The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin

BACKGROUND: The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. MATERIAL AND METHODS: We deeply sequenced 46 genes in normal skin biopsies from 127 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. RESULTS: Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma (cSCC) cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest loss of fidelity in transcription-coupled repair later in life. CONCLUSION: Our findings reveal that aging is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events

Interactive-predictive neural multimodal systems

[EN] Despite the advances achieved by neural models in sequence to sequence learning, exploited in a variety of tasks, they still make errors. In many use cases, these are corrected by a human expert in a posterior revision process. The interactive-predictive framework aims to minimize the human effort spent on this process by considering partial corrections for iteratively refining the hypothesis. In this work, we generalize the interactive-predictive approach, typically applied in to machine translation field, to tackle other multimodal problems namely, image and video captioning. We study the application of this framework to multimodal neural sequence to sequence models. We show that, following this framework, we approximately halve the effort spent for correcting the outputs generated by the automatic systems. Moreover, we deploy our systems in a publicly accessible demonstration, that allows to better understand the behavior of the interactive-predictive framework.The research leading to these results has received funding from MINECO under grant IDIFEDER/2018/025 Sistemas de fabricacion inteligentes para la industria 4.0, action co-funded by the European Regional Development Fund 2014-2020 (FEDER), and from the European Commission under grant H2020, reference 825111 (DeepHealth). We also acknowledge NVIDIA Corporation for the donation of GPUs used in this work.Peris, Á.; Casacuberta Nolla, F. (2019). Interactive-predictive neural multimodal systems. Springer. 16-28. https://doi.org/978-3-030-31332-6_2S162

Distributionally chaotic families of operators on Fréchet spaces

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Communications on Pure and Applied Analysis (CPAA) following peer review. The definitive publisher-authenticated version Conejero, J. A., Kostić, M., Miana, P. J., & Murillo-Arcila, M. (2016). Distributionally chaotic families of operators on Fréchet spaces.Communications on Pure and Applied Analysis, 2016, vol. 15, no 5, p. 1915-1939, is available online at: http://dx.doi.org/10.3934/cpaa.2016022The existence of distributional chaos and distributional irregular vectors has been recently considered in the study of linear dynamics of operators and C-0-semigroups. In this paper we extend some previous results on both notions to sequences of operators, C-0-semigroups, C-regularized semigroups, and alpha-timesintegrated semigroups on Frechet spaces. We also add a study of rescaled distributionally chaotic C-0-semigroups. Some examples are provided to illustrate all these results.The first and fourth authors are supported in part by MEC Project MTM2010-14909, MTM2013-47093-P, and Programa de Investigacion y Desarrollo de la UPV, Ref. SP20120700. The second author is partially supported by grant 174024 of Ministry of Science and Technological Development, Republic of Serbia. The third author has been partially supported by Project MTM2013-42105-P, DGI-FEDER, of the MCYTS; Project E-64, D.G. Aragon, and Project UZCUD2014-CIE-09, Universidad de Zaragoza. The fourth author is supported by a grant of the FPU Program of Ministry of education of Spain.Conejero, JA.; Kostic, M.; Miana Sanz, PJ.; Murillo Arcila, M. (2016). Distributionally chaotic families of operators on Fréchet spaces. Communications on Pure and Applied Analysis. 15(5):1915-1939. https://doi.org/10.3934/cpaa.2016022S1915193915

El modelo integrador y de innovación docente del Grado en Veterinaria de Zaragoza: integración en équidos

Desde hace cuatro años se ha comenzado a impartir en la Universidad de Zaragoza el nuevo Grado en Veterinaria, de 300 créditos ECTS distribuidos en 5 cursos. En el diseño de este nuevo Plan de Estudios se ha tratado de dotar a la Titulación de un enfoque basado, fundamentalmente, en las competencias que la profesión exige y la sociedad necesita de un t itulado (graduado) en veterinaria. Tras una formación inicial básica el alumno llega al CUARTO CURSO del grado, en el que las materias se han organizado en asignaturas siguiendo una estructura totalmente novedosa para los estudios de veterinaria en España. Como consecuencia de esta nueva estructura desaparecen como tales muchas de las asignaturas tradicionales que han estado presentes como asignaturas propias (con denominaciones idénticas o similares) en la práctica totalidad de los planes de estudio de veterinaria españoles desde la década de los 70 del siglo pasado. Al cursar estas asignaturas, los alumnos de esos planes, estudiábamos las particularidades de las diferentes especies animales de interés veterinario desde el enfoque, inevitablemente compartimentalizado, de esas asignaturas

Antiasthmatic prescriptions in children with and without congenital anomalies: a population-based study.

