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L'intelligenza artificiale e la pericolosità sociale: misure cautelari e di prevenzione. Parte I
No full textSome time-inhomogeneous pseudo-first-order kinetic models in random environment (Extended Abstract)
No full textPrestazioni antincendio delle pavimentazioni in conglomerato bituminoso
No full textIn questo articolo si riportano i risultati di uno studio finalizzato a mostrare l’influenza dell’aggiunta di ritardanti di fiamma nei conglomerati bituminosi impiegati nelle sovrastrutture stradali sulla sicurezza degli utenti in caso di incendio in galleria. A tal fine, è stato sviluppato un modello tridimensionale della galleria e della sovrastruttura stradale, ed è stato simulato in analisi fluidodinamica computazionale un incendio di grandi dimensioni che ha interessato un veicolo pesante. I risultati, in termini di concentrazioni di gas tossici e temperature, sono stati integrati con simulazioni di evacuazione degli utenti verso un luogo sicuro. Il confronto con una sovrastruttura stradale in conglomerato bituminoso tradizionale, ha evidenziato che l’aggiunta dei ritardanti di fiamma comporta una riduzione del livello di concentrazione dei fumi in galleria in caso di incendio e quindi un minor numero di utenti esposti al rischio di incapacità di autosalvarsi durante il percorso di evacuazione
Long-term memory in epithelia: transient IFNγ exposure drives stable repression of TFF1 in gastric epithelial cells via epigenetic changes
No full textIntroduction Interferon-gamma (IFN gamma) is a pro-inflammatory cytokine that is transiently produced and typically activates short-lived JAK-STAT1 signaling, yet it can also induce long-term transcriptional changes. During Helicobacter pylori infection, IFN gamma persists in the gastric environment, contributing both to host defense and epithelial injury that promotes tumorigenesis. While long-term IFN gamma memory has been described in immune cells, its impact on gastric epithelial reprogramming remains unclear.Methods We exposed gastric epithelial cells to brief IFN gamma stimulation and analyzed gene expression, transcription factor involvement, and epigenetic modifications. Chromatin remodeling at the TFF1 locus was assessed through histone modification analyses, and the role of DNA methylation was evaluated using pharmacological inhibitors. Findings were validated in primary gastric mucosoids exposed to inflammatory mediators released by H. pylori-activated immune cells.Results Transient IFN gamma exposure caused stable repression of TFF1, a gastric tumor suppressor frequently lost in H. pylori-associated cancer. This repression persisted after cytokine removal and was mediated by the IFN gamma-responsive transcription factor C/EBP beta. Mechanistically, TFF1 silencing was associated with chromatin remodeling, including altered histone H3S10 phosphorylation and H3K9 acetylation at the TFF1 locus. Inhibition of DNA methylation prevented both TFF1 downregulation and C/EBP beta upregulation, indicating that de novo methylation stabilizes the silenced state. Similar durable TFF1 repression was observed in primary gastric mucosoids following exposure to inflammatory mediators.Discussion Overall, our findings show that transient inflammatory signals cause durable gene silencing through epigenetic remodeling, revealing how chronic inflammation can reprogram epithelial cells and promote cancer, while suggesting strategies to reverse these effects
Il regime dei bona materna nella legislazione di Costantino. Concordanze e discordanze tra Codex Theodosianus e Codex repetitae praelectionis
