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Design synthetic 3D scaffold for skeletal muscle tissue differentiation
Get PDFSkeletal muscle (SKM) loss is largely irreversible, and current therapeutic options to restore muscle mass remain limited. Despite the regenerative capacity of SKM due to resident satellite cells, in vitro and in vivo studies using stem cells have shown low regenerative and self-renewal properties. Conventional 2D monolayer culture systems fail to replicate the in vivo environment due to the lack of cell-cell and cell-matrix interactions, often resulting in misleading outcomes. New strategies are needed to address the limitations of current tissue repair and regeneration methods.Tissue engineering (TE) has emerged as a promising approach for SKM tissue renewal both in vitro and in vivo. TE combines scaffolds, cells, and regulatory signals to create a biomimetic extracellular matrix (ECM), supporting cell attachment and proliferation. This study evaluated a poly (L-lactic acid)-co-poly-(ε-caprolactone) (PLCL) electrospun scaffold coated with type I collagen to support SKM fabrication in vitro. The PLCL scaffold promoted myoblast attachment, elongation, and myotube formation, offering insights into 3D tissue-like structure development. To investigate SKM functionality, Atomic Force Microscopy (AFM) was used to monitor contractile activity on the scaffold, simulating excitation-contraction coupling. A 3D bioprinted scaffold with collagen, laminin, and fibronectin mimicked the native SKM environment. This model facilitated myoblast differentiation from healthy (CTRL) and Limb-Girdle Muscular Dystrophy Type D2 (LGMDD2) conditions, analyzing Myogenic Regulatory Factors (MRFs), MEF2C isoforms, and splicing factors like SRSF1 and RBM4, cargoes of TNPO3 implicated in LGMDD2 pathology. Using a micropillar system, early differentiation impairments caused by TNPO3 mutations were identified.These findings highlight the potential of TE-based models in understanding SKM development and LGMDD2 pathology while offering platforms for drug screening and therapeutic exploration. Future studies aim to refine these TE platforms for targeted therapeutic applications and improved muscular dystrophy treatments
The impact of Del Nido Cardioplegia on perioperative serum electrolytes balance and on the onset of postoperative atrial fibrillation after cardiac surgery in patients with reduced left ventricle ejection fraction
No full textIntroduzione: La fibrillazione atriale postoperatoria (POAF) si presenta in una percentuale variabile tra il 20% ed il 40% dei pazienti che vengono sottoposti ad intervento cardiochirurgico e può complicarne il decorso postoperatorio, soprattutto nei pazienti con ridotta frazione d’eiezione del ventricolo sinistro. Si sviluppa solitamente come conseguenza del trauma chirurgico o delle fluttuazioni nella volemia o nelle concentrazioni sieriche dei principali elettroliti che si verificano nel periodo postoperatorio. Dal momento che le soluzioni cardioplegiche possono impattare in maniera significativa su questi ultimi fattori, lo scopo di questo lavoro è stato quello di indagare il ruolo della Cardioplegia Del Nido nell’insorgenza di fibrillazione atriale postoperatoria.
Materiali e Metodi: È stato condotto uno studio retrospettivo di singolo centro su 93 pazienti sottoposti ad intervento di rivascolarizzazione chirurgica del miocardio in circolazione extracorporea ed arresto cardioplegico, suddivisi poi in due gruppi in base al tipo di cardioplegia utilizzata (cardioplegia Del Nido vs cardioplegia ematica fredda) .
Risultati: L’incidenza di POAF nell’intera coorte di studio è stata del 21.5%. I pazienti trattati con cardioplegia ematica fredda hanno mostrato un’incidenza circa 3 volte più alta di POAF rispetto al gruppo trattato con Cardioplegia Del Nido (OR: 3.44; 95% CI: 1.1 to 10.5; p=0.029).
Il gruppo cardioplegia ematica fredda ha mostrato livelli significativamente più alti di potassio sierico sia al declampaggio aortico (p<0.001), sia all’arrivo in terapia intensiva (p=0.007), sia durante i primi tre giorni di degenza postoperatoria (p=0.009). La frequenza di defibrillazioni al declampaggio aortico (p=0.003), il dosaggio di adrenalina nell’immediato postoperatorio (p<0.001), ed il picco di troponina I sierica postoperatoria (p=0.01), sono risultati più bassi nel gruppo Del Nido.
Conclusioni: Il Gruppo Cardioplegia Del Nido ha mostrato un tasso di POAF significativamente più basso, probabilmente attraverso una sua azione indiretta sul bilancio elettrolitico peri-operatorio, sulla protezione miocardica e sul bisogno di supporto inotropo postoperatorio.Background: Postoperative atrial fibrillation (POAF) hits up to 40% of patients who have undergone cardiac surgery; it can complicate the postoperative course, especially in those with reduced left ventricular ejection fraction. The most frequent causes are related to surgical trauma and the high variations in volemic and electrolyte balance in the postoperative period.
Objectives: As cardioplegic solutions can significantly modify these last factors, the present study aimed to evaluate the role of Del Nido (DN) cardioplegia on the onset of POAF.
Methods: A retrospective single-center analysis was carried out on 93 patients who have undergone coronary artery bypass graft surgery where cardioplegia was used. The patients were divided into two groups according to the cardioplegic solution (Cold Blood vs Del Nido), and perioperative outcomes were compared.
Results: POAF occurred in 21.5% of patients; the Cold blood cardioplegia (CBC) group showed a 3-times higher rate of POAF compared to the DN patients (OR: 3.44; 95% CI: 1.1 to 10.5; p=0.029). The CBC group showed higher serum potassium levels both after the cross-clamp removal (p<0.001), at the ICU admission (p=0.007), and during the first 3 postoperative days (p=0.009). The defibrillation rate at cross-clamp removal (p=0.003), the dose of postoperative epinephrine (p<0.001), and the peak of serum troponin (p=0.01), were lower in the patients treated with Del Nido cardioplegia.
Conclusion: DN cardioplegia showed significantly reduced POAF rates after cardiac surgery by acting on the electrolyte balance, myocardial protection, and on the need for postoperative inotropic support
Mapping tense-aspect coding strategies in the explicit instruction of Italian to Chinese learners: an experimental study
Get PDFQuesta ricerca esamina l’acquisizione del sistema tempo-aspettuale dell’italiano da parte di apprendenti sinofoni, concentrandosi su tre principali difficoltà: la decodifica dell’azionalità verbale (Rastelli, 2023), la selezione dei tempi verbali appropriati (Crippa, 2014) e l’uso dei tempi con complementi di durata (Limonta, 2009). Tali difficoltà derivano dalle differenze nella codifica delle informazioni temporali tra cinese e italiano, con gli apprendenti sinofoni che devono ricategorizzare le informazioni solitamente espresse tramite marche aspettuali. Lo studio valuta l’impatto dell’insegnamento esplicito sull’azionalità verbale e sulla mappatura dei sistemi TAM (Tempo, Aspetto, Modalità) per i tempi Presente Indicativo, Passato Prossimo e Imperfetto. Confrontando le strategie di codifica, gli apprendenti riflettono simultaneamente sulla duratività verbale e sulle strutture tempo-aspettuali nelle due lingue, come illustrato negli esempi: Verbo durativo: V_IndPre + da + NP_time = V-le_PFV + NP + le_CDS; Verbo puntuale: V_PassPros + da + NP_time = V + NP + le_CDS. Il trattamento sperimentale ha coinvolto due gruppi (sperimentale: n = 34, controllo: n = 25) con sei sessioni di insegnamento esplicito, task di traduzione e feedback. Un test temporizzato, somministrato almeno tre mesi dopo, ha valutato l’acquisizione del TAM tramite test di grammaticalità (33 item) e di completamento testuale (19 item). I risultati hanno mostrato che l’insegnamento esplicito ha migliorato le performance sul tempo-aspetto (p = 0,041), soprattutto con complementi di durata (p = 0,015). Il gruppo sperimentale ha ottenuto punteggi superiori nella categoria tempo (p = 0,003, r = 0,382), ma non nell’aspetto (p = 0,06, r = 0,243). Lo studio conclude che l’insegnamento esplicito ha facilitato l’acquisizione del tempo, ma non dell’aspetto, probabilmente perché quest’ultimo è già familiare in cinese. Inoltre, i task di traduzione hanno rivelato un miglioramento significativo nella consapevolezza metalinguistica (Δ = -1,110, p < 0,001), con il gruppo sperimentale che ha mostrato una maggiore consapevolezza metalinguistica e punteggi superiori.This research investigates the acquisition of the Italian tense-aspect system by L1 Chinese learners, focusing on three main errors: decoding verbal actionality (Rastelli, 2023), selecting appropriate tenses (Crippa, 2014), and using correct tenses with durational complements (Limonta, 2009). These challenges stem from differences in how temporal information is encoded in Chinese and Italian, with Chinese learners needing to recategorize information typically expressed through aspectual markers. The study evaluates the impact of explicit instruction on verbal actionality and the mapping of L1 and L2 TAM (Tense, Aspect, Modality) systems for the following tenses: Presente Indicativo, Passato Prossimo, and Imperfetto. By comparing codification strategies, learners are encouraged to reflect simultaneously on verbal durativity and tense-aspectual structures in both languages, as illustrated in (1) and (2): (1) Durative verb: VIndPre + da + NPTime = V-lePFV + NP + leCDS; (2) Punctual verb: VPassPros + da + NPTime = V + NP + leCDS. The experimental treatment involved two groups (experimental: n = 34, control: n = 25) with six sessions (9 hours) of explicit instruction, three translation tasks, individual assignments, and feedback. A timed test at least three months later assessed TAM acquisition through grammaticality judgment (33 items) and textual completion (19 items). Results showed that explicit instruction improved tense-aspect performance (p = 0.041), particularly with durational phrases (p = 0.015). The experimental group outperformed the control group in tense competence (p = 0.003, r = 0.382), but not in aspect (p = 0.06, r = 0.243). The study concluded that explicit instruction helped decode tense information but not aspect, probably because aspect as a category was already familiar to participants in Chinese. Additionally, translation tests showed significant improvement in metalinguistic awareness (Δ = -1.110, p < 0.001), with the experimental group exhibiting deeper metalinguistic awareness and higher scores
The role of gender differences in tissue biophysical properties in osteoarthritis progression
Get PDFObjectives
This study investigates gender differences in primary hip osteoarthritis (OA) progression through a prospective observational approach, analyzing functional, radiographic, and biophysical disparities between male and female patients. The findings aim to enhance patient treatment and management from clinical and biomechanical perspectives.
Materials and Methods
Patients undergoing total hip arthroplasty (THA) due to primary hip OA were divided into two cohorts based on gender. Preoperative evaluations included functional disability assessment and standard hip and pelvis X-rays graded by the Tönnis classification. During surgery, femoral heads were preserved for microstructural analysis. A subset (13 males, 12 females) underwent micro-computed tomography to assess bone volume fraction, porosity, trabecular thickness, and separation. Follow-ups at 6 and 12 months included postoperative X-rays and functional assessments.
Results
Both cohorts showed significant functional improvement postoperatively, consistent with literature. Return-to-work time ranged from 4 to 12 weeks, averaging 6 weeks. Statistically significant gender differences emerged in postoperative Harris Hip Score (HHS) and WOMAC scores at both follow-ups, as well as return-to-work time. Preoperatively, the HHS also showed a less pronounced difference. Analysis of 125 femoral head specimens revealed no significant gender differences in bone mineral density or bone volume fraction. However, trabecular anisotropy, thickness, and separation differed significantly. Correlation analysis indicated moderate preoperative associations between bone mineral density, anisotropy degree, and clinical scores, but these weakened postoperatively. Laboratory findings did not strongly correlate with clinical outcomes at 6 or 12 months.
