Archivio Istituzionale della Ricerca - Università degli Studi di Pavia
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Notes on Schauder Estimates by Scaling for Second Order Linear Elliptic PDEs in Divergence Form
No full textInvestigating novel therapeutic targets and biomarkers tackling neuroinflammation: GPNMB and AXL in ALS
No full textLa sclerosi laterale amiotrofica (SLA) è una malattia neurodegenerativa fatale caratterizzata dalla degenerazione selettiva dei motoneuroni. Il coinvolgimento dei muscoli respiratori riduce la sopravvivenza dei pazienti a due-quattro anni dall’esordio dei sintomi. Le strategie terapeutiche attuali non sono risolutive e non esistono ancora marcatori molecolari distintivi. Evidenze crescenti indicano che i processi neuroinfiammatori svolgono un ruolo cruciale nell’insorgenza e progressione della malattia. L’attivazione dei processi di gliosi, insieme all’infiltrazione di macrofagi nei nervi periferici, genera un microambiente infiammatorio complesso che può inizialmente avere effetti protettivi, ma che contribuisce infine alla perdita neuronale. Questa tesi ha indagato il ruolo di due proteine, GPNMB e AXL, come modulatori dei processi neuroinfiammatori nella SLA. È stata valutata la loro regolazione da parte delle metalloproteasi ADAM10/17, nonché il loro potenziale come bersagli terapeutici e biomarcatori. Mediante ibridazione in situ e analisi immunoistochimica su tessuti di diversi modelli animali di SLA, è stato dimostrato che l’espressione di Gpnmb migra progressivamente dai neuroni alle microglia e macrofagi reattivi durante la progressione della malattia. La co-localizzazione con microglia Arginase-1-positiva suggerisce un ruolo in risposte neuroprotettive tardive, potenzialmente insufficienti. Analisi parallele hanno rivelato che il rilascio dell’ectodominio di Gpnmb e Axl è strettamente regolato da ADAM10/17. L’inibizione farmacologica di ADAM10/17 ha ridotto il rilascio degli ectodomini e attenuato la secrezione di citochine infiammatorie, stabilendo un legame diretto tra proteolisi e regolazione neuroinfiammatoria. Il frammento extracellulare ricombinante di Gpnmb ha migliorato significativamente la sopravvivenza dei motoneuroni in colture primarie derivate sia da topi wild-type che SOD1.G93A, preservando la vitalità cellulare in condizioni di stress. La somministrazione in vivo di Gpnmb ricombinante nei ratti SLA ha prodotto effetti modesti, probabilmente a causa di limiti di dosaggio e somministrazione. È stato quindi sviluppato e validato in vitro un costrutto lentivirale per la sovraespressione di GPNMB umano, rappresentando uno strumento promettente per studi futuri di neuroprotezione in vivo. Le analisi dei biomarcatori hanno mostrato incrementi progressivi di Gpnmb solubile (sGpnmb) sia nel liquido cerebrospinale (CSF) che nel siero dei modelli SLA, con tendenze distinte: aumenti repentini nel CSF riflettono neurodegenerazione centrale e microgliosi, mentre incrementi più lenti nel siero riflettono il coinvolgimento immunitario periferico. Analisi su un modello di Charcot–Marie–Tooth hanno confermato che il sGpnmb sierico rispecchia efficacemente l’infiammazione periferica. Anche Axl solubile (sAxl) si è rivelato un biomarcatore promettente, con livelli sierici aumentati nei topi SLA, soprattutto negli stadi avanzati. Nelle misurazioni su biofluidi di pazienti SLA, sGPNMB sierico risulta significativamente elevato rispetto ai controlli, con valori più alti nei casi di esordio spinale. Inoltre, sAXL nel siero nel CSF risulta significativamente aumentato, con un promettente valore prognostico nel CSF. In conclusione, questo lavoro identifica GPNMB e Axl come modulatori chiave della neuroinfiammazione nella SLA, regolati dalle metalloproteasi ADAM10/17. Il ruolo neuroprotettivo di GPNMB incoraggia ulteriori studi come candidato terapeutico, mentre GPNMB e Axl solubili mostrano forte potenziale come biomarcatori diagnostici e prognostici. Questi risultati offrono nuove intuizioni meccanicistiche e traslazionali sulla patogenesi della SLA, favorendo lo sviluppo di strategie innovative per monitorare e modulare la neuroinfiammazione.