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Chemical selection for the Thyroid Validation Study coordinated by EURL ECVAM and involving EU-NETVAL laboratories
No full textThe aim of the Thyroid Validation Study, coordinated by EURL ECVAM and involving EU-NETVAL laboratories, was to validate selected non-animal methods for the identification of chemicals that can potentially disrupt the thyroid hormone system in humans. The validation study was organized in two parts: Part 1 was to assess method performance and develop standard operating procedures, where needed, and Part 2 was to assess the mechanistic relevance of the methods using a set of validation chemicals. This paper describes the stepwise process to select this validation set of chemicals, mainly based on extensive literature review and expert judgment elicitation to identify chemicals for which there was evidence to show their (lack of) ability to perturb the thyroid hormone signaling mechanisms or modes of action covered by the methods. A unique contribution of the study lies in its mechanistic coverage of molecular targets within the thyroid gland but also regulatory mechanisms in peripheral tissues, reflecting a multifaceted perspective on thyroid hormone action. The validation set consisted of 30 chemicals, providing a balanced representation across a broad chemical space and offering insights into the mechanistic relevance of the selected methods. Once validated, these methods will contribute to advancing the identification and evaluation of endocrine disruptors, informing regulatory decisions, and promoting alternative testing strategies
Invited review: Barriers and potential strategies in the implementation of cow-calf contact systems—Insights from dairy cattle farmers and from other livestock production systems
No full textCow-calf contact (CCC) systems are of growing scientific interest due to the public concern about early separation of the calf from the dam on dairy cattle farms, which currently occurrs soon after calving. Despite the scientifically demonstrated beneficial effects of CCC for both the cow (improving udder health and promoting maternal behaviors) and calf (growth, social learning and reduction of abnormal behaviors), only a small number of dairy cattle farmers practice CCC. Although unpredictable, new animal welfare legislation or best practice guidelines might suggest the adoption of CCC systems in the future. Therefore, the aim of this review is to identify common barriers that prevent farmers from implementing CCC systems and suggest suitable strategies to overcome them. Thus, this review focuses first on identifying barriers that prevent farmers from choosing CCC or transitioning to CCC, considering influencing factors such as region, demographics, and farm characteristics. Second, the review proposes suitable research and knowledge transfer strategies (i.e., communication, dissemination, and education) to address these barriers. For the proposal of research strategies, an overview of mother-offspring management strategies used in other livestock production systems (e.g., beef cattle and dairy sheep) that could potentially be used by dairy cattle farmers to implement CCC systems is provided. The results show that many dairy cattle farmers without CCC experience expressed concerns about the effects of CCC on economic viability, management and staff wellbeing, and animal welfare. However, farmers who practice(d) CCC reported generally positive experiences and did not confirm some of the concerns raised by farmers without CCC experience. This implies that these concerns are knowledge barriers that could be addressed with effective knowledge transfer strategies. Nevertheless, there were also concerns (e.g., separation distress) that were confirmed by farmers who practice(d) CCC, suggesting that these practical barriers require the exploration of novel strategies. Despite differences in biology or productive values, inspiration could be drawn from mother-offspring management in other livestock systems. For instance, future research on dairy cattle could explore the efficacy of restricted suckling to increase milk yield, as well as the efficacy of keeping calves together with familiar peers to reduce separation distress. Combined with research into economic viability and effective knowledge transfer, insights from other livestock systems could improve the implementation of CCC systems in a way that is sustainable for dairy cattle farmers, beneficial for the welfare of cows and calves, and socially acceptable
MODELING APPROACHES FOR CLIMATE MITIGATION IN ALPINE FORESTS.
