Archivio Istituzionale della Ricerca - Università degli Studi di Pavia
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Development Of Horizontal Analytical Platforms To Be Used For Monoclonal Antibodies Quality Control
No full textGli anticorpi monoclonali (mAbs) sono farmaci bioterapici essenziali. Durante il loro ciclo di vita subiscono modificazioni post-traduzionali che aumentano la complessità ed eterogeneità dei prodotti, influenzandone qualità ed efficacia. Il progetto di dottorato, in collaborazione con l’Istituto Superiore di Sanità, è stato incentrato su varianti di carica e di massa, che, essendo considerate attributi critici di qualità, devono essere monitorate con attenzione. L’obiettivo principale è stato lo sviluppo di piattaforme analitiche trasversali per la caratterizzazione e il controllo qualità (QC) dei mAbs, seguendo le linee guida ICH e l’approccio Analytical Quality by Design. Le varianti di carica sono state studiate tramite la tecnica di Imaged Capillary Isoelectric Focusing, partendo dalle condizioni di Ph. Eur. e portando a due nuovi metodi ottimizzati per valori di pI più accurati ed applicabili a diversi mAbs. Le varianti di massa sono state studiate con la tecnica di Size Exclusion Chromatography per identificarne i parametri critici e tendere ad ottimizzare sensibilità e risoluzione. I risultati evidenziano l’importanza di sviluppare metodi orizzontali a supporto delle attività di QC e della sorveglianza post-marketing.Monoclonal antibodies (mAbs) are essential biotherapeutics. Post-translational modification occurs during the entire drugs life cycle, increasing product complexity and heterogeneities that can affect quality and efficacy. The PhD project, in collaboration with the Istituto Superiore di Sanità, focused on charge and size variants that are considered Critical Quality Attributes that must be closely monitored. The aim was to design transversal analytical platforms for mAbs characterization and Quality Control (QC), principally following ICH guidelines and the Analytical Quality by Design approach. Charge variants were studied by imaged capillary isoelectric focusing technique, starting from the Ph. Eur. conditions and lead to two novel optimized methods with enhanced accuracy of pI measurement and applicability across different therapeutic mAbs. Furthermore, size variants were addressed with size exclusion chromatography technique to identify critical analytical parameters and optimize sensitivity and resolution. The results showed the importance of developing horizontal methods to support and standardize regulatory QC and post-marketing surveillance of mAb-based drugs
Marcus Aper and the Ala Apriana
No full textThis chapter attempts to reconstruct the early history of the ala Apriana, a cavalry unit present in Egypt from the Julio-Claudian period, and of early auxiliary units of the Roman army in Egypt, on the basis of Latin and Greek documentary papyri. It then looks at Claudius’ reorganisation of permanent alae with standardised names, and investigates the identity and role of Aper, the first eponymous commander of the ala Apriana, suggesting an identification with the Gaulish orator Marcus Aper, Tacitus’ teacher and a speaker in the Dialogus de oratoribus
Investigazione delle interazioni e meccanismi di regolazione tra ABA e DDR nella germinazione
No full textL'impatto del fitormone acido abscissico (ABA) sulla risposta al danno al DNA (DDR) risulta poco esplorata, specialmente nei semi. Le questioni irrisolte riguardano il contributo dei fattori di trascrizione (TFs) al mantenimento del genoma e come i loro geni target che agiscono sul riparo del DNA vengano regolati in risposta allo stress da disseccamento, durante la transizione a plantula e nel deterioramento dei semi. In questa tesi, le dinamiche ABA-DDR esistenti durante la germinazione e in risposta allo stress da disseccamento sono state investigate in semi di Medicago truncatula sottoposti a priming (P) e overpriming (OP) prima e dopo il disseccamento