Conclusions
While no significant gender disparities in clinical outcomes were identified, differences in microstructural tissue characteristics suggest the need for gender-specific considerations in managing end-stage OA. This study provides a rigorous and replicable framework for investigating osteoarthritis progression
Statelessness in international and European law
Get PDFThis investigation questions the capability of the international framework on statelessness in providing concrete protection to stateless persons. Though the international community has drafted several instruments that should support a protection status of stateless individuals and prevent the insurgence of statelessness, this phenomenon perdures. It has been often argued that the focal point behind this inability to produce an incisive effect on the matter is attributable to the lack of shared criteria and consistent implementation of Status Determination Procedures, without which, any right human right attributed to stateless individuals becomes inconsequential. After a review of the elements and their limitation, it emerged that regulating statelessness and providing solutions seems to represent a threat to the well-established sovereignty of states.
Taking into account the inability of the international framework to produce binding legislation and related supervising mechanisms, this investigation identifies a regional approach as a first step towards closing these gaps, namely through the establishment of an EU directive on statelessness. It will be argued that the Union’s competence on the migration policy, combined with the equivalence of stateless individuals to TCNs within the Treaty of Lisbon, offers enough basis to compel the EU to require identification of statelessness within its border and to regulate their condition of entry and stay. Given the developing approximation of TCN’s status to that of citizens within the Union, to fully recognize statelessness through a right-based approach would provide the guarantees that the international framework has failed to secure
Linguistic analysis of green content in italian high school english textbooks: an ecolinguistic perspective
Get PDFThe ultimate objective of ecological education is to spread awareness regarding issues caused by damage to the ecosystem and how to protect it and endorse behaviors that play a contributing role in ecological sustainability. Nevertheless, traditional, conventional academic and educational content often falls short of tackling ecological sustainability, with minimum stress on green content. This dissertation intends to investigate green content in three Italian high school English textbooks that are representative of this genre, English File, Empower and Speakout. This dissertation is descriptive and qualitative in nature, it uses corpus-based deductive approach and content analysis by using Stibbe’s (2015) ecolinguistic theory, notably its three stories, metaphors, evaluation and erasure, to dig out green content in the above-mentioned textbooks. Using the categorization framework of ecological discourse analysis (EDA), the study examines how ecological themes and contents are represented in English textbooks. This research addresses two main research questions 1) The first research question investigated if there is significant relationship between observed and expected frequency of green content related to words in selected textbooks 2) second research question explored significant relationship between observed and expected frequency of green content related to sentences in selected textbooks. The findings indicated that there is no significant difference between expected and observed frequency of the green content, which means that the three textbooks have not presented enough educational content related to environmental issues, and thus the null hypothesis are rejected. The practical implications of this dissertation are grounded in Stibbe’s ecolinguistic framework and contribute to the domain of green linguistics and environmental educational discourse analysis
Polatuzumab vedotin plus bendamustine and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: a multicentric observational retrospective study.
Get PDFLa prognosi per i pazienti affetti da linfoma diffuso a grandi cellule B recidivati o refrattari (DLBCL R/R) dopo terapia di prima linea che non possono essere candidati a terapia con CAR-T o a trapianto autologo di cellule staminali è infausta. Nonostante i regimi chemioterapici attuali e l'introduzione di nuove classi di farmaci dell’algoritmo terapeutico abbiano significativamente migliorato i risultati in questo gruppo di pazienti, la malattia continua a presentare elevati tassi di recidiva, con la maggior parte dei pazienti che muoiono per progressione della malattia. Polatuzumab vedotin è un anticorpo monoclonale diretto contro CD79b, coniugato con l'agente antimitotico monometil auristatina. Uno studio di fase 1 ha dimostrato ottimi dati di efficacia e un profilo di sicurezza accettabile nell'impiego di polatuzumab vedotin, sia come monoterapia che in combinazione con la chemioterapia a base di bendamustina e rituximab (Pola-BR) in pazienti con DLBCL R/R pluritrattati. Di conseguenza il regime di terapia Pola-BR è stato approvato dalla Food and Drug Administration (FDA) negli Stati Uniti e successivamente dall'Agenzia Europea per i Medicinali (EMA) nel trattamento di pazienti affetti da DLBCL R/R non idonei a terapia trapiantologica.
