University of Modena and Reggio Emilia
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Pulmonary intravascular mononuclear cell accumulation in cases of mechanical asphyxia due to external neck compression
No full textPulmonary intravascular mononuclear cell accumulations have been described in mechanical asphyxia, but their diagnostic value and independence from demographic or post-mortem factors remain uncertain. This study assessed the frequency of these accumulations in asphyxial deaths due to external neck compression compared with non-asphyxial deaths, and evaluated whether the association persists after adjustment for potential confounders. Lung tissue samples from 31 external neck-compression deaths and 151 non-asphyxial controls were examined histologically. A subset underwent immunohistochemical phenotyping. Univariable comparisons were performed using χ2 and Mann–Whitney U tests. A multivariable logistic regression model—including age, sex, post-mortem interval (PMI), and body mass index (BMI)—was used to evaluate the independence of the association. Intravascular mononuclear accumulations were observed in 41.9 % of neck-compression deaths versus 17.2 % of controls (p < 0.01; unadjusted OR 3.47, 95 % CI 1.52–7.96). In the multivariable model, external neck compression remained independently associated with the presence of intravascular accumulations (adjusted OR 2.93, 95 % CI 1.14–7.52; p = 0.025), while age, sex, PMI, and BMI showed no significant effect. Immunohistochemistry confirmed that accumulations consisted of mature mononuclear cell subsets. Pulmonary intravascular mononuclear accumulations occur significantly more often in asphyxial deaths involving external neck compression, and this association persists after adjustment for key demographic and post-mortem variables. Although not specific to mechanical asphyxia, these accumulations represent a practical ancillary marker that may support the diagnosis of neck-compression vitality, especially in cases with limited external findings
The aporetic dialogues of Modena on gender differences: Is it all about testosterone? Episode II: Empathy
No full textThe exploration of gender differences in non-andrological fields was the core focus of a series of discussions, which took place at the Endocrinology Unit in Modena, Italy in the form of the aporetic dialogue of ancient Greece. This second episode reports the transcript of the actual debate on testosterone's role in defining empathic behavior in males and females. The two groups of discussants sustained that empathic gender differences may rely either on testosterone exposure (group 1) or on other factors (group 2). The first group supported the hypothesis that females are more empathic than males due to reduced exposure to fetal testosterone, which correlates with higher empathic scores at all ages and lower sensitivity to testosterone in adulthood. This hypothesis is also supported by evolutionary mechanisms and evidence in animal ethology. Conversely, the second group affirmed that gender differences rely on structural diversities in brain organization, hormonal factors such as vasopressin, oxytocin, and cortisol, as well as sociological aspects. An expert in neurophysiology, acting as a referee, moderated the discussion and decided whether the two theories were equivalent or one was predominant
Spectrally Efficient Time-Frequency Space Modulation: A Delay-Doppler Domain FTN Waveform for ISAC Systems
No full textLes funérailles princières de Mme de Modène entre France et Italie
No full textLa présente publication, s’inscrivant dans le prolongement des travaux menés par le Centre de recherche du château de Versailles sur les funérailles princières, se concentre sur la figure de Charlotte-Aglaé d’Orléans (1700-1761) et sur le rôle que sa mort a joué dans la dynamique cérémonielle et diplomatique du xviiie siècle. Pour retracer l’histoire de ses funérailles, cette étude s’appuie sur des sources éditées ainsi que sur des documents inédits conservés aux Archives d’État de Modène, en particulier les dépêches de l’envoyé extraordinaire Giuseppe Paolucci. Cette correspondance ne se limite pas au récit des événements liés à son décès et à l’organisation des obsèques ; elle offre également un éclairage précieux sur les aspects protocolaires régissant les relations entre les cours de Versailles et de Modène. L’analyse prend pour point de référence une princesse du sang de France, destinée à devenir duchesse de Modène et de Reggio
