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Certification of visiting professor Presented to Federico Canavese, MD
No full textCertification of visiting professor Presented to Federico Canavese, MD In recognition of your outstanding and invaluable service to our hospital January 16th-17th . 2026 IRCCS Giannina Gaslini Institute, Genoa, Italy, University of Genoa, Italy Department of Orthopedics Taiyuan Great Wall Orthopedic and Hand Surgery Hospital, ZhanHai Wang JianFeng L
Boosting NAD+ pathways to counteract Doxorubicin-induced cardiotoxicity
No full textCancer and cardiovascular diseases are among the main causes of death worldwide. Very powerful drugs have been developed in order to cure cancers, and among them we find anthracyclines, which include Doxorubicin (DOX). However, this chemotherapeutic has important side effects, which limit its usage. DOX’s most prevalent side effect is cardiotoxicity; thus, many efforts have been made to find drugs and therapeutic approaches to counteract it.
NAD+ is a fundamental coenzyme for the cell, both as a redox co-substrate and as a substrate for enzymes regulating different cellular processes, like post-translational modifications, epigenetic regulation, and so on. NAD+ levels are often decreased in pathologies and during aging, making their restoration a potential strategy to reverse these phenomena. This could be done either by decreasing its consumption, limiting the activity of the aforementioned enzymes, or by boosting its synthesis, by feeding precursors or analogues.
LGD SARL is interested in NAD+ boosting approaches to counteract different pathologies, including DOX-induced cardiotoxicity. They have already published that a physiological NAD+ precursor, Nicotinamide Mononucleotide (NMN), is able to counteract Doxorubicin-induced mortality, body weight loss, and cardiotoxicity in mice. Recently, they have become interested in another NAD+-related molecule, whose name and structure cannot be disclosed (called hereafter undisclosed compound, U.C.). Preliminary data in the DOX-induced cardiotoxicity mouse model show that this molecule exerted beneficial biological effects, comparable to those of NMN (which has consequently been used as a positive control).
This project aimed to characterize the mechanism of action of U.C., using in vivo and in vitro models and by finding potential U.C. interactors.
The first step was characterizing the mechanism underlying the cardioprotection observed in DOX-induced cardiotoxicity in vivo model. Therefore, we measured the levels of NAD+ and its related metabolites in blood, heart and kidneys collected from U.C.- or vehicle-treated animals exposed to DOX. While NMN co-treatment with DOX was able to increase the levels of NAD+ and of its downstream products, N1-Methyl-2-pyridone-5-carboxamide (2PY) and 1-MethylNicotinamide (1-MeNam), reversing the effects of DOX on these metabolites, U.C. co-treatment did not lead to such effects, suggesting a mechanism of action distinct from that of NMN. However, U.C. caused an increase in the levels of ATP and non-significant tendency toward restoring cyclic ADPR (cADPR) levels, suggesting a possible involvement of calcium signaling, which was not observed in NMN-treated animals. In the heart, kidneys and blood of animals treated with U.C. and DOX, a side product of U.C. (called U.C.+1) was formed, which could support U.C.’s mechanism of action.
The second aim was to mimic the effects observed in vivo in a cellular system, where we could study a higher number of parameters. We were able to recapitulate these effects in a primary murine cardiomyocyte cell line (mNVCM) treated with DOX, where we found that U.C. reversed the increase in Malondialdehyde (MDA), an oxidative stress biomarker. This suggests that U.C. is not just involved in NAD+ pathways, but also in protection from oxidative stress. Treatment of these cells with DOX and U.C.+1, instead of U.C. itself, showed similar effects, suggesting that it could indeed mediate U.C.’s observed effects. This was further supported in a primary cardiac fibroblast cell line, that massively produced the downstream product rapidly after U.C.’s administration, rather than raising levels of any of the NAD+-pathway classical metabolites.
Lastly, we focused on potential U.C.’s interactors, to determine which pathways could be activated after its administration. U.C. is not a substrate or modulator of several NAD+-related enzymes (NMNAT, CD38, SARM-1), as determined on the recombinant form of these enzymes (for NMNAT and SARM-1) or on a cell line (HUVECs) overexpressing CD38.
