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"Di Francesco, Andrea"
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Al-Qurainiyah, Failaka : Kuwaiti-Italian excavations 2010-2015
Geology, stratigraphic; Kuwait ; excavations (archaeology); Kuwait; Kuwait, antiquities.
Book
A time to fast
Nutrient composition and caloric intake have traditionally been used to devise optimized diets for various phases of life. Adjustment of meal size and frequency have emerged as powerful tools to ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without reduced energy intake, can have profound health benefits. The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health. Future research endeavors should be directed to the integration of a balanced nutritious diet with controlled meal size and patterns and periods of fasting to develop better strategies to prevent, postpone, and treat the socioeconomical burden of chronic diseases associated with aging.
Journal Article
Age and diet shape the genetic architecture of body weight in diversity outbred mice
Understanding how genetic variation shapes a complex trait relies on accurately quantifying both the additive genetic and genotype–environment interaction effects in an age-dependent manner. We used a linear mixed model to quantify diet-dependent genetic contributions to body weight measured through adulthood in diversity outbred female mice under five diets. We observed that heritability of body weight declined with age under all diets, except the 40% calorie restriction diet. We identified 14 loci with age-dependent associations and 19 loci with age- and diet-dependent associations, with many diet-dependent loci previously linked to neurological function and behavior in mice or humans. We found their allelic effects to be dynamic with respect to genomic background, age, and diet, identifying several loci where distinct alleles affect body weight at different ages. These results enable us to more fully understand and predict the effectiveness of dietary intervention on overall health throughout age in distinct genetic backgrounds. Body weight is one trait influenced by genes, age and environmental factors. Both internal and external environmental pressures are known to affect genetic variation over time. However, it is largely unknown how all factors – including age – interact to shape metabolism and bodyweight. Wright et al. set out to quantify the interactions between genes and diet in ageing mice and found that the effect of genetics on mouse body weight changes with age. In the experiments, Wright et al. weighed 960 female mice with diverse genetic backgrounds, starting at two months of age into adulthood. The animals were randomized to different diets at six months of age. Some mice had unlimited food access, others received 20% or 40% less calories than a typical mouse diet, and some fasted one or two days per week. Variations in their genetic background explained about 80% of differences in mice’s weight, but the influence of genetics relative to non-genetic factors decreased as they aged. Mice on the 40% calorie restriction diet were an exception to this rule and genetics accounted for 80% of their weight throughout adulthood, likely due to reduced influence from diet and reduced interactions between diet and genes. Several genes involved in metabolism, neurological function, or behavior, were associated with mouse weight. The experiments highlight the importance of considering interactions between genetics, environment, and age in determining complex traits like body weight. The results and the approaches used by Wright et al. may help other scientists learn more about how the genetic predisposition to disease changes with environmental stimuli and age.
Journal Article
Iron-Dependent Trafficking of 5-Lipoxygenase and Impact on Human Macrophage Activation
5-lipoxygenase (5-LOX) is a non-heme iron-containing dioxygenase expressed in immune cells that catalyzes the two initial steps in the biosynthesis of leukotrienes. It is well known that 5-LOX activation in innate immunity cells is related to different iron-associated pro-inflammatory disorders, including cancer, neurodegenerative diseases, and atherosclerosis. However, the molecular and cellular mechanism(s) underlying the interplay between iron and 5-LOX activation are largely unexplored. In this study, we investigated whether iron (in the form of Fe
and hemin) might modulate 5-LOX influencing its membrane binding, subcellular distribution, and functional activity. We proved by fluorescence resonance energy transfer approach that metal removal from the recombinant human 5-LOX, not only altered the catalytic activity of the enzyme, but also impaired its membrane-binding. To ascertain whether iron can modulate the subcellular distribution of 5-LOX in immune cells, we exposed THP-1 macrophages and human primary macrophages to exogenous iron. Cells exposed to increasing amounts of Fe
showed a redistribution (ranging from ~45 to 75%) of the cytosolic 5-LOX to the nuclear fraction. Accordingly, confocal microscopy revealed that acute exposure to extracellular Fe
, as well as hemin, caused an overt increase in the nuclear fluorescence of 5-LOX, accompanied by a co-localization with the 5-LOX activating protein (FLAP) both in THP-1 macrophages and human macrophages. The functional relevance of iron overloading was demonstrated by a marked induction of the expression of interleukin-6 in iron-treated macrophages. Importantly, pre-treatment of cells with the iron-chelating agent deferoxamine completely abolished the hemin-dependent translocation of 5-LOX to the nuclear fraction, and significantly reverted its effect on interleukin-6 overexpression. These results suggest that exogenous iron modulates the biological activity of 5-LOX in macrophages by increasing its ability to bind to nuclear membranes, further supporting a role for iron in inflammation-based diseases where its homeostasis is altered and suggesting further evidence of risks related to iron overload.
