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SALICYLALDEHYDE-TAGGED PEPTIDES FOR THE REVERSIBLE-COVALENT ENGAGEMENT OF PROTEIN LYSINE RESIDUES
No full textCovalent drug discovery has recently re-emerged as a powerful approach for targeting
clinically-relevant proteins, offering enhanced potency and selectivity through controlled
covalent interactions. In particular, reversible covalent (RC) chemistry combines the strength
of covalent binding with the tunability of non-covalent interactions, mitigating the risks of
permanent off-target reactivity. Within this context, this PhD thesis explores the use of
salicylaldehyde (SA) as a reversible electrophilic warhead for peptide-based ligand design.
The first part of this thesis focuses on the synthesis of SA-modified amino acids and their
incorporation into model peptides. Later on, a more straightforward and versatile approach
was devised, consisting in the late-stage peptide functionalization with copper-catalyzed azide-
alkyne cycloaddition (CuAAC). This second strategy enabled efficient installation of SA
moieties onto pre-assembled peptides specific for two protein targets, namely SHP2 and
NEMO. Moreover, using human serum albumin as model target, the CuAAC protocol was
instrumental for the design of a new combinatorial approach to SA-tagged small molecules.
The final part of the work, carried out at the University of Tokyo, integrates SA-based reversible
covalent chemistry into the RaPID (Random nonstandard Peptides Integrated Discovery)
platform, paving the way to a novel strategy towards macrocyclic peptide libraries displaying a
Lys-engaging electrophile.
Overall, this work expands the chemical space of peptide-based RC ligands, providing new
synthetic and methodological tools to access selective, tunable covalent binders to target
specific proteins or to inhibit clinically-relevant protein-protein interactions
Impact of Strip Subdivision on Water Conservation in Border Irrigation for Irregularly Shaped Fields
No full textBorder irrigation remains the most widely adopted surface irrigation method for row crops globally and is also extensively used in the Padana Plain (Italy), particularly for forage crops. In the Lombardy region, observations indicate that irrigation volumes can reach up to 3000 m3 /ha per event, often leading to excessive and inefficient water use. Given the ongoing decline in surface water availability, such practices are considered unsustainable in the long term. However, it is also unfeasible to replace them with more hard-path irrigation systems everywhere. In this context, a more realistic approach is to focus on optimizing irrigation scheduling and field layout, which can significantly reduce water consumption in gravity-fed surface irrigation. This study explores the water-saving potential of geometric reconfiguration in a 1.9-hectare, irregularly shaped, closed-end field in the Padana Plain, which is traditionally irrigated with an average volume of 2600 m3 /ha per irrigation event. High-resolution topographic data and the two-dimensional hydrodynamic model IrriSurf2D were used to simulate various land preparation scenarios, including strip subdivision and irrigation timing adjustments. Field implementation of the strip layout alone led to a 34 % reduction in water use, while model-based optimization of the irrigation durations suggested the potential for a total savings of up to 42 %. These findings demonstrate that precision surface irrigation strategies can significantly enhance the sustainability of border irrigation, even in complex field geometries, without abandoning traditional practices
L’amministrazione giudiziaria nell’esperienza della magistratura milanese: analisi organizzativa dei casi del settore logistico e della moda
No full textPreaching to the Unconverted: How Politicians Attacking the Media Influence Citizens' Evaluation of News Credibility
No full textIn the contemporary digital information landscape, the dissemination of news is frequently intertwined with critiques from political figures. Populist politicians, especially, have used social media platforms to target journalists and question the legitimacy of news media. Despite the concerning nature of this behavior, the empirical evidence on how such accusations influence public perceptions of news credibility remains limited. To address this research gap, this study investigates the impact of politicians' attacks on citizens' perceived credibility of news content in Norway, a highly trusting society with strong national publishers and public service media. We conduct a vignette experiment to assess whether a politician's act of shaming a traditional media outlet (ideologically distant from his/her viewpoints) on social media affects the perceived credibility of the news story. The findings suggest that politicians' attacks on news stories significantly affect citizens' perceptions of news credibility, particularly when a right-wing populist politician targets a liberal media outlet. Interestingly, the effect was stronger among individuals who were ideologically distant from the politician's party and those with high trust in the targeted media outlet. These results indicate that politicians attacking the media are not merely preaching to the converted; rather, their behavior can influence broader public perceptions of news credibility. By highlighting these dynamics, this research contributes to a deeper understanding of the relationship between elite political discourse, social media, and public trust in news content
