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Italy is one of the richest European countries in terms of plant biodiversity with more than 7000 species recorded, some of which are endemic. In addition to its intrinsic ecological value, plant biodiversity may also represent a source of molecules with possible therapeutic applications. In this context, natural compounds derived from plants have shown promising results in the prevention and treatment of several diseases in vitro1,2. Amongst these conditions, colorectal cancer (CRC) and non-alcoholic fatty liver disease (NAFLD) are of particular interest because of their growing incidence in the population. Therefore, we are focusing on the screening of numerous natural extracts derived from different species of the national flora to tackle these two diseases. In particular, concerning CRC, the aim is to identify compounds that are not toxic towards healthy colon cells but show anticancer properties when administered to different tumoral cell lines, and to characterize their mechanisms of action. Instead, regarding NAFLD, the purpose is to find extracts able to reduce lipids accumulation, thus restoring a healthy phenotype. So far, a few extracts with possible applications in the treatment of CRC have been selected.

PURPOSE: To establish whether deep learning methods are able to improve the signal-to-noise ratio of time-domain (TD) OCT images to approach that of spectral-domain (SD) OCT images. DESIGN: Method agreement study and progression detection in a randomized, double-masked, placebo-controlled, multicenter trial for open-angle glaucoma (OAG), the United Kingdom Glaucoma Treatment Study (UKGTS). PARTICIPANTS: The training and validation cohort comprised 77 stable OAG participants with TD OCT and SD OCT imaging at up to 11 visits within 3 months. The testing cohort comprised 284 newly diagnosed OAG patients with TD OCT images from a cohort of 516 recruited at 10 United Kingdom centers between 2007 and 2010. METHODS: An ensemble of generative adversarial networks (GANs) was trained on TD OCT and SD OCT image pairs from the training dataset and applied to TD OCT images from the testing dataset. Time-domain OCT images were converted to synthesized SD OCT images and segmented via Bayesian fusion on the output of the GANs. MAIN OUTCOME MEASURES: Bland-Altman analysis assessed agreement between TD OCT and synthesized SD OCT average retinal nerve fiber layer thickness (RNFLT) measurements and the SD OCT RNFLT. Analysis of the distribution of the rates of RNFLT change in TD OCT and synthesized SD OCT in the two treatment arms of the UKGTS was compared. A Cox model for predictors of time-to-incident visual field (VF) progression was computed with the TD OCT and the synthesized SD OCT images. RESULTS: The 95% limits of agreement were between TD OCT and SD OCT were 26.64 to -22.95; between synthesized SD OCT and SD OCT were 8.11 to -6.73; and between SD OCT and SD OCT were 4.16 to -4.04. The mean difference in the rate of RNFLT change between UKGTS treatment and placebo arms with TD OCT was 0.24 (P = 0.11) and with synthesized SD OCT was 0.43 (P = 0.0017). The hazard ratio for RNFLT slope in Cox regression modeling for time to incident VF progression was 1.09 (95% confidence interval

The spatial distribution of atrophy in neurodegenerative diseases suggests that brain connectivity mediates disease propagation. Different descriptors of the connectivity graph potentially relate to different underlying mechanisms of propagation. Previous approaches for evaluating the influence of connectivity on neurodegeneration consider each descriptor in isolation and match predictions against late-stage atrophy patterns. We introduce the notion of a topological profile - a characteristic combination of topological descriptors that best describes the propagation of pathology in a particular disease. By drawing on recent advances in disease progression modeling, we estimate topological profiles from the full course of pathology accumulation, at both cohort and individual levels. Experimental results comparing topological profiles for Alzheimer's disease, multiple sclerosis and normal ageing show that topological profiles explain the observed data better than single descriptors. Within each condition, most individual profiles cluster around the cohort-level profile, and individuals whose profiles align more closely with other cohort-level profiles show features of that cohort. The cohort-level profiles suggest new insights into the biological mechanisms underlying pathology propagation in each disease.

Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.