No full textIl presente contributo prende le mosse dal testo della costituzione di Costantino - la cui datazione è incerta, poiché databile tra il 315 e il 319 d.C. - contenuta in Cod. Th. 8.18.1, per poi porla a confronto con la corrispondente statuizione riportata dai compilatori giustinianei in Cod. Iust. 6.60.1, con l'obiettivo di comprendere come questa legge abbia contribuito alla definizione del regime dei bona materna, introducendo una delle principali innovazioni del diritto successorio tardoantico, consistente nell’attribuzione al pater familias non già della proprietà di tali beni, destinati ai figli, ma soltanto il godimento e l’amministrazione. Il lavoro cerca inoltre di concentrare l'attenzione sulle analogie e le differenze tra i testi legislativi per una ricognizione dei mutamenti conosciuti da questa disciplina tra la compilazione teodosiana e quella giustinianea, nonché sulle finalità perseguite dal riutilizzo dei testi giuridici nel tardoantico.This essay begins with the text of Constantin’s constitution – the dating of which is uncertain, being placed between 315 and 319 AD – contained in Cod. Th. 8.18.1, and then compares it with the corresponding provision reported by Justinian’s compilers in Cod. Iust. 6.60.1. The aim is to understand how this law contributed to the definition of the bona materna regime, introducing one of the principal innovations of late antique inheritance law: the pater familias was not vested in such assets, which were intended for his children, but only in their fruition and administration. The essay also focuses on the similarities and differences between the legislative texts in order to explore the mutations in this regulation between the Theodosian and Justinian compilations, as well as to reflect on the objectives pursued by the reuse of legal texts in late antiquity
CLASSICAL AND INNOVATIVE APPLICATIONS OF NMR SPECTROSCOPY IN THE METABOLOMIC PROFILING OF BIOLOGIAL SAMPLES
No full textMETABOLOMICS IS AN OMIC SCIENCE WITH RAPIDLY EXPANDING APPLICATIONS, INCLUDING DRUG DISCOVERY. WITHIN THIS FIELD, PHARMACOMETABOLOMICS HAS DEVELOPED AS A BRANCH DEDICATED TO STUDYING DRUG-INDUCED METABOLIC EFFECTS. IT PLAYS A CRUCIAL ROLE IN HYPOTHESIS GENERATION, AS DEMONSTRATED BY ITS ABILITY TO UNCOVER PREVIOUSLY UNRECOGNIZED PATHWAYS INVOLVED IN DRUG ACTION. A MAJOR STRENGTH OF PHARMACOMETABOLOMICS LIES IN ITS USE TO EXPLORE CELLULAR MECHANISMS OF ACTION (MOA), OFFERING AN UNBIASED ALTERNATIVE TO TRADITIONAL HYPOTHESIS-DRIVEN APPROACHES THAT TYPICALLY FOCUS ON SPECIFIC RECEPTORS OR ISOLATED PATHWAYS. IN CONTRAST, UNTARGETED METABOLOMICS PROVIDES A COMPREHENSIVE VIEW OF TREATMENT-INDUCED METABOLIC CHANGES AND CAN REVEAL UNEXPECTED OR OFF-TARGET EFFECTS.
AS PART OF MY PHD RESEARCH, I INVESTIGATED THE IN VITRO BIOLOGICAL MOA OF NICOTINE AND NERVE GROWTH FACTOR (NGF) USING THE POTENTIAL OF UNTARGETED METABOLOMICS. EMPLOYING SH-SY5Y NEUROBLASTOMA CELLS, I ANALYZED BOTH THE EXOMETABOLOME (CULTURE MEDIUM) AND ENDOMETABOLOME (CELLULAR EXTRACTS) FOLLOWING TREATMENT WITH THESE MOLECULES, WHICH ARE OF POTENTIAL INTEREST FOR ALZHEIMER’S DISEASE (AD) THERAPY.
AS A PRELIMINARY STEP, WE CONFIRMED THAT EXPOSURE TO RECOMBINANT AMYLOID Β PEPTIDE AΒ(1–42) REPRODUCED IN OUR MODEL THE KEY METABOLIC DYSREGULATIONS CHARACTERISTIC OF AD. WE THEN EVALUATED WHETHER NICOTINE AND NGF COULD COUNTERACT THESE ALTERATIONS. TO CAPTURE THE DYNAMIC EXCHANGE OF METABOLITES BETWEEN COMPARTMENTS ESSENTIAL FOR INTERPRETING CELLULAR FUNCTION WE BUILT FOR THE FIRST TIME A STATISTICAL MODEL THAT COMBINES THE QUANTIFICATION MATRICES OF INTRA- AND EXTRACELLULAR METABOLITES.
