An Overview of the Ferroptosis Hallmarks in Friedreich's Ataxia

Friedreich's ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths

OMNICAM: Bifocal Panoramic Camera for Human and Robotic Exploration

Situational awareness is the key for maximizing the return of any operation, both for scientific and engineering assessments. SPACECLICK and INAF propose the OMNICAM, a novel camera system which can capture a 360° context view and an optically magnified portion of the same panorama with a single lens and sensor. The Bifocal Panoramic Lens (BPL) (designed by INAF researchers) is a lens capable of warping a panoramic Field-of-View (FoV) of 360° x 100° and simultaneously a round FoV of 20° in high-resolution. While the panoramic portion is always available for continuous monitoring surrounding environment, assets and ongoing operations, additionally the OMNICAM makes use of a pan/tilt mechanism to provide users of orientation capabilities for the magnified portion of the FoV

Aligning Immanuel Kant’s Work and its Translations

his chapter discusses using CLARIN to edit Kant’s work and to con- sider how to align it with its translations, with special attention to Chinese. Kangde 康德 is the two-character phonetic loan that renders Kant’s name in Chinese. We have chosen Kangde 康德 as the name for our vision to express the challenge of setting up the new edition of the Druckschriften and their Chinese translation in the form of aligned corpora, thus opening up the way to further alignments with versions in other languages. From a philosophical-historical and cultural-political perspective, the chapter presents the idea of aligning two parallel corpora of around 1,580,000 German words and the corresponding characters in Chinese. The project is curiosity-driven and lays the foundations for investigating Kant’s philosophy and discussing it in a global context, a long- term effort that relies on the synergies among philosophy, computational lin- guistics, machine learning, translation studies, and China studies. The idea of the alignment is to offer unrivalled material for historical-philosophical investi- gations and serve as a viable infrastructure to be scaled up to other languages. To date, few aligned corpora exist that connect German and Chinese philosoph- ical texts. The tools are not statistically implemented. As suggested by Franco Moretti’s notion of distant reading, experimentation on meaningful patterns in philosophical corpora is a step towards making new machine learning technol- ogies usable for tackling issues in the humanities. Looking forward, we focus on the assumption that philosophers ought to explore new technologies to rethink conventional ways of interpreting texts in the humanities

Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth

Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy

Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism

Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich's ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA

Hyperbaric exposure and oxidative Stress in occupational activities (HEOxS): the study protocol

Background: Hyperbaric exposure (HE) is proven to be a stressor to several mechanisms in living cells. Even if after homeostasis restoration, harmful effects are expected, in particular a presence of free radicals. These latter are the stimulus to negative phenomenon as inflammation or cancer. In Italy, with 7500 km of sea shores, a large quantity of workers is exposed to HE during occupational activities. A deep knowledge of HE and bodily effects is not well defined; hence a multidisciplinary assessment of risk is needed. To detect one or more indicators of HE a research group is organised, under the INAIL sponsorship. The research project focused on the oxidative stress (OxS) and this paper details on the possible protocol to estimate, with a large amount of techniques on several human liquids, the relationship between OxS and HE. Specific attention will be paid to identify confounding factors and their influence. Methods: Blood and urine will be sampled. Several lab techniques will be performed on samples, both targeted, to measure the level of well-known biomarkers, and untargeted. Regard the formers: products of oxidation of DNA and RNA in urine; inflammation and temperature cytokines and protein carbonyles in blood. Untargeted evaluation will be performed for a metabolomics analysis in urine. Confounding factors: temperature, body fat, fitness, allergies and dietary habits. These factors will be assessed, directly or indirectly, prior and after HE. The final scope of the project is to determine one or more indicators that relates to HE in hits twofold nature: depth and duration. Conclusion: The relationship between OxS and HE is not deeply investigated and literature proposes diverging results. The project aims to define the time dependence of biomarkers related to OxS, to rise knowledge in risk assessment in workers exposed to HE

Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%

Single case study: effects of the physical activity and exercise in a sedentary subjet suffering from metabolic turner's sindrome

Turner’s Syndrome (TS) is a genetic disorder associated with abnormalities of the X chromosome. TS, is usually related with reduced adult height, gonad dysgenesis and thus insufficient circulation levels of female sex steroids leading to premature ovarian failure and infertility. Often show high levels of cholesterol and increased triglycerides, determined by obesity and hyperinsulinemia. In the women with Turner’s Syndrome is impaired glucose tolerance (10- 34%). In addition, adult women tend to develop insulin resistance and propensity for type 2 Diabetes Mellitus. Physical activity is important in the management of type 2 diabetes mellitus The aim of this study was to examine the effects of the physical activity and exercise in sedentary subject suffering from metabolic TS. The patient with TS, was recruited during the counseling for exercise in the diabetes clinic. For counseling has used the transtheoretical model in accordance with the guidelines of the American College of Sports Medicine. She was monitored for one year, and before and after the start of the educational exercise has undergone a series of tests: blood, and anthropometric. The level of physical activity was estimated by the 7 day physical activity recall (7-DR).. The exercise prescription is in accordance with the guidelines of the American Diabetes Association for the improvement of metabolic fitness