Screening Sanctity: Matilda, the Politics of Offense and Moral Values in Russia’s Public Religion
No full textDevelopment of a new prototypal natural whey starter production system to study biodiversity and technological features fluctuations during back-slopping practice used in Parmigiano Reggiano PDO cheese production: penicillin G as a case study
No full textNatural whey starter (NWS) is an undefined and variable microbial community of starter lactic acid bacteria (SLAB), traditionally produced by back-slopping and used in the manufacture of several hard-cooked Italian cheeses, including Parmigiano Reggiano PDO. Despite its importance, the parameters influencing the microbial composition and technological performance of NWS remain poorly investigated, largely due to the lack of controlled studies that do not interfere with actual cheese production. Although the Parmigiano Reggiano PDO regulations strictly forbid the use of selected starters and require NWS to be obtained exclusively through spontaneous whey fermentation following curd extraction, we developed a freeze-dried prototypical natural starter culture (NSC) system that simulates, under laboratory conditions, the back-slopping process used in Parmigiano Reggiano dairies to ferment sweet whey into NWS. This system (referred to as NSC0) effectively replicated fresh NWS and was successfully propagated through three consecutive rounds of laboratory-scale cheese-making. Using this validated system, we demonstrated that raw cow milk spiked with penicillin G at or below the maximum residue limits (MRL) negatively impacted NSC fermentative performance during the first round of caseification and significantly reduced microbial counts during the second round, suggesting a cumulative inhibitory effect of penicillin G, non-observable in a single back-slopping cycle. As SLAB declined, spoilage yeasts increased. qPCR analysis revealed that 2 and 4 ppb penicillin G impaired NWS biodiversity by inhibiting Lactobacillus delbrueckii and streptococci, whereas Lactobacillus helveticus remained unaffected. The validated NSC system developed in this study offers a robust platform for future investigations into the abiotic and biotic factors affecting NWS, advancing our ability to predict the behavior of undefined starter cultures under realistic cheese-making conditions
NFATc1 and NFATc2 regulate glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia through modulation of cholesterol biosynthesis and the WNT/β-catenin pathway
No full text: The glucocorticoid (GC) resistance onset in pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients remains one of the biggest challenges in current cancer treatment. The mechanisms driving this resistance are still not fully understood, making it difficult to predict patient outcomes and to develop effective therapies. Our study uncovered critical insights into the biological processes underlying GC resistance, offering potential breakthroughs for future treatments. Building on our previous research on lymphocyte cell-specific protein-tyrosine kinase (LCK) hyperactivation in GC-resistant T-ALL patients, we have now delved deeper into the LCK downstream nuclear factor of activated T cells (NFAT) transcription factor family's contribution to GC resistance. We discovered that, even at the time of diagnosis, GC resistant T-ALL patients exhibit an intrinsic low glucocorticoid receptor (GR) activity coupled with high NFATc1 and NFATc2 activity. This dysregulation creates a roadblock to effective GC therapy. Indeed, in the absence of either NFATc1 or NFATc2, the normal transcriptional activity of GR is restored, re-sensitizing leukemia cells to dexamethasone treatment both in vitro and in vivo. This suggests that NFATc1 and NFATc2 are central to driving GC resistance, as they directly regulate crucial pathways like cholesterol biosynthesis and WNT/β-catenin signaling. The identification of NFAT transcription factors as key players in leukemia therapy resistance offers a promising target for future therapeutic strategies, potentially transforming the way we approach treatment for these challenging conditions or autoimmune disorders where glucocorticoids are a cornerstone of treatment
Trend-Error Decomposition for Self-Supervised Time Series Learning in Multivariate Forecasting Task
