento). Se describe también el comportamiento friccional de hilos con acrílico H.B. frente a acrílico en mezclas con lana.This work presents a study of the frictional behaviour of acrylic yarn and acrylic/wool and acrylic/mohair mixtures as a function of the metric number of the yarn and the working conditions (friction material, angle of slip and displacement velocity). The frictional behaviour of yarn with HB acrylic compared with acrylic yarn mixed with wool is also described.La présente étude s’intéresse au comportement frictionnel de fils acryliques et de mélanges Acryliques /Laine et Acryliques /Mohair en fonction du nombre métrique des fils et des conditions de travail (matériau de frottement, angle de glissement et vitesse de déplacement). S’y trouve également décrit le comportement frictionnel de fils avec de l’acrylique H.B. face à de l’acrylique mélangé avec de la laine

An Integrated Approach for Gear Health Prognostics

In this paper, an integrated approach for gear health prognostics using particle filters is presented. The presented method effectively addresses the issues in applying particle filters to gear health prognostics by integrating several new components into a particle filter: (1) data mining based techniques to effectively define the degradation state transition and measurement functions using a one-dimensional health index obtained by whitening transform; (2) an unbiased l-step ahead RUL estimator updated with measurement errors. The feasibility of the presented prognostics method is validated using data from a spiral bevel gear case study

Estudio de la sorción de hidrolizados proteicos en lana tratada con tioglicolato amónico. Parte 1: Influencia en las propiedades químicas.

La sorción de hidrolizados proteicos anfifílicos en fibras queratínicas produce mejoras en relación con las propiedades químicas y físicas de fibras dañadas aportando, además, nuevas cualidades. En este trabajo se presentan las modificaciones químicas, tales como solubilidad en álcali y en urea-bisulfito, causadas en lana tratada con tioglicolato amónico e hidrolizado proteico bien de colágeno, de queratina o de sus respectivos derivados anfifilicos cuaternizados y se comparan con las obtenidas para lana solamente reducida.Sorption of amphiphilic hydrolysed proteics by keratin fibres induces improvement in their chemical and mechanical properties by imparting new characteristics. In this paper chemical modifications are discussed like alkaline, and urea bisulphate solubility produced by treating wool with ammonium thioglicolate and hydrolysed proteics of callogen, queratine or its respective amphiphelic derivatives and are compared with wool characteristics only reduced.La sorption d'hydrolysés protéiques amphiphiles sur des fibres kératiniques produit des améliorations en ce qui concerne les propriétés chimiques et physiques des fibres abimées, leur apportant en outre, de nouvelles qualités. Dans ce travail, sont présentées les modfications chimiques, telles que la solubilité en alcali et en urée-bisulfite, causée sur la laine traitée au thioglycolate ammonique et hydrolysé protéique soit au collagène, de kératine, soit à leur dérivés amphiphiles respectifs quaternisés et elles sont comparées à celles obtenues pour de la laine uniquement réduite.Peer Reviewe

Optimización de las condiciones de ensayo para la determinación de la voluminosidad y resiliencia de lana merina peinada.

En este trabajo se estudian las condiciones óptimas para la realización del ensayo de voluminosidad y resiliencia para cintas de lana merina española peinada mediante la utilización del equipo bulkómeter. Para realizar esta optimización se escogieron tres lanas con diferentes características estructurales y basándonos en el procedimiento descrito en la norma IWS TM 265 para lanas cardadas, se variaron las condiciones de ensayo (carga y tiempo de ciclo), obteniendo unas condiciones óptimas. Finalmente se correlacionaron los parámetros de voluminosidad y resiliencia con las otras características estructurales para las lanas estudiadas.Optimal conditions required to make the test of bulkiness and resilience of Spanish Merino worsted slivers in a bulk measuring device have been studied. Three types of wool with different characteristics were selected for this optimization and based on the IWS TM 265 norm for carded wool, the test condicitons (load and time cycle) were changed and the optimal conditions being obtained. Bulkiness and resilience parameters were correlated with the other structural characteristics of wools studied.Nous avons étudié les conditions optimales pour la réalisation de l'essai de voluminosité et de résilience pour des rubans de laine mérinos espagnole peignée en utilisant l'appareil bulkometer. Pour réaliser cette optimisation, nous avons sélectionné trois laines de différentes caractéristiques structurelles et avons suivi la procédure décrite dans la norme IWS TM 265 pour les laines cardées. Nous avons modifié les conditions d'essai (charge et durée du cycle) et obtenus des conditions optimales. Finalement, nous avons établi une corrélation entre les parametres de voluminosité et de résilience et les autres caractéristiques structurelles pour les laines étudiées.Peer Reviewe

The interplay between redox signalling and proteostasis in neurodegeneration: In vivo effects of a mitochondria-targeted antioxidant in Huntington's disease mice.

Abnormal protein homeostasis (proteostasis), dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders, such as Huntington's (HD), Alzheimer's and Parkinson's diseases. It remains incompletely understood, however, how changes in redox signalling affect proteostasis mechanisms, including protein degradation pathways and unfolded protein responses (UPR). Here we address this open question by investigating the interplay between redox signalling and proteostasis in a mouse model of HD, and by examining the in vivo effects of the mitochondria-targeted antioxidant MitoQ. We performed behavioural tests in wild-type and R6/2 HD mice, examined markers of oxidative stress, UPR activation, and the status of key protein degradation pathways in brain and peripheral tissues. We show that R6/2 mice present widespread markers of oxidative stress, with tissue-specific changes in proteostasis that were more pronounced in the brain and muscle than in the liver. R6/2 mice presented increased levels of cytosolic and mitochondrial chaperones, particularly in muscle, indicating UPR activation. Treatment with MitoQ significantly ameliorated fine motor control of R6/2 mice, and reduced markers of oxidative damage in muscle. Additionally, MitoQ attenuated overactive autophagy induction in the R6/2 muscle, which has been associated with muscle wasting. Treatment with MitoQ did not alter autophagy markers in the brain, in agreement with its low brain bioavailability, which limits the risk of impairing neuronal protein clearance mechanisms. This study supports the hypotheses that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment in HD, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD