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Computational Methods to Investigate Dual-Target-Directed Ligands
No full textMolecules designed to modulate single targets typically lack efficacy when dealing with
multifactorial diseases. Even combining single-target agents through drug cocktails
represents a less-than-ideal strategy, as it can lead to less predictable pharmacokinetics
and an increased risk of drug-drug interactions. To overcome these limitations,
researchers shift their attention to the rational design of compounds capable of
simultaneously modulating multiple targets, thus influencing interconnected biological
pathways within a single molecular framework. These compounds, commonly referred to
as MultiTarget-Directed Ligands (MTDLs), hold the potential to elicit an additive, and
ideally synergistic, disease-modifying effect, while avoiding the issues arising from drug
drug interactions. However, their rational design remains challenging, as it depends on
both the biological and structural similarity of targets of interest and on the existence of
common chemical space between their ligands.
In this thesis, we aimed to expand the current understanding of this growing field,
focusing primarily on the simplest example of MTDLs, which is represented by
compounds rationally designed to modulate two distinct proteins, commonly known as
Dual-Target-Directed Ligands (DTDLs). Several computational approaches were
employed to systematically analyze the state-of-the-art of the field, revealing common
methodologies adopted in the target selection and rational design of dual-active
compounds. Building on the obtained insights, we also developed a data-driven pipeline
to identify and leverage candidate target pairs that are “hidden in plain sight”,
demonstrating that, before venturing into more complex polypharmacological scenarios,
many readily available target combinations remain unexplored. One of these identified
candidate target pairs, consisting of the Serotonin 3a (5-HT3A) receptor and soluble
epoxide hydrolase (sEH), is presented and discussed in detail as a case study.
Subsequently, we shifted our attention from data-driven chemoinformatic approaches to
the actual discovery of dual dopamine D3 receptor (D3R) / glycogen synthase kinase-3
beta (GSK-3β) modulators from ultra-large libraries-derived chemical space, with
potential applications in neuropsychiatric disorders. By combining two complementary
computational approaches, we successfully prioritized and identified compound
ARN27663, which exhibited the desired dual pharmacological profile.Molecules designed to modulate single targets typically lack efficacy when dealing with
multifactorial diseases. Even combining single-target agents through drug cocktails
represents a less-than-ideal strategy, as it can lead to less predictable pharmacokinetics
and an increased risk of drug-drug interactions. To overcome these limitations,
researchers shift their attention to the rational design of compounds capable of
simultaneously modulating multiple targets, thus influencing interconnected biological
pathways within a single molecular framework. These compounds, commonly referred to
as MultiTarget-Directed Ligands (MTDLs), hold the potential to elicit an additive, and
ideally synergistic, disease-modifying effect, while avoiding the issues arising from drug
drug interactions. However, their rational design remains challenging, as it depends on
both the biological and structural similarity of targets of interest and on the existence of
common chemical space between their ligands.
In this thesis, we aimed to expand the current understanding of this growing field,
focusing primarily on the simplest example of MTDLs, which is represented by
compounds rationally designed to modulate two distinct proteins, commonly known as
Dual-Target-Directed Ligands (DTDLs). Several computational approaches were
employed to systematically analyze the state-of-the-art of the field, revealing common
methodologies adopted in the target selection and rational design of dual-active
compounds. Building on the obtained insights, we also developed a data-driven pipeline
to identify and leverage candidate target pairs that are “hidden in plain sight”,
demonstrating that, before venturing into more complex polypharmacological scenarios,
many readily available target combinations remain unexplored. One of these identified
candidate target pairs, consisting of the Serotonin 3a (5-HT3A) receptor and soluble
epoxide hydrolase (sEH), is presented and discussed in detail as a case study.