No full textSelf-Supervised Learning (SSL) has become a powerful paradigm in Artificial Intelligence, enabling the training of machine learning models using unlabeled data. However, in time series forecasting, SSL models are generally less effective than supervised models due to the complexity of temporal patterns, including trends, seasonality, and noise. To address this, we introduce TED4STL (Trend-Error Decomposition for Self-supervised Time-series Learning), a pipeline that decomposes each time series into two additive components, trend and error, and empirically test whether this decomposition improves the performance of SSL models. We adapt it to four SSL forecasting models and evaluate it on ten datasets. Experiments show that the decomposition consistently improves SSL forecasting accuracy, narrowing the gap with state-of-the-art supervised models and often surpassing them at short horizons
Epilessie genetiche e farmacoresistenti: caratterizzazione clinica, studio funzionale e prospettive terapeutiche
No full textBackground: Le encefalopatie epilettiche e dello sviluppo (DEE, Developmental and Epileptic Encephalopathies) sono un gruppo di gravi disordini neurologici caratterizzati da epilessia ad esordio precoce, farmacoresistente, e da disturbi neurocognitivi, con severe conseguenze sulla qualità di vita. Nella maggior parte dei casi riconoscono un’eziologia genetica. Le terapie attuali sono spesso inefficaci nel controllo delle crisi e raramente modificano il neurosviluppo. Sono quindi necessarie strategie terapeutiche più efficaci, basate su una maggiore accuratezza diagnostica e una comprensione più approfondita dei meccanismi molecolari coinvolti, sia specifici di singoli geni sia condivisi tra diverse entità eziologiche. La diagnosi di precisione riveste un ruolo chiave e si fonda sull’integrazione tra un’attenta fenotipizzazione clinica, studi genetici e, quando indicato, studi funzionali.
Obiettivi: Questa tesi ha avuto lo scopo di esplorare, attraverso approcci complementari, come l’integrazione tra fenotipizzazione approfondita, interpretazione dei dati genetici e studi funzionali possa migliorare l’accuratezza diagnostica e favorire nuove strategie terapeutiche. In particolare, gli obiettivi specifici sono stati:
a) indagare i disturbi associati a varianti patogenetiche del gene KCNT2 come modello di integrazione tra fenotipizzazione approfondita, interpretazione genetica e studi elettrofisiologici al fine di migliorare la diagnosi e orientare terapie personalizzate mirate alla singola variante;
b) discutere strategie terapeutiche innovative, mirate a meccanismi epilettogeni condivisi, con particolare attenzione al cannabidiolo (CBD) come potenziale trattamento orientato al fenotipo;
c) analizzare, mediante una revisione sistematica della letteratura, le condizioni genetiche associate allo stato epilettico di assenza atipica (AASE), come esempio di come una fenotipizzazione accurata possa guidare l’analisi e l’interpretazione genetica.
Metodi: I pazienti portatori di varianti patogenetiche in KCNT2 sono stati raccolti nell’ambito di una collaborazione internazionale; gli studi funzionali e farmacologici sono stati condotti mediante elettrofisiologia whole-cell.
È stato eseguito uno studio retrospettivo in due centri per valutare l’efficacia e la tollerabilità del CBD in una coorte di pazienti con epilessia farmacoresistente.
È stata inoltre condotta una revisione sistematica della letteratura per identificare le condizioni genetiche associate all’AASE.
Risultati: Lo studio multicentrico sul gene KCNT2 ha evidenziato un’eterogeneità genotipica e fenotipica, con manifestazioni comprendenti epilessia, disabilità intellettiva o ritardo dello sviluppo, dismorfismi e disturbi dello spettro autistico. Gli studi funzionali hanno mostrato che sia le varianti loss-of-function (LOF) che gain-of-function (GOF) possono essere patogenetiche, con caratteristiche cliniche parzialmente differenti. La Chinidina e la Fluoxetina hanno bloccato tutte le varianti GOF studiate, mentre il Riluzolo e la Loxapina hanno ripristinato la funzione del canale solo in alcuni casi LOF. Il trattamento con CBD ha determinato una significativa riduzione della frequenza delle crisi ed è risultato ben tollerato. La revisione della letteratura ha identificato numerose condizioni genetiche associate ad AASE: nella maggior parte dei casi si tratta di anomalie cromosomiche, mentre le varianti a carico di singoli geni interessano soprattutto geni coinvolti nello sviluppo e regolazione sinaptica.
