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Stereochemical insight for MexXY-OprM efflux system inhibition in Pseudomonas aeruginosa from a pool of dihydro and tetrahydro berberine derivatives
No full text: Pseudomonas aeruginosa is a Gram-negative pathogen responsible for severe infections, particularly in immunocompromised patients. Its widespread antibiotic resistance is a growing concern, primarily due to the overexpression of efflux pumps (EPs) such as the MexXY-OprM system, which plays a major role in aminoglycoside resistance. Targeting EPs with specific inhibitors (EPIs) represents a promising strategy to restore antibiotic efficacy. In this study, we performed High-Throughput Virtual Screening (HTVS) of a library of synthetic berberine derivatives (tetrahydro and dihydro) targeting MexY, the inner membrane protein of the MexXY-OprM system. Based on affinity data, four racemic compounds were selected for further investigation, but only two exhibited in vitro activity against P. aeruginosa laboratory and clinical strains. Subsequent experimental and computational analyses identified compound 2f as the most effective inhibitor, selectively binding to the allosteric pocket ALP. Notably, the differences in activity between its enantiomers highlighted the importance of the chiral environment at the binding cleft, with the (S)-enantiomer showing significantly higher efficacy than the (R)-enantiomer, particularly against PA7 and CF48 clinical strain. Structural investigations comparing all previously identified berberine derivatives revealed key interactions at the ALP site, mainly involving apolar and aromatic residues, providing a valuable framework for rational drug design. These findings led to the rationalization of a 3D-pharmacophoric model for berberine-derived EPIs, offering a foundation for further optimization
NEW INSIGHTS INTO LEISHMANIASIS: IDENTIFICATION OF POTENTIAL DRUGS, INFECTION BIOMARKERS AND NON-INVASIVE DIAGNOSTIC APPROACHES
No full textLeishmaniasis is a vector-borne parasitic disease and a major global health concern, caused by protozoa of the Leishmania genus. These parasites exist as promastigotes in insect vectors and amastigotes within host macrophages. In humans, the disease manifests in three primary forms: cutaneous, mucocutaneous and visceral leishmaniasis, the latter being potentially fatal if not diagnosed and adequately treated. In dogs, infection typically presents with skin lesions, organomegaly and fever. Currently, no effective vaccine is available and existing treatments are limited and often toxic, underscoring the urgent need for new therapeutic options. An effective management of this re-emerging disease needs combined strategies including the discovery of safer treatments and an accurate, early and non-invasive diagnosis. In this context, microRNAs (miRNAs), which several studies have been shown to be influenced by Leishmania infection, could serve as potential biomarkers for rapid diagnosis and disease monitoring.
This thesis focuses on three major research areas in leishmaniasis: drug discovery, biomarker identification and the development of a non-invasive diagnostic approach. In the drug discovery section, four different compound libraries were screened against Leishmania infantum through phenotypic assays, leading to the identification of nine compounds that significantly reduced in vitro infection rates, two of which appear suitable for in vivo testing. Additionally, Gallium Protoporphyrin (GaPPIX), a heme analog, was evaluated as a repurposed compound. GaPPIX demonstrated potent activity against both L. infantum and L. major promastigotes by inhibiting cytochrome c oxidase (COX) activity. Notably, it showed synergy with miltefosine, a current anti-leishmanial drug, and exhibited low toxicity toward human cells.
For biomarker identification, human, canine and murine in vitro infection models were used. In human and canine macrophage-like cells and/or in extracellular vesicles (EVs), miR-1246, miR-451, and miR-1290 were found to be dysregulated during L. infantum infection, suggesting their potential as diagnostic biomarkers. Instead, in L. amazonensis-infected murine bone marrow-derived macrophages miR-686, miR-99 and miR-342 were found dysregulated and their differential regulation was also validated ex vivo in lesions from infected mice.
