Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes

Beyond its role in providing structure to the nuclear envelope, lamin A/C is involved in transcriptional regulation. However, its cross talk with epigenetic factors--and how this cross talk influences physiological processes--is still unexplored. Key epigenetic regulators of development and differentiation are the Polycomb group (PcG) of proteins, organized in the nucleus as microscopically visible foci. Here, we show that lamin A/C is evolutionarily required for correct PcG protein nuclear compartmentalization. Confocal microscopy supported by new algorithms for image analysis reveals that lamin A/C knock-down leads to PcG protein foci disassembly and PcG protein dispersion. This causes detachment from chromatin and defects in PcG protein-mediated higher-order structures, thereby leading to impaired PcG protein repressive functions. Using myogenic differentiation as a model, we found that reduced levels of lamin A/C at the onset of differentiation led to an anticipation of the myogenic program because of an alteration of PcG protein-mediated transcriptional repression. Collectively, our results indicate that lamin A/C can modulate transcription through the regulation of PcG protein epigenetic factors

Synaptic alterations as a neurodevelopmental trait of Duchenne muscular dystrophy

Dystrophinopaties, e.g., Duchenne muscular dystrophy (DMD), Becker muscular dystrophy and X-linked dilated cardiomyopathy are inherited neuromuscular diseases, characterized by progressive muscular degeneration, which however associate with a significant impact on general system physiology. The more severe is the pathology and its diversified manifestations, the heavier are its effects on organs, systems, and tissues other than muscles (skeletal, cardiac and smooth muscles). All dystrophinopaties are characterized by mutations in a single gene located on the X chromosome encoding dystrophin (Dp427) and its shorter isoforms, but DMD is the most devasting: muscular degenerations manifests within the first 4 years of life, progressively affecting motility and other muscular functions, and leads to a fatal outcome between the 20s and 40s. To date, after years of studies on both DMD patients and animal models of the disease, it has been clearly demonstrated that a significant percentage of DMD patients are also afflicted by cognitive, neurological, and autonomic disorders, of varying degree of severity. The anatomical correlates underlying neural functional damages are established during embryonic development and the early stages of postnatal life, when brain circuits, sensory and motor connections are still maturing. The impact of the absence of Dp427 on the development, differentiation, and consolidation of specific cerebral circuits (hippocampus, cerebellum, prefrontal cortex, amygdala) is significant, and amplified by the frequent lack of one or more of its lower molecular mass isoforms. The most relevant aspect, which characterizes DMD-associated neurological disorders, is based on morpho-functional alterations of selective synaptic connections within the affected brain areas. This pathological feature correlates neurological conditions of DMD to other severe neurological disorders, such as schizophrenia, epilepsy and autistic spectrum disorders, among others. This review discusses the organization and the role of the dystrophin-dystroglycan complex in muscles and neurons, focusing on the neurological aspect of DMD and on the most relevant morphological and functional synaptic alterations, in both central and autonomic nervous systems, described in the pathology and its animal models

The mechanisms and possible sites of acetylcholine release during chick primary sensory neuron differentiation

Aims: In this study, we evaluated the ability of differentiating embryonic chick DRG neurons to release and respond to acetylcholine (ACh). In particular, we investigated the neuronal soma and neurites as sites of ACh release, as well as the mechanism(s) underlying this release. Main methods: ACh release from DRG explants in the Campenot chambers was measured by a chemiluminescent assay. Real-time PCR analysis was used to evaluate the expression of ChAT, VAChT, mediatophore and muscarinic receptor subtypes in DRGs at different developmental stages. Key findings: We found that ACh is released both within the central and lateral compartments of the Campenot chambers, indicating that ACh might be released from both the neuronal soma and fibers. Moreover, we observed that the expression of the ChAT and mediatophore increases during sensory neuron differentiation and during the post-hatching period, whereas VAChT expression decreases throughout development. Lastly, the kinetics of the m2 and m3 transcripts appeared to change differentially compared to the m4 transcript during the same developmental period. Significance: The data obtained demonstrate that the DRG sensory neurons are able to release ACh and to respond to ACh stimulation. ACh is released both by the soma and neurite compartments. The contribution of the mediatophore to ACh release appears to be more significant than that of VAChT, suggesting that the non-vesicular release of ACh might represent the preferential mechanism of ACh release in DRG neurons and possibly in non-cholinergic systems. © 2012 Elsevier Inc