utilizzando le tecniche ATAC-Seq (Assay for Transposase-Accessible Chromatin with sequencing) e RNA-Seq. Questa analisi ha evidenziato e differenze in termini di accessibilità alla cromatina e nei profili di espressione genica tra semi tolleranti il disseccamento (P) e i semi sensibili al disseccamento (OP). Inoltre, l’integrazione di delle due tecniche ha permesso l’identificazione dei network trascrizionali che coinvolgono i TF sensibili al fitormone ABA ed i rispettivi geni target appartenenti al DDR e ad altri sistemi di riparo del seme. Il cross-talk tra ABA e DDR durante la transizione da seme a piantina è stato investigato in semi di Medicago truncatula sottoposti ad un trattamento con Abamine SG (AbSG), un inibitore dell’enzima 9-cis-epossicarotenoide diossigenasi (NCED), il quale riveste un ruolo chiave nella sintesi di ABA. Un nuovo sistema sperimentale, basato sull’applicazione di AbSG e del composto radiomimetico Zeocina, singolarmente o in modo combinato. Il principale risultato osservato riguarda la riduzione della frequenza di piantine sviluppatesi in modo aberrante in risposta al trattamento combinato rispetto ai singoli trattamenti. Similarmente, la presenza di AbSG è in grado di ridurre l’accumulo di 8-OHdG (8-idrossi-2’-deossiguanosina). Le analisi condotte su questo sistema sperimentale hanno evidenziato la rilevanza dei sistemi di riparo mediante Homologous Recombination e non-Homologous End Joining, oltre al contributo dei geni codificanti cicline nella mitigazione del danno al DNA indotto da Abamine SG. Le dinamiche tra ABA-DDR sono state anche investigate in semi di Arabidopsis thaliana appartenenti alle linee dog1-5 e dog1-2 in risposta a deterioramento controllato. In riferimento ai dati, i semi della linea dog1-5 soggetti ad aging hanno riportato una minore sensibilità al deterioramento rispetto ai semi controllo e dog1-2. L’accumulo di 8-OHdG e I cambi nei profili di espressione dei geni coinvolti nel DDR e nella segnalazione di ABA sono stati analizzati in entrambe le linee, rivelando pattern distinti. In conclusione, questi risultati contribuiscono ad espandere la letteratura riguardante le interazioni tra ABA e DDR a livello molecolare, fornendo nuovi marcatori di qualità del seme spendibili per migliorare i protocolli di tecniche di miglioramento della germinazione.The impact of abscisic acid (ABA) on DNA damage response (DDR) is still poorly explored, particularly in seeds. Open research questions are related to the contribution of abscisic acid-responsive transcription factors (TFs) to genome maintenance, and how their target genes acting in DNA repair are modulated under desiccation stress, seedling establishment and seed deterioration. In this thesis, ABA-DDR dynamics during germination and in response to desiccation stress were investigated in Medicago truncatula primed (P) and overprimed (OP) seeds before and after desiccation using ATAC-Seq (Assay for Transposase-Accessible Chromatin with sequencing) and RNA-Seq. This investigation highlighted differences in terms of chromatin accessibility and gene expression profiles between desiccation tolerant (P) and desiccation sensitive (OP) seeds. Additionally, the integration of the two omic data allowed the identification of transcriptional networks encompassing ABA-responsive TFs and their target genes encoding for DDR and other players in seed repair mechanisms. The crosstalk between ABA and DDR in the transition from seed germination to seedling development was investigated using M. truncatula seeds treated with abamine SG, a known inhibitor of 9-cis-epoxycarotenoid 11,12-dioxygenase (NCED), the rate-limiting enzyme in ABA biosynthesis. An experimental system was designed, based on treatments with abamine SG and the radiomimetic chemical zeocin supplied to seeds as single and combined compounds. The key aspect observed was a reduction of the population of aberrant seedlings when both chemicals were combined, compared with the frequency detected with zeocin alone. Similarly, the presence