On sums of dependent random lifetimes under the time-transformed exponential model

For a given pair of random lifetimes whose dependence is described by a time-transformed exponential model, we provide analytical expressions for the distribution of their sum. These expressions are obtained by using a representation of the joint distribution in terms of bivariate distortions, which is an alternative approach to the classical copula representation. Since this approach allows one to obtain conditional distributions and their inverses in simple form, then it is also shown how it can be used to predict the value of the sum from the value of one of the variables (or vice versa) by using quantile regression techniques.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. JN and JM are supported by Ministerio de Ciencia e Innovación of Spain under Grant PID2019-103971GB-I00/AEI/10.13039/501100011033. FP is partially supported by the Grant Progetto di Eccellenza, CUP: E11G18000350001 and by the Italian GNAMPA research group of INdAM (Istituto Nazionale di Alta Matematica)

Generalized Marshall-Olkin Distributions, and Related Bivariate Aging Properties

National Natural Science Foundation of China [10771090]A class of generalized bivariate Marshall-Olkin distributions, which includes as special cases the Marshall-Olkin bivariate exponential distribution and the Marshall-Olkin type distribution due to Muliere and Scarsini (1987) [19] are examined in this paper. Stochastic comparison results are derived, and bivariate aging properties, together with properties related to evolution of dependence along time, are investigated for this class of distributions. Extensions of results previously presented in the literature are provided as well. (C) 2011 Elsevier Inc. All rights reserved

The Local Microenvironment Limits The Regenerative Potential Of The Mouse Neonatal Heart

Neonatal mice have been shown to regenerate their hearts during a transient window of time of approximately 1 week after birth. However, experimental evidence for this phenomenon is not undisputed, because several laboratories have been unable to detect neonatal heart regeneration. We first confirmed that 1-day-old neonatal mice are indeed able to mount a robust regenerative response after heart amputation. We then found that this regenerative ability sharply declines within 48 hours, with hearts of 2-day-old mice responding to amputation with fibrosis, rather than regeneration. By comparing the global transcriptomes of 1- and 2-day-old mouse hearts, we found that most differentially expressed transcripts encode extracellular matrix components and structural constituents of the cytoskeleton. These results suggest that the stiffness of the local microenvironment, rather than cardiac cell-autonomous mechanisms, crucially determines the ability or inability of the heart to regenerate. Testing this hypothesis by pharmacologically decreasing the stiffness of the extracellular matrix in 3-day-old mice, we found that decreased matrix stiffness rescued the ability of mice to regenerate heart tissue after apical resection. Together, our results identify an unexpectedly restricted time window of regenerative competence in the mouse neonatal heart and open new avenues for promoting cardiac regeneration by local modification of the extracellular matrix stiffness

Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.We thank A. Arbos, S. Turon, M. Morro, J. Barrero, L. Hernandez, a. Vazquez, V. Melgarejo, and L. Noya for technical assistance. This work was supported by grants from the Ministerio de Ciencia, Innovacion y Universidades, Plan Nacional I+D+I and the European Union through Regional Development Funds (ERDF) (SAF2017-86166-R), Generalitat de Catalunya (2017SGR1508 and ICREA Academia Award to F.B.) and MPS Espana Foundation. This work is part of a public-private partnership on gene therapy between UAB and ESTEVE Pharmaceuticals, Spain. V.S. and G.E. received a predoctoral fellowship from the Generalitat de Catalunya, Spain.S

Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer

The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA

La Webquest: una metodología apoyada en la red para renovar la docencia en Educación Superior

La WebQuest responde a una estrategia didáctica basada en la incorporación de las TIC en el aula, cuyo sustento teórico está en las corrientes constructivistas y el aprendizaje colaborativo, siendo de este modo pertinente a las directrices del EEES. En virtud de ello, nos hemos propuesto enfocar nuestras prácticas docentes aprovechando dicha estrategia didáctica y los recursos disponibles en la Web 2.0. Ahora bien, consideramos que como paso previo a la implementación de cualquier recurso TIC necesitamos tener un profundo conocimiento sobre el mismo. Es por ello que, para el desarrollo del trabajo, hemos considerado llevar a cabo un proceso gradual dividido en tres fases. La primera, centrada en la apropiación de la WebQuest como herramienta metodológica, la unificación de criterios y significados en torno al qué, al cómo y al para qué de su implementación. La segunda, focalizada en el diseño de WebQuest y la generación de espacios colaborativos de evaluación de las mismas. La tercera, enfatiza la aplicación directa de WebQuest en nuestras clases y el seguimiento de éstas con fines investigativos. En esta comunicación damos cuenta del proceso llevado a cabo en la primera fase, destacando la multidisciplinaridad que caracteriza al equipo de trabajo

FGF21 gene therapy as treatment for obesity and insulin resistance

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.This work was supported by grants from Ministerio de Economía y Competi- tividad (MINECO) and FEDER, Plan Nacional I+D+I (SAF2014-54866R), andGeneralitat de Catalunya (2014SGR1669and ICREA Academia Award to F.B.), Spain, from the European Commission (MYOCURE, PHC-14-2015 667751) and the European Foundation for the Study of Diabetes (EFSD/MSD European Research Programme on Novel Therapies for Type 2 Diabetes,2013). V.J. was recipient of a post-doctoral research fellowship from EFSD/ Lilly. E.C., V.S., and C.M. received a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and J.R. from Ministerio de Economía y Competitividad, Spain. The authors thank Marta Moya and Maria Molas for technical assistance.S