Archivio Istituzionale della Ricerca- Università del Piemonte Orientale
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Monadic Type-And-Effect Soundness
Get PDFWe introduce the abstract notions of monadic operational semantics, a small-step semantics where computational effects are modularly modeled by a monad, and type-and-effect system, including effect types whose interpretation lifts well-typedness to its monadic version. In this meta-theory, as usual in the non-monadic case, we can express progress and subject reduction, and provide a proof, given once and for all, that they imply soundness. The approach is illustrated on a lambda calculus with generic effects, equipped with an expressive type-and-effect system We provide proofs of progress and subject reduction, parametric on the interpretation of effect types. In this way, we obtain as instances many significant examples, such as checking exceptions, preventing/limiting non-determinism, constraining order/fairness of outputs. We also provide an extension with constructs to raise and handle computational effects, which can be instantiated to model different policies
Platinum(IV) anticancer therapies and cathepsin B: innovative strategies for overcoming resistance in glioblastoma cells
No full textGlioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Due to its heterogeneity, the abundance of altered signaling pathways within the same tumoral mass, its low immunogenicity, and the presence of the blood–brain barrier, standard therapies based on surgical resection, radiotherapy, and chemotherapy result in ineffective tumor removal. For these reasons, the development of new drugs is mandatory to ameliorate patients’ life expectancy and quality of life. Cathepsins are lysosomal proteases involved in several physiological and pathological processes, and they play key roles in modulating cell death and pharmacological resistance. In particular, cathepsin B is a crucial regulatory protein in different types of cell death, and its overexpression contributes to GBM angiogenesis and tumor progression. Octahedral platinum(IV) (Pt(IV))-based prodrugs have already demonstrated improved anticancer efficacy compared to routinely used cisplatin. This work aims to investigate the effects of two such prodrugs—Pt(IV)Ac-POA ((OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV)) and DB178 ((OC-6-44)-acetatodiamminedichlorido(4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylato)platinum(IV))—on two different glioblastoma cell lines, U251 and T98G, with particular attention to their effects on cathepsin B. The immunocytochemical and biochemical results obtained on the two cell lines highlight the maintenance of basal levels of cathepsin B while efficiently activating programmed cell death mechanisms, as investigated by optical and electronic microscopy. These findings may serve as a valid starting point for further approaches that incorporate cathepsins’ inhibitors to improve therapeutic efficacy and possibly reveal novel pharmacological targets
High-flux hemodialysis with polymethylmethacrylate membranes reduces soluble CD40L, a mediator of cardiovascular disease in uremia
Get PDFBackground and hypothesis: Major Adverse Cardiovascular Events (MACE) are the main cause of mortality in hemodialysis (HD). Soluble CD40Ligand (sCD40L) binds to CD40 on endothelial cells (EC) and vascular smooth muscle cells (VSMC), playing a potential role in MACE. HD Registries showed a reduced mortality for MACE using the polymethylmethacrylate (PMMA) membrane. Study objectives: (1) to confirm the role of sCD40 L as independent predictor and mediator of MACE; (2) to evaluate the effect of PMMA on sCD40L-mediated vascular aging.
Methods: In 201 patients treated by high-flux HD, sCD40 L levels were measured and correlated with MACE; 54/201 patients with sCD40L ≥ median value were randomized for 9 months in 2 cross-over groups alternatively treated with PMMA or polysulfone (PS): sCD40 L and dialytic parameters were recorded. In vitro, the role of sCD40 L was studied on EC dysfunction and VSMC calcification after incubation with patients' sera: cells engineered to knock down CD40 by siRNA were also used to confirm the role of CD40-CD40 L pathway activation.
Results: At study admission, the sCD40 L median level of 8.4 ng/ml (IQR 2.9-12.7) showed the best statistical performance to identify MACE, that occurred in 51/201 (25.4%) patients. Indoxyl sulfate (IS) and p-Cresyl Sulfate (pCS) directly correlated with sCD40L levels and induced its release by platelets. In comparison to PS, PMMA treatment significantly reduced sCD40 L levels, in accordance with its enhanced mass removal by adsorption. In vitro, sera collected after PMMA treatment reduced EC dysfunction and VSMC osteoblastic differentiation through a mechanism involving the CD40-CD40 L pathway.