No full textThis thesis investigates the complex relationship between forests, climate change and management, focusing on their interactions through the lens of ecosystem services and sustainability. The aim of the thesis is to analyse the role of alpine forests, harvested wood product and forest management in climate change mitigation and adaptation, and how different development trajectories can affect this role. The study area covers the forests of Valle Camonica and part of Valtellina, key Alpine landscapes in Lombardy (Italy). Three main research papers compose the work: the first analyzes substitution effects of wood products through Life Cycle Assessment and remote sensing, demonstrating the short-term importance of timber substitution for decarbonization. The second integrates ecological modeling with optimization to simulate forest growth, harvested wood products, and substitution effects under different climate and management scenarios, highlighting the importance of forest carbon stocks preservation and the relevance of preventive silviculture. The third paper applies sustainability indicators within the DPSIR framework and ecological modeling to evaluate scenarios inspired by SSP narratives, linking environmental, social and economic dimensions. Results show that collaborative and sustainability-oriented pathways provide greater long-term benefits, while fragmented exploitation undermines both resilience and equity. Overall, the thesis offers insights and decision-support information for climate-smart forestry in Alpine contexts, providing results about climate and management impact on forests with three different approaches
DISSECTING IMMUNE DYSREGULATION IN PATIENTS WITHTHYMIC EPITHELIAL TUMORS BY AUTOANTIBODY ANDSINGLE-CELL PROFILING
No full textThymic epithelial lesions (TELs) are a heterogeneous and rare group of diseases arising from the epithelial cells of the thymus. TELs include both benign conditions, such as thymic hyperplasia (TH), and malignant lesions, collectively referred to as thymic epithelial tumors (TETs). According to the 2021 WHO classification, TETs are further subdivided into thymomas comprising type A, AB, B1, B2, and B3 and thymic carcinomas (TC), based on tumor architecture, the morphology of malignant cells and the proportion of intratumoral immune cells. Prognosis progressively worsened from type A thymomas to TCs.
Patients with thymomas showed an elevated susceptibility to paraneoplastic syndromes, in particular autoimmune diseases (ADs), which affects around 30% of thymoma patients. Evidence indicates that thymomas, but not TCs, can sustain intratumoral T-cell development, a process that appears dysregulated and likely contributes to thymoma-associated immune dysfunction, although the precise mechanisms linking TETs to ADs remain unclear.
To address these knowledge gaps, we combined complementary approaches, including clinical and high-throughput autoAbs screening, a 39-color spectral flow cytometry panel to deeply characterize αβ, γδ and MAIT compartments, and single-cell RNA sequencing paired with αβ TCR sequencing to reconstruct developmental trajectories, functional states and clonal relationships. Pediatric thymuses were used as the healthy tissue counterpart whereas PBMCs from age-matched healthy donors were used as healthy peripheral blood controls. Public single-cell datasets were integrated to enable direct transcriptomic comparisons between patients and healthy individuals.
Our results indicate that TEL patients can be classified into two main categories. One group, comprising TH and type AB, B1, B2 thymomas, retained intratumoral thymopoiesis, whereas type A, A-MNT, B3 thymomas and TC were predominantly infiltrated by mature T cells. Within this spectrum each histotype showed distinctive features: B1 thymomas supported efficient thymopoiesis and released CD4, CD8 and Vδ1 recent thymic emigrants (RTE) cells into the blood stream; B2 thymomas mirrored the intratumoral program but released predominantly Vδ1 RTE cells, indicating lower output of conventional naïve T cells; AB displayed a developmental bottleneck with accumulation of immature thymocytes and reduced naïve CD4 and CD8 pools; B3 thymomas showed little αβ thymopoiesis by flow cytometry but residual activity detectable by single-cell analysis; A thymomas and TCs resembled typical solid tumors dominated by memory T cells, with TCs uniquely enriched in highly immunosuppressive Tregs and exhausted TRM-like CD8 cells.
Serology revealed that immune dysregulation extends beyond overt disease. Clinical screening detected autoAbs in most patients without symptoms and anti-AChR was frequent in asymptomatic thymoma, indicating tolerance breach before clinical onset. A high-content autoantigen array uncovered a distinct IgG cluster almost entirely composed of AB and B thymomas without overt ADs, characterized by anti-dsDNA, anti-IL-12, anti-AQP4 and anti-TIF1γ autoAbs with strong internal correlations. In contrast, IgM autoreactivity was reduced in AB and B thymomas yet increased in TH, consistent with sustained unswitched memory B cells and long-term IgM secretion. Together these findings support a model in which aberrant intratumoral thymopoiesis fails to enforce central tolerance, seeds autoreactive T cells and promotes autoreactive B-cell activation.
