Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene ...(c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.
We perform simulations of intra-granular fission gas bubble evolution in UO2 using both a relatively simple, computationally inexpensive single-size model and a detailed cluster dynamics model. ...Simulations encompass 36 experimental cases from 4 different databases, covering various temperature and burnup levels. We systematically compare results from the two models to each other and to post-irradiation experimental data of bubble average size and number density. Overall, the model-to-model comparisons reveal an excellent agreement across the set of simulations. This outcome indicates that, in spite of the underlying assumptions, the single-size model provides a good approximation of the complex physical behavior that is more rigorously described by the cluster dynamics model. Qualitatively, both models reproduce the trends of the experimental data with temperature and burnup correctly. Quantitatively, calculated results are either in good agreement with the data or within errors that appear consistent with the inherent uncertainties. Moreover, for the single-size model, we demonstrate and assess a multiscale approach whereby values for the fission gas atom diffusion coefficient from separate atomistic calculations are used. Systematic comparisons to experimental data point out a credible accuracy of the multiscale model.
The late Miocene evolution of the Mediterranean Basin is characterized by major changes in connectivity, climate and tectonic activity resulting in unprecedented environmental and ecological ...disruptions. During the Messinian Salinity Crisis (MSC, 5.97-5.33 Ma) this culminated in most scenarios first in the precipitation of gypsum around the Mediterranean margins (Stage 1, 5.97-5.60 Ma) and subsequently > 2 km of halite on the basin floor, which formed the so-called Mediterranean Salt Giant (Stage 2, 5.60-5.55 Ma). The final MSC Stage 3, however, was characterized by a "low-salinity crisis", when a second calcium-sulfate unit (Upper Gypsum; substage 3.1, 5.55-5.42 Ma) showing (bio)geochemical evidence of substantial brine dilution and brackish biota-bearing terrigenous sediments (substage 3.2 or Lago-Mare phase, 5.42-5.33 Ma) deposited in a Mediterranean that received relatively large amounts of riverine and Paratethys-derived low-salinity waters. The transition from hypersaline evaporitic (halite) to brackish facies implies a major change in the Mediterranean’s hydrological regime. However, even after nearly 50 years of research, causes and modalities are poorly understood and the original scientific debate between a largely isolated and (partly) desiccated Mediterranean or a fully connected and filled basin is still vibrant. Here we present a comprehensive overview that brings together (chrono)stratigraphic, sedimentological, paleontological, geochemical and seismic data from all over the Mediterranean. We summarize the paleoenvironmental, paleohydrological and paleoconnectivity scenarios that arose from this cross-disciplinary dataset and we discuss arguments in favour of and against each scenario.
•We review onshore and offshore data from Stage 3 (5.55-5.33 Ma) of the Mediterranean Messinian Salinity Crisis.•Sedimentological, seismic, paleontological and geochemical data are summarized and evaluated.•Non-marine contributions from Paratethys and rivers dominated the hydrological budget.•A clear paleontological imprint of Atlantic inflow is missing.•Two end member models, isolated and half-full, density-stratified Mediterranean, are discussed.
Over the past two decades, the US-DOE has funded multiple projects that rely on high-performance computing and exascale computing platforms to accelerate scientific discoveries and address grand ...scientific challenges, such as harnessing fusion energy. In this article, we review in detail one of these efforts aimed at enhancing our capability to model plasma-facing materials subject to plasma and high-energy ion/neutron irradiation. The plasma surface interactions project has built a multi-scale modeling framework where many of the plasma- and high-energy ion/neutron irradiation-induced effects occurring in tungsten are explored. This knowledge is used to develop atomistically-informed, high-fidelity continuum and meso‑scale models that can be validated against experiments. We review the developments within this project, with attention to experimental validation efforts, and specifically highlight activities associated with: helium bubble bursting and equation of state, and hydrogen-helium interactions in tungsten; atomistically-informed model development for beryllium-tungsten material mixing; coupling of scrape-of-layer plasma, sheath and material models; and coupling of stochastic cluster-dynamics and crystal plasticity models to address radiation effects in tungsten under stress. Finally, we present how the project is preparing for future computational architectures, for instance through efforts to adapt atomistic methods to exascale computing.
Abstract Integrated modeling of plasma-surface interactions provides a comprehensive and self-consistent description of the system, moving the field closer to developing predictive and design ...capabilities for plasma facing components. One such workflow, including descriptions for the scrape-off-layer plasma, ion-surface interactions and the sub-surface evolution, was previously used to address steady-state scenarios and has recently been extended to incorporate time-dependence and two-way information flow. The new model can address dynamic recycling in transient scenarios, such as the application presented in this paper: the evolution of W samples pre-damaged by helium and exposed to ELMy H-mode plasmas in the DIII-D DiMES. A first set of simulations explored the effect of ELM frequency. This study was discussed in detail in this conference’s proceedings and is summarized here. The 2nd set of simulations, which is the focus of this paper, explores the effect of code-coupling frequency. These simulations include initial SOLPS solutions converged to the inter-ELM state, ion impact energy ( E in ) and angles ( A in ) calculated by hPIC2, and an improved heat transfer description in Xolotl. The model predicts increases in particle fluxes and decreases in heat fluxes by 10%–20% with the coupling time-step. Compared with the first set of simulations, the less shallow impact angle leads to smaller reflection rates and significant D implantation. The higher fraction of implanted flux (and deeper), in particular during ELMs, increases the accumulated D content in the W near-surface region. Future expansion of the workflow includes coupling to hPIC2 and GITR to ensure accurate descriptions of E in and A in , and W impurity transport.
Most of the consumers are favourable to the quality of food products but how much are they willing to pay for? This question is crucial because if their willingness to pay is too little, nobody in ...the channel will promote the introduction of quality. With experimental procedures, we have studied one sign of quality, organic farming, for wine and apples. An experimental design allows us to control the treatment of information and observe real individual decisions with an incentive scheme. The decisions in the lab were choices between conventional and biological identical products, with various prices, and buying prices for both products. It has been observed in the literature that choices and buying prices can be inconsistent. However, the consumers appear here consistent in their decisions. They pay significantly more for conventional food than conventional food (approximately 20%) and the richer ones are willing to pay significantly more than the others are.
Abstract The full data set of the NEMO-3 experiment has been used to measure the half-life of the two-neutrino double beta decay of $$^{100}$$ 100 Mo to the ground state of $$^{100}$$ 100 Ru, ...$$T_{1/2} = \left 6.81 \pm 0.01\,\left( \text{ stat }\right) ^{+0.38}_{-0.40}\,\left( \text{ syst }\right) \right \times 10^{18}$$ T1/2=6.81±0.01stat-0.40+0.38syst×1018 year. The two-electron energy sum, single electron energy spectra and distribution of the angle between the electrons are presented with an unprecedented statistics of $$5\times 10^5$$ 5×105 events and a signal-to-background ratio of $$\sim $$ ∼ 80. Clear evidence for the Single State Dominance model is found for this nuclear transition. Limits on Majoron emitting neutrinoless double beta decay modes with spectral indices of $$\mathrm{n}=2,3,7$$ n=2,3,7 , as well as constraints on Lorentz invariance violation and on the bosonic neutrino contribution to the two-neutrino double beta decay mode are obtained.
The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules ...have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.
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