Dopo l'approvazione di polatuzumab vedotin da parte di FDA ed EMA, tra giugno 2019 e febbraio 2020, è stato concesso in Italia un accesso anticipato a questo trattamento tramite uso compassionevole. Studi clinici sono fondamentali per valutare l'impiego di pola-BR nella pratica clinica quotidiana, poiché possono evidenziare dati circa effetti collaterali aggiuntivi o variazioni dei dati di efficacia rispetto ai dati ottenuti da studi clinici controllati. L'obiettivo di questo progetto di ricerca è stato quello di analizzare i dati provenienti da uno studio osservazionale multicentrico, al fine di valutare l'efficacia e la sicurezza di pola-BR nella pratica clinica quotidiana, al di fuori di studi controllati.Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL R/R) who are not eligible for CAR-T therapy or autologous stem cell transplant have a poor prognosis. Although current chemotherapy regimens and the introduction of new drugs have led to significantly improved outcomes in this setting, this patient group still experiences high rates of relapse and death due to disease progression.
Polatuzumab vedotin is a monoclonal antibody targeting CD79b, conjugated with the antimitotic agent monomethyl auristatin. A phase 1 study demonstrated excellent efficacy and tolerability data for polatuzumab vedotin, both as monotherapy and in combination with bendamustine and rituximab chemotherapy (Pola-BR) in patients with heavily pretreated DLBCL R/R. This study led to the approval of the Pola-BR regimen by the U.S. Food and Drug Administration (FDA) and later by the European Medicines Agency (EMA) for the treatment of patients with DLBCL R/R who are not eligible for transplant therapy.
After the approval of polatuzumab vedotin by the FDA and EMA, early access to this treatment was granted in Italy between June 2019 and February 2020 through a Named Patient Program. The aim of this multicenter observational study is to assess the effectiveness and safety profile of Pola-BR in real-world settings, in order to identify additional side effects or variations in outcomes compared to controlled clinical trials.
Strategie avanzate di diagnostica e controllo per azionamenti elettrici trifase e multifase
Get PDFThe increasing demand for variable speed motors that offer high-performance and high-power has led to a significant increase in the research on multiphase machines over the past two decades. Indeed, one of the primary benefits of multiphase technology is the possibility to split the power among a greater number of lower-rated power electronic components. Furthermore, a greater number of phases corresponds to an higher number of degrees of freedom, which can be utilized for purposes such as fault diagnosis and to increase the machine torque density.
A great part of the thesis work focuses on modeling faulty three-phase and multiphase electrical machines along with the utilization of Artificial Intelligence (AI) techniques for accurately identify and distinguish various types of failures. The failures studied comprises manufacturing defects, high-resistance connections, and inter-turn short circuits. The approaches presented in the thesis exhibit extensive applicability for surface-mounted permanent magnet synchronous motors but can be extended to different electrical machines types.
An investigation was conducted on the control of two-level multiphase voltage source inverters. A control strategy was developed for reducing the root mean square of the output current ripple produced by multiphase inverters with an odd number of phases. Furthermore, the frequency of commutations of the power electronic components is reduced.
All the investigations have been assessed through simulations and experimental tests employing prototypes of three-phase and multiphase electric drives.La crescente richiesta di motori aventi velocità variabile in grado di offrire alte prestazioni ha portato a un significativo aumento della ricerca sulle macchine multiphase negli ultimi due decenni. Infatti, uno dei principali vantaggi della tecnologia multiphase è la capacità di distribuire la potenza su un numero maggiore di componenti elettronici di potenza. Inoltre, un numero maggiore di fasi corrisponde ad un aumento dei gradi di libertà che possono essere utilizzati per scopi come la diagnostica di guasto e l'aumento della densità di coppia della macchina elettrica.
Una grande parte del lavoro di tesi è centrata sulla modellizzazione dei guasti in macchine elettriche trifase e multifase insieme all'utilizzo di tecniche di intelligenza artificiale per identificare e distinguere accuratamente varie tipologie di guasto. I guasti studiati comprendono difetti di fabbricazione, connessioni ad alta resistenza e cortocircuiti spira-spira. Gli approcci presentati nella tesi mostrano una vasta applicabilità per motori sincroni a magneti permanenti montati sulla superficie rotorica ma possono essere estesi a diversi tipi di macchine elettriche.