Regulatory T cells (Treg) provided an additional link to tolerance failure. Within tumors we identified a developing and mature Treg subsets, both depleted in AB and B1 thymomas. Circulating Tregs were also reduced, supporting the idea of an impaired Treg generation and maintenance. This aligns with a possible defective peripheral B-cell tolerance checkpoints and offers a plausible route from local thymic dysfunction to systemic autoantibody production.
TCs illustrated a different but targetable immune state, in which TRM-like cells retained cytotoxic programs but co-expressed multiple inhibitory receptors such as PD1, TIM3, CD38 and CD39, supporting the investigation of PD1 and TIM3 blockade as strategies to reinvigorate resident effectors.
Paired scTCR analyses revealed clonal bridges between tumor and blood in all groups. In AB, B1 and B2 thymoma patients, shared clones were often singletons in tumor while expanded in blood, consistent with new emigrants arising intratumorally and expanding systemically. Recurrent clonotypes across individuals suggest convergent antigenic selection.
Taken together, our integrated serological, spectral flow cytometric, and scRNAseq analyses provide a comprehensive immunological characterization of TEL patients linking disordered intratumoral T-cell development, failures of Treg and B-cell tolerance checkpoints and checkpoint-restrained resident effector programs to the dual clinical phenotype of autoimmunity and cancer. Future work should define the epithelial cues that misroute thymopoiesis, map the antigens driving shared clonotypes and test mechanism-guided interventions in prospective cohorts
TADF Emission in Supramolecular Assemblies through Cooperativity and Polymorphism
No full textSupramolecular assemblies exhibiting thermally activated delayed fluorescence (TADF) represent a still poorly explored field of research. Here, the photophysical properties of a novel anthraquinone-based dye 1 emitting in a wide range between orange and near-infrared, depending on the aggregation form (polymorphs or fibers) are investigated. 1 exhibits a near orthogonal D-A-D molecular structure with a dimethylated phenyl ring between D and A, which is not hampering the molecular packing. The self-assembly mechanism exhibits a cooperative process regardless of the encumbered phenyl units, allowing the formation of emitting fibers and polymorphs with TADF character. Computational investigations carried out in solution and in the solid state support the interpretation of the photophysical data and reveal the role of the environment. The possibility of applying these TADF fibers is finally demonstrated in solution-processed organic light-emitting diodes
Large norovirus GII.17 outbreak in a school in Northern Italy: A novel emerging sublineage within an emerging genotype?
No full textNorovirus (NoV) is one of the leading causes of acute gastroenteritis worldwide, being responsible for millions of cases each year. We report a large NoV outbreak occurred in a Northern Italy school complex, and the genomic characterization of the outbreak strain. Stool samples from 105 subjects involved in the outbreak were collected and tested for enteric pathogens by real-time RT-PCR. The infecting NoV strain was genotyped by whole genome sequencing (WGS). Finally, a phylogenetic analysis was carried out including all whole genomes available online for the same genotype. NoV GII genogroup was detectable in 85 of 105 (81%) tested stool samples. WGS performed on 32 (32/85, 37.6%) positive samples evidenced the infecting NoV strain as belonging toGII.17[P17] genotype. The phylogenetic analysis showed that its sequences clustered with recent GII.17[P17] isolates, mostly from Europe, while they formed a separated subclade with distinct mutational patterns. Our analysis confirmed all sequenced isolates belonged to the same transmission event.