OUR FINDINGS DEMONSTRATE THAT NICOTINE EXERTS NEUROPROTECTIVE EFFECTS BY RESTORING METABOLIC IMBALANCES ASSOCIATED WITH AD PATHOLOGY. IN PARTICULAR, NICOTINE REVERSED THE MAJORITY OF AΒ(1–42)-INDUCED ALTERATIONS, INCLUDING DISRUPTIONS IN NEUROTRANSMISSION-RELATED PATHWAYS, ENERGY METABOLISM, AND MEMBRANE PHOSPHOLIPID TURNOVER. NGF, BY CONTRAST, EXHIBITED NEUROPROTECTIVE ACTIVITY PRIMARILY BY REDUCING GLUTAMATE AND GLYCINE CONCENTRATIONS AND FUNCTIONING AS AN EARLY MODULATOR OF KEY BIOCHEMICAL PATHWAYS, THEREBY PREVENTING REDOX DISEQUILIBRIUM AND ALTERATIONS IN ENERGY METABOLISM.
DURING MY INTERNATIONAL RESEARCH PERIOD, I FURTHER SPECIALIZED IN NMR SPECTROSCOPY WITH FOCUSING ON NON-HYDROGENATIVE PARAHYDROGEN-INDUCED HYPERPOLARIZATION (NHPHIP). AT THE MAGNETIC RESONANCE RESEARCH CENTER OF RADBOUD UNIVERSITY, UNDER THE SUPERVISION OF DR. MARCO TESSARI, I CONDUCTED THE FIRST TARGETED AND CHIRAL METABOLOMIC ANALYSIS OF AMINO ACID CONTENT IN ANIMAL TISSUES USING THIS APPROACH. THIS TECHNIQUE ENABLED THE DISCRIMINATION BETWEEN D- AND L-AMINO ACID ENANTIOMERS AND REVEALED AMINO ACID IMBALANCES ASSOCIATED WITH ALTERED D-ASPARTATE LEVELS. NHPHIP PROVED PARTICULARLY VALUABLE FOR THIS STUDY, AS SEVERAL AMINO ACIDS ARE DIRECTLY OR INDIRECTLY INVOLVED IN NEUROTRANSMISSION. TAKEN TOGETHER, THE APPLICATION OF NHPHIP IN THIS CONTEXT HIGHLIGHTS THE POTENTIAL OF NMR HYPERPOLARIZATION TECHNIQUES FOR TARGETED METABOLOMICS INVESTIGATIONS OF AMINO ACID DYSREGULATION.METABOLOMICS IS AN OMIC SCIENCE WITH RAPIDLY EXPANDING APPLICATIONS, INCLUDING DRUG DISCOVERY. WITHIN THIS FIELD, PHARMACOMETABOLOMICS HAS DEVELOPED AS A BRANCH DEDICATED TO STUDYING DRUG-INDUCED METABOLIC EFFECTS. IT PLAYS A CRUCIAL ROLE IN HYPOTHESIS GENERATION, AS DEMONSTRATED BY ITS ABILITY TO UNCOVER PREVIOUSLY UNRECOGNIZED PATHWAYS INVOLVED IN DRUG ACTION. A MAJOR STRENGTH OF PHARMACOMETABOLOMICS LIES IN ITS USE TO EXPLORE CELLULAR MECHANISMS OF ACTION (MOA), OFFERING AN UNBIASED ALTERNATIVE TO TRADITIONAL HYPOTHESIS-DRIVEN APPROACHES THAT TYPICALLY FOCUS ON SPECIFIC RECEPTORS OR ISOLATED PATHWAYS. IN CONTRAST, UNTARGETED METABOLOMICS PROVIDES A COMPREHENSIVE VIEW OF TREATMENT-INDUCED METABOLIC CHANGES AND CAN REVEAL UNEXPECTED OR OFF-TARGET EFFECTS.
AS PART OF MY PHD RESEARCH, I INVESTIGATED THE IN VITRO BIOLOGICAL MOA OF NICOTINE AND NERVE GROWTH FACTOR (NGF) USING THE POTENTIAL OF UNTARGETED METABOLOMICS. EMPLOYING SH-SY5Y NEUROBLASTOMA CELLS, I ANALYZED BOTH THE EXOMETABOLOME (CULTURE MEDIUM) AND ENDOMETABOLOME (CELLULAR EXTRACTS) FOLLOWING TREATMENT WITH THESE MOLECULES, WHICH ARE OF POTENTIAL INTEREST FOR ALZHEIMER’S DISEASE (AD) THERAPY.
