Nmrk2 gene is upregulated in dilated cardiomyopathy and required for cardiac function and nad levels during aging

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential

Magnetic Resonance Thermometry at 7T for Real-Time Monitoring and Correction of Ultrasound Induced Mild Hyperthermia

While Magnetic Resonance Thermometry (MRT) has been extensively utilized for non-invasive temperature measurement, there is limited data on the use of high field (≥7T) scanners for this purpose. MR-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for localized hyperthermia and drug delivery. MRT based on the temperature sensitivity of the proton resonance frequency (PRF) has been implemented in both a tissue phantom and in vivo in a mouse Met-1 tumor model, using partial parallel imaging (PPI) to speed acquisition. An MRgFUS system capable of delivering a controlled 3D acoustic dose during real time MRT with proportional, integral, and derivative (PID) feedback control was developed and validated. Real-time MRT was validated in a tofu phantom with fluoroptic temperature measurements, and acoustic heating simulations were in good agreement with MR temperature maps. In an in vivo Met-1 mouse tumor, the real-time PID feedback control is capable of maintaining the desired temperature with high accuracy. We found that real time MR control of hyperthermia is feasible at high field, and k-space based PPI techniques may be implemented for increasing temporal resolution while maintaining temperature accuracy on the order of 1°C

Plasma-wall interaction studies within the EUROfusion consortium: Progress on plasma-facing components development and qualification

This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 under grant agreement No 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission.The provision of a particle and power exhaust solution which is compatible with first-wall components and edge-plasma conditions is a key area of present-day fusion research and mandatory for a successful operation of ITER and DEMO. The work package plasma-facing components (WP PFC) within the European fusion programme complements with laboratory experiments, i.e. in linear plasma devices, electron and ion beam loading facilities, the studies performed in toroidally confined magnetic devices, such as JET, ASDEX Upgrade, WEST etc. The connection of both groups is done via common physics and engineering studies, including the qualification and specification of plasma-facing components, and by modelling codes that simulate edge-plasma conditions and the plasma-material interaction as well as the study of fundamental processes. WP PFC addresses these critical points in order to ensure reliable and efficient use of conventional, solid PFCs in ITER (Be and W) and DEMO (W and steel) with respect to heat-load capabilities (transient and steady-state heat and particle loads), lifetime estimates (erosion, material mixing and surface morphology), and safety aspects (fuel retention, fuel removal, material migration and dust formation) particularly for quasi-steady-state conditions. Alternative scenarios and concepts (liquid Sn or Li as PFCs) for DEMO are developed and tested in the event that the conventional solution turns out to not be functional. Here, we present an overview of the activities with an emphasis on a few key results: (i) the observed synergistic effects in particle and heat loading of ITER-grade W with the available set of exposition devices on material properties such as roughness, ductility and microstructure; (ii) the progress in understanding of fuel retention, diffusion and outgassing in different W-based materials, including the impact of damage and impurities like N; and (iii), the preferential sputtering of Fe in EUROFER steel providing an in situ W surface and a potential first-wall solution for DEMO.European Commission; Consortium for Ocean Leadership 633053; Institute of Solid State Physics, University of Latvia as the Center of Excellence has received funding from the European Union’s Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART

J Clin Invest

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPN). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPN suggests that vascular function is altered. Consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice, resulting from disturbed endothelial nitric oxide pathway and increased endothelial oxidative stress. This response was reproduced in wild-type mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for microvesicles effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes supressed their effect on oxidative stress. Antioxidants, such as simvastatin and N-acetyl-cysteine, improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPN are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears as promising therapeutic strategy in this setting

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions

Mammalian prions are unusual infectious agents, as they are thought to consist solely of aggregates of misfolded prion protein (PrP). Generation of synthetic prions, composed of recombinant PrP (recPrP) refolded into fibrils, has been utilised to address whether PrP aggregates are, indeed, infectious prions. In several reports, neurological disease similar to transmissible spongiform encephalopathy (TSE) has been described following inoculation and passage of various forms of fibrils in transgenic mice and hamsters. However, in studies described here, we show that inoculation of recPrP fibrils does not cause TSE disease, but, instead, seeds the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). Importantly, both WT-recPrP fibrils and 101L-recPrP fibrils can seed plaque formation, indicating that the fibrillar conformation, and not the primary sequence of PrP in the inoculum, is important in initiating seeding. No replication of infectious prions or TSE disease was observed following both primary inoculation and subsequent subpassage. These data, therefore, argue against recPrP fibrils being infectious prions and, instead, indicate that these pre-formed seeds are acting to accelerate the formation of PrP amyloid plaques in 101LL Tg mice. In addition, these data reproduce a phenotype which was previously observed in 101LL mice following inoculation with brain extract containing in vivo-generated PrP amyloid fibrils, which has not been shown for other synthetic prion models. These data are reminiscent of the “prion-like” spread of aggregated forms of the beta-amyloid peptide (Aβ), α-synuclein and tau observed following inoculation of transgenic mice with pre-formed seeds of each misfolded protein. Hence, even when the protein is PrP, misfolding and aggregation do not reproduce the full clinicopathological phenotype of disease. The initiation and spread of protein aggregation in transgenic mouse lines following inoculation with pre-formed fibrils may, therefore, more closely resemble a seeded proteinopathy than an infectious TSE disease

Inkjet printing technology : a novel bottom-up approach for multilayer ceramic components and high definition printed electronic devices

International audienc

Measuring Semantic and Emotional Responses to Bio-inspired Design

This research explores the relation between specific inspirations such as animals postures and the expressiveness of the design solutions provided by the designers. The prediction of semantic and emotional responses underlying animals’ postures and attitudes might help designers to define design specifications and imagine design solutions with a high expressivity. To address this issue, an experiment was conducted with designers in watching six sets of animal posture images and corresponding product images. This experiment derived quantitative and qualitative results from the combination of cogntive/physiological methods: a questionnaire, Galvanic Skin Reponse (GSR), and eye tracking system

Potential of X-Band TerraSAR-X and COSMO-SkyMed SAR Data for the Assessment of Physical Soil Parameters

International audienceThe aim of this paper is to analyze the potential of X-band SAR measurements (COSMO-SkyMed and TerraSAR-X) made over bare soils for the estimation of soil moisture and surface geometry parameters at a semi-arid site in Tunisia (North Africa). Radar signals acquired with different configurations (HH and VV polarizations, incidence angles of 26° and 36°) are statistically compared with ground measurements (soil moisture and roughness parameters). The radar measurements are found to be highly sensitive to the various soil parameters of interest. A linear relationship is determined for the radar signals as a function of volumetric soil moisture, and a logarithmic correlation is observed between the radar signals and three surface roughness parameters: the root mean square height (Hrms), the parameter Zs = Hrms2/l (where l is the correlation length) and the parameter Zg = Hrms × (Hrms/l)alpha (where alpha is the power of the surface height correlation function). The highest dynamic sensitivity is observed for Zg at high incidence angles. Finally, the performance of different physical and semi-empirical backscattering models (IEM, Baghdadi-calibrated IEM and Dubois models) is compared with SAR measurements.The results provide an indication of the limits of validity of the IEM and Dubois models, for various radar configurations and roughness conditions. Considerable improvements in the IEM model performance are observed using the Baghdadi-calibrated version of this model