The detected genotype and the mutational pattern of the outbreak strain further support the emergent role of GII.17[P17] among NoV strains worldwide and the need of its close epidemiological monitoring
La giurisprudenza amministrativa sul cambio di destinazione d’uso per fini di culto (riflessioni a partire dal Consiglio di Stato, sez. III, sent. 9 dicembre 2024, n. 9823)
No full textLa prassi del mutamento di destinazione d’uso di immobili per fini di culto mette in luce le tensioni tra libertà religiosa e poteri pubblici. La giurisprudenza amministrativa in materia tenta di bilanciare due esigenze, nessuna delle quali totalmente sacrificabile: l’esercizio del culto, in particolare da parte delle comunità religiose minoritarie, e il controllo edilizio necessario al buon governo del territorio. L’orientamento interpretativo consolidato, incentrato sulla verifica in concreto dell’impatto del carico urbanistico, pare prima facie promuovere l’esercizio del culto. A partire dal caso di Seregno, il contributo ripercorre i principi enunciati dalla Corte costituzionale per interrogarsi su quanto questa chiave di lettura attui efficacemente il sistema di garanzie costituzionali. Ne emerge una tutela ancora incompleta: il bilanciamento continua a privilegiare le esigenze urbanistiche, confinando il culto alla sola dimensione privata.The practice of changing the designated use of buildings for religious purposes highlights the tensions between religious freedom and public power. Administrative case law on this subject seeks to balance two needs, neither of which can be entirely sacrificed: the exercise of worship, particularly by religious minorities, and the building controls necessary for the good governance of the territory. The established interpretive approach, centered on a concrete assessment of the impact on the urban load, appears prima facieto promote the exercise of worship. Starting from the Seregno case, this article retraces the principles articulated by the Constitutional Court in order to examine how effectively this interpretive framework implements the system of constitutional guarantees. What emerges is still an incomplete protection: the balancing continues to privilege urban-planning requirements, confining worship to the private sphere alone
SPOROCYTELESS/NOZZLE cooperates with MADS-domain transcription factors to regulate an auxin-dependent network controlling Megaspore-Mother-Cell differentiation
No full textThe formation of the female gamete is a complex developmental process that begins with the differentiation of the Megaspore Mother Cell (MMC) within the ovule. SPOROCYTELESS/NOZZLE (SPL/NZZ) is the principal regulator of the MMC formation, as mutations in the SPL/NZZ gene lead to the failure of the MMC differentiation. Nonetheless, the SPL/NZZ-dependent regulatory pathway governing the MMC development remains largely unknown. Using a multi-omics approach, we identify direct SPL/NZZ targets and their downstream network. We discover that SPL/NZZ interacts with ovule-identity MADS-domain transcription factor complexes to regulate the expression of common target genes. By integrating the omics data with the analysis of either complementation or mutant lines, we describe a comprehensive regulatory mechanism in which SPL/NZZ controls the differentiation of the MMC by acting on an auxin-dependent downstream network
TOWARD ENHANCED BIMODAL SENSING: TIO₂-COATED METALLIC NANOSTRUCTURES FOR ELECTROCHEMICAL ANDPHOTOELECTROCHEMICAL DETECTION
No full textThis thesis presents a study on the synthesis, modification, and optimization of titanium dioxide (TiO2)
thin films for electrochemical and photoelectrochemical sensing applications. After preparing TiO2
films via a sol-gel process, using titanium isopropoxide as a precursor, a systematic investigation of
sol aging revealed a strong dependence between aging duration and the properties of the resulting
film. Among the conditions analyzed, a period of 14 days produced the best results, with more
homogeneous films, more uniform surface coverage, and a significantly increased photocurrent
response. These results confirmed the importance of sol aging as a key parameter in modulating the
properties of TiO2.
To expand the system's functionality, the films were subsequently modified with gold nanoparticles
(AuNPs) synthesized using wet chemical methods. The aim was to evaluate the influence of metal
nanostructures on the behavior of the material. It emerged that TiO2 plays a crucial role in stabilizing
the nanoparticles: in the absence of the oxide layer, the AuNPs show poor adhesion and rapid
dissolution, while the TiO2 coating preserves their structural integrity. The TiO2/AuNP hybrid system
showed improved electrochemical performance, allowing the detection of ciprofloxacin, an antibiotic,
even in the presence of common interferents, confirming the synergy between metal nanoparticles
and the TiO2 matrix.
