Differential Effect of Calsequestrin Ablation on Structure and Function of Fast and Slow Skeletal Muscle Fibers

We compared structure and function of EDL and Soleus muscles in adult (4–6 m) mice lacking both Calsequestrin (CASQ) isoforms, the main SR Ca2+-binding proteins. Lack of CASQ induced ultrastructural alterations in ~30% of Soleus fibers, but not in EDL. Twitch time parameters were prolonged in both muscles, although tension was not reduced. However, when stimulated for 2 sec at 100 hz, Soleus was able to sustain contraction, while in EDL active tension declined by 70–80%. The results presented in this paper unmask a differential effect of CASQ1&2 ablation in fast versus slow fibers. CASQ is essential in EDL to provide large amount of Ca2+ released from the SR during tetanic stimulation. In contrast, Soleus deals much better with lack of CASQ because slow fibers require lower Ca2+ amounts and slower cycling to function properly. Nevertheless, Soleus suffers more severe structural damage, possibly because SR Ca2+ leak is more pronounced

Malignant Hyperthermia and Heat Stroke in Calsequestrin-1 Knockout Mice

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Initial Characterization of CASQ1/CASQ2 Knockout (double CASQ-Null) Mice

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New evidence of MIS 3 relative sea level changes from the Messina Strait, Calabria (Italy)

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Antonioli, F., Calcagnile, L., Ferranti, L., Mastronuzzi, G., Monaco, C., Orru, P., Quarta, G., Pepe, F., Scardino, G., Scicchitano, G., Stocchi, P., & Taviani, M. New evidence of MIS 3 relative sea level changes from the Messina Strait, Calabria (Italy). Water, 13(19), (2021): 2647, https://doi.org/10.3390/w13192647.Investigation of sea-level positions during the highly-dynamic Marine Isotope Stage 3 (MIS 3: 29–61 kyrs BP) proves difficult because: (i) in stable and subsiding areas, coeval coastal sediments are currently submerged at depths of few to several tens of meters below the present sea level; (ii) in uplifting areas, the preservation of geomorphic features and sedimentary records is limited due to the erosion occurred during the Last Glacial Maximum (LGM) with sea level at a depth of −130 m, followed by marine transgression that determined the development of ravinement surfaces. This study discusses previous research in the Mediterranean and elsewhere, and describes new fossiliferous marine deposits overlaying the metamorphic bedrock at Cannitello (Calabria, Italy). Radiocarbon ages of marine shells (about 43 kyrs cal BP) indicate that these deposits, presently between 28 and 30 m above sea level, formed during MIS 3.1. Elevation correction of the Cannitello outcrops (considered in an intermediate-to-far-field position with respect to the ice sheet) with the local vertical tectonic rate and Glacial Isostatic Adjustment (GIA) rate allows the proposal of a revision of the eustatic depth for this highstand. Our results are consistent with recently proposed estimates based on a novel ice sheet modelling technique.This research received no external funding

TORINO 2030. A prova di futuro

Il progetto “Torino 2030: a prova di futuro” nasce come iniziativa di un gruppo di ricercatrici e ricercatori del mondo accademico torinese che, nella primavera/estate del 2020, hanno condiviso l’esigenza di ripensare la strategia di sviluppo dell’area metropolitana. Tale ripensamento è generato da due fattori concomitanti: da una parte, la contingenza della crisi pandemica che obbliga l’area vasta torinese a una trasformazione in chiave rigenerativa; dall’altra, la crisi strutturale dell’economia locale e della struttura sociale, da lungo tempo caratterizzate da diseguaglianze e debolezze. Il progetto che ne è nato “Torino 2030: a prova di futuro” è stato condiviso con i Rettori dei due Atenei e rappresenta un’opportunità per mettersi al servizio del territorio e della comunità al fine di contribuire, con i propri saperi e strumenti, a una visione integrata e strategica dello sviluppo e della trasformazione della metropoli postpandemia. La preparazione di questo documento si inserisce quindi nelle attività della cosiddetta “terza missione”. I saperi alla base del progetto di “Torino 2030: a prova di futuro” sono quelli specialistici e complementari delle diverse discipline SSH (Social Science & Humanities) e STEM (Science-Technology-Engineering-Mathematics) tipiche delle nostre due comunità accademiche. A fianco di questi, grazie al caratteristico percorso metodologico adottato,basato sull’approccio scientifico dei future studies, sono state incorporate e ricomprese tutte quelle preziose forme di conoscenza diffusa sul territorio che appartiene agli attori e operatori dei diversi settori toccati dalla ricerca. “Torino 2030: a prova di futuro” si caratterizza quindi per essere una “ricerca-azione”, con solide basi scientifiche e una fondamentale capacità di risposta a quel bisogno di futuro messo in evidenza nella introduzione e nei capitoli successivi. L’area torinese, nel suo insieme, si è spesso caratterizzata come ambito di sperimentazione e innovazione e, anche in questi anni difficili, è in grado di progettare un futuro all’altezza delle sfide che la attendono. Da questa ricerca-azione è nato un progetto che ha individuato 6 sfide, 12 missioni e 41 azioni volte a affrontare i problemi sociali, economici, ambientali e territoriali dell’area vasta metropolitana. Problematiche che richiedono una classe dirigente coesa e capace di mettere a valore la diversità organizzata che caratterizza il tessuto economico, civile e culturale del territorio

Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss

Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with genetically-labelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML

Influenza del carsismo sulla falesia e negli ipogei di Roca Vecchia

ItNumerosi e frequenti crolli di blocchi di roccia interessano la falesia di Roca Vecchia e gli ipogei delle Grotte della Poesia. Le ricerche condotte hanno individuato i processi ed evidenziato le differenti azioni carsiche attive all'origine dei fenomeni gravitativi. In particolare, il mescolamento delle acque dolci meteoriche e di falda con quelle marine è causa di ipercarsismo chimico, molto aggressivo sul calcare. Altri processi ipercarsici derivano dall’idrodinamismo costiero che causa, specie nel sopratidale e intertidale, variazioni di umidità e salinità. Importanti risultano anche le azioni di bioerosione esercitate da organismi, specie in corrispondenza del solco di battente alla base della falesia. Di modesta entità risultano invece gli effetti delle azioni meccaniche dovute all'idrodinamismo costiero. Il carsismo contribuisce significativamente a determinare il "rapido" arretramento della linea di costa.EnSalento peninsula is one of the most interesting areas to study coastal karst in the Mediterranean Basin. This paper deals with analysis of geological, morphological and biological factors upon the evolution on the coastal slope and karst cave system ("Grotte della Poesia") of the Roca Vecchia area. The Roca Vecchia area is set up by highly weathered carbonate deposits which are interested by four joint systems. Several rockfalls have been observed along the coastal slope as well as inside the cave system. We notice that the shoreline has been retrograding.Different morphological processes and active karstic phenomena have been characterized. The mixing of fresh groundwater and rainfall with sea water causes "hyperkarst" conditions, as the brackish water dissolves more calcium carbonate. As well as humidity and salinity changes especially in the intermediate tide "band" cause rock dissolution.Moreover, many living beings are responsible for "biological karst" erosion on the notch at the foot of the slope. On the base of the field features, karst phenomena are among the main causes of the high rate of the retrograding shoreline along the Roca Vecchia coast

Prevalence, Characteristics and Outcomes of Older Patients with Hereditary versus Wild-Type Transthyretin Amyloid Cardiomyopathy

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged >70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of TTR variants among elderly patients diagnosed with ATTR-CM. METHODS: Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. RESULTS: The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.2% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n=421) of the study population of whom 329 (76.3%) carried V122I, 49 (11.4%) T60A, 18 (4.2%) V30M and 35 (8.1%) other pathogenic TTR variants. During a median (range) follow up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p<0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p<0.001), female sex (OR 2.73, p<0.001), Afro-Caribbean ethnicity (OR 65.5, p<0.001), atrial fibrillation (OR 0.65, p=0.015), ischemic heart disease (OR 0.54, p=0.007), peripheral polyneuropathy (OR 5.70, p<0.001) and orthostatic hypotension (OR 6.29, p<0.001) to be independently associated with ATTRv-CM. CONCLUSION: Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age. This article is protected by copyright. All rights reserved

Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis

Objectives: The aim of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of patients with ATTR-CM; and to study the association with mortality. Background: The clinical significance of LA involvement in ATTR-CM is of great clinical interest. Methods: Congo red staining and immunohistochemistry was performed to assess the presence, type, and extent of amyloid and associated changes in 5 explanted ATTR-CM atria. Echo speckle tracking was used to assess LA reservoir, conduit, contractile function, and stiffness in 906 patients with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other). Results: There was extensive ATTR amyloid infiltration in the 5 atria, with loss of normal architecture, vessels remodeling, capillary disruption, and subendocardial fibrosis. Echo speckle tracking in 906 patients with ATTR-CM demonstrated increased atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]) that remained independently associated with prognosis after adjusting for known predictors (lnLA stiff: HR: 1.23; 95% CI: 1.03-1.49; P = 0.029). There was substantial impairment of the 3 phasic functional atrial components (reservoir 8.86% [5.94%-12.97%]; conduit 6.5% [4.53%-9.28%]; contraction function 4.0% [2.29%-6.56%]). Atrial contraction was absent in 22.1% of patients whose electrocardiograms showed sinus rhythm (SR) “atrial electromechanical dissociation” (AEMD). AEMD was associated with poorer prognosis compared with patients with SR and effective mechanical contraction (P = 0.0018). AEMD conferred a similar prognosis to patients in atrial fibrillation. Conclusions: The phenotype of ATTR-CM includes significant infiltration of the atrial walls, with progressive loss of atrial function and increased stiffness, which is a strong independent predictor of mortality. AEMD emerged as a distinctive phenotype identifying patients in SR with poor prognosis