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective degeneration of motor neurons. Respiratory muscle involvement reduces patient survival to two to four years after symptom onset. Current therapeutic strategies are not resolutive, and no distinct molecular marker are yet available. Increasing evidence indicates that neuroinflammatory processes play a pivotal role in disease onset and progression. Activation gliosis processes, together with macrophage infiltration in peripheral nerves, creates a complex inflammatory milieu that may initially exert protective effects but ultimately contributes to neuronal loss. This thesis investigated the role of two proteins, GPNMB and AXL, as modulators of neuroinflammatory processes in ALS. Their regulation by the metalloproteases ADAM10 and ADAM17 was assessed, as well as their potential as therapeutic targets and biomarkers. By situ hybridization and immunohistochemistry analysis on tissues from multiple ALS animal models, I demonstrated that Gpnmb expression, progressively shifts from neurons to reactive microglia and macrophages during disease progression. Its co-localization with Arginase-1-positive microglia suggests a role in late, potentially insufficient, neuroprotective responses. Parallel analyses revealed that ectodomain shedding of both Gpnmb and Axl is tightly regulated by ADAM10/17. Importantly, pharmacological inhibition of ADAM10/17 reduced the release of Gpnmb and Axl ectodomains and attenuated inflammatory cytokine secretion, establishing a direct link between proteolytic cleavage and neuroinflammatory signaling. The recombinant extracellular fragment of Gpnmb significantly enhanced motor neuron survival in primary cultures derived from both wild-type and SOD1.G93A mice, preserving cells viability under stress conditions. On the other hand, in vivo administration of recombinant Gpnmb in ALS rats produced only modest effects, likely due to limitations in dosage and delivery. To overcome these constraints, a lentiviral construct enabling stable overexpression of human GPNMB was developed and validated in vitro, representing a promising tool for future in vivo neuroprotection studies. Biomarker analyses demonstrated progressive increases in soluble Gpnmb (sGpnmb) levels in both cerebrospinal fluid (CSF) and serum of ALS models, with distinct trends: steep rises in CSF reflected central neurodegeneration and microgliosis, while slower increases in serum paralleled peripheral immune involvement. Comparative analyses in a Charcot–Marie–Tooth model confirmed that serum sGpnmb effectively tracks peripheral inflammation, whereas CSF levels remain largely unchanged. Soluble Axl (sAxl) also emerged as promising biomarker, showing increased levels in the serum of ALS mice, particularly at advanced stages. Translation to patient cohorts validated these observations. Serum sGPNMB was significantly elevated in ALS patients compared to controls, with higher levels in spinal-onset cases. Moreover, both serum and CSF sAXL levels were significantly increased, and CSF measurements has shown promising prognostic value. In conclusion, this work identifies GPNMB and Axl as critical modulators of neuroinflammation in ALS, under the regulation of ADAM10/17 metalloproteases. The neuroprotective role of GPNMB supports its further exploration as a therapeutic candidate, while soluble GPNMB and Axl demonstrate strong potential as diagnostic and prognostic biomarkers. Collectively, these findings provide novel mechanistic and translational insights into ALS pathogenesis, advancing the development of innovative strategies for monitoring and modulating neuroinflammation in ALS
High-fidelity ptychographic imaging of non-repeatable plasma dynamics
No full textLaboratory-scale gaseous plasma events offer a rich environment for the study of ionization, energy transfer, and non-equilibrium dynamics, whose understanding plays a critical role in wakefield accelerators, inertial confinement fusion, and plasma ignition devices. Probing these dynamics, however, has been historically difficult due to their weak absorption of visible light and inherently challenging spatial and temporal scales. Recent advances in computational imaging have opened the door for advanced forms of plasma diagnostics with techniques such as single-shot ptychography (SSP); however, fidelity challenges and reduced resolution have limited the application of SSP to non-repeatable plasma dynamics. Here we introduce a near-field implementation of SSP that delivers enhanced fidelity and resolution, as well as improved robustness to noise compared to far-field methods, verified through systematic experimental and numerical comparisons. Using this method, we demonstrate ptychographic imaging of non-repeatable plasma dynamics through the analysis of a full temporal trace of an electrostatic discharge event. These results establish near-field SSP as a powerful plasma diagnostic tool, opening the pathway toward 3D, hyperspectral, and single-shot ultrafast motion-picture ptychographic imaging of complex plasma systems
Comparison of interferometric and electrical analyses for the spectral dynamic characterization of a suspended piezo-actuated panel
No full textMapping digital public health training: are we preparing the European workforce?