Information needs of patients with melanoma : a challenge for hospital providers

Evidence continues to suggest that patients with cancer require more information about their disease and its consequences. To evaluate the information needs of patients with advanced melanoma compared to patients with other malignancies, a cross-sectional study was conducted on 221 unselected patients from the oncology department of a dermatologic hospital In Italy. Patients completed the Edmonton Symptom Assessment System and the Need Evaluation Questionnaire, two standardized tools for symptoms and psychosocial needs assessment. Results highlight that patients with advanced melanoma have, in general, a higher need for information compared to patients with other cancers, even if they report fewer symptoms. Future studies on the needs of patients with melanoma may contribute to tailored and more satisfactory patient-centered care. Recommendations for clinical practice include that particular attention should be paid by the oncology team to the need for a strong therapeutic relationship

Interazione assone-glia: l'acetilcolina rilasciata lungo gli assoni regola il differenziamento delle cellule di Schwann verso il fenotipo mielinizzante.

Nel sistema nervoso, durante lo sviluppo e nell’adulto, l’interazione tra neuroni e cellule gliali e fra gli assoni in crescita e la glia mielinizzante favorisce, attraverso la produzione di specifici segnali, la modulazione della proliferazione, sopravvivenza e differenziamento di ambedue le popolazioni cellulari. Vari fattori di crescita (es.NRGs) sono stati identificati come principali modulatori di questa interazione, ma molteplici evidenze hanno indicato che anche i neurotrasmettitori (es. GABA, adenosina e ACh) possono avere un ruolo chiave in tale interazione. Negli ultimi anni la nostra attenzione si è focalizzata sul ruolo svolto dall’ACh nel modulare la crescita e il differenziamento delle cellule di Schwann, la popolazione gliale mielinizzante del SNP. Nostri precedenti dati avevano dimostrato che l’ACh, attraverso il recettore muscarinico M2, è in grado di indurre nelle cellule di Schwann, un blocco della progressione nel ciclo cellulare e una aumentata espressione delle proteine della mielina (P0, PMP22 e MBP). Per verificare se l’attivazione del recettore M2 fosse in grado di indirizzare le cellule di Schwann verso il fenotipo mielinizzante, abbiamo analizzato l’espressione di una serie di fattori responsabili della fase proliferativa e di quella differenziativa dopo attivazione del recettore M2. Cellule di Schwann, isolate dal nervo sciatico di ratti neonati (2 gg post-natale), sono state trattate in vitro con l’agonista del recettore M2, arecaidina. Analisi mediante real time PCR e western blot hanno dimostrato che fattori notoriamente coinvolti nella fase proliferativa vengono significativamente repressi (es. c-jun, NRG1/1, recettori erbB2, Notch-1, Jagged-1). Al contrario, l’espressione di fattori coinvolti nel differenziamento verso il fenotipo mielinizzante, è significativamente aumentata (Krox20/egr2; Sox-10, NRG1/3). Il trattamento con arecaidina inoltre induce un significativo cambiamento nella morfologia delle cellule che appaiono più appiattite e che sviluppano zone di adesione tra cellule adiacenti, come suggerito dalla ridistribuzione di molecole di adesione cellulare e dall’analisi al SEM. Ipotizzando che il segnale colinergico differenziante per le cellule di Schwann provenga dall’assone, allestendo colture di espianti di gangli spinali (DRG) in camere di Campenot, abbiamo dimostrato che l’ACh viene rilasciata sia nel compartimento in cui sono presenti i corpi cellulari dei neuroni, sia in quelli dove si trovano i neuriti in crescita. Inoltre abbiamo osservato che i neuroni sensoriali esprimono il mediatoforo, una proteina che risulta coinvolta nel rilascio non vescicolato dell’acetilcolina. In conclusione i nostri dati dimostrano che l’acetilcolina può essere rilasciata lungo gli assoni dei neuroni sensoriali probabilmente proprio attraverso un meccanismo di rilascio non vescicolare; questo rilascio consentirebbe alle adiacenti cellule di Schwann di rispondere allo stimolo colinergico con il blocco della proliferazione e l’attivazione della mielinizzazione, condizione necessaria per consentire la corretta formazione e conduzione di assoni di grosso calibro