Subsequently, we shifted our attention from data-driven chemoinformatic approaches to
the actual discovery of dual dopamine D3 receptor (D3R) / glycogen synthase kinase-3
beta (GSK-3β) modulators from ultra-large libraries-derived chemical space, with
potential applications in neuropsychiatric disorders. By combining two complementary
computational approaches, we successfully prioritized and identified compound
ARN27663, which exhibited the desired dual pharmacological profile
Alfredo Oriani il corpo e la tecnologia, dalla scoperta dell'individuo liberale alla manipolazione fascista
No full textLa “scoperta” del corpo in Alfredo Oriani (1852–1909) costituisce un problema
storiografico. Curiosamente egli fu tra i primi ad avere coscienza dell’importanza della
corporeità nell’epoca liberale e al contempo sarà il principale simbolo dello
spossessamento di quel corpo, per opera di Mussolini e del fascismo, quando Oriani
era già morto da un quindicennio. Nell’Italia ancora rurale degli ultimi decenni
dell’Ottocento, l’avvento della tecnologia rivoluzionava l’idea del corpo e delle sue
possibilità. Molti ne furono spaventati temendo una deriva individualistica. Oriani
invece, intuiva nella bicicletta quella “protesi” meccanica capace di potenziare i corpi,
fino a vincere i limiti e le tradizionali paure degli elementi naturali. Oriani elevava così
il corpo fisico alla nobiltà delle tradizionali facoltà mentali, definendo un Io corporeo
e la conquista di un “tempo per sé”, come possiamo cogliere nel suo diario di un
lungo viaggio in bicicletta del 1897. Questo Oriani era sacrificato dall’appropriazione
compiuta da Mussolini, nel 1924, con cui il Duce inaugurava l’“orianesimo fascista”.
Oriani era dichiarato “precursore” del fascismo e fatto oggetto di un culto di tipo
collettivista che cancellava quell’emancipazione individuale, che Oriani aveva affidato al partito liberale, definito “partito del futuro”, per la difesa della libertà e della
sovranità dell’individuo
De novo cysteine biosynthesis in Pseudomonas aeruginosa: Characterization of the two main cysteine synthase isoforms
No full textMost bacteria synthesize L-cysteine via the reductive sulfate assimilation pathway, which is absent in humans and thus a promising source of antibiotic targets. Despite its relevance, this pathway remains poorly studied in Pseudomonas aeruginosa, a major antimicrobial resistance (AMR)-associated pathogen. We have identified the two main isoforms of cysteine synthase in P. aeruginosa (PA2709 and PA0932), which are pyridoxal 5′-phosphate-dependent enzymes that enable bacterial growth in minimal medium supplemented with either sulfate or thiosulfate. PA2709 is a classical O-acetylserine (OAS) sulfhydrylase, using bisulfide as a sulfur source. PA0932 also shows an OAS-dependent S-sulfocysteine synthase activity. Deletion of either one of the two genes does not lead to cysteine auxotrophy, which is reached only with the double deletion mutant. Interestingly, in the presence of thiosulfate as the only sulfur source, PA0932 displays a cysteine bradytrophic phenotype, suggesting the activation of an alternative sulfur assimilation pathway under these conditions
Selenoprotein N and SEPN1-Related Myopathies: Mechanisms, Models, and Therapeutic Perspectives
No full text: Selenoprotein N (SelN or SELENON) is a selenium-containing protein of the endoplasmic/sarcoplasmic reticulum (ER/SR), encoded by the SEPN1 gene. In skeletal muscle, SelN is particularly important for regulating SR calcium homeostasis. It acts as a calcium sensor, modulating the activity of the sarcoplasmic reticulum calcium pump (SERCA) through a redox-dependent mechanism. Loss-of-function mutations in the SEPN1 gene give rise to a spectrum of skeletal muscle disorders collectively referred to as SEPN1-related myopathies (SEPN1-RM). Histopathologically, SEPN1-RM is characterized by the presence of minicores, which are localized regions within muscle fibers exhibiting mitochondrial depletion (i.e., cores) and sarcomeric disarray. As no effective therapy is currently available for SEPN1-RM, understanding SelN biology through loss-of-function models remains essential for elucidating disease mechanisms and identifying potential therapeutic targets. This review examines the current knowledge on SelN function and the pathological mechanisms underlying SEPN1 loss-of-function, with a particular focus on the connection between calcium handling, oxidative/ER stress, and muscle dysfunction. It also highlights emerging strategies aimed at restoring SelN activity or mitigating downstream defects, outlining potential therapeutic avenues for SEPN1-RM
Causal Reversibility in Nondeterministic Process Calculi Extended with Time or Probabilities