Lastly, a novel diagnostic approach based on a previously published qPCR assay was tested using conjunctival swabs as non-invasive clinical sample. This approach successfully diagnosed a clinical case of human visceral leishmaniasis, demonstrating its potential as a rapid, non-invasive diagnostic tool that could also facilitate in treatment monitoring.Leishmaniasis is a vector-borne parasitic disease and a major global health concern, caused by protozoa of the Leishmania genus. These parasites exist as promastigotes in insect vectors and amastigotes within host macrophages. In humans, the disease manifests in three primary forms: cutaneous, mucocutaneous and visceral leishmaniasis, the latter being potentially fatal if not diagnosed and adequately treated. In dogs, infection typically presents with skin lesions, organomegaly and fever. Currently, no effective vaccine is available and existing treatments are limited and often toxic, underscoring the urgent need for new therapeutic options. An effective management of this re-emerging disease needs combined strategies including the discovery of safer treatments and an accurate, early and non-invasive diagnosis. In this context, microRNAs (miRNAs), which several studies have been shown to be influenced by Leishmania infection, could serve as potential biomarkers for rapid diagnosis and disease monitoring.
This thesis focuses on three major research areas in leishmaniasis: drug discovery, biomarker identification and the development of a non-invasive diagnostic approach. In the drug discovery section, four different compound libraries were screened against Leishmania infantum through phenotypic assays, leading to the identification of nine compounds that significantly reduced in vitro infection rates, two of which appear suitable for in vivo testing. Additionally, Gallium Protoporphyrin (GaPPIX), a heme analog, was evaluated as a repurposed compound. GaPPIX demonstrated potent activity against both L. infantum and L. major promastigotes by inhibiting cytochrome c oxidase (COX) activity. Notably, it showed synergy with miltefosine, a current anti-leishmanial drug, and exhibited low toxicity toward human cells.
For biomarker identification, human, canine and murine in vitro infection models were used. In human and canine macrophage-like cells and/or in extracellular vesicles (EVs), miR-1246, miR-451, and miR-1290 were found to be dysregulated during L. infantum infection, suggesting their potential as diagnostic biomarkers. Instead, in L. amazonensis-infected murine bone marrow-derived macrophages miR-686, miR-99 and miR-342 were found dysregulated and their differential regulation was also validated ex vivo in lesions from infected mice.
Lastly, a novel diagnostic approach based on a previously published qPCR assay was tested using conjunctival swabs as non-invasive clinical sample. This approach successfully diagnosed a clinical case of human visceral leishmaniasis, demonstrating its potential as a rapid, non-invasive diagnostic tool that could also facilitate in treatment monitoring
The impact of lean tools on sustainability dimensions: a systematic literature review
No full textPurpose – This study aims to understand the effects of lean tools on the different sustainability dimensions and to identify possible gaps and directions for future research.
Design/methodology/approach – A Systematic Literature Review (SLR) was conducted. Considering the
period from 2013 to 2024, a total of 106 articles were covered. The review identified 49 lean tools that can
contribute to the achievement of sustainable goals.
Findings – The application of lean techniques can increase economic performance, especially in terms of cost
reduction, time efficiency, inventory management, productivity, quality, and profitability. On the environmental side, the main contributions concern optimising the use of resources, reducing waste and pollution. Lean tools also have a positive impact on the social dimension, improving the well-being and satisfaction of employees, their skills and health and safety in the workplace. The 10 lean tools most investigated for their effects on sustainability were also identified. While all these techniques significantly increase economic performance, the positive effects on social and environmental sustainability differ across tools. Further studies are therefore needed to holistically evaluate the influence of lean techniques on sustainability and define models that can measure this interrelationship, with greater efforts to include the social pillar.
