New Synthetic Approaches to Alk-1-enyl Sulfones and Sulfoxides

This thesis is devoted to the finding of new synthetic approaches to alk-1-enyl sulfones and sulfoxides. In particular, uncomplexed organoaluminum reagents reacted with aluminium sulfinates to afford alkenyl sulfoxides in good yields (72-75%). Sulfonyl chlorides reacted with pyridine-complexed alanes in the presence of PPh3 to afford sulfoxides in up to 94% yields; a reasonable mechanism is proposed. Sulfinyl chlorides react with alkynyl aluminium reagents to give alkynyl sulfoxides in modest yields (43-57%). Pyridine-complexed organoalanes react with sulfonyl chlorides in the presence of Ph3PO to give alkenyl sulfones in good yields (75%). Uncomplexed organoalanes reacted with pyridine-sulfonyl chloride complexes to afford sulfones in variable yields (40-90%). Finally, N-acyl-2-alkenyl-2H-dihydropyridine and dihydroisoquinoline derivatives are obtained via reaction of organoalane-pyridine complexes with acid halides

Development and validation of the Remote Working Benefits & Disadvantages scale

The changes that are constantly occurring in the labour sector have led organisations and companies to move towards digital transformation. This process was accelerated by the COVID-19 pandemic and  conducted to a massive recourse to the practice of remote working, which in this study is understood as the term for the way of performing work outside the usual workplace and with the support of ICT. Currently, there are no flexible scales in the literature that allow measuring the benefits and disadvantages of remote working with a single instrument. Thus, the distinction between the positive and negative consequences of working remotely, substantiated by a solid literature, provides a framework for a systematical understanding of the issue. The aim of the present study is to develop and validate a scale on remote working benefits and disadvantages (RW-B&D scale). For this end, a preliminary Exploratory Factor Analysis (EFA) with 304 participants, a tailored EFA with a sample of 301 workers and a Confirmatory Factor Analysis (CFA) with 677 workers were conducted. Participants were all Italian employees who worked remotely during the period of the COVID-19 health emergency. Data were collected between October 2020 and April 2021. The psychometric robustness of the model was assessed through bootstrap validation (5000 resamples), fit indices testing and measurement of factorial invariance. The statistical analyses demonstrated the bifactorial nature of the scale, supporting the research hypothesis. The model showed good fit indices, bootstrap validation reported statistically significant saturations, good reliability indices, and convergent and discriminant validity. Measurement invariance was tested for gender and organisational sector. The results suggested that the novel scale facilitates the quantitative measurement of the benefits and disadvantages associated with remote working in empirical terms. For this reason, it could be a streamlined and psychometrically valid instrument to identify the potential difficulties arising from remote working and, at the same time, the positive aspects that can be implemented to improve organisational well-being

Ligand signature in the membrane dynamics of single TrkA receptor molecules

The neurotrophin receptor TrkA (also known as NTRK1) is known to be crucially involved in several physio-pathological processes. However, a clear description of the early steps of ligand-induced TrkA responses at the cell plasma membrane is missing. We have exploited single particle tracking and TIRF microscopy to study TrkA membrane lateral mobility and changes of oligomerization state upon binding of diverse TrkA agonists (NGF, NGF R100E HSANV mutant, proNGF and NT-3). We show that, in the absence of ligands, most of the TrkA receptors are fast moving monomers characterized by an average diffusion coefficient of 0.47 μm^2/second; about 20% of TrkA molecules move at least an order of magnitude slower and around 4% are almost immobile within regions of about 0.6 mm diameter. Ligand binding results in increased slow and/or immobile populations over the fast one, slowing down of non-immobile trajectories and reduction of confinement areas, observations that are consistent with the formation of receptor dimeric and oligomeric states. We demonstrate that the extent of TrkA lateral mobility modification is strictly ligand dependent and that each ligand promotes distinct trajectory patterns of TrkA receptors at the cell membrane (ligand ‘fingerprinting’ effect). This ligand signature of receptor dynamics results from a differential combination of receptor-binding affinity, intracellular effectors recruited in the signalling platforms and formation of signalling and/or recycling endosome precursors. Thus, our data uncover a close correlation between the initial receptor membrane dynamics triggered upon binding and the specific biological outcomes induced by different ligands for the same receptor