No full textIn addition to forward computations, a reversible system also features backward computations along which the effects of forward ones can be undone. This is accomplished by reverting executed actions starting from the last one. Since the last performed action may not be uniquely identifiable in a concurrent setting, Danos and Krivine proposed causal reversibility: an executed action can be undone provided that all of its consequences have been undone already. Phillips and Ulidowski then showed how to define nondeterministic process calculi that meet causal reversibility by construction. Lanese, Phillips, and Ulidowski subsequently classified the basic properties that ensure causal reversibility. In this paper we investigate the extent to which those techniques apply to reversible nondeterministic process calculi that include quantitative aspects. Firstly, we consider the introduction of time described via numeric delays with action execution separated from time passing like in the calculus of Moller and Tofts, where actions can be lazy or eager and time is subject to time determinism and time additivity. Secondly, we address the introduction of probabilities like in the calculus of Hansson and Jonsson, in which action execution and probabilistic choices alternate. We show that both resulting reversible calculi satisfy causal reversibility provided that suitable variants of the aforementioned techniques are developed to guarantee the proper forward and backward interplay of nondeterminism and quantitative aspects. The use of the former calculus is illustrated on a timeout mechanism, whereas the use of the latter is exemplified on quantum teleportation
ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets
No full text: Proteostasis maintains the balance between protein synthesis, folding, and degradation within the endoplasmic reticulum (ER). This quality-control system ensures that proteins undergo proper post-translational modifications-such as PDI-ERO1-mediated oxidative folding and STT3-dependent N-glycosylation-so that only correctly folded proteins proceed through the secretory pathway. Impairment of protein load, folding capacity, or degradation via the ER-associated degradation (ERAD) pathway leads to the accumulation of unfolded proteins, triggering ER stress and activating the unfolded protein response (UPR), which, in the first instance, is an adaptive signaling network designed to restore homeostasis by adjusting protein synthesis, enhancing folding capacity, and promoting the clearance of misfolded proteins. During ER stress, the ER undergoes morphological and functional remodeling to manage the increased folding burden, including an increase of ER-mitochondria contact sites (ERMCs). These nanometric junctions (~10-100 nm) facilitate lipid and metabolite exchange and mediate calcium and reactive oxygen species signaling to support cellular metabolism. However, chronic ER stress can further tighten ERMCs, leading to calcium overload, mitochondrial dysfunction, and apoptosis. This review examines the core mechanisms underlying ER proteostasis in the context of ER stress and explores how ER stress first boosts mitochondrial activity and later impairs it through ERMCs, contributing to cell death and disease. Finally, emerging therapeutic strategies aimed at restoring proteostasis and modulating the dynamics of ERMCs are highlighted as promising interventions for conditions, such as cancer and congenital myopathies, where ER and mitochondrial dysfunction play central roles in pathogenesis
Semiotica e forme di vita musicale. Ambienti co-evolutivi tra biosfera, semiosfera e tecnosfera
No full textThe thesis examines the co-evolutionary ties between musical cultures, enunciative practices, and contemporary media technologies. It is based on the assumption that technologies are shaped through relations of co-dependence among the biosphere, technosphere, and semiosphere. The aim is to describe how certain media affordances influence current musical forms of life, understood as discursive configurations composed of signs, texts, objects, and social practices.
From a socio-semiotic perspective, the study analyzes the processes of meaning-making generated by cultural practices associated with musical enunciation in new mediatized environments. The research is structured into three analytical units: (i) a transnational urban music circuit and its digital ecosystem; (ii) creative practices enabled by the generative AI platform Suno;
and (iii) human–machine interaction through the Neural DSP Quad Cortex device.
The methodological approach combines ethnography, participant and non-participant observation, and netnography. The conclusions articulate micro-level findings, specific to each case, and meso-level reflections that identify general patterns of transformation in contemporary musical forms of life, enunciation, and language. The thesis also proposes theoretical and methodological tools for future research on similar co-evolutionary phenomena.
Keywords: forms of life – musical cultures – enunciative practices – digital platforms – socio-
semiotics.La tesi esamina le relazioni co-evolutive tra culture musicali, pratiche enunciative e tecnologie
mediali contemporanee. Il lavoro parte dal presupposto che le tecnologie si configurino attraverso
relazioni di co-dipendenza tra biosfera, tecnosfera e semiosfera. L’obiettivo è descrivere come
determinate affordance mediali influenzino le forme di vita musicali attuali, intese come
configurazioni discorsive composte da segni, testi, oggetti e pratiche sociali.
