Pathogenic implications of dysregulated miRNAs in propionic acidemia related cardiomyopathy

Cardiac alterations (hypertrophic/dilated cardiomyopathy, and rhythm alterations) are one of the major causes of mortality and morbidity in propionic acidemia (PA), caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC), involved in the catabolism of branched-chain amino acids, cholesterol, and odd-chain fatty acids. Impaired mitochondrial oxidative phosphorylation has been documented in heart biopsies of PA patients, as well as in the hypomorphic Pcca−/−(A138T) mouse model, in the latter correlating with increased oxidative damage and elevated expression of cardiac dysfunction biomarkers atrial and brain natriuretic peptides (ANP and BNP) and beta-myosin heavy chain (β-MHC). Here we characterize the cardiac phenotype in the PA mouse model by histological and echocardiography studies and identify a series of upregulated cardiac-enriched microRNAs (miRNAs) in the PA mouse heart, some of them also altered as circulating miRNAs in PA patients’ plasma samples. In PA mice hearts, we show alterations in signaling pathways regulated by the identified miRNAs, which could be contributing to cardiac remodeling and dysfunction; notably, an activation of the mammalian target of rapamycin (mTOR) pathway and a decrease in autophagy, which are reverted by rapamycin treatment. In vitro studies in HL-1 cardiomyocytes indicate that propionate, the major toxic metabolite accumulating in the disease, triggers the increase in expression levels of miRNAs, BNP, and β-MHC, concomitant with an increase in reactive oxygen species. Our results highlight miRNAs and signaling alterations in the PCC-deficient heart which may contribute to the development of PA-associated cardiomyopathy and provide a basis to identify new targets for therapeutic interventionThis work was supported by Spanish Ministry of Economy and Competitiveness and European Regional Development Fund (grant number SAF2016-76004-R) and by Fundación Isabel Gemio and Fundación La Caixa (LCF/PR/PR16/ 11110018). AFG is funded by the FPI-UAM program, EAB and ARB by the Spanish Ministry of Science, Innovation and Universities (predoctoral fellowships FPU15/02923 and BES-2014-069420, respectively

Minibeam Radiation Therapy Treatment (MBRT): Commissioning and First Clinical Implementation.

BACKGROUND Minibeam radiation therapy (MBRT) is characterized by the delivery of submillimeter wide regions of high "peak" and low "valley" doses throughout a tumor. Preclinical studies have long shown the promise of this technique, and we report here the first clinical implementation of MBRT. METHODS A clinical orthovoltage unit was commissioned for MBRT patient treatments using 3, 4, 5, 8, and 10 cm diameter cones. The 180 kVp output was spatially separated into minibeams using a tungsten collimator with 0.5 mm wide slits spaced 1.1 mm on center. Percentage depth dose (PDD) measurements were obtained using film dosimetry and plastic water for both peak and valley doses. PDDs were measured on central axis for offsets of 0, 0.5, and 1 cm. The peak-to-valley ratio (PVR) was calculated at each depth for all cones and offsets. To mitigate the effects of patient motion on delivered dose, patient-specific 3D printed collimator holders were created. These conformed to the unique anatomy of each patient and affixed the tungsten collimator directly to the body. Two patients were treated with MBRT, both received 2 fractions. RESULTS Peak PDDs decreased gradually with depth. Valley PDDs initially increased slightly with depth, then decreased gradually beyond 2 cm. PVRs were highest at the surface for smaller cone sizes and offsets. In vivo film dosimetry confirmed a distinct delineation of peak and valley doses on both patients treated with MBRT with no dose blurring. Both patients experienced prompt improvement in symptoms and tumor response. CONCLUSIONS We report commissioning results, treatment processes, and the first two patients treated with MBRT using a clinical orthovoltage unit. While demonstrating feasibility of this approach is a crucial first step toward wider translation, clinical trials are needed to further establish safety and efficacy

Advanced Data Chain Technologies for the Next Generation of Earth Observation Satellites Supporting On-Board Processing for Rapid Civil Alerts