No full textIntroduction: Digital transformation and artificial intelligence are reshaping public health practice, yet the extent to which the workforce is being prepared for these changes remains unclear. This mapping review aimed to characterize digital public health training initiatives targeting public health professionals in Europe.Methods: Training initiatives delivered between January 2020 and December 2025 were systematically identified across five European countries (Italy, Germany, France, Spain, United Kingdom) and major international organizations. Sources included websites, archives, and social media of public health associations, schools of public health, and health organizations. Systematic searching was complemented by direct institutional contact. Initiatives were classified by format, provider, and thematic content using domains from the ASPHER Core Curriculum framework.
Results: A total of 367 training initiatives were identified. Activity increased sharply after 2022, with over half of all initiatives (56.7%) delivered in 2024-2025 alone. Conference sessions (54.5%) and webinars (22.3%) predominated, while structured courses (18.3%) and degree programmes (3.3%) were less common. Scientific associations delivered most initiatives (69.5%), with academic institutions accounting for less than one-third (30.5%). International organizations contributed to nearly one-third of all initiatives (32.4%). Thematic content focused primarily on digital tools (66.8%) and leadership for digital transformation (53.1%), whereas training on the infosphere and health misinformation was notably underrepresented (2.5%).Conclusion: Digital public health training for the European workforce is expanding rapidly but remains fragmented, dominated by short formats, and insufficiently integrated into academic curricula. Strengthening formal educational pathways and addressing content gaps will be essential to build sustainable digital competencies across the profession
"Alma dies magnis celebratur coetibus": sul reimpiego di alcuni versus natalicii di Paolino di Nola nella Chronica monasterii Casinensis di Leone Marsicano
No full textIn the Chronica monasterii Casinensis, within the narrative of the ceremony of consecration of the new church, Leo inserts eighteen hexameters taken from the third natalicium of Paulinus Nolanus. The paper analyses the modalities and purposes of this re-use, which shows the persistence of the exercises of versification of scholastic tradition and provides indications for the history of the reception, but also of the textual transmission, of Natalicia
The biology of Aedes albopictus invasion capacity
No full textAedes albopictus is one of the most invasive mosquito species globally and it is responsible for the re-emergence of several arboviral diseases in both tropical and temperate regions of the world. Its rapid expansion has been linked to traits such as diapause, desiccation-resistant eggs and adaptability to urban environments. However, Ae. albopictus populations show variation in other phenotypic traits, including reproductive capacity and thermal tolerance, which could impact Ae. albopictus invasion success especially as the climate crises progress. On this basis, my PhD thesis aimed at studying Ae. albopictus thermal resilience to heatwaves (HWs) and its reproductive capacity, to unravel the impact of these traits on the invasion capacity of Ae. albopictus. I designed two separate projects to study each trait.
Because the increase in the frequency and intensity of HWs under global warming is expected to have more dramatic biological impacts on insects than mean temperature increases, in the first project I examined the biological consequences of an ecologically relevant HW on the different life stages of Ae. albopictus. Through fitness assessments, physiological measurements, transcriptomics, and microbiota profiling, I found stage- and sex-specific responses to heat stress. Eggs and males were most vulnerable stages, with high embryo mortality and male mortality following exposure to HW. In contrast, larvae and females exhibited thermal resilience: larvae delayed development and upregulated heat shock proteins, while females showed extensive transcriptional shifts involving oxidative stress pathways and metabolic adjustments. Notably, only blood-fed females exhibited reduced reproductive output post-HW, suggesting that recovery periods within HWs may mitigate some reproductive costs. These findings highlight the multifaceted nature of mosquito thermal tolerance and underscore the ecological importance of studying multiple traits across developmental stages. Together, these results provide valuable data to refine predictive models and design adaptive control strategies under climate change.