Cardiac risk after elective endovascular repair for infrarenal abdominal aortic aneurysm, results from the Italian Collaborators for EVAR multicenter registry

Objectives: Major adverse cardiac events (MACEs) were common complications after endovascular aortic repair (EVAR) causing significant post-operative morbidity and mortality. The aim of the study was to evaluate the cardiac risk after elective EVAR for uncomplicated non infected infrarenal abdominal aortic aneurysm (iAAA) in a large multicenter cohort. Materials and methods: This is a multicenter, retrospective, financially unsupported physician-initiated observational cohort study conducted by four academic tertiary referral hospitals from January 2018 to March 2021. Baseline, perioperative, and postoperative information of elective EVARs was evaluated. The primary outcome was the incidence of MACE after EVAR, which was defined as acute coronary syndrome, non-ST-elevation myocardial infarction, unstable angina pectoris, de novo atrial fibrillation, hospitalization for heart failure and revascularization as well as cardiovascular death. Secondary outcomes were one year overall survival (all-cause mortality) and freedom from aorta-related mortality. Comparative analysis was conducted between MACE and overall population and univariate and multivariate logistic regression analyses were used to analyse factors associated with the risk of MACE occurrence and early 1-year mortality. Results: The study has enrolled 497 patients (35 females, 7%) with a mean age of 75.3±7.8 years. MACE rate was 6.4% (32/497, events/patients) and the majority of the events were recorded in the post-operative period (24/32, 75%, overall 24/497, 4.8%). One-year survival from all-cause mortality was 94% (95%CI 91-96) and MACEs population showed a significant lower survival estimation rate (Overall-MACEs, 95.8% [95%CI 93-97] - 67.9% [95%CI 47-82], log-rank 41.950, p= .0001). Freedom from aorta-related mortality was 99.3% (95%CI 98-100). The perioperative needing for red blood cells (RBC) transfusions was strongly related to MACEs occurrence (odds ratio [OR] 2.67, 95%CI 1.52-4.68, p= .001) and one-year mortality (hazard ratio [HR] 2.14, 95%CI 1.48-3.09, p= .0001). Conclusion: MACEs represent a common complication in the post-operative and early period after elective EVAR. Blood loss requiring RBC transfusions is associated with increased post-operative MACEs and early mortality, suggesting that all the efforts should be carried out to reduce the bleeding during and after elective interventions

Muscle Damage in Dystrophic mdx Mice Is Influenced by the Activity of Ca2+-Activated KCa3.1 Channels

Duchenne muscular dystrophy (DMD) is an X-linked disease, caused by a mutant dystrophin gene, leading to muscle membrane instability, followed by muscle inflammation, infiltration of pro-inflammatory macrophages and fibrosis. The calcium-activated potassium channel type 3.1 (KCa3.1) plays key roles in controlling both macrophage phenotype and fibroblast proliferation, two critical contributors to muscle damage. In this work, we demonstrate that pharmacological blockade of the channel in the mdx mouse model during the early degenerative phase favors the acquisition of an anti-inflammatory phenotype by tissue macrophages and reduces collagen deposition in muscles, with a concomitant reduction of muscle damage. As already observed with other treatments, no improvement in muscle performance was observed in vivo. In conclusion, this work supports the idea that KCa3.1 channels play a contributing role in controlling damage-causing cells in DMD. A more complete understanding of their function could lead to the identification of novel therapeutic approaches

QEEG abnormalities in cognitively unimpaired patients with delirium

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