To deepen our understanding of U.C.’s mechanism of action, we administered it to DOX- and H2O2-treated murine myoblasts (C2C12 cell line), which is a non-cardiac muscle cell model. U.C. was not effective in counteracting DOX effects on these cells but successfully prevented H2O2 induced mortality. Thus, these results confirm the involvement of U.C. in protection against oxidative stress, consistently with the decreased levels of MDA measured in mNVCM upon U.C. treatment.
Altogether, U.C. appears to modulate cellular energetic and oxidative stress responses independently of NAD+ biosynthesis, potentially involving calcium-related signaling pathways, although the molecular mediator remains unidentified. These findings could provide fundamental insights into the prevention of DOX-induced cardiotoxicity
Analysis of Blade Tip Timing Data From Nonuniformly-Spaced Sensors By Discrete Wavelet Transform
No full textEmergenza e CEDU. Una ricerca sull'articolo 15 della Convenzione europea dei diritti dell'uomo
No full textThis thesis provides a thorough analysis of Article 15 of the European Convention on Human Rights, examining the practices of Council of Europe member states and the case law of the European Court of Human Rights derived from this article. First, it compares Article 15 of the ECHR with theoretical models of states of emergency inherited from the Western legal tradition. It then traces the historical origins of the provision and its initial practical application. The research then focuses on the most recent uses of the ECHR derogation clause, particularly in relation to emergency events of the last decade, such as the Covid-19 pandemic. The research concludes that the derogation clause in the Convention has gradually changed in meaning through the Court's interpretation. The Court now favours other instruments that are better suited to addressing emergency circumstances, thus implicitly rejecting the normality/emergency dualism inherent in the Article 15 model. Nevertheless, the research reveals that several Council of Europe states continue to rely heavily on the derogation. This creates a conflict between the practices of the states and the Court's interpretation, and the position of Article 15 within the Convention is now uncertain and in need of redefinition — a necessity given the numerous emergencies of our time
Probing the geological setting of exoplanets through atmospheric analysis: Using Mars as a test case
No full textOne of the frontier research fields of exoplanetary science is the study of the composition and variability of exoplanetary atmospheres. This field is now moving from the gas giant planets towards the smaller and colder telluric planets, and future instruments like ANDES will focus on the observations of the atmosphere of telluric planets in the habitable zone in reflected light. These future observations will possibly find variable signals due to the view of different hemispheres of the planet. Particularly, the strength of the signal may be linked to the thickness of the atmospheric layer probed, and therefore to the average altitude variations of the planetary surface, that are related to the global geodynamic evolution of the planet. To better prepare for the interpretation and exploitation of these future data, we used Mars as a Solar System analog of a spatially resolved telluric exoplanet. We observed the reflected light of Mars with the high-resolution near-infrared (NIR) spectrograph GIANO-B (widely used in exoplanetary atmospheric studies) during a 3 month period: we studied the spatial and temporal variations of the Martian CO2 signal using the least-squared deconvolution technique (LSD), to mimic as closely as possible the standard exoplanetary atmospheric analysis. We linked the variations found to the wellknown Martian geological surface characteristics: we found a clear dependence of the strength of the CO2 signal with the thickness of the Martian atmospheric layer by comparing the retrieved CO2 signal with the altitudes of our pointings. The proposed strategy is promising: it proved to be effective on Mars and may shed light on the variations in the strength of atmospheric signal of telluric exoplanets
Design of a chiral waveguide with mechanically-tunable stiffness for Bloch wave propagation control
No full textChemoselective Enzymatic Acylation of Glycine as a Green Route to N-Acyl aminoacid Surfactants
No full textN-acyl aminoacids are very important industrial surfactants, being gentle on the skin and completely biodegradable. The synthetic routes described in the literature involve the use of highly reactive acid chlorides or harsh reaction conditions. Following the latest trends in sustainable chemistry, in this work we found an efficient, chemoselective, and environmentally friendly method for their synthesis, which involves the use of non-toxic enzymes as catalysts. Determining the most suitable starting materials and reaction conditions made it possible to achieve 97% product formation under mild reaction conditions
Physics Informed Machine Learning for Power Flow Analysis: Injecting Knowledge via Pre-, In-, and Post-processing
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