Originality/value – The paper offers a new systematic perspective on the interrelation between Lean tools and sustainability, highlighting how most studies focus on economic and environmental aspects, while the social impact of Lean tools is less explored. It therefore suggests the need for further research to better assess this dimension
UNRAVELING MONOCYTE AND PLATELET MORPHO-FUNCTIONAL ALTERATIONS IN SEPSIS: EMERGING BIOMARKERS FOR EARLY DIAGNOSIS
No full textSepsis remains a leading cause of morbidity and mortality worldwide. It is characterized by a complex immune dysregulation and an intricate interplay between inflammation and thrombosis in the host. Identifying early and reliable biomarkers is crucial for timely diagnosis and risk stratification. This PhD thesis investigated the role of Damage-Associated Molecular Patterns, Pathogen-Associated Molecular Patterns and live bacteria in morpho-functional changes in monocytes and platelets, which are key players in thrombo-inflammation. Through an integrated approach combining ex vivo whole blood model and in vivo clinical data, this work examined how Monocyte Distribution Width (MDW) and platelet indices, such as Platelet Distribution Width (PDW) and Mean Platelet Volume (MPV), mirror qualitative alterations in monocytes and platelets, evaluating their diagnostic and prognostic value. Whole blood from healthy donors (EDTAK2/K3) was treated with a mixture of histones (0-200 μg/mL), Lipopolysaccharide (LPS) from E. coli (0-10 μg/mL), and live E. coli (106-1010 CFU/mL) to simulate a septic condition. Complete blood counts were performed using DxH690T/900 (Beckman Coulter) up to 3h after treatment. Peripheral blood smears were prepared for digital cell morphology analyses using CellaVision. Plasma samples were used to assay a panel of 27 cytokines using the Bio-Plex 200 system. Our results demonstrated that free histones, LPS and live E. coli induce a significant, early, dose- and time- dependent increase in MDW, as confirmed by enlarged volume, cytoplasmic vacuolization, increased granularity, nuclear deformation and phagocytosis, only in the case of E. coli. Comparing MDW kinetics across stimuli, considering appropriate anticoagulant-specific cut-off, emerged differences in both timing and intensity of increase. E. coli and LPS induced an earlier and higher increase in MDW than histone, according to the different activated signalling. Moreover, MDW values obtained in our ex vivo model with E. coli and LPS overlap those found in septic patients with a positive blood culture for E. coli, confirming the reliability of the whole blood model. This evidence suggested that bacterial components start the early inflammatory signalling, recognised by increased MDW and cytokine release. Meanwhile, extracellular histones amplify the host response by causing the release of further histones and inflammatory mediators. In this vicious cycle, histones promote platelet activation and aggregation, constituting a key target for both biomarkers and potential therapeutic approaches. Our experimental results confirmed that histones induced a very significant and early decrease in platelet count, due to aggregation by consumption, and a significant increase in MPV and PDW. This thesis sustains that assessing MDW and platelet indices, and possibly quantifying circulating histones, may provide an integrated panel of early biomarkers for identifying patients at risk of sepsis.Sepsis remains a leading cause of morbidity and mortality worldwide. It is characterized by a complex immune dysregulation and an intricate interplay between inflammation and thrombosis in the host. Identifying early and reliable biomarkers is crucial for timely diagnosis and risk stratification. This PhD thesis investigated the role of Damage-Associated Molecular Patterns, Pathogen-Associated Molecular Patterns and live bacteria in morpho-functional changes in monocytes and platelets, which are key players in thrombo-inflammation. Through an integrated approach combining ex vivo whole blood model and in vivo clinical data, this work examined how Monocyte Distribution Width (MDW) and platelet indices, such as Platelet Distribution Width (PDW) and Mean Platelet Volume (MPV), mirror qualitative alterations in monocytes and platelets, evaluating their diagnostic and prognostic value. Whole blood from healthy donors (EDTAK2/K3) was treated with a mixture of histones (0-200 μg/mL), Lipopolysaccharide (LPS) from E. coli (0-10 μg/mL), and live E. coli (106-1010 CFU/mL) to simulate a septic condition. Complete blood counts were performed using DxH690T/900 (Beckman Coulter) up to 3h after treatment. Peripheral blood smears were prepared for digital cell morphology analyses using CellaVision. Plasma samples were used to assay a panel of 27 cytokines using the Bio-Plex 200 system. Our results demonstrated that free histones, LPS and live E. coli induce a significant, early, dose- and time- dependent increase in MDW, as confirmed by enlarged volume, cytoplasmic vacuolization, increased granularity, nuclear deformation and phagocytosis, only in the case of E. coli. Comparing MDW kinetics across stimuli, considering appropriate anticoagulant-specific cut-off, emerged differences in both