Da una prospettiva socio-semiotica, lo studio analizza la produzione di senso generata dalle
pratiche culturali associate all’enunciazione musicale nei nuovi ambienti mediatizzati. La ricerca è
articolata in tre unità analitiche: (i) un circuito musicale urbano transnazionale e il suo ecosistema
digitale; (ii) le pratiche creative rese possibili dalla piattaforma di intelligenza artificiale generativa
Suno; e (iii) l’interazione uomo-macchina nel dispositivo Neural DSP Quad Cortex.
L’approccio metodologico combina etnografia, osservazione (partecipante e non partecipante) e netnografia. Le conclusioni articolano risultati di livello micro, specifici di ciascun caso, e riflessioni di livello meso, che identificano modelli generali di trasformazione nelle forme di vita e nell’enunciazione e linguaggio musicale contemporaneo, proponendo inoltre strumenti teorici e metodologici utili per future ricerche su fenomeni co-evolutivi simili.
Parole chiavi: forme di vita – culture musicali – pratiche enunciative – piattaforme digitali – socio-
semiotica
In vitro activity of gallium-protoporphyrin IX against Leishmania major and Leishmania infantum
No full textLeishmania spp., the causative agents of leishmaniasis, pose significant global health threats, with visceral leishmaniasis being the most severe and fatal form. The increasing drug resistance in the treatment of leishmaniasis emphasizes the urgent need for novel therapeutic approaches. One promising strategy involves targeting essential cellular mechanisms such as nutrient acquisition, particularly iron, which is critical for energy metabolism and signal transduction. Leishmania spp. cannot synthesize heme de novo and rely on host-derived iron and heme for survival and pathogenicity. Gallium [Ga(III)] is an iron [Fe(III)]-mimetic molecule that has emerged as a promising antimicrobial agent, offering a novel approach to combat infections, mainly by replacing Fe(III) in redox enzymes thereby disrupting essential metabolic pathways and impairing microbial viability. In this study, the antiparasitic activity of Ga (III)-protoporphyrin IX (GaPPIX) was tested against Leishmania major and Leishmania infantum, both in promastigotes and intracellular amastigotes. Our results demonstrate that GaPPIX inhibits the viability of both species, specifically targeting the enzymatic activity of cytochrome c oxidase, with a higher sensitivity observed in L. major. The inhibitory effect is reversed by hemin, suggesting specificity for Leishmania heme-dependent cellular processes and a possible cytostatic action. Moreover, we found that GaPPIX can effectively synergize with miltefosine. This feature, coupled with its minimal toxicity toward human cells, makes GaPPIX a good candidate to be potentially developed as a novel anti-Leismania agent.IMPORTANCEThis study is significant as it addresses a critical challenge in leishmaniasis management, namely, the increasing incidence of drug resistance and toxicity, compounded by the scarcity of effective therapeutic options. We demonstrate that GaPPIX, a heme-mimetic compound, exhibits potent antiparasitic activity against both Leishmania major and Leishmania infantum, while displaying minimal cytotoxicity toward human cells, underscoring its potential as a safe and targeted therapeutic candidate. Importantly, the ability of GaPPIX to synergize with the first-line drug miltefosine highlights its translational relevance in combination therapies, which are essential for overcoming resistance and improving treatment efficacy. Collectively, these findings advance GaPPIX as a promising approach for the development of innovative therapeutics against a neglected but globally significant disease
Access to Fused Indolines with a Quaternary N,N′-Aminal Center: Aza-Wacker-Type Cyclization for a Telescoped Reaction Sequence
No full text: A highly efficient one-pot sequence has been developed for the rapid construction of fused polycyclic indolines bearing a C2-N,N'-aminal quaternary center. The process, which employs 1,2-diaza-1,3-dienes and 2-substituted indoles as key substrates, proceeds through a Zn(II)-catalyzed Michael addition, followed by an intramolecular Cu(II)-catalyzed dearomative oxidative cyclization. This sequence enabling N-C(sp2) bond formation via formal C(sp2)-H activation, azoalkene addition, and aza-Wacker-type cyclization exhibits broad substrate tolerance and delivers unprecedented tricyclic indole architectures (namely 9a-substituted 9,9a-dihydro-1H-pyridazino[3,4-b]indoles) in good to excellent yields