OBJECTIVES: To explore the risk of being prescribed/dispensed medications for respiratory symptoms and breathing difficulties in children with and without congenital anomalies. DESIGN: A EUROlinkCAT population-based data linkage cohort study. Data on children with and without congenital anomalies were linked to prescription databases to identify children who did/did not receive antiasthmatic prescriptions. Data were analysed by age, European region, class of antiasthmatic, anomaly, sex, gestational age and birth cohort. SETTING: Children born 2000-2014 in six regions within five European countries. PARTICIPANTS: 60 662 children with congenital anomalies and 1 722 912 reference children up to age 10 years. PRIMARY OUTCOME MEASURE: Relative risks (RR) of >1 antiasthmatic prescription in a year, identified using Anatomical Therapeutic Chemical classification codes beginning with R03. RESULTS: There were significant differences in the prescribing of antiasthmatics in the six regions. Children with congenital anomalies had a significantly higher risk of being prescribed antiasthmatics (RR 1.41, 95% CI 1.35 to 1.48) compared with reference children. The increased risk was consistent across all regions and all age groups. Children with congenital anomalies were more likely to be prescribed beta-2 agonists (RR 1.71, 95% CI 1.60 to 1.83) and inhaled corticosteroids (RR 1.74, 95% CI 1.61 to 1.87). Children with oesophageal atresia, genetic syndromes and chromosomal anomalies had over twice the risk of being prescribed antiasthmatics compared with reference children. Children with congenital anomalies born <32 weeks gestational age were over twice as likely to be prescribed antiasthmatics than those born at term (RR 2.20, 95% CI 2.10 to 2.30). CONCLUSION: This study documents the additional burden of respiratory symptoms and breathing difficulties for children with congenital anomalies, particularly those born preterm, compared with children without congenital anomalies in the first 10 years of life. These findings are beneficial to clinicians and healthcare providers as they identify children with greater morbidity associated with respiratory symptoms, as indicated by antiasthmatic prescriptions

Prescription of cardiovascular medication in children with congenital heart defects across six European Regions from 2000 to 2014: data from the EUROlinkCAT population-based cohort study.

OBJECTIVES: Advances in surgical management strategies have substantially reduced fatality from congenital heart defects (CHD). Decreased infant mortality might be expected, consequentially to result in greater morbidity in older children due to complications later in childhood and adolescence. This study aims to evaluate the use of cardiovascular medication (CVM) as an indicator of disease burden in children born with CHD in the first 10 years of life. DESIGN: Population-based cohort study. SETTING: Six population-based registries from the European Surveillance of Congenital Anomalies (EUROCAT) network participated. Data from live born children with major congenital anomalies (CA) born from 2000 to 2014 were linked to prescription databases. Four groups of children were analysed: CA, CHD, severe CHD (sCHD) and ventricular septal defect (VSD) without sCHD. Live born children without CA were included as reference group. PARTICIPANTS: We obtained data on 61 038 children born with a CA, including 19 678 with CHD, 3392 with sCHD, 12 728 children with VSD without sCHD, and 1 725 496 reference children. RESULTS: Children born with sCHD were the most likely to receive a CVM prescription (42.9%, 95% CI, 26.3 to 58.5) in the first year of life compared with 13.3% (6.7 to 22.0) of children with any CHD, 5.9% (3.7 to 8.7) of children with any CA and 0.1% (0.0 to 0.1) of reference children. Medication was less likely to be prescribed after the first year of life for sCHD; 18.8% (14.8 to 23.1) for children 1-4 years and 15.8% (12.0 to 20.1) 5-9 years. Children with sCHD were most likely to receive a diuretic (36.4%, 18.6 to 54.5), an antihypertensive (6.9%, 3.7 to 11.3) or a beta-blocker (5.5%, 2.9 to9.2). CONCLUSION: Almost half of all children with sCHD were prescribed CVM in their first year of life. For all four groups of children with anomalies, the proportion of children with a CVM prescription decreased with age

M2 Macrophages Activate WNT Signaling Pathway in Epithelial Cells: Relevance in Ulcerative Colitis

Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of β-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, β-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of β-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation

Rivastigmine Lowers Aβ and Increases sAPPα Levels, Which Parallel Elevated Synaptic Markers and Metabolic Activity in Degenerating Primary Rat Neurons

Overproduction of amyloid-β (Aβ) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence Aβ precursor protein (APP) processing and Aβ production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and Aβ on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and Aβ. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased α-secretase cleaved sAPPα and decreased Aβ secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity

Potent Antioxidant and Genoprotective Effects of Boeravinone G, a Rotenoid Isolated from Boerhaavia diffusa

Background and Aims: Free radicals are implicated in the aetiology of some gastrointestinal disorders such as gastric ulcer, colorectal cancer and inflammatory bowel disease. In the present study we investigated the antioxidant and genoprotective activity of some rotenoids (i.e. boeravinones) isolated from the roots of Boerhaavia diffusa, a plant used in the Ayurvedic medicine for the treatment of diseases affecting the gastrointestinal tract. Methods/Principal Findings: Antioxidant activity has been evaluated using both chemical (Electron Spin Resonance spectroscopy, ESR) and Caco-2 cells-based (TBARS and ROS) assays. DNA damage was evaluated by Comet assay, while pERK 1/2 and phospho-NF-kB p65 levels were estimated by western blot. Boeravinones G, D and H significantly reduced the signal intensity of ESR induced by hydroxyl radicals, suggesting a scavenging activity. Among rotenoids tested, boeravinone G exerted the most potent effect. Boeravinone G inhibited both TBARS and ROS formation induced by Fenton's reagent, increased SOD activity and reduced H 2O 2-induced DNA damage. Finally, boeravinone G reduced the levels of pERK 1 and phospho-NF-kB p65 (but not of pERK 2) increased by Fenton's reagent. Conclusions: It is concluded that boeravinone G exhibits an extraordinary potent antioxidant activity (significant effect in the nanomolar range). The MAP kinase and NF-kB pathways seem to be involved in the antioxidant effect of boeravinone G. Boeravinone G might be considered as lead compound for the development of drugs potentially useful against those pathologies whose aetiology is related to ROS-mediated injuries