Knowledge translation in surgery: a scoping review of implementation strategies, effectiveness and contextual barriers and enablers
No full textBackground: Knowledge translation (KT) interventions are essential for implementing evidence-based practices in healthcare. However, despite their proven effectiveness in addressing global health challenges, KT strategies in surgery remain challenging to apply. This scoping review examines KT strategies in surgery, their effectiveness, and key barriers and enablers to their implementation. Methods: This scoping review followed the Arksey and O'Malley and Levac et al. frameworks, integrating the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) and the PRISM (Practical Robust Implementation Sustainability Model) models to evaluate the effectiveness of knowledge translation interventions in surgical practice change and associated contextual barriers and facilitators. A systematic search was conducted across MEDLINE (PubMed, OVID), CINAHL (EBSCO), and PsycINFO (ProQuest). Articles were screened using predefined selection criteria, emphasizing experimental and quasi-experimental studies. Data extraction categorized KT interventions: knowledge diffusion, dissemination, and implementation approaches. Results: A total of 34 studies met the inclusion criteria. Most were hospital-based (88%) and focused on guideline adherence. The review identified three primary KT strategies: (i) educational materials and educational outreach, (ii) reminders and prompts, and (iii) audit and feedback systems. The most effective KT strategies used a combination of these interventions to maximize impact. Barriers included physician resistance, limited leadership support, financial constraints, and workflow disruptions, while enablers included institutional leadership, structured training programs, financial incentives, and interdisciplinary collaboration. A notable finding was the lack of standardized validation processes for adopting changes in the surgical setting, which often burdens individual surgeons and their institutions, thereby constraining both capacity and motivation for practice change. Conclusions: Findings suggest that layered, interdisciplinary KT strategies are the most effective for driving surgical practice change and overcoming institutional barriers. The integrated application of RE-AIM and PRISM frameworks proved valuable in assessing the interventions' sustainability and real-world effectiveness. This comprehensive analysis contributes to the growing body of knowledge on effective implementation strategies in surgical settings and provides a foundation for future practice improvement initiatives. Future research should focus on refining KT methodologies, expanding implementation frameworks, and addressing barriers to sustainability across diverse surgical settings
Strength training in the gym versus specific strength training on the bike in young off-road cyclists
No full textBackground
The benefits of strength training in cyclists are still a topic of debate. The aim of this study was to compare the effects of strength training performed in the gym with specific strength training performed on the bike in young off-road cyclists.
Sources of data
Nineteen participants were divided into the following two groups: (i) the group A performed 12 weeks of endurance training combined with two sessions/week of strength training in the gym; (ii) the group B performed 12 weeks of endurance training combined with two sessions/week of specific strength training on the bike. Incremental test, 30 s Wingate test, and countermovement jump test were conducted at pre (T0) and post (T1) training programs.
Areas of agreement
The findings are in line with previous research showing that heavy strength training in cyclists has significant improvements in some aerobic and anaerobic performance outcomes. Indeed, our results showed that in the group A, the Mean Power Output (MPO) of the 30 s Wingate test increased significantly between T0 and T1 (P = .002). In the group B, no significant differences were found in the MPO of the 30 s Wingate test between T0 and T1 (P = .276). In the group A, the Maximum Power Achieved (MPA) increased significantly between T0 and T1 (P < .001). In the group B, no significant differences were found in the MPA between T0 and T1 (P = .889).
