University of Modena and Reggio Emilia
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Ruolo del lncRNA NEAT1 nella regolazione trascrizionale: Meccanismo molecolare e nuovi approcci terapeutici nel mieloma multiplo.
No full textIl mieloma multiplo (MM) è una neoplasia ematologica incurabile delle cellule B, caratterizzata dalla proliferazione anomala di plasmacellule (PC) clonali nel midollo osseo. Nonostante i progressi terapeutici, la maggior parte dei pazienti sviluppa recidiva e farmaco-resistenza. La deregolazione dei trascritti lunghi non codificanti (lncRNAs) contribuisce alla complessità della malattia, distinguendo le PC maligne da quelle normali. Tra questi, NEAT1 risulta overespresso nei pazienti affetti da MM, favorendo la proliferazione delle cellule cancerose. Oltre al ruolo canonico nell’assemblaggio delle paraspecole nucleari, recenti evidenze suggeriscono un coinvolgimento diretto di NEAT1 nella regolazione trascrizionale, indicando un possibile ruolo nella modulazione dei programmi genici implicati nella patogenesi della malattia.
In questo lavoro abbiamo identificato NEAT1 come una vulnerabilità terapeutica, rivelandone un ruolo inedito nella definizione di un programma genico, associato a un comportamento clinico aggressivo. Integrando approcci trascrizionali, computazionali e di prioritizzazione farmacologica, abbiamo mostrato che il silenziamento di NEAT1 rende le cellule di MM sensibili all’inibizione farmacologica di AURKA, regolatore della dinamica del fuso mitotico, e di CDK9, chinasi coinvolta nell’elongazione trascrizionale. Abbiamo dimostrato che AURKA coopera funzionalmente con NEAT1. Infatti, i pazienti con elevata espressione di entrambi presentano una prognosi infausta. L’inibizione di NEAT1 comporta un aumento dei difetti mitotici indotti dal blocco di AURKA e altera fortemente il programma trascrizionale che promuove la mitosi, influenzando in modo particolare TPX2, regolatore allosterico di AURKA e possibile mediatore di tale cooperazione. Questa evidenza, insieme alla sinergia osservata inibendo la funzione di NEAT1 e CDK9, ha motivato ulteriori studi sul ruolo di NEAT1 nella regolazione della trascrizione. Abbiamo identificato FOXM1, fattore di trascrizione chiave per i geni della transizione di fase G2/M, e CDK9, come regolatori a monte del programma genico di NEAT1, utilizzando approcci computazionali. Entrambi i fattori partecipano allo stesso apparato trascrizionale, chiamato MMB:FOXM1. Coerentemente, il 60% dei geni target di NEAT1 presentano il motivo CHR sul loro promotore, riconosciuto dal complesso. Questa evidenza suggerisce che NEAT1 possa favorire il reclutamento del complesso trascrizionale sui geni G2/M.
Esperimenti di RNA-FISH combinati con immunofluorescenza hanno mostrato la co-localizzazione di NEAT1 con i condensati trascrizionali di FOXM1 ed esperimenti di RIP hanno confermato il legame diretto tra NEAT1-FOXM1 e NEAT1-CDK9. Esperimenti di ChIP hanno dimostrato una riduzione del legame di FOXM1 sui promotori dei geni essenziali della G2/M, a seguito del silenziamento di NEAT1, confermando il coinvolgimento di NEAT1 nell’apparato trascrizionale mitotico.
Analizzando la rilevanza clinica del programma genico di NEAT1, abbiamo definito due gruppi distinti di pazienti, con differenti esiti di sopravvivenza. I pazienti con prognosi peggiore mostrano elevata espressione dei geni target di NEAT1 della G2/M e il 20% di questi risulta associato ad un rischio elevato di progressione. Tali pazienti mostrano anomalie citogenetiche ad alto rischio quali il guadagno/amplificazione 1q e delezione di 17p, suggerendo che tali sottogruppi potrebbero trarre particolare beneficio dall’inibizione di NEAT1.