Conclusion: sCD40 L is an independent predictor and mediator of MACE in chronic HD patients. PMMA membrane stably reduced sCD40 L under the high-risk cut-off of 8.4 ng/ml. In vitro studies confirmed the role of PMMA in the reduction of EC dysfunction and VSMC calcification in association with sCD40 L modulation
Juntos, pero no revueltos. El personaje colectivo en el "Persiles"
Get PDFPersiles y Sigismunda, como buenos héroes épicos, son acompañados en su peregrinación a Roma por un grupo de personajes, que se va conformando a medida que encuentran a nuevos viandantes. Ese personaje colectivo posee unas dinámicas internas que regulan su constitución y su manifestación sucesiva, para cuyo análisis me serviré de algunos conceptos de la psicología social; esas dinámicas lo convierten en una especie de superpersonaje, poliédrico, capaz de poner de realce las varias facetas de la historias secundarias que va escuchando, gracias a la multiplicidad de perspectivas a las que las someten en sus juicios. A su vez, este grupo entrará en relación con otros grupos, coadyuvantes o antagonistas de su acción, cuya tipología estudio aquí, siguiendo la clasificación de Canetti, para comprender las diferencias entre la primera y la segunda parte de la obra. Tanto la fisionomía del superpersonaje como la tipología de los otros grupos sufrirá un cambio entre las dos partes del libro, entre el norte y el sur, en consonancia con el cambio de subgénero narrativo de la obra
ATM knock out alters calcium signalling and augments contraction in skeletal muscle cells differentiated from human urine-derived stem cells
Get PDFAtaxia-telangiectasia (A-T) is a rare neurodegenerative disorder caused by the deficiency of the serine/threonine kinase ataxia telangiectasia mutated (ATM) protein, whose loss of function leads to altered cell cycle, apoptosis, oxidative stress balance and DNA repair after damage. The clinical manifestations are multisystemic, among them cerebellar degeneration and muscular ataxia. The molecular mechanism by which ATM loss leads to A-T is still uncertain and, currently only symptomatic treatments are available. In this study, we generated a functional skeletal muscle cell model that recapitulates A-T and highlights the role of ATM in calcium signalling and muscle contraction. To this aim, by using CRISPR/Cas9 technology, we knocked out the ATM protein in urine-derived stem cells (USCs) from healthy donors. The resulting USCs-ATM-KO maintained stemness but showed G2/S cell cycle progression and an inability to repair DNA after UV damage. Moreover, they showed increased cytosolic calcium release after ATP stimulation to the detriment of the mitochondria. The alterations of calcium homoeostasis were maintained after differentiation of USCs-ATM-KO into skeletal muscle cells (USC-SkMCs) and correlated with impaired cell contraction. Indeed, USC-SkMCs-ATM-KO contraction kinetics were dramatically accelerated compared to control cells. These results highlight the relevant function of ATM in skeletal muscle, which is not only dependent on a non-functional neuronal communication, paving the way for future studies on a muscular interpretation of A-T ataxia
Does Fetal Size Affect Umbilical Artery Pulsatility Index in Pregnancies Complicated by Gestational Diabetes?
Get PDFIl Presidente della Repubblica
No full textIl contributo esamina il ruolo costituzionale e le funzioni del Presidente della Repubblica italiana, con particolare attenzione all'evoluzione dei poteri presidenziali nell'odierna forma di governo parlamentare
Resilience of mobility network to dynamic population response across COVID-19 interventions: Evidences from Chile
Get PDFThe COVID-19 pandemic highlighted the importance of non-traditional data sources, such as mobile phone data, to inform effective public health interventions and monitor adherence to such measures. Previous studies showed how socioeconomic characteristics shaped population response during restrictions and how repeated interventions eroded adherence over time. Less is known about how different population strata changed their response to repeated interventions and how this impacted the resulting mobility network. We study population response during the first and second infection waves of the COVID-19 pandemic in Chile and Spain. Via spatial lag and regression models, we investigate the adherence to mobility interventions at the municipality level in Chile, highlighting the significant role of wealth, labor structure, COVID-19 incidence, and network metrics characterizing business-as-usual municipality connectivity in shaping mobility changes during the two waves. We assess network structural similarities in the two periods by defining mobility hotspots and traveling probabilities in the two countries. As a proof of concept, we simulate and compare outcomes of an epidemic diffusion occurring in the two waves. While differences exist between factors associated with mobility reduction across waves in Chile, underscoring the dynamic nature of population response, our analysis reveals the resilience of the mobility network across the two waves. We test the robustness of our findings recovering similar results for Spain. Finally, epidemic modeling suggests that historical mobility data from past waves can be leveraged to inform future disease spatial invasion models in repeated interventions. This study highlights the value of historical mobile phone data for building pandemic preparedness and lessens the need for real-time data streams for risk assessment and outbreak response. Our work provides valuable insights into the complex interplay of factors driving mobility across repeated interventions, aiding in developing targeted mitigation strategies
Co-progettazione culturale per combattere la povertà relazionale: apprendimenti da una rete multi-attore a Torino
Get PDFIn questo articolo si presentano le caratteristiche ed elementi di apprendimento del progetto La cultura dietro l’angolo. L’intervento, realizzato dal 2022 nella Città di Torino, ha coinvolto un partenariato composito di enti di diversa natura nella co-progettazione di un palinsesto di attività culturali indirizzate a persone con povertà relazionali. La proposta voleva servire a generare occasioni per la socialità e la costruzione di legami. Il focus è posto sugli aspetti organizzativi della progettazione. In particolare, le motivazioni della partecipazione e gli apprendimenti dalla prospettiva degli enti coinvolti. I risultati possono essere di interesse per policy maker interessati alla realizzazione di progetti sociali che vedono il coinvolgimento di reti multi-attore eterogenee