Conclusioni: Questo lavoro sottolinea il valore di un approccio traslazionale e integrato nello studio delle epilessie genetiche e farmacoresistenti, che collega fenotipo, genotipo e meccanismi molecolari, al fine di individuare nuove e potenzialmente più precise strategie terapeutiche.Background: Developmental and epileptic encephalopathies (DEEs) are a group of severe neurological disorders, characterized by early-onset, pharmocoresistant epilepsy and neurocognitive impairment with major consequences on quality of life. In most cases a genetic etiology can be identified. Current treatments are often ineffective in achieving adequate seizure control and rarely impact the developmental trajectory of affected patients. There is therefore a pressing need for more effective therapeutic strategies that require improved diagnostic accuracy and a deeper understanding of the molecular mechanisms involved, both those specific to individual genes and those shared across different etiological entities. Precision diagnosis is essential in this process and relies on the integration of careful clinical phenotyping, genetic testing and, when appropriate, functional studies.
Objectives: this thesis aimed to explore, through complementary approaches, how integrating precise phenotyping, genetic data interpretation and functional studies could improve diagnostic accuracy and lead to novel treatment strategies for DEEs. Specifically, it aimed to:
a) investigate the disorders associated with pathogenic variants in KCNT2 gene as a model for integrating deep phenotyping, genetic testing and electrophysiological studies both for diagnostic accuracy and for potential personalized, variant-targeted therapies;
b) discuss newer therapeutic strategies, targeting shared epileptogenic mechanisms, with a particular focus on cannabidiol (CBD) as a potential phenotype-oriented therapy;
c) analyze through a systematic literature review, the genetic conditions associated with atypical absence status epilepticus (AASE), as an example of how accurate phenotyping can guide genetic testing and interpretation of genetic data.
Methods: a systematic literature review was performed to identify the genetic conditions associated with AASE.
A retrospective, two-center study evaluated the efficacy and tolerability of CBD in a cohort of patients with drug-resistant epilepsy.
Patients harboring pathogenic KCNT2 variants were collected through an international collaboration; functional and pharmacological studies were performed using whole-cell electrophysiology.
Results: The multicenter KCNT2 study uncovered a significant genotypic and phenotypic variability with manifestations including epilepsy, intellectual disability/developmental delay, dysmorphisms, autistic spectrum disorder. The functional studies revealed that both loss-of-function (LOF) and gain-of-function (GOF) variants in this gene can be pathogenic with partly different clinical correlates. Quinidine and Fluoxetine were able to block all GOF variants studied, whereas Riluzole and Loxapine were able to correct the channel function only in some LOF cases. CBD showed a significant seizure frequency reduction in our cohort of patients and was overall well tolerated.
The literature review identified multiple genetic conditions associated with AASE reported in literature, most of which involved chromosomal variants. Single-gene variants associated with AASE were mainly found in genes implicated in synaptic development and regulation of synaptic transmission.
Conclusions: this study emphasizes the relevance of a translational and integrative approach to the study of epilepsy, connecting phenotype, genotype and molecular mechanisms to novel and potentially more precise therapeutic strategies
From Rigid Order to Radical Variation: Mitogenome Evolution in the Main Lineages of a Lesser-Known Animal Phylum (Gastrotricha)
No full textMitochondrial genomes offer valuable insights into biological and phylogenetic processes, yet the factors shaping their architecture across metazoan lineages remain poorly understood, largely due to limited taxonomic sampling. To address this gap, we analyzed mitochondrial genomes from 20 species spanning a broad taxonomic spectrum of the phylum Gastrotricha. Our findings, supported by phylogenetic analyses based on mitochondrial datasets, reveal two distinct evolutionary patterns: one lineage displays remarkable conservation in genome structure, while the other exhibits variability in gene content, arrangement, strand polarity, and repeat abundance. These contrasting patterns appear to be related to differences in reproductive strategies (hermaphroditism vs. parthenogenesis) and ecological habitats (marine vs. freshwater). While these associations are intriguing, further data are needed to understand the underlying processes. This study highlights the importance of broad phylum-scale mitogenomic sampling for uncovering genomic diversity and advancing our understanding of mitochondrial evolution across Metazoa