Complessivamente, i nostri risultati dimostrano che NEAT1 coordina l’espressione dei geni mitotici attraverso l’interazione con FOXM1 e CDK9, fornendo un razionale per lo sviluppo di strategie terapeutiche mirate nei pazienti ad alto rischio.Multiple myeloma (MM) is an incurable hematological neoplasia characterized by abnormal proliferation of clonal bone marrow plasma cells (BMPCs). Despite recent advances in therapeutic options, most patients ultimately relapse and develop resistance to current treatments. Deregulation of non-coding RNAs (ncRNAs) contributes to MM complexity, with aberrant long ncRNAs (lncRNA) expression distinguishing malignant PCs from their normal counterpart. Emerging evidence positions lncRNAs as a key element of genome regulation, driving MM progression and therapy resistance. Among them, the lncRNA NEAT1 has been described as overexpressed in MM patients, promoting malignant PC proliferation. Besides its conventional function in paraspeckles (PSs) assembly, recent findings suggest a direct contribution of NEAT1 in transcription, supporting the idea that it may actively shape the gene expression programs that sustain MM pathogenesis.
Here, we described NEAT1 as a therapeutic vulnerability and uncovered its previously unrecognized role in the mitotic transcriptional apparatus, linked to the clinical aggressive behavior of MM. Through integrated transcriptional, computational, and drug-prioritization approaches, we described that NEAT1 targeting sensitizes MM cells to inhibition of AURKA, which regulates spindle dynamics, and CDK9 involved in transcriptional elongation. We demonstrated that AURKA exhibits functional cooperation with NEAT1. To support this, we showed that MM patients with high NEAT1 and AURKA expression experienced a worse clinical outcome. Exploring the bases behind this cooperation, we proved that NEAT1 inhibition exacerbates mitotic spindle defects, conferred by AURKA inhibition. Coherently, we found that NEAT1 inhibition strongly perturbs the mitotic transcriptional program, notably affecting TPX2, the main AURKA allosteric regulator, which emerged as a putative mediator of the NEAT1-AURKA interplay. This evidence, along with the synergy observed between NEAT1 and CDK9 functional inhibition, prompts us to investigate the mechanistic mode of action of NEAT1 in controlling the expression of mitotic genes. By applying computational approaches we identified FOXM1, a key G2/M transcriptional factor (TF) and CDK9 transcriptional kinase, as upstream regulators of the NEAT1 gene expression program. Both FOXM1 and CDK9 participate in the same transcriptional apparatus, named MMB:FOXM1. In line, 60% of NEAT1 target genes harbor a Cell cycle homology region (CHR) motif, recognized by MMB:FOXM1 complex, suggesting that NEAT1 can facilitate the recruitment of this molecular machinery to G2/M gene promoters. Combined RNA-FISH and immunofluorescence revealed the co-localization between NEAT1 and FOXM1 transcriptional condensates, and RIP experiments confirmed direct NEAT1 binding to both FOXM1 and CDK9. ChIP experiments demonstrated a reduced FOXM1 binding to essential G2/M genes upon NEAT1 inhibition, confirming NEAT1 involvement in the mitotic transcriptional machinery. Exploring the clinical relevance of NEAT1 function in gene regulation, we discovered that the NEAT1 program defined two different clusters of patients exhibiting different survival outcomes. Patients with the poorest prognosis showed higher expression of NEAT1’s target G2/M genes, with 20% of them linked to a high risk of progression. Interestingly, these patients presented high-risk chromosomal abnormalities as 1q gain/amp and del17p, suggesting that these genetic subgroups can benefit most from inhibition of NEAT1 and its regulatory circuitry.
Overall, these findings demonstrate that NEAT1 coordinates the expression of mitotic genes through FOXM1 and CDK9 interaction, providing a mechanistic rationale for targeted interventions in high-risk patients
High Flow Nasal Therapy vs Conventional Oxygen Therapy in Mild COVID-19 Hypoxaemia: A Bayesian Reanalysis of the COVID-HIGH Trial.
No full textBackground- Clinical effectiveness of high-flow nasal therapy (HFNT) over conventional oxygen therapy (COT) in patients with mild COVID-19-related acute hypoxaemic respiratory failure (AHRF) remains uncertain. The COVID-HIGH trial did not demonstrate statistically significant benefits of HFNT over COT. However, the trial was slightly underpowered, and the event rate lower-than-expected. Bayesian methods provide deeper insight by incorporating prior knowledge and quantifying uncertainty intuitively. This analysis aimed to quantify the probability of benefit or harm associated with HFNT, adopting a Bayesian approach.
Methods- We performed a Bayesian reanalysis of the COVID-HIGH trial (NCT, which randomised 364 patients with PaO2/FiO2 between 200–300 mmHg to receive HFNT or COT. The primary outcome was escalation of respiratory support (continuous positive airway pressure, noninvasive ventilation or invasive mechanical ventilation) within 28 days. A key secondary outcome was clinical recovery at day 14. Bayesian logistic models with noninformative and informative priors were used to estimate the posterior probability of treatment effects.