AS A PRELIMINARY STEP, WE CONFIRMED THAT EXPOSURE TO RECOMBINANT AMYLOID Β PEPTIDE AΒ(1–42) REPRODUCED IN OUR MODEL THE KEY METABOLIC DYSREGULATIONS CHARACTERISTIC OF AD. WE THEN EVALUATED WHETHER NICOTINE AND NGF COULD COUNTERACT THESE ALTERATIONS. TO CAPTURE THE DYNAMIC EXCHANGE OF METABOLITES BETWEEN COMPARTMENTS ESSENTIAL FOR INTERPRETING CELLULAR FUNCTION WE BUILT FOR THE FIRST TIME A STATISTICAL MODEL THAT COMBINES THE QUANTIFICATION MATRICES OF INTRA- AND EXTRACELLULAR METABOLITES.
OUR FINDINGS DEMONSTRATE THAT NICOTINE EXERTS NEUROPROTECTIVE EFFECTS BY RESTORING METABOLIC IMBALANCES ASSOCIATED WITH AD PATHOLOGY. IN PARTICULAR, NICOTINE REVERSED THE MAJORITY OF AΒ(1–42)-INDUCED ALTERATIONS, INCLUDING DISRUPTIONS IN NEUROTRANSMISSION-RELATED PATHWAYS, ENERGY METABOLISM, AND MEMBRANE PHOSPHOLIPID TURNOVER. NGF, BY CONTRAST, EXHIBITED NEUROPROTECTIVE ACTIVITY PRIMARILY BY REDUCING GLUTAMATE AND GLYCINE CONCENTRATIONS AND FUNCTIONING AS AN EARLY MODULATOR OF KEY BIOCHEMICAL PATHWAYS, THEREBY PREVENTING REDOX DISEQUILIBRIUM AND ALTERATIONS IN ENERGY METABOLISM.
DURING MY INTERNATIONAL RESEARCH PERIOD, I FURTHER SPECIALIZED IN NMR SPECTROSCOPY WITH FOCUSING ON NON-HYDROGENATIVE PARAHYDROGEN-INDUCED HYPERPOLARIZATION (NHPHIP). AT THE MAGNETIC RESONANCE RESEARCH CENTER OF RADBOUD UNIVERSITY, UNDER THE SUPERVISION OF DR. MARCO TESSARI, I CONDUCTED THE FIRST TARGETED AND CHIRAL METABOLOMIC ANALYSIS OF AMINO ACID CONTENT IN ANIMAL TISSUES USING THIS APPROACH. THIS TECHNIQUE ENABLED THE DISCRIMINATION BETWEEN D- AND L-AMINO ACID ENANTIOMERS AND REVEALED AMINO ACID IMBALANCES ASSOCIATED WITH ALTERED D-ASPARTATE LEVELS. NHPHIP PROVED PARTICULARLY VALUABLE FOR THIS STUDY, AS SEVERAL AMINO ACIDS ARE DIRECTLY OR INDIRECTLY INVOLVED IN NEUROTRANSMISSION. TAKEN TOGETHER, THE APPLICATION OF NHPHIP IN THIS CONTEXT HIGHLIGHTS THE POTENTIAL OF NMR HYPERPOLARIZATION TECHNIQUES FOR TARGETED METABOLOMICS INVESTIGATIONS OF AMINO ACID DYSREGULATION
ISOCHROMAN-3-ONE AS A KEY BUILDING BLOCK FOR THE SYNTHESIS OF VERSATILE SPIRO, BRIDGED, AND POLYCYCLIC SCAFFOLDS
No full textFIRST, IN COLLABORATION WITH OFIAL’S GROUP, QUANTIFICATION OF THE NUCLEOPHILICITY OF 3-ISOCHROMANONES AND 2-COUMARANONES ON THE MAYR SCALE HAS BEEN DONE. DEPROTONATION IN DMSO GENERATED ENOLATES WHOSE SECOND-ORDER RATE CONSTANTS TOWARD QUINONE METHIDES AND ARYLIDENEMALONATES WERE MEASURED BY STOPPED-FLOW UV–VIS. FITTING TO THE MAYR–PATZ EQUATION GAVE N = 25.39, Sn = 0.53 (ISOCHROMANONE) AND N = 19.60, Sn = 0.75 (COUMARANONE), SHOWING THAT THEIR BRØNSTED ACIDITY CORRELATES WITH HIGH NUCLEOPHILICITY.