of abamine SG was able to lower 8-OHdG (8-hydroxy-2’-deoxyguanosine) levels. The investigation conducted on this experimental system reported the relevance of HR (Homologous Recombination) and NHEJ (Non-Homologous End Joining) players, as well as the contribution of cyclin encoding genes in the abamine SG-mediated mitigation of genotoxic stress. ABA-DDR dynamics were also investigated in Arabidopsis thaliana seeds of the mutant dog1-5 and dog1-2 lines exposed to controlled deterioration. Based on the reported data, the dog1-5 aged seeds showed reduced sensitivity to deterioration compared to dog1-2 and Col0 (control) aged seeds. 8-OHdG accumulation and changes in the expression patterns of DDR genes and genes involved in ABA-signalling were also assessed in both atdog1 mutant seeds, revealing distinctive patterns. Taken together, these results will contribute to expand the understanding of ABA-DDR interactions at a molecular level, providing new hallmarks of seed quality which can be used to improve the current seed germination enhancements technologies
Sexual Hormones Determination in Biofluids by In-Vial Polycaprolactone Thin-Film Microextraction Coupled with HPLC-MS/MS
No full textThe in-vial microextraction technique is emerging as an alternative sample treatment, as it integrates sorbent preparation, adsorption, and desorption of analytes in a single device before instrumental analysis. In this work, the applicability of polycaprolactone polymeric film, recently used for the in-vial microextraction of sex hormones from environmental waters, is studied in a low-capacity format for unconjugated sex hormones determination in biological samples by HPLC-MS/MS. Its performance was evaluated in urine and serum, achieving extraction in a short time (10 and 30 min, in turn) and satisfactory elution with ethanol, with recovery in the range of 65–111% in urine, 55–122% in bovine serum albumin (BSA) solution, and 66–121% in fetal bovine serum (FBS). In the case of protein matrices, a dilution to 20 g L−1 protein content and washing step (3 × 1 mL
ultrapure water) afore the elution are required to achieve clean extract, as verified by a Bradford assay. Matrix-matched calibration was used for quantification, obtaining correlation coefficients greater than 0.9929; limits of detection and quantification were in the range of 0.01–0.65 and 0.03–1.96 ng mL−1 in urine, 0.02–0.8 and 0.05–2.5 ng mL−1 in BSA, and 0.02–1.0 and 0.06–3.0 g mL−1 in FBS, respectively. The in-vial polycaprolactone film
proved to be reusable for several cycles (up to ten), and the greenness assessment revealed a good adhesion to green sample preparation principles. All these achievements further strengthen its feasibility for efficient extraction/clean-up of trace sex hormones in complex biological samples
Pier Silverio Leicht e le associazioni bibliotecarie internazionali
No full textL'articolo approfondisce il ruolo di Pier Silverio Leicht nella nascita delle associazioni bibliotecarie italiana (AIB) e internazionale (IFLA) a Roma nel 192
RECAPITULATING HERITAGE ECOLOGY AND CULTURAL CONSCIENCE
No full textHeritage ecology, a way of knowing, is the line of thought that involves multidisciplinary and multi-code research and is deeply conditioned by beliefs about our built nature (landscape architecture) cultures, as well as the ways to follow the path of sustainable development. Heritage Ecology, conceived as the yoga of place, is allied to geomancy and linked to the Gaia theory, as well as the human psyche and the earth’s spirit. As a cultural resource, heritage represents the sacredscapes of mystic religious sites, built structures, historical monuments and the perceived natural scenarios and landscapes. Environmental problems arise from people living out of harmony with nature.
Heritage ecology can help research the cosmic integrity of our intrinsic value, which is deeply rooted in our cultural traditions and maintained through rituals, festivities, pilgrimages, and other associative religious activities.