Results- Escalation of respiratory support occurred in 23.6% (HFNT) versus 30.2% (COT) (risk difference −6.6%, 95% CI −15.1 to 2.1; p=0.14). Across a wide range of priors, the posterior probability mass on the beneficial side remained high, generally >70%, while the proportion on the harm side remained consistently low at ≤6% for all models, underscoring a favourable benefit-risk profile. The acute respiratory failure meta-analysis model (OR 0.76, 95% CrI 0.60 - 0.97), the COVID-19 randomised evidence model (OR 0.76, 95% CrI 0.60 - 0.97), the COVID-19 observational evidence model (OR 0.60, 95% CrI 0.45 - 0.80), and the COVID-19 Bayesian meta-analysis mixed evidence model (OR 0.66, 95% CrI 0.52 - 0.86) showed posterior probability mass on the beneficial side of 70% - 94%. Clinical recovery at day 14 occurred in 61.5% (HFNT) versus 53.3% (COT), with 61-73% of posterior probability mass on the clinical benefit side.
Conclusions- This Bayesian re-analysis of the COVID-HIGH trial suggests that HFNT likely reduces escalation of respiratory support and improves clinical recovery in patients with COVID-19 pneumonia and mild hypoxaemia, although the magnitude of benefit remains uncertain and sensitive to prior assumptions
Terahertz Volume Plasmon‐Polariton Modulation in All‐Dielectric Hyperbolic Metamaterials
No full textThe development of plasmonics and related applications in the terahertz range faces limitations due to the intrinsic high electron density of the standard metals. All-dielectric systems are profitable alternatives, which allows for customized modulation of the optical response upon doping. Here, plasmon-based hyperbolic metamaterials are realized stacking doped III-V semiconductors that have been shown to be optically active in the terahertz spectral region. By using a multi-physics multi-scale theoretical approach, the role of doping and geometrical characteristics (e.g., thickness, composition, grating) in the modulation of high-k plasmon-polariton modes across the metamaterial is unraveled
Anthropometric Indicators and Early Cardiovascular Prevention in Children and Adolescents: The Role of Education and Lifestyle
No full textBackground: Childhood obesity represents the most common nutritional and metabolic disorder in industrialized countries and constitutes a major public health concern. In Italy, 20–25% of school-aged children are overweight and 10–14% are obese, with marked regional variability. Excess adiposity in childhood is frequently associated with hypertension, dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease (NAFLD), predisposing to future cardiovascular disease (CVD). Objective: To investigate anthropometric indicators of cardiometabolic risk in 810 children and adolescents aged 7–17 years who underwent assessment for competitive sports eligibility at the Sports Medicine Unit of Modena, evaluate baseline knowledge of cardiovascular health aligned with ESC, AAP (2023), and EASO guidelines. Methods: 810 children and adolescents aged 7–17 years undergoing competitive sports eligibility assessment at the Sports Medicine Unit of Modena underwent evaluation of BMI percentile, waist circumference (WC), waist-to-height ratio (WHtR), and blood pressure. Cardiovascular knowledge and lifestyle habits were assessed via a previously used questionnaire. Anthropometric parameters, blood pressure (BP), and lifestyle-related knowledge and behaviors were assessed using standardized procedures. Overweight and obesity were defined according to WHO BMI-for-age percentiles. Elevated BP was classified based on the 2017 American Academy of Pediatrics age-, sex-, and height-specific percentiles. Statistical analyses included descriptive statistics, group comparisons, chi-square tests with effect size estimation, correlation analyses, and multivariable logistic regression models. Results: Overall, 22% of participants were overweight and 14% obese. WHtR > 0.5 was observed in 28% of the sample and was more frequent among overweight/obese children (p < 0.001). Elevated BP was detected in 12% of participants with available measurements (n = 769) and was significantly associated with excess adiposity (χ2 = 7.21, p < 0.01; Cramér’s V = 0.27). In multivariable logistic regression analyses adjusted for age and sex, WHtR > 0.5 (OR 2.14, 95% CI 1.32–3.47, p = 0.002) and higher sedentary time (OR 1.41 per additional daily hour, 95% CI 1.10–1.82, p = 0.006) were independently associated with elevated BP, whereas BMI percentile lost significance when WHtR was included in the model. Lifestyle knowledge scores were significantly lower among overweight and obese participants compared with normal-weight peers (p < 0.01). Conclusions: WHtR is a sensitive early marker of cardiometabolic risk, often identifying at-risk children missed by BMI alone. Baseline cardiovascular knowledge was suboptimal. The observed gaps in cardiovascular knowledge underscore the importance of integrating anthropometric screening with structured educational interventions to promote healthy lifestyles and long-term cardiovascular prevention