Given the decisive role of nanoparticles, research then turned to alternative techniques for their
manufacture. Although widespread, chemical methods in solution have limitations such as low
structural stability, poor control of surface distribution, and complex synthesis procedures. To
overcome these critical issues, a physical approach based on solid state dewetting was adopted. In
this method, a thin metal film is deposited by sputtering onto a conductive substrate and then heated
to induce the formation of nanoparticles. This technique has made it possible to obtain uniform and
stable nanostructures, with dimensions that can be adjusted by varying the initial thickness of the
metal film.
The interaction between TiO2 and metal nanoparticles was subsequently studied by depositing a layer
of TiO2 on top of the gold nanostructures. As expected, the insulating nature of TiO2 reduced the
electrochemical sensitivity of the electrodes. However, the introduction of TiO2 conferred new
properties on the system, including photoactivity. This feature was exploited for the
photoelectrochemical detection of hydrogen peroxide (H2O2), demonstrating that the same device can
operate via two distinct mechanisms: electrochemical (EC) and photoelectrochemical (PEC). This
dual functionality was defined as bimodality.
Based on this bimodal approach, a new device was developed combining TiO2 with silver
nanostructures. The aim was to evaluate the effect of replacing gold with silver and to verify the
feasibility of bimodality in a context closer to real-world applications. In this configuration, TiO2
enabled PEC oxidation thanks to its photoactivity, while silver facilitated the electrochemical
reduction of the target molecule, the antihistamine cetirizine, thanks to its known catalytic activity.
The integration of the two materials produced a synergistic effect: the device allowed PEC and EC
measurements to be performed with the same electrode and the same experimental setup, while
improving stability and reusability. The analytical parameters obtained—sensitivity, detection limit,
and reproducibility—were satisfactory for both techniques. Furthermore, the ability to compare two
independent signals increased the reliability of the measurements. This dual-channel strategy proved
particularly effective in mitigating the effect of interferents, which often affect one technique but not
the other.
Overall, the work demonstrates the potential of TiO2-based hybrid systems as versatile, stable, and
high-performance platforms for chemical sensing. Through systematic material optimization and the
development of bimodal strategies, the thesis makes significant contributions to the design of
multifunctional devices capable of addressing real-world analytical challenges
Percutaneous Transthoracic Embolization for Hemothorax Due to Suspected Secondary Rupture After Chimney TEVAR
No full textPurpose
To describe a bailout percutaneous transthoracic embolization for the management of life-threatening hemothorax caused by suspected secondary aortic rupture following chimney thoracic endovascular aortic repair (ch-TEVAR), in a patient unsuitable for open surgical conversion.
Materials and Methods
A patient previously treated with ch-TEVAR for complex aortic pathology presented with acute hemodynamic instability and large left hemothorax on CTA, with imaging findings suspicious for contained secondary rupture and active bleeding adjacent to the excluded aortic segment. Due to prohibitive surgical risk and unfavorable anatomy for conventional endovascular re-intervention, a percutaneous transthoracic approach was planned.
Under cone-beam CT and fluoroscopic guidance, direct puncture of the hemothorax was performed, allowing selective catheterization of the bleeding site. Embolization was achieved using a combination of embolic agents until complete angiographic exclusion of the contrast extravasation was obtained. Technical success, hemodynamic stabilization, and imaging follow-up were assessed.
Results
The transthoracic approach enabled rapid control of active bleeding with immediate hemodynamic improvement. Final angiography and post-procedural cone-beam CT demonstrated complete embolization of the rupture site with no residual extravasation. No procedure-related complications occurred. Follow-up CT confirmed persistent exclusion of the bleeding source and progressive reduction of the hemothorax.
Conclusion
Percutaneous transthoracic embolization represents a feasible and lifesaving minimally invasive bailout technique for the treatment of hemothorax due to suspected secondary rupture after ch-TEVAR in selected high-risk patients. Advanced intraprocedural imaging guidance is essential to ensure accurate targeting and to expand the therapeutic options when conventional surgical or endovascular strategies are not viable