Areas of controversy
Strength training in the gym for cyclists has not been widely investigated, and, in fact, the literature shows conflicting results on the topic, with some research groups highlighting the importance of sport-specific strength training. In this way, in both groups, no significant differences in the vertical jump height between T0 and T1 (P = .331 and P = .184, for groups A and B, respectively) were detected. However, the small sample size and the numerical heterogeneity between males and females in the recruited sample do not allow to generalize findings.
Growing points
As the group of cyclists who performed strength training in the gym showed significant improvements, this study suggests integrating heavy strength sessions in the gym into the usual endurance training program.
Areas timely for developing research
Further studies should investigate the effectiveness of strength training in the gym both in all off-road cycling categories as well as in other cycling specialities
Chronic environmental temperature affects protein expression in the eye of adult zebrafish (Danio rerio)
No full textVision in vertebrates is mediated by the eye, a complex organ with developmental and functional similarities to the central nervous system. Eye proteomics has emerged as a powerful tool for investigating ocular function and disease mechanisms, including neurodegeneration and ocular toxicity. The zebrafish (Danio rerio) is a well-established model in biomedical research, including ophthalmology, due to its highly developed visual system, rapid eye maturation, and genetic homology with humans. Building on previous findings that thermal stress can affect neural tissues, this study investigates whether prolonged exposure to non-optimal temperatures also impacts the zebrafish eye proteome. Adult zebrafish were maintained for 21 days at elevated (34 °C), control (26 °C), or low (18 °C) temperatures, and eye proteomes were analysed by tandem mass spectrometry. Our results reveal that both low and high temperatures induce distinct alterations in the expression of proteins involved in critical eye processes. Notably, high-temperature exposure modulates pathways such as sirtuin signalling while downregulating proteins involved in oxidative phosphorylation, electron transport, and ATP synthesis, alongside decreased expression of proteins central to visual phototransduction. These data indicate that environmental temperature can directly impact eye protein homeostasis, supporting a potential role for the thermal stress in ocular dysfunction
L'educazione cattolica: un progetto poetico attraverso i materiali d'archivio
No full textL'articolo esamina e discute i materiali d'archivio relativi alla progettazione e alla stesura della plaquette "L'educazione cattolica" di Giovanni Giudici
No Evidence of Superior Graft Remodeling and Maturation When Adding a Lateral Extra-articular Procedure to Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis of Comparative Studies
No full textBackground: The use of postoperative magnetic resonance imaging (MRI) to investigate the effect of concomitant lateral extra-articular procedures (LEAPs) is not well documented in the literature. Few studies have assessed the MRI signal intensity-measured by the signal-to-noise quotient (SNQ)-of the anterior cruciate ligament (ACL) graft between individuals who underwent ACL reconstruction (ACLR) with simultaneous LEAP and those who did not. These comparative studies have produced conflicting results, though, which makes the topic particularly relevant. Purpose: To systematically compare existing evidence on graft maturation by performing a meta-analysis of combined ACLR and LEAP versus isolated ACLR. Study design: Systematic review and meta-analysis; Level of evidence, 3. Methods: The methodology adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, Embase, and Cochrane Library databases were searched to identify potentially relevant comparative studies that analyzed postoperative graft maturation, at least 10 months after surgery, using MRI with SNQ after isolated ACL or ACL plus LEAP. The Methodological Index for Non-Randomized Studies was used for quality assessment. Results: A total of 542 patients were included, with 307 receiving isolated ACLR and 235 undergoing combined ACL plus LEAP. Meta-analysis revealed no statistical difference between the groups regarding SNQ (P = .574), with a mean difference of -0.58 (95% CI, -2.62 to 1.45). Neither the rank correlation test nor the linear regression test indicated any funnel plot asymmetry (P = .272 and P = .642 respectively). Conclusion: Adding a lateral extra articular procedure to ACLR does not improve graft remodeling and maturation. Furthermore, graft maturation is not influenced by the time from surgery, age, or sex. Despite the limited number of studies considered, these findings suggest that a lateral extra-articular procedure does not play a significant role in graft maturation and should be performed selectively