Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease

Huntington's disease (HD) is themost common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approachesmay open the door to newandmore targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2mice, a widely used HD animalmodel. Chronic administration of low-dose (0.1mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HDmice fromthe classic progressivemotor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5may be also seen as an effective approach to target brain vasculature defects in the disease

Role of miR-9 in Modulating NF-κB Signaling and Cytokine Expression in COVID-19 Patients

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a significant impact on global health, with severe cases often characterized by a worsening cytokine storm. Since it has been described that the NF-kappa B signaling pathway, regulated by microRNAs, could play a pivotal role in the inflammatory response, in this study, the role of miR-9 in modulating NF-kappa B signaling and inflammatory cytokine expression in COVID-19 patients was investigated. This observational retrospective single-center study included 41 COVID-19 patients and 20 healthy controls. Serum samples were analyzed for miR-9, NF-kappa B, and I kappa B alpha expression levels using RT-PCR. The expression levels and production of pro-inflammatory cytokines IL-6, IL-1 beta, and TNF-alpha were measured using RT-PCR and ELISA. Statistical analyses, including correlation and regression, were conducted to explore relationships between these variables. COVID-19 patients, particularly non-survivors, exhibited significantly higher miR-9 and NF-kappa B levels compared to controls. A strong positive correlation was found between miR-9 and NF-kappa B expression (r = 0.813, p < 0.001). NF-kappa B levels were significantly correlated with IL-6 (r = 0.971, p < 0.001), IL-1 beta (r = 0.968, p < 0.001), and TNF-alpha (r = 0.968, p < 0.001). Our findings indicate that miR-9 regulates NF-kappa B signaling and inflammation in COVID-19. Elevated miR-9 levels in non-survivors suggest its potential as a severity biomarker. While COVID-19 cases have decreased, targeting miR-9 and NF-kappa B could improve outcomes for other inflammatory conditions, including autoimmune diseases, highlighting the need for continued research in this area

Correlation between Chest Computed Tomography Score and Laboratory Biomarkers in the Risk Stratification of COVID-19 Patients Admitted to the Emergency Department

background: it has been reported that mid-regional proadrenomedullin (MR-proADM) could be considered a useful tool to stratify the mortality risk in COVID-19 patients upon admission to the emergency department (ED). during the COVID-19 outbreak, computed tomography (CT) scans were widely used for their excellent sensitivity in diagnosing pneumonia associated with SARS-CoV-2 infection. however, the possible role of CT score in the risk stratification of COVID-19 patients upon admission to the ED is still unclear. aim: the main objective of this study was to assess if the association of the CT findings alone or together with MR-proADM results could ameliorate the prediction of in-hospital mortality of COVID-19 patients at the triage. moreover, the hypothesis that CT score and MR-proADM levels together could play a key role in predicting the correct clinical setting for these patients was also evaluated. methods: epidemiological, demographic, clinical, laboratory, and outcome data were assessed and analyzed from 265 consecutive patients admitted to the triage of the ED with a SARS-CoV-2 infection. results and conclusions: the accuracy results by AUROC analysis and statistical analysis demonstrated that CT score is particularly effective, when utilized together with the MR-proADM level, in the risk stratification of COVID-19 patients admitted to the ED, thus helping the decision-making process of emergency physicians and optimizing the hospital resources

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa

Impairment of individual finger movements in Parkinson's disease

By analyzing the kinematics of repetitive, constant- amplitude, finger oppositions, we compared the impairment of individual and nonindividual finger movements in patients with Parkinson’s disease. In one task, subjects tapped only the index finger against the thumb (individual oppositions); in the other task, they tapped all four fingers together against the thumb pad (nonindividual oppositions). We used an optoelectronic motion analysis system to record movements in three-dimensional space and recorded three 5-second trials for each task. We counted how many finger oppositions subjects performed during each trial and measured the duration and amplitude of the flexions and extensions. We also calculated the duration of the pauses after flexion and extension. We assessed the deterioration of motor performance in patients by investigating the changes in speed and amplitude with task completion. During both tasks, normal subjects and patients performed finger flexions faster than extensions, and they invariably paused longer after flexion than after extension. Patients performed individual and nonindividual finger movements slowly and with reduced amplitude. Patients were disproportionately slow during flexion and in switching from flexion to extension. Movement slowness increased as finger oppositions progressed but predominantly when patients had to move fingers individually. In conclusion, in patients with Parkinson’s disease, the motor performance deteriorated with task completion more during individual than during nonindividual finger movements. Parkinson’s diseasetherefore, impairs individual finger movements more than gross hand movements. This distinction reflects the finer cortical control needed to promote and sustain this highly fractionated type of motor output

Progetto preliminare e definitivo per la riqualificazione funzionale ed adeguamento strutturale dell’edificio ex dopolavoro universitario della Sapienza

L’intervento in oggetto nasce dall’esigenza di Sapienza di realizzare alloggi per studenti nell’edificio sito in Via Palestro n.63, prevedendo la localizzazione di attività di servizio e di supporto allo studentato, ovvero di servizi ricreativi, didattici, culturali nella sede dell’ex Dopolavoro, dal 2008 proprietà di Sapienza, all’interno della Città Universitaria. Il progetto prevede la ristrutturazione e la rifunzionalizzazione dell’ala nord-ovest dell’edificio con interventi di restauro e risanamento conservativo relativamente ai tre livelli e alle facciate, e l’adeguamento normativo anche nei confronti dell’accessibilità da parte di persone con difficoltà motorie. Il programma di Sapienza è dunque volto a riutilizzare l’ala del fabbricato come foresteria e studentato, pur mantenendo al piano terra l’esercizio di una caffetteria e al primo livello il ripristino del salone delle feste con la conseguente scopertura del solaio che ne ha cancellato la dimensione a doppia altezza, frutto di un precedente intervento che aveva anche obliterato il sistema radiale dei lucernari lungo la linea perimetrale della sua copertura. L’importanza di queste semplici operazioni consiste anche nel fatto di potere, con l’occasione, attivare un rinnovato sistema di accessibilità e riordinarne così gli accessi e renderne più chiari i percorsi fruitivi, ripensando i rapporti tra esterno e interno, le logge, i giardini, le aree pertinenziali che costituiscono un prezioso comparto di spazialità intermedie tra le Architetture e il Campus

A Fuzzy Decision Support System for the Environmental Risk Assessment of Genetically Modified Organisms

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