La falta de reglamentación del abogado del niño en la Provincia de Santa Fe ha impregnado de lagunas, incertezas e incertidumbres el esquema de participación de las niñas, niños y adolescentes. La investigación realizada analiza los reclamos y opiniones de la comunidad jurídica y las respuestas brindadas por las iniciativas parlamentarias en debate para indagar acerca de la formación, función y actuación de esta figura. Este trabajo pretende, a través de reflexiones, críticas y propuestas, realizar un aporte a la construcción de un modelo que garantice el pleno y efectivo ejercicio de los derechos de las niñas, niños y adolescentes. La utopía es el principio de todo progreso y el diseño de un futuro mejor (Anatole François Thibault, 1844-1924), The lack of regulation of child labor in the Province of Santa Fe has filled with gaps and uncertainties the scheme of participation of children and adolescents. The research carried out analyzes the claims and opinions of the legal community and the answers provided by the parliamentary initiatives in debate to inquire about the formation, function and performance of this figure. This article aims, through reflections, criticisms and proposals, at making a contribution to the construction of a model that guarantees the full and effective exercise of the rights of children and adolescents. Utopia is the beginning of all progress and the design of a better future (Anatole François Thibault, 1844-1924).

La falta de reglamentación del abogado del niño en la Provincia de Santa Fe ha impregnado de lagunas, incertezas e incertidumbres el esquema de participación de las niñas, niños y adolescentes. La investigación realizada analiza los reclamos y opiniones de la comunidad jurídica y las respuestas brindadas por las iniciativas parlamentarias en debate para indagar acerca de la formación, función y actuación de esta figura. Este trabajo pretende, a través de reflexiones, críticas y propuestas, realizar un aporte a la construcción de un modelo que garantice el pleno y efectivo ejercicio de los derechos de las niñas, niños y adolescentes. La utopía es el principio de todo progreso y el diseño de un futuro mejor (Anatole François Thibault, 1844-1924), The lack of regulation of child labor in the Province of Santa Fe has filled with gaps and uncertainties the scheme of participation of children and adolescents. The research carried out analyzes the claims and opinions of the legal community and the answers provided by the parliamentary initiatives in debate to inquire about the formation, function and performance of this figure. This article aims, through reflections, criticisms and proposals, at making a contribution to the construction of a model that guarantees the full and effective exercise of the rights of children and adolescents. Utopia is the beginning of all progress and the design of a better future (Anatole François Thibault, 1844-1924).

La falta de reglamentación del abogado del niño en la Provincia de Santa Fe ha impregnado de lagunas, incertezas e incertidumbres el esquema de participación de las niñas, niños y adolescentes. La investigación realizada analiza los reclamos y opiniones de la comunidad jurídica y las respuestas brindadas por las iniciativas parlamentarias en debate para indagar acerca de la formación, función y actuación de esta figura. Este trabajo pretende, a través de reflexiones, críticas y propuestas, realizar un aporte a la construcción de un modelo que garantice el pleno y efectivo ejercicio de los derechos de las niñas, niños y adolescentes. La utopía es el principio de todo progreso y el diseño de un futuro mejor (Anatole François Thibault, 1844-1924), The lack of regulation of child labor in the Province of Santa Fe has filled with gaps and uncertainties the scheme of participation of children and adolescents. The research carried out analyzes the claims and opinions of the legal community and the answers provided by the parliamentary initiatives in debate to inquire about the formation, function and performance of this figure. This article aims, through reflections, criticisms and proposals, at making a contribution to the construction of a model that guarantees the full and effective exercise of the rights of children and adolescents. Utopia is the beginning of all progress and the design of a better future (Anatole François Thibault, 1844-1924).

The lack of regulation of child labor in the Province of Santa Fe has filled with gaps and uncertainties the scheme of participation of children and adolescents. The research carried out analyzes the claims and opinions of the legal community and the answers provided by the parliamentary initiatives in debate to inquire about the formation, function and performance of this figure. This article aims, through reflections, criticisms and proposals, at making a contribution to the construction of a model that guarantees the full and effective exercise of the rights of children and adolescents. Utopia is the beginning of all progress and the design of a better future (Anatole François Thibault, 1844-1924)., La falta de reglamentación del abogado del niño en la Provincia de Santa Fe ha impregnado de lagunas, incertezas e incertidumbres el esquema de participación de las niñas, niños y adolescentes. La investigación realizada analiza los reclamos y opiniones de la comunidad jurídica y las respuestas brindadas por las iniciativas parlamentarias en debate para indagar acerca de la formación, función y actuación de esta figura. Este trabajo pretende, a través de reflexiones, críticas y propuestas, realizar un aporte a la construcción de un modelo que garantice el pleno y efectivo ejercicio de los derechos de las niñas, niños y adolescentes. La utopía es el principio de todo progreso y el diseño de un futuro mejor (Anatole François Thibault, 1844-1924)