Nella tesi, è stato condotto un studio sul controllo degli inverter multiphase a due livelli. È stata sviluppata una strategia di controllo per ridurre il valore efficace dell'ondulazione della corrente di uscita prodotta da inverter multiphase con un numero dispari di fasi. Inoltre, la frequenza delle commutazioni dei componenti elettronici di potenza è stata ridotta utilizzando la strategia proposta.
Tutte le indagini condotte sono state valutate attraverso simulazioni e test sperimentali utilizzando prototipi di motori e convertitori trifase e multifase
CRISPR/CAS9 Methodologies as a tool for investigating Fanconi Anemia pathway in cancer: perspective on pancreatic cancer treatment
Get PDFThe concept of precision medicine is advancing the discovery of new therapeutic targets for cancer treatment, offering tailored approaches based on the genetic profile of individual patients. One such approach is the paradigm of Synthetic Lethality, where cancer cells with specific genetic mutations are targeted by therapies that spare normal, healthy cells. This concept has been successfully applied in the treatment of various cancers, including ovarian, breast, and pancreatic cancers. The first synthetic lethality-based treatment to gain approval was for patients with BRCA1/2 mutations, using PARP inhibitors. These drugs disrupt the DNA repair machinery of cancer cells by inhibiting single-strand break repair, while the BRCA1/2 mutations prevent double-strand break repair. However, a major limitation of this approach is the development of resistance to PARP inhibitors, and the fact that not all cancer patients carry BRCA1/2 mutations. Therefore, there is a need to identify new synthetic lethal partners to expand the therapeutic potential of PARP inhibitors. The Fanconi Anemia pathway is involved in DNA repair and has a well-established connection with BRCA2-mediated repair processes. This PhD thesis aims to explore and validate advanced genomic methodologies to investigate the genes involved in the FA pathway, with a particular emphasis on their relationship with PARP inhibitor treatment. The ultimate goal is to identify therapeutic targets that could improve patient stratification for personalized cancer therapies, with a specific focus on pancreatic cancer cells. This study primarily focuses on utilizing genomic tools, specifically CRISPRSelect and CRISPR interference (CRISPRi), to investigate the Fanconi Anemia pathway and its relationship with sensitivity to the PARP inhibitor Talazoparib. The key genes explored include FANCA, FANCC, FANCD2, and FANCM
Multivariate information theoretic methods for the analysis of neural network function
Get PDFTo understand brain functions, it is necessary to characterize how neural systems encode, process, and transmit information. Information theory provides multivariate analysis tools to address these questions by analyzing activity recordings from real brains or neural network models. These tools are model-independent and can be applied to any recording modality and across different scales. In this thesis, we improved and used information-theoretic tools to study the brain in several ways.
We developed the Multivariate Information in Neuroscience Toolbox (MINT), designed for analyzing neural information. MINT includes tools such as Shannon entropy, mutual information, transfer entropy, and Partial Information Decomposition (PID). It enables researchers to quantify how neural populations encode and transmit behaviorally relevant information across brain regions, enhancing investigations into neural computation. By integrating dimensionality reduction techniques and bias-correction methods, MINT allows precise analysis of high-dimensional neural datasets.
A significant limitation in computing PID components from neural data is sampling bias, particularly in synergy, which increases quadratically with the number of possible neural responses, leading to overestimations. To address this, we developed bias-correction methods that enhance PID estimation accuracy. We applied these methods to data from the auditory cortex, posterior parietal cortex, and hippocampus of mice engaged in cognitive tasks, deriving accurate estimates of how synergy and redundancy vary across regions.
Additionally, we used MINT to analyze simulated spiking neural network models to explore contributions of different cortical interneurons to information encoding. Previous models with a single interneuron type revealed redundant encoding in the gamma frequency range. In contrast, our extended models showed distinct gamma frequencies carry synergistic information about sensory inputs, suggesting interneuron diversity enhances information encoding. Together, our methodological work and network model findings highlight the potential of information theory for advancing understanding of neural encoding and information transmission