Journal Article
Redox modulation of NQO1
NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain. Under normal cellular conditions NQO1 is not immunoprecipitated by these antibodies, however, following treatment with β-lapachone which caused rapid oxidation of NAD(P)H NQO1 could be readily pulled-down. Similarly, immunostaining for NQO1 was significantly increased in cells following treatment with β-lapachone demonstrating that under non-denaturing conditions the immunoreactivity of NQO1 is reflective of the NAD(P)+/NAD(P)H ratio. In untreated human cells, regions with high intensity immunostaining for NQO1 co-localize with acetyl α-tubulin and the NAD+-dependent deacetylase Sirt2 on the centrosome(s), the mitotic spindle and midbody during cell division. These data provide evidence that during the centriole duplication cycle NQO1 may provide NAD+ for Sirt2-mediated deacetylation of microtubules. Overall, NQO1 may act as a redox-dependent switch where the protein responds to the NAD(P)+/NAD(P)H redox environment by altering its structure promoting the binding or dissociation of NQO1 with target macromolecules.
Journal Article
Dietary restriction impacts health and lifespan of genetically diverse mice
Caloric restriction extends healthy lifespan in multiple species
1
. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored
2
–
8
. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity
9
. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling—an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.
Health effects of dietary restriction are uncoupled from longevity.
Journal Article
miR-103 promotes endothelial maladaptation by targeting lncWDR59
Blood flow at arterial bifurcations and curvatures is naturally disturbed. Endothelial cells (ECs) fail to adapt to disturbed flow, which transcriptionally direct ECs toward a maladapted phenotype, characterized by chronic regeneration of injured ECs. MicroRNAs (miRNAs) can regulate EC maladaptation through targeting of protein-coding RNAs. However, long noncoding RNAs (lncRNAs), known epigenetic regulators of biological processes, can also be miRNA targets, but their contribution on EC maladaptation is unclear. Here we show that hyperlipidemia- and oxLDL-induced upregulation of miR-103 inhibits EC proliferation and promotes endothelial DNA damage through targeting of novel lncWDR59. MiR-103 impedes lncWDR59 interaction with Notch1-inhibitor Numb, therefore affecting Notch1-induced EC proliferation. Moreover, miR-103 increases the susceptibility of proliferating ECs to oxLDL-induced mitotic aberrations, characterized by an increased micronucleic formation and DNA damage accumulation, by affecting Notch1-related β-catenin co-activation. Collectively, these data indicate that miR-103 programs ECs toward a maladapted phenotype through targeting of lncWDR59, which may promote atherosclerosis.
MicroRNAs play important roles in endothelial cells injury, proliferation and maladaptation by negatively regulating posttranscriptional gene expression. Here the authors uncover the role of the long non coding RNA lncWDR59, target of miR-103, in endothelial maladaptation.
Journal Article
Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice
Dense temporal measurements of physiological health, using simple and consistent assays, are essential to characterize biological processes associated with aging and evaluate the effectiveness of interventions on these processes. We measured body weight in 960 genetically diverse female mice, every 7-10 days over the full course of their lifespan. We used a state space model to characterize the trajectories of body weight throughout life and derived novel traits capturing the dynamics of body weight, 10 of which were both heritable and associated with lifespan. Genetic mapping of these body weight-derived traits identified 5 genomic loci, none of which were previously mapped to body weight. We observed that the ability to maintain stable body weight, despite fluctuations in energy intake and expenditure, was positively associated with lifespan in an age-dependent manner and mapped to a genomic locus linked to energy homeostasis. Our results highlight how dense longitudinal measurements of physiological phenotypes offer new insights into the biology of aging.
This study reveals that the ability to maintain a stable body weight predicts longevity in mice. By tracking weight dynamics throughout life, the authors identify genetic loci linked to body weight, energy homeostasis and healthy aging.
Journal Article
Towards a More Inclusive Society: The Social Return on Investment (SROI) of an Innovative Ankle–Foot Orthosis for Hemiplegic Children
Hemiplegia is a form of disability that affects one side of the body and has a prevalence of 0.5–0.7 per 1000 live births. It has consequences not only at the medical level but also on psychological, cognitive, and social aspects, and it prevents children from social participation, especially in sports settings. The studies demonstrating the social impact of sports on the hemiplegic population and, in particular, children, are limited. In addition, previous evaluations of healthcare sports initiatives in the hemiplegic population are not available, and traditional methods of evaluation, which are mostly focused on economic outcomes, are not applicable. Thus, this article employs the social return on investment (SROI) methodology, which is able to determine the socio-economic impacts of an initiative, to evaluate the impact of an innovative ankle–foot orthosis (AFO) for hemiplegic children that was created to promote the possibility of “sports for all”. The model was designed with the involvement of stakeholders in all the phases and with mixed methods to assess the input, outcomes, and impact indicators. The final SROI, computed for a time horizon of three years and with a focus on the Lombardy Region, was equal to 3.265:1. Based on this result, the initiative turned out to be worthy of investment.
Journal Article
A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin
Robust biomarkers of aging have been developed from DNA methylation in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats—a model with unique physical, physiological, and biochemical advantages—by incorporating behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relates to phenotypic aging. Reduced representation bisulfite sequencing (RRBS) data was used to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. This measure correlated with age at (r = 0.93) in an independent sample, and related to physical functioning (p=5.9e-3), after adjusting for age and cell counts. DNAmAge was also found to correlate with age in male C57BL/6 mice (r = 0.79), and was decreased in response to caloric restriction. Our signatures driven by CpGs in intergenic regions that showed substantial overlap with H3K9me3, H3K27me3, and E2F1 transcriptional factor binding.
Journal Article