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

Models of human psoriasis : Zebrafish the newly appointed player

Psoriasis is a human chronic, immune disease with severe cutaneous and systemic manifestations. Its prevalence, among the world population, highly varies with ethnicity and geography, but not sex from remarkable low levels in Asia to 2.3% in Spain, or an impressive 11.5% in Norway. The pathogenesis of psoriasis derives from complex genetic and environmental interactions, which creates aberrant crosstalk between keratinocytes and variated immune cell, resulting in open amplified inflammatory and pro-proliferative circuits. Both, innate and adaptive immune systems are known to be involved in the response at the cellular and humoral levels. Nevertheless, the exact molecular mechanisms are still under debate. Therefore, discovering useful therapeutic targets to stretch the molecular gaps in psoriasis pathogenesis and its associated comorbidities is still mandatory. So far, some mutagenic or pharmacological studies in vitro or using comparative vertebrate models have provided critical molecular insights and directed the human research. Although highly feasible in rodents, the versatile physiology, genetic similarity to humans and outstanding molecular toolbox available, suggest that elaborate forward genetic screenings are far easier to be conducted using the zebrafish model. Thus, in this review, we intend to briefly overview psoriasis and revise in a digested fashion the preclinical research models available, emphasizing the zebrafish as a powerful tool in the study of immune effectors on the same, and how it supports the discovering of new therapies that may help in controlling this widespread disease around the globe.publishedVersionUnit Licence Agreemen

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

Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

Background The molecular mechanisms by which PROS1 mutations result in protein S deficiency are still unknown for many of the mutations, particularly for those that result in a premature termination codon. The aim of this study was to analyze the functional relevance on mRNA and protein expression of 12 natural PROS1 mutations associated with protein S deficiency. Design and Methods Five mutations were nonsense, three were small frameshift deletions, one was c.258,259AG>GT at the 3' end of exon 3, one was p.M640T and the last two were c.-7C>G and p.L15H, found in double heterozygosis as [c.-7C>G;44T>A].The apparently neutral variant p.R233K was also analyzed. PROS1 cDNA was assessed by reverse transcriptase polymerase chain reaction of platelet mRNA. Expression of mutant proteins was determined by site-directed mutagenesis and analyses of transiently transfected PROS1 mutants in COS-7 cells. Results Only cDNA from the normal allele was observed from the five nonsense mutations, the frameshift deletion c.1731delT and from c.258,259AG>GT. Both the normal and the mutated alleles were observed from [c.-7C>G;44T>Aj, c.187,188delTG and p.M640T Transient expression analyses of PROS1 mutants whose mRNA was normally expressed revealed greatly reduced secretion of p.L15H and c.1272delA, mild secretion values of p.M640T and normal secretion levels of c.7C>G and, as expected, p.R233K. Conclusions Whereas the main cause of quantitative protein S deficiency associated with missense mutations is defective synthesis, stability or secretion of the mutated protein, the main mechanism for the deficiency associated with mutations that generate a premature termination codon is not the synthesis of a truncated protein, but the exclusion of the mutated allele, probably by nonsense-mediated mRNA decay

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

c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells

Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS: PI11/00377 to J.G.-C.; and RTICC: RD12/0036/0027 to J.G-C, RD12/0036/0020 to S.M.) and the Madrid Regional Government (CellCAM; P2010/BMD-2420 to J.G.-C) in Spain. A.A. was supported by Juan de la Cierva program of the Spanish Plan Nacional (MINECO) and Sara Borrell program of the ISCIII/FEDER. A.Al. was supported by the “Miguel Servet” program of the ISCIII/FEDER. We gratefully acknowledge support from Asociación Pablo Ugarte (CIF G86121019) and AFANION (CIF G02223733). The experiments were approved by the appropriate committees.S

Detection of cytomegalovirus in bronchoalveolar lavage fluid from immunocompromised patients with pneumonitis by viral culture and DNA quantification

Altres ajuts: acords transformatius de la UABTo compare the detection of human cytomegalovirus (HCMV) in bronchoalveolar lavage (BAL) fluid by viral culture and quantitative polymerase chain reaction (qPCR), and to establish a viral load threshold that can identify cases of HCMV replication indicative of pneumonitis. There is currently no universal viral load cut-off to differentiate between patients with and without pneumonitis, and the interpretation of qPCR results is challenging. 176 consecutive BAL samples from immunosuppressed hosts with signs and/or symptoms of respiratory infection were prospectively studied by viral culture and qPCR. Concordant results were obtained in 81.25% of the BAL samples. The rest were discordant, as only 34% of the qPCR-positive BAL samples were positive by culture. The median HCMV load was significantly higher in culture-positive than in culture-negative BAL samples (5038 vs 178 IU/mL). Using a cut-off value of 1258 IU/mL of HCMV in BAL, pneumonia was diagnosed with a sensitivity of 76%, a specificity of 100%, a VPP of 100% and VPN of 98%, and HCMV was isolated in 100% of the BAL cultures. We found that a qPCR-negative was a quick and reliable way of ruling out HCMV pneumonitis, but a positive result did not always indicate clinically significant replication in the lung. However, an HCMV load in BAL fluid of ≥ 1258 IU/mL was always associated with disease, whereas < 200 IU/mL rarely so