In the second project, I combined fitness analyses, physiological assays, proteomics, and genomics to compare the reproductive capacity of laboratory populations of Ae. albopictus. I found that mosquitoes from invasive areas optimize nutrient allocation during development and oogenesis, leading to higher fecundity despite delayed egg production. Mosquitoes from invasive populations displayed longer larval development, larger adult size, and more efficient blood digestion. Their fat bodies and ovaries were protein enriched despite reduced blood intake. Additionally, lipid and protein deposition into developing oocytes was more coordinated. Reciprocal crosses between long laboratory adapted and invasive mosquitoes revealed heterosis, with hybrid offspring exhibiting higher fertility than both parents, indicating a genetic component to this increased reproductive capacity. These findings suggest that physiological and genetic adaptations in reproductive investment contribute to the invasion success of Ae. albopictus.
Together, these studies offer new insights into the adaptive strategies that support Ae. albopictus’ global expansion. By highlighting the importance of heat resilience and reproductive capacity, this work contributes to a better understanding of the ecological success of this invasive vector and offers valuable perspectives for future control strategies in the face of climate change
Gambling in Italy: Epidemiological Evidence and Public Health Implications
No full textGambling represents an increasingly relevant public health concern. This doctoral project was developed to address the scarcity of independent population-based evidence on gambling in Italy, integrating multiple data sources to quantify its burden and explore its determinants. The research was articulated through a sequence of empirical studies ranging from local school-based surveillance to large national surveys of adults and adolescents, complemented by a methodological study on health monitoring in university populations. The findings show that gambling in Italy remains widely accessible to underage individuals despite formal legal restrictions, including through formats considered among the most addictive and those that should be subject to stricter regulatory controls. During adolescence, gambling behaviour tends to co-occur with other risk-taking activities and psychosocial vulnerabilities, indicating the need for multifaceted prevention strategies that address interconnected behavioural and environmental determinants. Gambling-related harm was shown to occur along a continuum of severity, with specific gambling formats and patterns of engagement associated with higher levels of adverse outcomes. Furthermore, the analyses indicate that digital gaming monetisation systems, such as loot boxes, likely exploit psychological vulnerabilities similar to those involved in gambling and may also function as a gateway to gambling among adolescents. Within the broader framework of the doctoral project, a rapid e-Delphi consensus study was also conducted to design a survey that will enable the longitudinal assessment of gambling trajectories and the evaluation of interventions aimed at influencing them during the major life transition represented by the entry into university life. Overall, the evidence produced supports the adoption of population-level strategies and evidence-informed preventive policies addressing the structural and commercial drivers of gambling-related harm.Gambling represents an increasingly relevant public health concern. This doctoral project was developed to address the scarcity of independent population-based evidence on gambling in Italy, integrating multiple data sources to quantify its burden and explore its determinants. The research was articulated through a sequence of empirical studies ranging from local school-based surveillance to large national surveys of adults and adolescents, complemented by a methodological study on health monitoring in university populations. The findings show that gambling in Italy remains widely accessible to underage individuals despite formal legal restrictions, including through formats considered among the most addictive and those that should be subject to stricter regulatory controls. During adolescence, gambling behaviour tends to co-occur with other risk-taking activities and psychosocial vulnerabilities, indicating the need for multifaceted prevention strategies that address interconnected behavioural and environmental determinants. Gambling-related harm was shown to occur along a continuum of severity, with specific gambling formats and patterns of engagement associated with higher levels of adverse outcomes. Furthermore, the analyses indicate that digital gaming monetisation systems, such as loot boxes, likely exploit psychological vulnerabilities similar to those involved in gambling and may also function as a gateway to gambling among adolescents. Within the broader framework of the doctoral project, a rapid e-Delphi consensus study was also conducted to design a survey that will enable the longitudinal assessment of gambling trajectories and the evaluation of interventions aimed at influencing them during the major life transition represented by the entry into university life. Overall, the evidence produced supports the adoption of population-level strategies and evidence-informed preventive policies addressing the structural and commercial drivers of gambling-related harm