WE THEN APPLIED THIS REACTIVITY IN PHASE-TRANSFER-CATALYZED MICHAEL ADDITIONS OF SUBSTITUTED ISOCHROMAN-3-ONES AND COUMARANONES TO CHALCONES UNDER MILD K2CO3/TBAB CONDITIONS, ESTABLISHING A GENERAL, CATALYTIC C–C BOND FORMATION WITH BROAD SCOPE. THIS ENABLED A ONE-POT DOUBLE-CASCADE TO 3-SPIROPIPERIDINES: ISOCHROMANONES FIRST COUPLED WITH 2-CYANOBENZALDEHYDES OR 2-ACETYLBENZONITRILES TO GIVE BINUCLEOPHILIC ISOINDOLINONE–ISOCHROMANONE HYBRIDS, WHICH UNDERWENT [3+3] SPIROCYCLIZATION WITH ACROLEIN OR HIGHER Α,Β-UNSATURATED ALDEHYDES. ACROLEIN GAVE SINGLE DIASTEREOMERS, AND SUBSTITUTION ON THE ISOINDOLINONE 3-POSITION CONTROLLED WHETHER A MICHAEL/HEMIAMINAL OR AZA-MICHAEL/CROSS-ALDOL PATHWAY DOMINATED. PRODUCTS WERE EASILY DIVERSIFIED (OXIDATION, DEHYDRATION, DEHYDROXYLATION).
NEXT, WORKING WITH 4-BROMOISOCHROMAN-3-ONE, WE UNCOVERED A TANDEM SEQUENCE: BASE-PROMOTED AUTOXIDATION TO ISOCHROMANE-3,4-DIONE FOLLOWED BY DIENOLIZATION/DEAROMATIZATION AND A DIELS–ALDER REACTION WITH ELECTRON-POOR ALKENES, PRODUCING REGIO- AND DIASTEREOSELECTIVE BRIDGED POLYCYCLIC LACTONES. USING ISOLATED 3,4-DIONES DIRECTLY IMPROVED ATOM ECONOMY AND EXPANDED THE SCOPE TO CHALCONES, ENONES, FUMARATES/MALEATES, NITRO- AND CYANO-ALKENES, OFTEN WITH STEREOSPECIFIC OUTCOMES CONSISTENT WITH A CONCERTED [4+2] PROCESS. REDUCTIVE LACTONE OPENING (LIBH4) AFFORDED TETRAHYDRONAPHTHALENE TETROLS RELATED TO BENZOCONDURITOL MOTIFS.
FINALLY, WE EXTENDED THIS DIELS–ALDER PLATFORM TOWARD ASYMMETRIC VARIANTS USING IN SITU GENERATED DIENES UNDER COOPERATIVE ORGANOCATALYSIS, AND ALSO SHOWED THAT HYDROXY-PYRONES OR ISOCHROMAN-3,4-DIONES WITH ALLENOATES OR BUTYNOATES DIRECTLY FURNISH 1,2,3-SUBSTITUTED PHENOLS AND NAPHTHOLS VIA CYCLOADDITION–DECARBOXYLATION–REAROMATIZATION.
OVERALL, THE RESULTS ESTABLISH 3-ISOCHROMANONE AS A QUANTITATIVELY VALIDATED, HIGHLY NUCLEOPHILIC BENZYLIC LACTONE ENABLING METAL-FREE MICHAEL ADDITIONS, CONCISE [3+3] SPIROCYCLIZATIONS, AND TANDEM OXIDATION/DIELS–ALDER IN THE CASE OF DIONE ROUTES TO COMPLEX POLYCYCLES WITH POTENTIAL FOR ASYMMETRIC AND MEDICINAL EXTENSIONS.FIRST, IN COLLABORATION WITH OFIAL’S GROUP, QUANTIFICATION OF THE NUCLEOPHILICITY OF 3-ISOCHROMANONES AND 2-COUMARANONES ON THE MAYR SCALE HAS BEEN DONE. DEPROTONATION IN DMSO GENERATED ENOLATES WHOSE SECOND-ORDER RATE CONSTANTS TOWARD QUINONE METHIDES AND ARYLIDENEMALONATES WERE MEASURED BY STOPPED-FLOW UV–VIS. FITTING TO THE MAYR–PATZ EQUATION GAVE N = 25.39, Sn = 0.53 (ISOCHROMANONE) AND N = 19.60, Sn = 0.75 (COUMARANONE), SHOWING THAT THEIR BRØNSTED ACIDITY CORRELATES WITH HIGH NUCLEOPHILICITY.