The lack of regulation of child labor in the Province of Santa Fe has filled with gaps and uncertainties the scheme of participation of children and adolescents. The research carried out analyzes the claims and opinions of the legal community and the answers provided by the parliamentary initiatives in debate to inquire about the formation, function and performance of this figure. This article aims, through reflections, criticisms and proposals, at making a contribution to the construction of a model that guarantees the full and effective exercise of the rights of children and adolescents. Utopia is the beginning of all progress and the design of a better future (Anatole François Thibault, 1844-1924)., La falta de reglamentación del abogado del niño en la Provincia de Santa Fe ha impregnado de lagunas, incertezas e incertidumbres el esquema de participación de las niñas, niños y adolescentes. La investigación realizada analiza los reclamos y opiniones de la comunidad jurídica y las respuestas brindadas por las iniciativas parlamentarias en debate para indagar acerca de la formación, función y actuación de esta figura. Este trabajo pretende, a través de reflexiones, críticas y propuestas, realizar un aporte a la construcción de un modelo que garantice el pleno y efectivo ejercicio de los derechos de las niñas, niños y adolescentes. La utopía es el principio de todo progreso y el diseño de un futuro mejor (Anatole François Thibault, 1844-1924)

The lack of regulation of child labor in the Province of Santa Fe has filled with gaps and uncertainties the scheme of participation of children and adolescents. The research carried out analyzes the claims and opinions of the legal community and the answers provided by the parliamentary initiatives in debate to inquire about the formation, function and performance of this figure. This article aims, through reflections, criticisms and proposals, at making a contribution to the construction of a model that guarantees the full and effective exercise of the rights of children and adolescents. Utopia is the beginning of all progress and the design of a better future (Anatole François Thibault, 1844-1924)., La falta de reglamentación del abogado del niño en la Provincia de Santa Fe ha impregnado de lagunas, incertezas e incertidumbres el esquema de participación de las niñas, niños y adolescentes. La investigación realizada analiza los reclamos y opiniones de la comunidad jurídica y las respuestas brindadas por las iniciativas parlamentarias en debate para indagar acerca de la formación, función y actuación de esta figura. Este trabajo pretende, a través de reflexiones, críticas y propuestas, realizar un aporte a la construcción de un modelo que garantice el pleno y efectivo ejercicio de los derechos de las niñas, niños y adolescentes. La utopía es el principio de todo progreso y el diseño de un futuro mejor (Anatole François Thibault, 1844-1924)

In this study we introduce the regional flux analysis, a novel approach to deformation based morphometry based on the Helmholtz decomposition of deformations parameterized by stationary velocity fields. We use the scalar pressure map associated to the irrotational component of the deformation to discover the critical regions of volume change. These regions are used to consistently quantify the associated measure of volume change by the probabilistic integration of the flux of the longitudinal deformations across the boundaries. The presented framework unifies voxel-based and regional approaches, and robustly describes the volume changes at both group-wise and subject-specific level as a spatial process governed by consistently defined regions. Our experiments on the large cohorts of the ADNI dataset show that the regional flux analysis is a powerful and flexible instrument for the study of Alzheimer's disease in a wide range of scenarios: cross-sectional deformation based morphometry, longitudinal discovery and quantification of group-wise volume changes, and statistically powered and robust quantification of hippocampal and ventricular atrophy.

Power output limitation is one of the main concerns that need to be addressed for full-scale applica- 28 tions of the microbial fuel cell technology. Fouling and biofilm growth on the cathode of single 29 chamber microbial fuel cells (SCMFC) affects their performance in long-term operation with 30 wastewater. In this study, the authors report the power output and cathode polarization curves of a 31 membraneless SCMFC, fed with raw primary wastewater and sodium acetate for over 6 months. At 32 the end of the experiment, the whole cathode surface is analyzed through x-ray microcomputed to- 33 mography (microCT), scanning electron microscopy, and energy-dispersive x-ray spectroscopy 34 (EDX) to characterize the fouling layer and the biofilm. EDX shows the distribution of Ca, Na, K, 35 P, S, and other elements on the two faces of the cathode. Na-carbonates and Ca-carbonates are pre- 36 dominant on the air (outer) side and the water (inner) side, respectively. The three-dimensional 37 reconstruction by x-ray microCT shows biofilm spots unevenly distributed above the Ca-carbonate 38 layer on the inner (water) side of the cathode. These results indicate that carbonates layer, rather 39 than biofilm, might lower the oxygen reduction reaction rate at the cathode during long-term 40 SCMFC operation