timing and intensity of increase. E. coli and LPS induced an earlier and higher increase in MDW than histone, according to the different activated signalling. Moreover, MDW values obtained in our ex vivo model with E. coli and LPS overlap those found in septic patients with a positive blood culture for E. coli, confirming the reliability of the whole blood model. This evidence suggested that bacterial components start the early inflammatory signalling, recognised by increased MDW and cytokine release. Meanwhile, extracellular histones amplify the host response by causing the release of further histones and inflammatory mediators. In this vicious cycle, histones promote platelet activation and aggregation, constituting a key target for both biomarkers and potential therapeutic approaches. Our experimental results confirmed that histones induced a very significant and early decrease in platelet count, due to aggregation by consumption, and a significant increase in MPV and PDW. This thesis sustains that assessing MDW and platelet indices, and possibly quantifying circulating histones, may provide an integrated panel of early biomarkers for identifying patients at risk of sepsis
Le forme della memoria urbana. Bologna e Firenze dal fascismo alla Repubblica (1920-1955)
No full textLa tesi analizza la costruzione e la trasformazione della memoria urbana tra fascismo e dopoguerra attraverso i casi di Bologna e Firenze, città decorate di Medaglia d’Oro al Valor Militare per la Resistenza. Il periodo considerato (1920–1955) comprende l’affermazione del regime, la guerra e i primi anni repubblicani, seguendo la sorte di monumenti, lapidi, intitolazioni e architetture del potere fascista nella transizione alla democrazia. Assumendo le città come luoghi di stratificazione e negoziazione della memoria, la ricerca indaga come il paesaggio urbano sia stato occupato, trasformato e successivamente riorganizzato. Partendo dal lavoro d’archivio, studiando le decisioni degli organi amministrativi e consultivi e analizzandone i riflessi nella stampa locale, lo studio mette in evidenza la centralità delle politiche commemorative e odonomastiche come strumenti di definizione identitaria, ma anche il loro carattere conflittuale. L’obiettivo è contribuire a spiegare perché l’eredità materiale del fascismo risulti oggi variamente distribuita e percepita. Bologna e Firenze – città di grande rilevanza sia nella geografia politica del fascismo sia in quella resistenziale – emergono come laboratori di rappresentazione del potere e del suo superamento, in cui i segni del fascismo, cancellati, sostituiti, ignorati o integrati nel contesto urbano, si intrecciano con la costruzione della memoria della Resistenza.This dissertation examines the construction and transformation of urban memory between Fascism and the postwar period through the cases of Bologna and Florence, both awarded the Gold Medal of Military Valor for the Resistance. Covering the years 1920–1955, it traces the evolution of monuments, plaques, street names, and Fascist architectures during the transition to democracy. Conceiving the city as a site of layered and negotiated memory, the research explores how the urban landscape was occupied, reshaped, and later reorganized. Based on extensive archival work, it examines the decisions of local authorities and consultative commissions and their echoes in the local press, highlighting the central role of commemorative and toponymic policies as instruments of identity-making, as well as their inherently conflictual nature. The aim is to contribute to explaining some of the reasons why the material heritage of Fascism continues to be unevenly distributed and perceived today. Bologna and Florence – key cities in both the political geography of Fascism and the Resistance – emerge as laboratories for the representation of power and its overcoming, where Fascist symbols, whether erased, replaced, ignored, or integrated into the urban fabric, intertwine with the construction of the memory of the Resistance
“I Am a Farmer and Do Other Chores of Womenfolk”. Uncovering Women’s Work in Rural Southern Europe: The Case of Nineteenth-Century Urbino, Italy
No full textAbstract
Women’s work in the past has long attracted scholarly attention, yet many aspects remain unexplored or contested. This is due to the complex methodological challenges of studying the theme, to the very definition of work for people in the past and for contemporary scholars, to the under-recording of female activities in the sources and the inadequacy of occupational labels to capture the variety of their activities. This paper contributes to current debates on the best methods for obtaining accurate data on women’s work by presenting the first results of an ongoing research on the territory of nineteenth-century Urbino, Italy, based on criminal trial records. These sources are analysed focusing on the self-presentations of the people questioned by the judges, offering insights into emic understandings of work. Furthermore, testimonies are studied through the verb-oriented method to people’s activities mentioned in the testimonies are studied with the so-called verb-oriented method. The results challenge traditional dichotomies such as domestic/non-domestic; unpaid/paid; reproductive/productive, showing their inadequacy for understanding pre-industrial societies and gender roles. Our research also contributes to the debate on the “little divergence” between the economic development of northern and southern Europe and the role of women in economic growth. It provides accurate data on Italy which challenge the assumption that Italian women were not involved in the labour market and in paid productive activities, showing that they worked inside and outside, for themselves, their families and for others