WE THEN APPLIED THIS REACTIVITY IN PHASE-TRANSFER-CATALYZED MICHAEL ADDITIONS OF SUBSTITUTED ISOCHROMAN-3-ONES AND COUMARANONES TO CHALCONES UNDER MILD K2CO3/TBAB CONDITIONS, ESTABLISHING A GENERAL, CATALYTIC C–C BOND FORMATION WITH BROAD SCOPE. THIS ENABLED A ONE-POT DOUBLE-CASCADE TO 3-SPIROPIPERIDINES: ISOCHROMANONES FIRST COUPLED WITH 2-CYANOBENZALDEHYDES OR 2-ACETYLBENZONITRILES TO GIVE BINUCLEOPHILIC ISOINDOLINONE–ISOCHROMANONE HYBRIDS, WHICH UNDERWENT [3+3] SPIROCYCLIZATION WITH ACROLEIN OR HIGHER Α,Β-UNSATURATED ALDEHYDES. ACROLEIN GAVE SINGLE DIASTEREOMERS, AND SUBSTITUTION ON THE ISOINDOLINONE 3-POSITION CONTROLLED WHETHER A MICHAEL/HEMIAMINAL OR AZA-MICHAEL/CROSS-ALDOL PATHWAY DOMINATED. PRODUCTS WERE EASILY DIVERSIFIED (OXIDATION, DEHYDRATION, DEHYDROXYLATION).
NEXT, WORKING WITH 4-BROMOISOCHROMAN-3-ONE, WE UNCOVERED A TANDEM SEQUENCE: BASE-PROMOTED AUTOXIDATION TO ISOCHROMANE-3,4-DIONE FOLLOWED BY DIENOLIZATION/DEAROMATIZATION AND A DIELS–ALDER REACTION WITH ELECTRON-POOR ALKENES, PRODUCING REGIO- AND DIASTEREOSELECTIVE BRIDGED POLYCYCLIC LACTONES. USING ISOLATED 3,4-DIONES DIRECTLY IMPROVED ATOM ECONOMY AND EXPANDED THE SCOPE TO CHALCONES, ENONES, FUMARATES/MALEATES, NITRO- AND CYANO-ALKENES, OFTEN WITH STEREOSPECIFIC OUTCOMES CONSISTENT WITH A CONCERTED [4+2] PROCESS. REDUCTIVE LACTONE OPENING (LIBH4) AFFORDED TETRAHYDRONAPHTHALENE TETROLS RELATED TO BENZOCONDURITOL MOTIFS.
FINALLY, WE EXTENDED THIS DIELS–ALDER PLATFORM TOWARD ASYMMETRIC VARIANTS USING IN SITU GENERATED DIENES UNDER COOPERATIVE ORGANOCATALYSIS, AND ALSO SHOWED THAT HYDROXY-PYRONES OR ISOCHROMAN-3,4-DIONES WITH ALLENOATES OR BUTYNOATES DIRECTLY FURNISH 1,2,3-SUBSTITUTED PHENOLS AND NAPHTHOLS VIA CYCLOADDITION–DECARBOXYLATION–REAROMATIZATION.
OVERALL, THE RESULTS ESTABLISH 3-ISOCHROMANONE AS A QUANTITATIVELY VALIDATED, HIGHLY NUCLEOPHILIC BENZYLIC LACTONE ENABLING METAL-FREE MICHAEL ADDITIONS, CONCISE [3+3] SPIROCYCLIZATIONS, AND TANDEM OXIDATION/DIELS–ALDER IN THE CASE OF DIONE ROUTES TO COMPLEX POLYCYCLES WITH POTENTIAL FOR ASYMMETRIC AND MEDICINAL EXTENSIONS
