Percorrer por data de Publicação, começado por "2025-12-11"
A mostrar 1 - 2 de 2
Resultados por página
Opções de ordenação
- Ciliopathy in cholangiocytes of biliary atresia patients – association with ischemic cholangiopathy, patterns of ductular reaction and disease severityPublication . Quelhas, Patrícia Alexandra Silveira ; Santos, Jorge Luiz dos; Vieira, Sandra Maria Gonçalves; Lusquinos, José Ignacio VerdeBiliary atresia (BA) is a rare neonatal cholangiopathy characterized by the progressive obstruction of the extrahepatic bile ducts, leading to cholestasis, liver fibrosis, and often the need for liver transplantation. Although affected infants appear clinically healthy at birth, laboratory evidence of cholestasis is already detectable. Despite advances in understanding the underlying pathophysiological mechanisms, the etiology of BA remains unclear, with proposed causes ranging from viral infections and immune dysregulation to genetic predispositions and vascular anomalies. Recent evidence suggests that hypoxia and primary cilia dysfunction in cholangiocytes may play a central role in BA pathogenesis, influencing cholangiopathy progression and clinical outcomes. This thesis investigates the interplay between hypoxia—specifically, the activation of the hypoxia-inducible factor 1-alpha (HIF-1α) pathway in cholangiocyte nuclei (ischemic cholangiopathy)—and the morphological and functional alterations of primary cilia in cholangiocytes of BA patients. The methodological approach included immunohistochemical, immunofluorescence, and molecular analyses of liver samples obtained from patients undergoing portoenterostomy, detailed characterization of ciliary morphology using advanced digital imaging techniques, and correlation of these findings with clinical and laboratory parameters and post-operative outcomes, including native liver survival. The results demonstrated increased nuclear HIF-1α expression in cholangiocytes of BA patients, particularly in areas near the peribiliary vascular plexus and progenitor cell niches. This activation was absent in liver samples from control patients with other neonatal cholestases (non-BA), suggesting a specific role of hypoxia in BA pathogenesis. Furthermore, gene expression analysis revealed the upregulation of molecular pathways related to ductular reaction, oxidative stress, and angiogenesis, reinforcing the hypothesis that hypoxia actively contributes to bile duct injury and tissue remodeling. These findings justify further studies focused on the mechanisms involved in HIF-1α activation and the clinical effects of hypoxia and/or oxidative stress on cholangiocytes. Additionally, the characterization of primary cilia in cholangiocytes revealed significant structural alterations in BA patient samples. A reduction in ciliary length and a possible disruption in the transport of acetylated tubulin 4α—a key marker of ciliary stability— from the cytoplasm to the cilium was observed. These alterations were associated with worse clinical outcomes, including a significant reduction in native liver survival. Regarding the association between hypoxia and ciliopathy, the co-localization of HIF- 1α and TUBA4A in BA samples suggests an inverse relationship between HIF-1α positivity and the presence of primary cilia on the luminal membrane of cholangiocytes, both in the portal tract and other microanatomical regions of the liver. Quantitative analysis of ciliary characteristics showed that biliary cells without hypoxic features maintained primary cilia integrity, suggesting that hypoxia may negatively impact ciliary formation or maintenance. The correlation between HIF-1α activation and ciliary dysfunction implies that hypoxia not only promotes inflammation and fibrosis but also compromises the structural and functional integrity of primary cilia, exacerbating disease progression. These findings offer new insights into the pathophysiological mechanisms underlying BA, suggesting that HIF-1α activation and ciliary dysfunction may serve as relevant biomarkers for prognosis and potential therapeutic targets. Identifying these molecular alterations not only facilitates the prediction of clinical outcomes but also opens avenues for innovative interventions aimed at modulating the hypoxic response and restoring ciliary function to improve liver survival and patient quality of life. Overall, this work advances the understanding of the relationship between hypoxia, ciliary dysfunction, and cholangiopathy in BA, paving the way for new research directions to develop more effective diagnostic and therapeutic strategies that mitigate the effects of hypoxia and preserve liver function in pediatric patients with this condition.
- Piezoresistive Sensing for Structural Health Monitoring in Liquid Hydrogen Tanks: A Study on Composite Cryotank TechnologiesPublication . Figueiredo, Matilde Rola; Pereira, João Pedro Nunes; Silva, Abílio Manuel Pereira daHydrogen has been emerging as a potential key energy carrier for sustainable aviation, yet its adoption is constrained by distinct engineering challenges, particularly its safe and lightweight storage. The present study investigates the feasibility of using the intrinsic piezoresistive properties of carbon-fibre reinforced prepreg composites, commonly employed in Type V cryogenic hydrogen tanks, for structural health monitoring. Given that matrix microcracking constitutes the predominant damage mechanism in these tanks and typically initiates at strain levels of 0.3%-0.5%, a preventive strain sensing approach was adopted based on these critical deformation thresholds. To achieve a proof of concept, 17-ply multidirectional carbon fibre/epoxy laminates based on Boeing’s cryotank from the Composite Cryotank Technologies and Demonstration program were produced and tested in their as-fabricated state and after controlled cryogenic cycling through five and ten cycles of immersion in liquid nitrogen (-196 ?) followed by reheating (52 ?). Unconditioned specimens showed a clear and repeatable piezoresistive response from surface measurements, with gauge factors ranging from -11.02 to -12.70, confirming their intrinsic self-sensing capability. Cryogenically cycled specimens exhibited moderate mechanical degradation and increased baseline electrical resistance, yet retained self-sensing performance, with gauge factor increases exceeding 85%. While volume (edge-to-edge) measurements were inconclusive, the consistent surface response demonstrates that unmodified carbon fibre/epoxy prepreg composites employed in Type V cryotanks can retain effective strain sensing functionality after cryogenic exposure and cycling, providing insights for the development of integrated structural health monitoring strategies in hydrogen storage applications.