In Vivo Recognition of Human Vascular Endothelial Growth Factor by Molecularly Imprinted Polymers

One of the mechanisms responsible for cancer-induced increased blood supply in malignant neoplasms is the overexpression of vascular endothelial growth factor (VEGF). Several antibodies for VEGF targeting have been produced for both imaging and therapy. Molecularly imprinted polymer nanoparticles, nanoMIPs, however, offer significant advantages over antibodies, in particular in relation to improved stability, speed of design, cost and control over functionalization. In the present study, the successful production of nanoMIPs against human VEGF is reported for the first time. NanoMIPs were coupled with quantum dots (QDs) for cancer imaging. The composite nanoparticles exhibited specific homing toward human melanoma cell xenografts, overexpressing hVEGF, in zebrafish embryos. No evidence of this accumulation was observed in control organisms. These results indicate that nanoMIPs are promising materials which can be considered for advancing molecular oncological research, in particular when antibodies are less desirable due to their immunogenicity or long production time

Fluorescence Lifetime Nanoscopy of Liposomal Irinotecan Onivyde: From Manufacturing to Intracellular Processing

: Onivyde was approved by the Food and Drug Administration (FDA) in 2015 for the treatment of solid tumors, including metastatic pancreatic cancer. It is designed to encapsulate irinotecan at high concentration, increase its blood-circulation lifetime, and deliver it to cells where it is enzymatically converted into SN-38, a metabolite with 100- to 1000-fold higher anticancer activity. Despite a rewarding clinical path, little is known about the physical state of encapsulated irinotecan within Onivyde and how this synthetic identity changes throughout the process from manufacturing to intracellular processing. Herein, we exploit irinotecan intrinsic fluorescence and fluorescence lifetime imaging microscopy (FLIM) to selectively probe the supramolecular organization of the drug. FLIM analysis on the manufacturer's formulation reveals the presence of two coexisting physical states within Onivyde liposomes: (i) gelated/precipitated irinotecan and (ii) liposome-membrane-associated irinotecan, the presence of which is not inferable from the manufacturer's indications. FLIM in combination with high-performance liquid chromatography (HPLC) and a membrane-impermeable dynamic quencher of irinotecan reveals rapid (within minutes) and complete chemical dissolution of the gelated/precipitated phase upon Onivyde dilution in standard cell-culturing medium with extensive leakage of the prodrug from liposomes. Indeed, confocal imaging and cell-proliferation assays show that encapsulated and nonencapsulated irinotecan formulations are similar in terms of cell-uptake mechanism and cell-division inhibition. Finally, 2-channel FLIM analysis discriminates the signature of irinotecan from that of its red-shifted SN-38 metabolite, demonstrating the appearance of the latter as a result of Onivyde intracellular processing. The findings presented in this study offer fresh insights into the synthetic identity of Onivyde and its transformation from production to in vitro administration. Moreover, these results serve as another validation of the effectiveness of FLIM analysis in elucidating the supramolecular organization of encapsulated fluorescent drugs. This research underscores the importance of leveraging advanced imaging techniques to deepen our understanding of drug formulations and optimize their performance in delivery applications