From Region to Route. An Ethnography of Solidarity Infrastructure along the Western Balkan Route
No full textThis dissertation investigates the transformations of the Western Balkan route as both an object of governance and a lived, contested space shaped by practices of solidarity. Since the summer of 2015, the route has become a key site where European border externalisation, regional cooperation, and local forms of resistance intersect. Drawing on ethnographic research conducted between October 2023 and November 2024 in Sarajevo (Bosnia and Herzegovina) and Zagreb (Croatia), this dissertation explores the ever-changing nature of the route by juxtaposing the macro and micro scales of analysis. To this aim, the discussion is structured around three key concepts – scales, borders, and infrastructures – which illuminate the tensions between the macro- and micro-social dynamics shaping the route.
At the macro level, the research analyses how the Western Balkan route has been constructed as an object of governance through securitarian discourses embedded in the EU accession process. By examining cooperation frameworks, funding mechanisms, and policy instruments, it shows how the borders of the Schengen area have become increasingly blurred, incorporating non-EU states such as Bosnia and Herzegovina into the European migration governance model.
At the micro level, the dissertation investigates solidarity actors operating in urban contexts outside institutional reception systems, supporting migrants’ presence and mobility. It argues that these initiatives, while non-confrontational, articulate a significant critique of the institutional governance models through infrastructures that facilitate the circulation of goods, information and practices.
Ultimately, the dissertation demonstrates that the Western Balkan route is a space of tension: on the one hand, a geopolitical construct of multi-scalar governance aimed at controlling and illegalising migrant mobility and criminalising solidarity initiatives; on the other, a lived space where encounters and relationships are forged, giving rise to solidaristic practices that uphold dignity and guarantee access to rights. The cases of Sarajevo and Zagreb illustrate how everyday encounters between solidarity actors and migrants play a crucial role in identifying and deconstructing the proliferation of borders along the route.This dissertation investigates the transformations of the Western Balkan route as both an object of governance and a lived, contested space shaped by practices of solidarity. Since the summer of 2015, the route has become a key site where European border externalisation, regional cooperation, and local forms of resistance intersect. Drawing on ethnographic research conducted between October 2023 and November 2024 in Sarajevo (Bosnia and Herzegovina) and Zagreb (Croatia), this dissertation explores the ever-changing nature of the route by juxtaposing the macro and micro scales of analysis. To this aim, the discussion is structured around three key concepts – scales, borders, and infrastructures – which illuminate the tensions between the macro- and micro-social dynamics shaping the route.
At the macro level, the research analyses how the Western Balkan route has been constructed as an object of governance through securitarian discourses embedded in the EU accession process. By examining cooperation frameworks, funding mechanisms, and policy instruments, it shows how the borders of the Schengen area have become increasingly blurred, incorporating non-EU states such as Bosnia and Herzegovina into the European migration governance model.
At the micro level, the dissertation investigates solidarity actors operating in urban contexts outside institutional reception systems, supporting migrants’ presence and mobility. It argues that these initiatives, while non-confrontational, articulate a significant critique of the institutional governance models through infrastructures that facilitate the circulation of goods, information and practices.
Ultimately, the dissertation demonstrates that the Western Balkan route is a space of tension: on the one hand, a geopolitical construct of multi-scalar governance aimed at controlling and illegalising migrant mobility and criminalising solidarity initiatives; on the other, a lived space where encounters and relationships are forged, giving rise to solidaristic practices that uphold dignity and guarantee access to rights. The cases of Sarajevo and Zagreb illustrate how everyday encounters between solidarity actors and migrants play a crucial role in identifying and deconstructing the proliferation of borders along the route