The growing number of planned Earth Observation (EO) satellites, together with the increase in payload resolution and swath, brings to the fore the generation of unprecedented volumes of data that needs to be downloaded, processed and distributed with low latency. This creates a severe bottleneck problem, which overloads ground infrastructure, communications to ground, and hampers the provision of EO products to the End User with the required performances. The EO-ALERT project (http://eo-alert-h2020.eu/), an H2020 European Union research activity, proposes the definition of next-generation EO missions by developing an on-board high speed EO data processing chain, based on a novel flight segment architecture that moves optimised key EO data processing elements from the ground segment to on-board the satellite. EO-ALERT achieves, globally, latencies below five minutes for EO products delivery, reaching latencies below 1 minute in some scenarios. The proposed architecture solves the above challenges through a combination of innovations in the on-board elements of the data chain and the communications link. Namely, the architecture introduces innovative technological solutions, including on-board reconfigurable data handling, on-board image generation and processing for generation of alerts (EO products) using Artificial Intelligence (AI), high-speed on-board avionics, on-board data compression and encryption using AI and reconfigurable high data rate communication links to ground including a separate chain for alerts with minimum latency and global coverage. Those key technologies have been studied, developed, implemented in software/hardware (SW/HW) and verified against previously established technologies requirements to meet the identified user needs. The paper presents the development of the innovative solutions defined during the project for each of the above mentioned technological areas and the results of the testing campaign of the individual SW/HW implementations within the context of two operational scenarios: ship detection and extreme weather observation (nowcasting), both requiring a high responsiveness to events to reduce the response time to few hours, or even to minutes, after an emergency situation arises. The technologies have been experimentally evaluated during the project using relevant EO historical sensor data. The results demonstrate the maturity of the technologies, having now reached TRL 4-5. Generally, the results show that, when implemented using COTS components and available communication links, the proposed architecture can generate alerts with a latency lower than five minutes, which demonstrates the viability of the EO-ALERT concept. The paper also discusses the implementation on an Avionic Test Bench (ATB) for the validation of the integrated technologies chain

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Is it in the Game? Reconsidering play spaces, game definitions, theming and sports videogames

From the very first days of digital gaming, sport-themed videogames have been a constant and ever-popular presence. However, compared with many other genres of games, sports-themed videogames have remained relatively under-research. Using the case of ‘sports videogames’ this paper advocates a critical and located approach to understanding videogames and gameplay. Unlike many existing theorisations of gameplay, such as the ‘magic circle’ (Huizinga 1949 [1938]), which theorise play as a break from ordinary life, this paper argues for a consideration of play as a continuation of ‘the control of the established order’ (Lefebvre (1991 [1974]: 383). It argues that many videogames, and in particular sports videogames, can be understood as ‘themed’ spaces; which share similarities to other themed locations, such as fast-food restaurants and theme parks. These are ‘non-places’ (Augé 1995) themed to provide a sense of individuality, control and escape in a society that increasingly offers none

The Compact Linear Collider (CLIC) - 2018 Summary Report

The Compact Linear Collider (CLIC) is a TeV-scale high-luminosity linear $e^+e^-$ collider under development at CERN. Following the CLIC conceptual design published in 2012, this report provides an overview of the CLIC project, its current status, and future developments. It presents the CLIC physics potential and reports on design, technology, and implementation aspects of the accelerator and the detector. CLIC is foreseen to be built and operated in stages, at centre-of-mass energies of 380 GeV, 1.5 TeV and 3 TeV, respectively. CLIC uses a two-beam acceleration scheme, in which 12 GHz accelerating structures are powered via a high-current drive beam. For the first stage, an alternative with X-band klystron powering is also considered. CLIC accelerator optimisation, technical developments and system tests have resulted in an increased energy efficiency (power around 170 MW) for the 380 GeV stage, together with a reduced cost estimate at the level of 6 billion CHF. The detector concept has been refined using improved software tools. Significant progress has been made on detector technology developments for the tracking and calorimetry systems. A wide range of CLIC physics studies has been conducted, both through full detector simulations and parametric studies, together providing a broad overview of the CLIC physics potential. Each of the three energy stages adds cornerstones of the full CLIC physics programme, such as Higgs width and couplings, top-quark properties, Higgs self-coupling, direct searches, and many precision electroweak measurements. The interpretation of the combined results gives crucial and accurate insight into new physics, largely complementary to LHC and HL-LHC. The construction of the first CLIC energy stage could start by 2026. First beams would be available by 2035, marking the beginning of a broad CLIC physics programme spanning 25-30 years