miR-210 is a key player of cell response to hypoxia, modulating cell survival, VEGF-driven endothelial cell migration, and the ability of endothelial cells to form capillary-like structures. A crucial step in understanding microRNA (miRNA) function is the identification of their targets. However, only few miR-210 targets have been identified to date. Here, we describe an integrated strategy for large-scale identification of new miR-210 targets by combining transcriptomics and proteomics with bioinformatic approaches. To experimentally validate candidate targets, the RNA-induced silencing complex (RISC) loaded with miR-210 was purified by immunoprecipitation along with its mRNA targets. The complex was significantly enriched in mRNAs of 31 candidate targets, such as BDNF, GPD1L, ISCU, NCAM, and the non-coding RNA Xist. A subset of the newly identified targets was further confirmed by 3b-untranslated region (UTR) reporter assays, and hypoxia induced down-modulation of their expression was rescued blocking miR-210, providing support for the approach validity. In the case of 9 targets, such as PTPN1 and P4HB, miR-210 seed-pairing sequences localized in the coding sequence or in the 5′-UTR, in line with recent data extending miRNA targeting beyond the "classic" 3′-UTR recognition. Finally, Gene Ontology analysis of the targets highlights known miR-210 impact on cell cycle regulation and differentiation, and predicts a new role of this miRNA in RNA processing, DNA binding, development, membrane trafficking, and amino acid catabolism. Given the complexity of miRNA actions, we view such a multiprong approach as useful to adequately describe the multiple pathways regulated by miR-210 during physiopathological processes.

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Advanced age per se is a major risk factor for cardiovascular disease (CVD). Apart from the chronic exposure to known cardiovascular risk factors, intrinsic aging of the cardiovascular system amplifies the vulnerability to various stressors, ultimately favoring the development of CVD in late life. The process of cardiac aging involves derangements in multiple cellular pathways. Among these, impairments in mitochondrial function arising from failure of mitochondrial quality control are considered to be a major contributing factor to heart senescence. Besides being less bioenergetically efficient, damaged mitochondria produce larger amounts of reactive oxygen species and are more prone to induce apoptosis. This results in oxidative damage to cardiomyocyte components and dismissal of postmitotic and virtually irreplaceable cardiac cells. The chapter summarizes the current knowledge about prominent mechanisms and consequences of mitochondrial decay and failure of mitochondrial quality control in the context of cardiac aging. The therapeutic potential of targeting specific mitochondrial pathways is also discussed.

Introduction We evaluated the gene expression levels of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha in skeletal muscle samples of patients with gastric cancer and controls. Methods We studied 38 cancer patients and 12 controls who underwent surgery for gastric adenocarcinoma and benign abdominal diseases, respectively. A biopsy specimen was obtained from the rectus abdominis muscle from all participants. The relative gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha was determined by qRT-PCR analysis. Results Atrogin-1 and MuRF1 mRNA expression was similar between cancer patients and controls and was unaffected by the disease stage or the severity of body weight loss. Transcript levels of myostatin and follistatin did not differ between cases and controls and were similar across disease stages and categories of weight loss. Finally, no differences were detected in activin A and inhibin alpha gene expression between cancer patients and controls. Discussion In skeletal muscle, the gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha is not affected by the presence of cancer. The expression of atrophy-related genes is unaffected by the disease stage and the degree of weight loss. © 2013 Wiley Periodicals, Inc.

The impact of alcohol on brain morphology was studied in a large group of cognitively intact people whose consumption of alcohol was below the threshold for abuse. Participants were 367 healthy subjects, aged 18 years or older, who underwent magnetic resonance imaging (MRI) for reasons other than cognitive impairment. MRI analyses were carried out using SPM8 software on the MATLAB 7.9 platform. Gray matter (GM) and white matter (WM) volumes were normalized for intracranial volume. Participants were interviewed about their lifetime consumption of alcohol, nicotine and other available illicit substances. Direct WM and GM comparisons between alcohol users and non-users did not detect significant differences. Differences also did not emerge from multiple regression analyses or in the subgroup aged 65 or older. Based on this study's findings, we cannot infer a detrimental effect of alcohol on the brain of normal adults. These data may be considered to provide reference information for clinical studies.

We evaluated the gene expression levels of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha in skeletal muscle samples of patients with gastric cancer and controls.