Biological Effects of Transforming Growth Factor Beta in Human Cholangiocytes

: TGF-β is a cytokine implicated in multiple cellular responses, including cell cycle regulation, fibrogenesis, angiogenesis and immune modulation. In response to pro-inflammatory and chemotactic cytokines and growth factors, cholangiocytes prime biliary damage, characteristic of cholangiopathies and pathologies that affect biliary tree. The effects and signaling related to TGF-β in cholangiocyte remains poorly investigated. In this study, the cellular response of human cholangiocytes to TGF-β was examined. Wound-healing assay, proliferation assay and cell cycle analyses were used to monitor the changes in cholangiocyte behavior following 24 and 48 h of TGF-β stimulation. Moreover, proteomic approach was used to identify proteins modulated by TGF-β treatment. Our study highlighted a reduction in cholangiocyte proliferation and a cell cycle arrest in G0/G1 phase following TGF-β treatment. Moreover, proteomic analysis allowed the identification of four downregulated proteins (CaM kinase II subunit delta, caveolin-1, NipSnap1 and calumin) involved in Ca2+ homeostasis. Accordingly, Gene Ontology analysis highlighted that the plasma membrane and endoplasmic reticulum are the cellular compartments most affected by TGF-β. These results suggested that the effects of TGF-β in human cholangiocytes could be related to an imbalance of intracellular calcium homeostasis. In addition, for the first time, we correlated calumin and NipSnap1 to TGF-β signaling

Nuove tecniche di prospezione archeologica mediante strumenti multifrequenza

EnIn this work we present some results obtained in a measurement survey performed with a stepped frequency Ground Penetrating Radar (GPR). The GPR and the survey at hand have been conceived for archaeological purposes.The stepped frequency GPR has been developed by the Italian Research Consortium CO.RI.S.T.A. in the framework of the ARCHEO project, founded by Italian M.U.R.S.T. The system can work within a large bandwidth and both in ungated and gated mode. It is equipped with a positioning system able to move the transmitting and receiving antennas of the GPR independently on each other and to place them automatically and in a precise fashion. The GPR has been tested first in laboratory of CO.RI.S.T.A., then in a controlled site, and finally in the real archaeological site of Cales, near Capua (Southern Italy), preventively and appositely studied by a team of archaeologists. The final results obtained in the field have been coherent with a previous prospecting performed at Cales and have individuated some new further buried targets, whose nature is still unknown at the moment

Wellbeing Costs of Technology Use during Covid-19 Remote Working: An Investigation Using the Italian Translation of the Technostress Creators Scale

During the first months of 2020, the Covid-19 pandemic has affected several countries all over the world, including Italy. To prevent the spread of the virus, governments instructed employers and self-employed workers to close their offices and work from home. Thus, the use of remote working increased during the pandemic and is expected to maintain high levels of application even after the emergency. Despite its benefits for both organizations and workers, remote working entails negative consequences, such as technostress. The present study had a double aim: to test the psychometric characteristics of the Italian translation of the brief version of the technostress creators scale and to apply the scale to investigate technostress during the Covid-19 emergency. The research involved 878 participants for the first study and 749 participants for the second one; they completed a self-report online questionnaire. Results confirmed the three-factor structure of the Italian technostress creators scale and highlighted positive relationships between workload, techno-stressors, work–family conflict and behavioural stress. The role of remote working conditions has been analysed as well. The study provided a useful tool for the investigation of technostress in the Italian context. Moreover, it provided indications for practice in the field of remote working and workers’ wellbein

Disability as a job resource: The role of job crafting and organizational citizenship behaviours. Towards an approach to value diversity in organizations

The number of employment opportunities afforded to people with disabilities in Italy is still not entirely satisfactory. Managerial policies should build a more favourable context, full of stimuli, support and backing for the promotion of good disability management practices within both private and public organizations. The aim of this study was to investigate how disability understood as a resource can positively influence the organizational climate and, consequently, the enactment of supportive and proactive behaviors, using the Job Demands-Resources model (JD-R) as a starting paradigm. Analyses were performed on 129 school educators in May 2021, who answered a structured questionnaire comprising several constructs, such as the perception of disability as a resource (2 items), job crafting (9 items) and extra-role behaviours (4 items). The mean age of the respondents was 51.6 years; most of them were female, married or cohabiting, and had a university degree. The study was performed through a non-parametric approach (PLS-SEM) and validated through bootstrap. Analyses showed that the relationship between disability as a resource and extra-role behaviors was partially mediated by the effect of job crafting. Results highlighted that workers with a predisposition to consider their colleagues with disabilities as a tool for growth are more likely to implement those behaviors that can improve the quality of organizational life and individual well-being, such as those oriented to proactivity and those aimed at expressing support, voluntary actions, and professional development even when this is not immediately required by the role