Freeze-Drying Effects on Viability and Cellular Stability in a Subset of Sourdough Lactic Acid Bacteria Strains
No full textMicrobial resources are essential for food biotechnology, where they contribute to product quality, process efficiency, and safety. Their long-term preservation is critical for culture collections (CCs) and microbial biological resource centers (mBRCs). This study investigates the effects of freeze-drying on five lactic acid bacteria (LAB) strains from the Unimore Microbial Culture Collection (UMCC), comparing non-lyophilized and lyophilized cultures under two pre-freezing protocols: overnight incubation at -20 degrees C (PF-20) and 2-hour incubation at -80 degrees C (PF-80). Viability, fermentative performance, metabolite production, and cell integrity were assessed using microbial counts, HPLC profiling, and SEM imaging, respectively. Lactiplantibacillus plantarum UMCC 2996 maintained over 95% viability and stable fermentative traits across all conditions. In contrast, Fructilactobacillus sanfranciscensis UMCC 2990 and Leuconostoc citreum UMCC 3011 showed significant viability losses (down to 54.45% and 73.89%, respectively) and altered metabolic profiles, particularly under PF-80. SEM analysis confirmed structural damage in sensitive strains, with visible cellular debris and membrane wrinkling. This study provides novel perspectives on the customized assessment of freeze-drying protocols for sourdough-derived LAB strains with industrial potential, confirming the need for tailored preservation strategies to ensure the long-term functionality of LAB strains in CCs and mBRCs
Strong solutions and optimal control for Duffing differential inclusions with Dirichlet conditions.
No full textExistence of strong solutions for a Dirichlet problem driven by a Duffing-type differential inclusion is achieved in the setting of separable reflexive Banach spaces. This general framework makes it possible to model and analyse complex phenomena such as periodic or chaotic dynamics as well as oscillatory behavior. The method used to obtain the existence results is based on the combination of a fixed point theorem and a selection theorem. By using the weak topology we avoid assumptions of compactness on the multivalued term. Our abstract results allow to deduce the existence of an admissible pair for a control problem driven by a Duffing-type differential equation. The paper ends with the study of optimal control problem involving a suitable functional
There is No Such Thing as Maternal Instinct: Unwanted Pregnancy, Infanticide, and Child Abandonment in Sade Adeniran’s Imagine This (2008) and Fatou Diome’s The Belly of the Atlantic (2003)
No full textMeasuring and Understanding Visualization Latency Performance for Smart City Applications
No full textA three-way decision framework integrating grey clustering and TOPSIS for sustainable urban project prioritization
No full textAmid accelerating urbanization and stringent sustainability targets, cities face acute challenges in prioritizing sustainable urban development projects (SUDPs) under tight budgets and policy deadlines. Traditional binary evaluation frameworks often misclassify borderline projects and are distorted by redundant criteria. We introduce a three-phase evidence-based decision framework that integrates (1) grey clustering model (GCM) to eliminate indicator redundancy while preserving conceptual coverage, (2) a difference-driven technique for order preference by similarity to ideal solution (TOPSIS) model for objective weighting and ranking, and (3) a three-way decision (TWD) mechanism with risk-averse thresholds calibrated via the analytic hierarchy process (AHP). Applied to ten competing SUDPs in Xi’an, China, the framework delivered decisive actions: it approved four projects outright, deferred one for targeted refinement, and rejected the remainder. Comparative analysis revealed that only the TWD model produced unequivocal accept/reject/defer recommendations without arbitrary cutoffs, whereas TOPSIS, fuzzy comprehensive evaluation (FCE) and grey fixed-weight clustering (GFWC) either required subjective threshold setting or failed to handle borderline cases. Sensitivity analysis across eleven risk levels confirmed stable outcomes and a smoothly shrinking defer zone, proving robust adaptability. The modular design equips urban planners worldwide with a transparent, replicable tool for strategic, risk-informed SUDP selection