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes - including oxidative stress, quality control mechanisms and apoptotic signaling - on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Elsevier Ltd. All rights reserved.

Introduction: We evaluated the gene expression levels of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha in skeletal muscle samples of patients with gastric cancer and controls. Methods: We studied 38 cancer patients and 12 controls who underwent surgery for gastric adenocarcinoma and benign abdominal diseases, respectively. A biopsy specimen was obtained from the rectus abdominis muscle from all participants. The relative gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha was determined by quantitative real-time polymerase chain reaction analysis. Results: Atrogin-1 and MuRF1 mRNA expression was similar between cancer patients and controls and was unaffected by the disease stage or the severity of body weight loss. Transcript levels of myostatin and follistatin did not differ between cases and controls and were similar across disease stages and categories of weight loss. Finally, no differences were detected in activin A and inhibin alpha gene expression between cancer patients and controls. Conclusions: In skeletal muscle, the gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha is not affected by the presence of cancer. The expression of atrophy-related genes is unaffected by the disease stage and the degree of weight loss. Muscle Nerve, 2014.

Introduction We evaluated the gene expression levels of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha in skeletal muscle samples of patients with gastric cancer and controls. Methods We studied 38 cancer patients and 12 controls who underwent surgery for gastric adenocarcinoma and benign abdominal diseases, respectively. A biopsy specimen was obtained from the rectus abdominis muscle from all participants. The relative gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha was determined by qRT-PCR analysis. Results Atrogin-1 and MuRF1 mRNA expression was similar between cancer patients and controls and was unaffected by the disease stage or the severity of body weight loss. Transcript levels of myostatin and follistatin did not differ between cases and controls and were similar across disease stages and categories of weight loss. Finally, no differences were detected in activin A and inhibin alpha gene expression between cancer patients and controls. Discussion In skeletal muscle, the gene expression of atrogin-1, MuRF1, myostatin, follistatin, activin A, and inhibin alpha is not affected by the presence of cancer. The expression of atrophy-related genes is unaffected by the disease stage and the degree of weight loss. © 2013 Wiley Periodicals, Inc.

We used DNA microsatellites to study colony kin structure and breeding patterns in the primitively eusocial wasp Polistes biglumis. P. biglumis inhabits cool areas at high altitudes and, as a consequence, has a reduced colony cycle compared to more temperate Polistes. P. biglumis colonies are always founded and controlled by a single foundress, but nest failure is common and foundresses losing their nests do not have time to start new ones due to the short season. Instead, nests are characterized by frequent female turnover, in the form of females taking over (usurpation) other con-specific nests. Our results showed that most nests had offspring from multiple unrelated females, including some where multiple females were not observed in monitoring. Reconstruction of behavioural events from the genetic data revealed three types of multiple matriline nests: (a) nests that were usurped by another female, where the original nest owner disappeared following the usurpation event, (b) nests that were joined by another female, where the original nest owner stayed following the joining event, (c) nests that were both usurped and joined by other females. We also found, for the first time, a clear indication of multiple mating by Polistes females. Moreover, males mating with the same female were related, which may be explained by the lek mating system of P. biglumis. Finally, we analysed the nest sex ratios and how it changed during the season and found that sexes were produced sequentially, males before females.

Sexual selection is often quantified using Bateman gradients, which represent sex-specific regression slopes of reproductive success on mating success and thus describe the expected fitness returns from mating more often. Although the analytical framework for Bateman gradients aimed at covering all sexual systems, empirical studies are biased toward separate-sex organisms, probably because important characteristics of other systems remain incompletely treated. Our synthesis complements the existing Bateman gradient approach with three essential reproductive features of simultaneous hermaphrodites. First, mating in one sex may affect fitness via the opposite sex, for example, through energetic trade-offs. We integrate cross-sex selection effects and show how they help characterizing sexually mutualistic versus antagonistic selection. Second, male and female mating successes may be correlated, complicating the interpretation of Bateman gradients. We show how to quantify the impact of this correlation on sexual selection and propose a principal component analysis on male and female mating success to facilitate interpretation. Third, self-fertilization is accounted for by adding selfed progeny as a separate category of reproductive success to analyses of Bateman gradients. Finally, using a worked example from the snail Biomphalaria glabrata, we illustrate how the extended analytical framework can enhance our understanding of sexual selection in hermaphroditic animals and plants.