Heritage resource conservation is a strategy of sustainable development. The spatial-religious view, cosmicmovement context, and human psyche together develop a theosphere called faithscape, which is more concerned with experiences and emotional bondage than mere speculations, observations, and participation. The manifested
power of sacralisation, regulated by ritualisation, ultimately promotes the cosmicising of the harmonic relation between human beings and the divine nature. In pilgrimage, deeper understanding, feeling and meaning are intertwined, and at one point, they become one. The question of moral ethics extends beyond human greed and interest at times; in fact, it provides a way for one to pass on a carrying heritage to future human generations. This
paper aims to revisit heritage ecology within the cultural conscience, envisioning a harmonious and happy world
Editing Sugars: Decatungstate Photocatalyzed Site- and Stereoselective C-H Functionalization in ß-Fucosides
No full textC–H bond functionalization via (photoinduced) Hydrogen Atom Transfer (HAT) catalysis is emerging as a powerful eco-sustainable tool for sugar editing, albeit challenges in governing the reactivity patterns and site-selectivity remain. Quite surprisingly, no functionalization of the C-5 position in pyranoses via C–H activation has been described to date. We herein report the development of an efficient methodology for the site-selective and stereoselective alkylation of position 5 of β-fucosides by means of decatungstate photocatalyzed C(sp3)–C(sp3) bond formation. The experimental work is accompanied by spectroscopical studies based on laser flash photolysis and supplemented by computational simulations, offering insights into the reasons underlying the selectivity profile of the reported transformations
Sella turcica bridging and skeletal sagittal patterns in patients with third molar agenesis: A retrospective observational study
No full textObjectives: To investigate the associations between sella turcica bridging (STB) and skeletal malocclusion patterns in orthodontic patients with third molar agenesis (TMA). Methods: Panoramic radiographs were taken from patients aged 8–18 years to identify TMA. All the patients were included between March 2023 and June 2023. Lateral cephalometric radiographs were obtained from both patients with TMA (agenesis group, AG) and those without TMA (control group, CG). Cephalometric measurements between the two groups were compared using the Mann-Whitney U test. The analysis of the sella turcica was carried out on lateral cephalometric radiographs based on Leonardi's classification. Linear regressions were performed between bridging, agenesis, cephalometric measurements, sex and age. Significance was set at P < 0.05. Results: Four hundred patients were included in the study, 200 for the AG group and 200 for the CG. A statistically significant influence of agenesis on the sella depth measurement, which was on average higher in the AG compared to the CG, was found, particularly in cases of mandibular agenesis. Both ANB and A0B0 were significantly lower in the AG compared to the CG (P < 0.05), especially in the mandibular agenesis subgroup. Although the results are statistically significant for the A0B0 and SNB values, they were not clinically relevant. The intermaxillary angle is generally reduced in AG, indicating a greater tendency towards a hypodivergent skeletal pattern. The values of the joint angles, the total gonial angle, and the upper and lower gonial angles are slightly increased on average in AG compared to CG. The percentage ratio between posterior and anterior facial height is higher in AG compared to CG. The most important finding is that the mandibular body length is significantly shorter in AG. Conclusions: No significant association was found between TMA and the skeletal parameters of the sella turcica. A possible association was found between TMA and skeletal malocclusions, particularly Class III malocclusions
Failure of shape-memory polymers: Experimentation and modeling
No full textDriven by practical applications, studies on the thermo-mechanics of shape-memory polymers (SMPs) grew in quantity and quality. Most of these studies are focused on experiments and modeling of the SMP deformation including phase transition. Various theories with essentially different approaches are available and compete. The present work deals with the less explored issue related to the SMP failure. Results of conducted experimental studies of the onset of damage are reported for a polymer whose shape-memory behavior is based on a glass transition temperature. These results are obtained under uniaxial tension as well as via bulge – membrane inflation – tests under varying temperatures. The combination of these tests provides a better understanding of SMP behavior, compared to the popular, and easier to perform, purely uniaxial tension tests which might give an inaccurate view of material response. Experimental results are further used for calibrating hyperelastic models of glassy and rubbery phases of the SMP material. Two novel features of the theory include a simple switch between descriptions of glassy and rubbery phases and enforcement of energy limiters in the constitutive equations to account for material failure. A general theoretical setting is also provided for modeling cracks, yet they are not simulated in the present work
Wikidata and SBN: An Assessment of Two Years of Work (2023–2025)
No full textThe article presents the theoretical foundations and the reconstruction of the intensive bibliographic control, correction,
and reconciliation activities that have progressively strengthened the link between SBN authority records and Wikidata
entities, particularly over the past two years. It provides a detailed account and analysis of the most recent interventions
carried out through the collaboration between ICCU and the Wikidata community. Building on this experience, the paper
proposes a set of key strategies to further enhance the representation of Italian cultural entities within the Semantic Web
and the network of Linked Data. Two main directions are suggested to pursue this goal: developing reliable pathways of
access to and from SBN in order to foster interoperability among information systems, and promoting awareness of best
practices in metadata creation within ordinary cataloguing workflows