Muscle fibers lacking dystrophin undergo a long-term alteration of Ca2+ homeostasis, partially caused by a leaky Ca2+ release ryanodine (RyR) channel. S48168/ARM210, an RyR calcium release channel stabilizer (a Rycal compound), is expected to enhance the rebinding of calstabin to the RyR channel complex and possibly alleviate the pathologic Ca2+ leakage in dystrophin-deficient skeletal and cardiac muscle. This study systematically investigated the effect of S48168/ARM210 on the phenotype of mdx mice by means of a first proof-of-concept, short (4 wk), phase 1 treatment, followed by a 12-wk treatment (phase 2) performed in parallel by 2 independent laboratories. The mdx mice were treated with S48168/ARM210 at two different concentrations (50 or 10 mg/kg/d) in their drinking water for 4 and 12 wk, respectively. The mice were subjected to treadmill sessions twice per week (12 m/min for 30 min) to unmask the mild disease. This testing was followed by in vivo forelimb and hindlimb grip strength and fatigability measurement, ex vivo extensor digitorum longus (EDL) and diaphragm (DIA) force contraction measurement and histologic and biochemical analysis. The treatments resulted in functional (grip strength, ex vivo force production in DIA and EDL muscles) as well as histologic improvement after 4 and 12 wk, with no adverse effects. Furthermore, levels of cellular biomarkers of calcium homeostasis increased. Therefore, these data suggest that S48168/ARM210 may be a safe therapeutic option, at the dose levels tested, for the treatment of Duchenne muscular dystrophy (DMD).—Capogrosso, R. F., Mantuano, P., Uaesoontrachoon, K., Cozzoli, A., Giustino, A., Dow, T., Srinivassane, S., Filipovic, M., Bell, C., Vandermeulen, J., Massari, A. M., De Bellis, M., Conte, E., Pierno, S., Camerino, G. M., Liantonio, A., Nagaraju, K., De Luca, A. Ryanodine channel complex stabilizer compound S48168/ARM210 as a disease modifier in dystrophin-deficient mdx mice: proof-of-concept study and independent validation of efficacy.
In this paper, for the first time, a regional-scale 1:100,000 landslide-susceptibility map (LSM) is presented for Sisak-Moslavina County in Croatia. The spatial relationship between landslide occurrence and landslide predictive factors (engineering geological units, relief, roughness, and distance to streams) is assessed using the integration of a statistically based frequency ratio (FR) into the analytical hierarchy process (AHP). Due to the lack of landslide inventory for the county, LiDAR-based inventories are completed for an area of 132 km2. From 1238 landslides, 549 are chosen to calculate the LSM and 689 for its verification. Additionally, landslides digitized from available geological maps and reported via the web portal “Report a landslide” are used for verification. The county is classified into four susceptibility classes, covering 36% with very-high and high and 64% with moderate and low susceptibility zones. The presented approach, using limited LiDAR data and the extrapolation of the correlation results to the entire county, is encouraging for primary regional-level studies, justifying the cost-benefit ratio. Still, the positioning of LiDAR polygons prerequires a basic statistical analysis of predictive factors.
Gender, age and education differences in food consumption within a region: Case studies of Belgrade and Novi Sad (Serbia) Special issue-Franciscean cadaster as a source of studying landscape changes Matej GABROVEC, Ivan BIČÍK, Blaž KOMAC Land registers as a source of studying long-term land-use changes Ivan BIČÍK, Matej GABROVEC, Lucie KUPKOVÁ Long-term land-use changes: A comparison between Czechia and Slovenia Lucie KUPKOVÁ, Ivan BIČÍK, Zdeněk BOUDNÝ Long-term land-use / land-cover changes in Czech border regions Drago KLADNIK, Matjaž GERŠIČ, Primož PIPAN, Manca VOLK BAHUN Land-use changes in Slovenian terraced landscapes Daniela RIBEIRO, Mateja ŠMID HRIBAR Assessment of land-use changes and their impacts on ecosystem services in two Slovenian rural landscapes Mojca FOŠKI, Alma ZAVODNIK LAMOVŠEK Monitoring land-use change using selected indices
The Mediterranean freshwater resources, mostly represented by groundwater, are under increasing pressure due to natural and anthropogenic factors. In this study, we investigated possible negative effects of climate change and land-use practices on water quality and availability from five springs in the karstic catchments in southern Croatia. The investigated springs are used in the regional public water supply system. Firstly, we employed hydrogeochemical field and laboratory analyses to detect possible traces of anthropogenic activity originating from specific land use. Additionally, we performed hydrological and climate modeling to detect changes in the air temperature, precipitation, and runoff. In particular, we used three regional climate models (Aladin, RegCM3, and Promes). The results estimated an increase in the mean annual air temperature, changes in the precipitation patterns, and reductions in runoff in the study area. Hydrochemical analyses showed standard ion concentrations for karst groundwaters, elevated sulfates due to evaporite deposits in the hinterland, surprisingly low nitrate levels which disproved expected agricultural pollution, and high microbiological activity. Significant water losses are expected in the near future which require immediate attention in order to develop adaptation strategies that focus on sustainable utilization and resilience of freshwater resources. This paper was based on the Interreg Central Europe PROLINE-CE project research in the South Dalmatia.
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